treatment of diabetic eye disease

Treatment of Diabetic Eye Disease

D. W. HILL

The eye, a microcosm within the body, is variously involved in diabetes mellitus, though relatively few aspects of this involvement need treatment. Diabetic retinopathy is the most significant and obdurate problem in this field, and consequently will occupy the larger part of this chapter. Other aspects of diabetic eye disease will be briefly considered by approaching them diagnostically and indicating their management.

OCULAR SYMPTOMS

The manifestations of eye disease are varied. Some of the more important, which may have therapeutic implications in diabetic eye disease, are shown in Table 1, which is selective and includes only those manifestations chosen for discussion. In any clinical situation the presence of intercurrent eye disease unrelated to diabetes must also be considered.

Table 1. Ocular Symptoms

Visual loss - - gradual - - sudden

Other visual symptoms - - blurring difficulty with reading

Diplopia Glaucoma

V i s u a l l o s s

This is the presenting symptom of a wide range of disease affecting the eye, the visual pathways and the cerebral cortex. Conditions causing gradual visual loss as a complication of diabetes are indicated in Table 2, those causing sudden visual loss in Table 3. In the discussion that follows, the causes of gradual visual loss mentioned in Table 2 will be considered seriatim, and reference will also be made to the causes of sudden visual loss complicating diabetic retinopathy shown in Table 3. The remaining conditions shown in Table 3 are beyond the scope of this chapter.

The quotation of references in this chapter has been limited, but a great deal of information on all aspects of the subject, and a comprehensive bibliography may be obtained from Diabetes and the Eye (Caird, Pirie and Ramsell, 1968). Further advances since that publication are principally concerned with photocoagulation for diabetic retinopathy, and are more fully documented in this chapter.

Clinics in Endocrinology and Metabolism-Vol. 1, No. 3, November 1972. 789

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T a b l e 2. Gradual Visual Loss Complicating Diabetes

Cataract Diabetic retinopathy -- macular oedema

- - preretinal fibrosis Toxic amblyopia Optic atrophy Glaucoma

CATARACT of sudden onset and rapidly progressive is a rare complication of diabetes in the young patient. It is usually severe enough to require surgical treatment and its onset is often associated with a period of bad diabetic control. Transient lens opacities may be associated with diabetic coma but they do not interfere with vision and regress rapidly.

T a b l e 3. Sudden Visual Loss Complicating Diabetes

Vitreous haemorrhage ") complicating Preretinal haemorrhage ) diabetic Retinal detachment retinopathy Retinal vascular accidents Cerebro-vascular accidents with hemianopia

In the older age group, senile cataract is indistinguishable from the same condition in non-diabetic patients and appears to have a similar incidence. There is a higher incidence of cataract extraction operations recorded in the diabetic population than in the non-diabetic and this is usually held to be due to the more rapid progress of the complication in the diabetic group. The management of senile cataract is similar in diabetic and non-diabetic patients and operation should be done as soon as the visual impairment is judged to handicap the patient seriously, taking into consideration all the circumstances of his life. With present surgical techniques the incidence of ocular complications after cataract extraction in diabetic patients is not much more than that in non-diabetics. Many surgeons currently prefer to perform the operation under general anaesthesia, but a local anaesthetic with adequate pre-medication may be used if necessary. In all cases of cataract it is important to obtain a view of the fundus oculi, and particularly of the macula, if the patient is seen before the lens opacities have become too dense. This applies with added emphasis to the diabetic patient because of the frequent occurrence of diabetic retinopathy, which may prevent the "recovery of useful vision after successful cataract extraction.

DIABETIC RETINOPATHY. Vision may be lost gradually or suddenly in diabetic retinopathy, involvement of the macula by oedema and exudates, subhyaloid haemorrhage and the collection of turbid fluid in front of the retina after posterior vitreous detachment, opacification of the detached posterior vitreous face, haemorrhage into the vitreous and traction retinal detachment being the more important mechanisms.

TOXIC AMBLYOPIA is a term covering a wide variety of conditions in which there is a gradual bilateral loss of vision associated with a central scotoma of

TREATMENT OF DIABETIC EYE DISEASE 791

variable size and density. The fundus oculi often appears normal, especially in the early stage of the disease. The diabetic is more susceptible than the non-diabetic to this type of disease of which the best documented example is tobacco amblyopia, treated by discontinuing smoking and the administration of hydroxocobalamine, 1000 ttg parenterally, daily for 2 weeks, twice weekly for 4 weeks, then monthly. In recent years, iatrogenic toxic amblyopia due to a wide range of therapeutic drugs has been described; in these cases, immediate withdrawal of any suspected drug is essential, and this may be followed by a gradual though often incomplete recovery of vision.

OPTIC ATROPHY. A genetically determined optic atrophy which is not susceptible to treatment has been described in patients with diabetes mellitus. Optic atrophy may also be seen as a result of diabetic retinopathy or following degenerative vascular disease of the retina, or lower visual pathway, to which diabetes may predispose.

Diplopia Double vision due to extra ocular muscle palsy is not uncommon in diabetic patients over the age of 50 years. It is usually sudden in onset, often accompanied by pain, affecting the third nerve, but sparing the pupil; the sixth nerve is also affected, but the fourth rarely. The palsy is self-limited, the majority of cases recovering in 6 to 8 weeks; no specific treatment is required but the affected eye may be covered in the early stages if, as is often the case, double vision incapacitates the patient.

Glaucoma Glaucoma as a complication of diabetes is confined to 'haemorrhagic (thrombotic) glaucoma', though other types may occur as intercurrent diseases. Haemorrhagic glaucoma accompanies proliferative diabetic retinopathy, and is the result of a neovascularising process which affects the iris and angle of the anterior chamber through which aqueous humor drains. In its early stages the condition is symptomless, and only detected by clinical assessment of the intra-ocutar pressure, later the eye becomes painful and red and the cornea hazy; vision, which is usually already impaired by retinopathy, becomes further depressed and blindness follows. Occasionally the eye may be lost from secondary corneal ulceration, or removed because of intractable pain. There is little effective treatment for this condition, miotic drops and systemic acetazolamide, usually effective in lowering the pressure in other forms of glaucoma, produce only slight improvement, particularly in the later stages of the disease. Pain may be relieved by the retrobulbar injection of ethyl alcohol 70 per cent, 1.5 ml preceded by local anaesthetic; a careful technique is required to avoid permanent muscle palsies.

Other visual symptoms Blurring of vision may be an early manifestation of visual loss, but is sometimes due to acute changes in refraction. These may occur when diabetes is brought under control, resulting in hypermetropia, or less dramatically, in uncontrolled diabetes, when myopia is usually found. In either event, the

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changes are not lasting, and it is customary to wait for the refraction to stabilise before ordering a change of glasses. Hypoglycaemia is sometimes accompanied by very transient blurring of vision, which lasts only during the attack. Difficulty with reading is another symptom which may result from the transient hypermetropia induced by treating diabetes, or may be associated with a weakness of accommodation, precipitating presbyopia unexpectedly early in life. In this event reading glasses may be required.

DIABETIC RETINOPATHY

Clinical manifestations

The principal symptom of diabetic retinopathy is loss of vision, which has already been discussed. The ophthalmoscopic appearances of diabetic retinopathy vary and have been the subject of many classifications and systems of grading. Empirically, there are three manifestations of retinopathy which are relevant to the treatment. They are:

Background retinopathy Proliferative retinopathy Exudative retinopathy

Figures 1 to 3 illustrate these manifestations.

Figure 1. Background retinopathy. Optic disc and macular area of the left eye, showing in the infero-temporal quadrant scattered haemorrhages, rnicroaneurysms and small hard exudates; in the upper temporal quadrant above and lateral to the rnacula, the haemorrhages and microaneurysms are confluent and a surrounding ring of hard exudates is beginning to form a circinate figure.


BACKGROUND RETINOPATHY consists of scattered punctate and blot haemorrhages, microaneurysms and occasional small deposits of hard exudate. It is the earliest stage of diabetic retinopathy which may increase or remit with the passage of time, and even in those cases where it appears stationary, careful studies show that a gradual turnover of individual lesions is occurring, with haemorrhages, microaneurysms and exudates disappearing and flesh ones appearing.

Figure 2. Exudative retinopathy. Right eye showing a horseshoe shaped patch of hard exudate surrounding the macula in the centre of the picture. The optic disc lies beyond the righthand margin of the picture, whilst to the left of the macula, that is lateral to the macula, in the area of the vascular raphe confluent haemorrhages and microaneurysms are associated with patches of hard exudate, some of which form incomplete ring figures. Running from right to left above and below the macula are the macular branches of the upper and lower temporal arterioles; these branches may serve as markers in some forms of photocoagulation treatment. Early new vessel formation is seen near the upper macular arteriole towards the left-hand margin of the picture.

PROLIFERATIVE RETINOPATHY marks a worsening of the disease with the development of new vessels in response to the chronic microcirculatory insufficiency; accompanying this change venous abnormalities, dilatation, calibre irregularity and loops may appear. The new vessels form at first on the surface of the retina, and later grow forward into the vitreous chamber, possibly pulled by retracting strands of diseased vitreous. Initially they are difficult to see on account of their fine calibre, but later they become obvious and their forward proliferation is followed inevitably by the development of a connective tissue framework which contracts and pulls on the retina. Retinoschisis (splitting of the layers of the retina) and retinal detachment may

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follow, and when these changes involve the macula, central vision is lost. New vessels are always more f~agile than normal and bleeding occurs into the retina, in front of the retina and into the vitreous; the latter is slow to clear and stimulates reparative fibrosis with thickening of areas of retinitis proliferans (forward growth of vessels and fibrous tissue into the vitreous). In proliferative retinopathy the posterior surface of the detached vitreous may thicken and a cellular membrane form; this is particularly likely to involve the macula area and results in opacity, obstructing the vision.

Figure 3. Proliferative retinopathy. Upper nasal quadrant of the left eye of a myopic patient with light fundus pigmentation. Grossly irregular retinal veins with a large frond of new vessels and an abnormal arterio-venous communication can be seen against the background of choroidal vessels.

EXUDATIVE RETINOPATHY: exudative changes are also results from the chronic microcirculatory insufficiency characteristic of diabetic retinopathy. Altera- tions in the permeability of the capillary wall result in retinal oedema and later waxy hard exudates, formed of lipoid-containing macrophages. These may be in isolated patches or in clusters, but frequently they form rings and circinate figures with prominent central microaneurysms. The macula is often involved by these exudative changes, at first oedema and later hard exudates forming; the hard exudates may lie in a large ring around the maeula when the descriptive term 'circinate retinopathy' is applied (though originally this term was applied to a specific non-diabetic fundus appearance), and within this ring there may be smaller rings centered on groups of microaneurysms and bordering on the macula. The oedema depresses macular


function and leads to a fall in visual acuity; after a period of time cystic changes occur in the retina and irreversible damage results. The presence of a large plaque of hard exudate at the macula is also a sign of irreversible visual loss. Direct involvement of the fovea by haemorrhage is an uncommon cause of visual loss.

This description of the ophthalmoscopic changes in diabetic retinopathy emphasises a few salient features, but each patient's case shows a different combination of changes progressing in a particular way. The progress of retinopathy is erratic, periods of remission and exacerbation occur, and for no particular reason one eye is often well in advance of the other. Certain factors seem to exert a unilateral restraining influence on the progress of retinopathy, producing a remarkable protecting effect on one eye; high myopia, extensive healed choroidoretinitis, glaucoma, and carotid occlusion have been cited, and it is suggested that they act by reducing the metabolic demand of the retina or lowering the perfusion pressure of the eye.

Methods of treatment

In a disease of such variability as diabetic retinopathy, of which the pathogenesis is still obscure, it is not surprising that a wide variety of treatment has been proposed, and choice has been dictated by fashion rather than by informed opinion. No measure yet proposed has produced such positive results as would establish it unquestionably; some on critical examination offer very little evidence of improvement. Before condemning this situation one must remember the pressure upon the clinician to give treatment when faced with the serious and highly emotive threat of blindness, and the slow and uncertain tempo of the disease which precludes a quick result when assessing the true effectiveness of treatment.

Table 4 lists some of the methods advocated for the treatment of diabetic retinopathy. A few currently in vogue will be presented in detail later in the chapter, whilst the others will be briefly reviewed in a general discussion in the ensuing paragraphs.

Table 4. Advocated Methods of Treatment

Systemic Modifying endocrine balance Anabolic steroids Adrenaleetomy Pituitary ablation

Lowering blood lipids Diet Para-amino-salicylic acid Clofibrate

Miscellaneous Rutin Anticoagulants Lipotropic agents Fructose Vitamin BIz

Local Steroids Radiotherapy Photocoagulation

796 D . W . H1LL

The first group of treatments have in common a modification of the endocrine balance in the attempt to influence the course of retinopathy. The use of anabolic steroids was introduced by Saskin, Waldman and Pelner (1951), for a variety of reasons, mainly associated with the restoration of normal plasma protein levels and supported empirically by encouraging evidence of the control of retinal haemorrhages. A number of favourable publications followed, and non-androgenic anabolic steroids were introduced, but a careful statistical controlled study (Hunter et al, 1967) failed to show any benefit from the treatment. The relationship between adrenal cortical function and diabetic retinopathy, and in particular the association of increased adrenal function with diabetic retinopathy, was comprehensively reviewed by Becker et al (1954). This association of increased adrenal function was the rationale for advising adrenalectomy in severe diabetic retinopathy, but the results were disappointing and the abandonment of this line of treatment was hastened by a report of a case in which retinopathy still progressed after adrenalectomy, but remitted after pituitary ablation (Lourie, Moses and Lloyd, 1962).

Pituitary ablation, though less popular than previously, is still indicated in some circumstances and will be fully discussed. It has been largely supplan- ted by photocoagulation, a local treatment applied to the retina, devoid of general complications.

The next group of treatments are directed against the lipid-containing hard exudates of diabetic retinopathy. Various methods of lowering the serum lipids have been shown to be effective in clearing the hard exudates, though their benefit to visual acuity is less positive. The use of a low fat diet is associated with the clearing of hard exudates. A controlled trial was reported by King et al (1963), in which saturated fatty acids in the diet were replaced by unsaturated, by substituting corn oil for the major part of the animal fats in the diet; a significant clearance of hard exudates occurred, but there was no improvement in vision. Para-amino-salicylic acid and clofibrate have been used for their action in lowering the serum lipids, and the use of the latter will be further discussed.

The final group of systemic treatments have a wide variety of attributed modes of action, but there is no more than sporadic evidence of their effectiveness, and none has been regularly adopted. They include rutin to combat the increased capillary fragility reported in diabetic retinopathy, lipotropic agents alleged to improve the condition of the microcirculation, vitamin B12 (of which the excretion is increased in diabetic retinopathy), anticoagulants for their effects on blood lipids as well as on circulation, and fructose.

Amongst the local measures of treatment which have been suggested is the topical application of steroids to the eye (Becker, 1967), which would raise the intraocular pressure in genetically susceptible subjects and might prevent progress of the retinopathy. A controlled trial of radiotherapy by Larsen (1959), using doses of 1500 to 3000R directed to the retinal neo- vascularisation, showed no significant beneficial effect. Photocoagulation, having shown promise, is currently being assessed. Circumscribed retinal

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burns are produced by an intense light source, derived from a high pressure xenon-arc or a laser of the ruby or argon type.

Surgical treatment is confined to the management of the complications of diabetic retinopathy, irrecoverable vitreous haemorrhage and retinal detachment. Some success has been achieved but the prognosis for vision remains poor because of the severity of the disease at the time these complications ensue.

Assessment of treatment

Since the pathogenesis of diabetic retinopathy is so far only partly understood, there is little hope of measuring the effect of treatment on the primary disease process, and assessment is confined to those aspects of retinopathy which are closely related to the pathogenetic process and to the effects of treatment on vision.

Visual acuity, measured on the Snellen test type after refraction has been corrected by the appropriate lens, is the most acceptable measure of central vision; what it lacks in precision is compensated by the practical value of stating the acuity in terms of the ability to perform an everyday task, that of recognising the letters of the alphabet. Peripheral vision can be assessed by various forms of perimetry, and campimetry, and by static perimetry determining the threshold levels of stimulus at selected sites on the retina. In the context of research, involving the assessment in depth of the effects of the disease process and of treatment, these methods are of the greatest value, but in the practical context the most important matter is that central visual acuity should be preserved or improved by treatment.

In assessing the progress of diabetic retinopathy, it is clearly important to document the changes in the background retinopathy, principally the microaneurysms and small haemorrhages which are the visible aspects of the underlying primary microcirculatory disease and to note the onset of proliferative retinopathy, heralded by the appearance of new vessels. From the therapeutic viewpoint it is desirable to differentiate between new vessels on the optic disc and those away from it, and between new vessels at the level of the retina and those growing forward into the vitreous. Exudative changes are less easily documented as retinal oedema is often only visible on biomicroscopy of the fundus, and the thickness of the oedematous retina is difficult to assess. The area of retina involved by hard exudates can be assessed, but there is good evidence that their appearance is a late manifestation determined at least in part by the degeneration of retinal elements and the release of lipid materials. The fibrous elements of retinitis proliferans are likewise of late onset and no existing treatment influences their course.

From these remarks it is apparent that the ophthalmoscopic changes of diabetic retinopathy result, in part from the primary microcirculatory disturbance, and in part from secondary changes progressing with varying degrees of autonomy, once the disease has progressed sufficiently far. Some changes become inevitable on reaching a certain stage, for example, the development and progress of hard exudates, the onset of cystic changes in macular oedema, and the increasing fibrosis of retinitis proliferans. Of these the evolution of retinitis proliferans appears completely autonomous and

798 D .W. HILL

uninfluenced by treatment, whilst the deposition of hard exudates may be controlled to some extent by measures which lower the serum lipids but do not directly influence the retinopathy.

In the course of research into methods of treatment various systems of grading have been evolved, none of them perfect, to assess the progress of the ophthalmoscopic signs of diabetic retinopathy. Retinal photography in colour has greatly added to these studies as changes are much more easily detected when colour transparancies of the same area, photographed at different times, are projected side by side and directly compared. A system of grading using this facility has been described and tested by Oakley et al (1967), in which photographs of specified areas of the fundus are compared to a set of standards, and graded by their ranking position amongst the standard photographs showing increasing severity of disease. The total of 20 standard photographs are divided into five sets of four, covering five separately assessed components of retinopathy, haemorrhages and microaneurysms, new vessels, retinitis proliferans, hard exudates and venous abnormalities.

The variability of diabetic reinopathy is important in relation to treatment. Twenty years after the initial diagnosis of diabetes 80 per cent of patients show some evidence of retinopathy, but only 10 per cent proliferative changes, and Beetham (1963) showed that 10 per cent of cases of proliferative retinopathy arrest without treatment. Against the background of variability, the effects of treatment can only be reliably discerned in the context of statistically controlled studies. Where the treatment is local the fellow eye can serve as a control, provided that the retinopathy is comparable in the two eyes, and the indications for treatment are of equal weight. Such cases are not common, but they are of particular interest because both eyes, treated and control, are in the same environment and subject equally to fluctuations of the diabetic state. When treatment is systemic, experimental design is more difficult, as comparison between patients is less satisfactory than comparison within patients. Not only are the short-term results of treatment important but in the present state of uncertainty about the fundamental nature of the disease, a long-term follow-up is necessary for a period related to the natural expec- tancy of deterioration in untreated disease. Simple (background) retinopathy moves slowly; after 5 years, only three per cent of those with good vision, whose diabetes was diagnosed before the age of 29, may expect to have experienced at least a moderate deterioration of vision--though the figure rises steadily to 38 per cent when the diagnosis is first made over the age of 60 (Caird and Garrett, 1963). Caird (1965) has calculated from data of Beetham (1963) t h a t 15 per cent or more of patients with good vision and proliferative retinopathy will have sustained a drop in vision to economic blindness (6/15 to 6/60) within two years if their diabetes is classified as of growth onset (diagnosed before 20 years of age), and 30 per cent or more if the diabetes is of maturity onset (diagnosed after the age 20). Corresponding figures for the five year follow-up period are 44 per cent and 70 per cent.

StatisticaUy controlled trials in diabetic retinopathy have serious limitations. The current forms of treatment by photocoagulation and pituitary ablation cannot be presented in any double-blind form, so that pressure for withdrawal from a trial grows if deterioration of a control subject occurs. In practice


this means that an end-point must be set short of irrecoverable damage, with the consequence that rigid proof of the efficacy of treatment is unlikely to be forthcoming, until enough is known of the mechanism of diabetic retinopathy to allow a much earlier decision about the effects of treatment on the primary lesion of the retinopathy.

DIABETIC RETINOPATHY--SPECIFIC TREATMENT

Pituitary ablation This was introduced by Luft et al (1955) from a consideration of the effects of hypophysectomy in animals. This concept gained support with the report by Poulsen (1953) of regression of proliferative diabetic retinopathy following postpartum necrosis of the pituitary. The original approach to ablation was surgical, by hypophysectomy, and subsequent diversification is set out in Table 5.

Table 5. Methods of Pituitary Ablation

Surgical By c ran io tomy - - t ransfronta l hypophysec tomy - - pi tui tary stalk section

T h r o u g h nasal s inuses - - t ransphenoida! hypophysec tomy - - t ranse thmoidal cryosurgery

Irradiat ion External Interstitial - - t ransphenoidal implanta t ion

of Yt t r ium 90

However produced, pituitary ablation is a major procedure, with the possibility of serious immediate complications and a certainty of far-reaching effects from the ablation. The decision to undertake it can only be made after a consideration of all aspects of the patient's case, together with an apprecia- tion of the facilities available for continued care after the ablation. The results of pituitary ablation include reduced insulin requirement, dependence on replacement therapy by corticosteroids and thyroxin, reduced sexual function, and a tendency to irreversible hypoglycaemia, so that the patient and physician must be meticulous in the management of the diabetes especially in relation to alterations in routine produced by illness or external circumstances.

The immediate effect of pituitary ablation on diabetic retinopathy is a rapid clearing of vitreous haze, often within 48 hours of operation. A reduction in the number of microaneurysms and haemorrhages, a regression of new vessels and some improvement in venous dilatation and irregularity follow over a period of months in favourable cases. There is no effect on the fibrous elements of retinitis proliferans, which, if they are marked initially, may produce disastrous traction effects despite treatment. Hard exudates are also little influenced by pituitary ablation. The effect on vitreous haemorrhages is difficult to gauge because of the great variability in the size of haemorrhages and consequently of their symptoms, and the confusion introduced by the

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presence of numerous vitreous floaters from previous haemorrhages, but most authors are of the opinion that they become less frequent after treatment. The most important measure of the success of pituitary ablation is its effect on visual acuity, and in most series the treated cases show a small advantage over control data, though the validity of the latter is often open to comment. Lundbaek et al (1969) in a fully controlled trial with 15 patients in each group, showed an improvement in vision in one third of the treated patients, but none of the controls, but a deterioration in one third of both groups.

An important issue has been the degree of ablation required to produce a remission of retinopathy, as assessed by the dependence upon substitution therapy and results of tests of endocrine function. Joplin et al (1967) found a definite correlation between the degree of ablation and response ofretin- opathy, both in terms of visual acuity and of improvement of ophthalmoscopic appearances assessed by serial retinal photography and grading. This inves- tigation showed complete ablation to be essential to a satisfactory improvement of the retinopathy.

Complications of pituitary ablation include cerebrospinal rhinorrhoea and meningitis after trans-sphenoidal implantation of radioactive Yttrium-90, meningitis after craniotomy for hypophysectomy or pituitary stalk section, damage to the optic nerves, necrosis of the brain and cranial nerve palsies after external irradiation, and diabetes insipidus, (usually of limited duration) which frequently complicates ablation by any method. Caird, Pirie and Ramsell (1969a) report that the early mortality of surgery is about 4 per cent, and of interstitial irradiation about 10 per cent, though in a large series of cases implanted for a variety of diseases treated by pituitary ablation it fell to 1 per cent.

The selection of cases on systemic criteria, as well as ocular, is important, and certain specific complications of diabetes are held by some authorities to be unfavourable. Renal disease with early uraemia may be worsened because of a reduction in perfusion following ablation, and a blood urea level greater than 75 mg/100 ml was taken as a contraindication to y90 implant by Joplin et al (1965). Marked postural hypotension in patients with diabetic neuropathy affecting the autonomic nervous system may be precipitated by ablation.

The late mortality following pituitary ablation is considerable, but this must be set against the background of established poor prognosis for diabetics with proliferative retinopathy, of whom about 40 per cent die in five years, and 60 per cent in 10 years (Root, Mirsky and Ditzel, 1959). Coronary occlusion, renal failure, irreversible hypoglycaemia and cerebrovascular accidents account for most of the deaths. There seems little to choose between the different methods of pituitary ablation, and each has its advocates; clearly it is a highly specialised procedure and choice is often limited by the methods available at any particular centre. Hypophysectomy by open craniotomy is perhaps the most reliable method of producing complete ablation, but it is a more severe procedure than the others. Hypophyseal stalk section is less reliable and apt to be followed by a late recovery of function even when an impermeable diaphragm is implanted. Trans-sphenoidal and trans-ethmoidal open surgical techniques, though less severe, are less consistent in the degree


of ablation produced. External irradiation is slow to act, complicated by cranial nerve palsies and brain necrosis and its use has been limited. Inter- stitial irradiation by the implantation of two radioactive Yttrium-90 rods through cannulae passed into the pituitary fossa under direct radiological control causes relatively little disturbance to the patient and can be performed with low morbidity and mortality by those experienced in the technique. Cerebrospinal rhinorrhoea is perhaps the most troublesome complication which, though treatable, cannot be entirely avoided.

Photocoagulation of the retina This was introduced after a long period of development by Meyer- Schwickerath and applied by him to a variety of ocular conditions including diabetic retinopathy. It has slowly gained ground, though irrefutable evidence of its efficacy in diabetic retinopathy is hard to come by. The popularity amongst ophthalmic surgeons is probably due to two facts, firstly that it is a local treatment, devoid of the complications of pituitary ablation, which to a large extent it has surplanted and secondly that many of the alarming appearances of the retinopathy can be ablated by the coagulation, conveying what is sometimes a false sense of achievement.

In essence the technique consists of the production of a localised retinal burn which proceeds to repair, with the formation of a glial scar with the loss of neural elements and closure of small blood vessels and with local adhesion of the retina to the choroid. The light energy is absorbed at the retinal pigment epithelium so that successful coagulation can only be produced in retina lying in contact with or close to the intact pigment epithelium, and not in detached retina. Vessels lying free in the vitreous cannot be success- fully coagulated, though in the early stages of their development they may be influenced indirectly. The recent introduction of the argon-laser, which will be discussed later, offers some hope of treating vessels directly. The ruby-laser has no advantage over the high pressure xenon-arc in this application as its radiation is absorbed only at the pigment epithelium.

Before treatment the pupil is widely dilated, and the eye anaesthetised and immobilised by a retrobulbar injection of 3 to 4 ml of 2 per cent lignocaine and topical anaesthetic. The patient lies on a couch and the surgeon observes the fundus through the ophthalmoscope head of the instrument. Operation of a switch produces an augmentation of the light to a coagulating level when required and, though the precise arrangements vary from one instrument to another, the surgeon is able to control the position, intensity and size of each coagulation. The number of applications in one treatment session varies according to the type of lesion being treated, and the views of the surgeon; up to 80 to 90 applications may be given, but usually the number is smaller.

Treatment has been applied for: 1. Destruction of vascular lesions 2. Reduction of the amount of functioning retinal tissue.

The latter is based on the observation of the sparing effect in diabetic retinopathy of uniocular disease accompanied by a considerable loss of functioning retina, for example high myopia and widespread choroidoretinitis. Some have used the term 'pattern bombing' to describe this form of treatment,

802 D.W.I-I ILL

a description appropriate to both the underlying concept and the appearance after treatment.

Local lesions treated by photocoagulation include patches of new vessels lying on the retina, leaking microaneurysms at the centre of exudate rings, and less descriminately, the background lesions of microaneurysms and haemorrhages. Fluorescence angiography is helpful in identifying areas of leakage around the macula before treatment.

'Pattern bombing' , whether applied as a primary technique or resulting from extensive coagulation of existing lesions, has been used to induce a remission of the proliferative activity of the retinopathy. A report by Taylor (1970) found a successful regression only where new vessels on the optic disc were in the early stage of development, without recognisable glial proliferation and confined to the plane of the retina. Five of 13 cases res- ponded, all had had extensive coagulation from 102 to 250 applications. Meyer-Schwickerath and Schott (1968) advocated early treatment of diabetic retinopathy in the stage of active background retinopathy, claiming considerable improvement in the state of the retina and a much lower rate of pro- gression to proliferative retinopathy involving forward growth into the vitreous than would have been expected from the published data on the progress of untreated cases.

Figure 4. Photocoagulation, proliferative retinopathy. The same area as seen in Figure 3, some weeks after photocoagulation. The large frond of vessels has regressed following photocoagulation which has produced some atrophy of the underlying choroid and stippled pigment scatter. The area of treatment is shown by the pallor of the fundus, but pigment reaction is less than usual because of the lack of fundus pigmentation. Some new vessels on the optic disc can also be seen, which were out of the field in the previous figure.


Much of the defective vision, especially in the older age groups, is due to macular oedema and hard exudate formation, including circinate and ring patterns. Promising results of a trial, which, though not strictly controlled, maintained a comparable untreated group, were reported by Rubinstein and Myska (1972). They adopted four approaches to coagulation, treatment of the centre of exudate rings, treatment of leaking vessels revealed by fluorescence angiography, treatment lateral to the macula on the horizontal vascular watershed, and regional treatment placed just outside the macular branches of the main upper and temporal arterioles (these are fairly constant branches leaving the upper and lower temporal arterioles and running parallel to them near the macula; they serve as markers to keep the coagulations at a safe distance from the fovea) (Figure 2).

Figure 5. Photocoagulation, recurrence. The same area as seen in Figure 3 and 4, some months later. The frond of vessels has partly recurred, further choroidal atrophy is manifest by the extreme pallor of the area. The frond now appears to be in vascular continuity with the new vessels on the optic disc.

There are numerous other reports of the results of photocoagulation. One of the largest series, 111 patients, was studied by Okun and Cibis (1966), who used an ophthalmoscopic grading to detect the effect of photocoagulation. Krill et al (1971) give a full report and discussion of the treatment. In general the remission induced is similar to that seen in pituitary ablation, haemhorrages and microaneurysms are reduced, new vessels are either directly destroyed or regress, and there is some improvement in venous abnormalities. Where hard exudate systems are treated the exudates slowly resolve, in contrast to the relative ineffectiveness of pituitary ablation. The influence on forward-

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growing vessels, either from coagulation at the base of peripheral fronds or from the indirect effects of extensive treatment ('pattern bombing'), is slight and fibrous retinitis proliferans is uninfluenced.

The introduction of the argon-laser with light output in the blue and green wave length (488 and 514.5nm) has provided a light source the energy of which may be directly absorbed (70 per cent of incident light) by haemoglobin, offering for the first time the possibility of the direct treatment of forward growing vessels. Preliminary results are encouraging (Zweng, Little and Peabody, 1971), though repeated treatment may be necessary to induce regression of vascular fronds and there is a risk of haemorrhage which could prove disastrous.

Xenon arc photocoagulation is not without its dangers, accidental mis- placement of a coagulation damaging the fovea or papillo-macular bundle with loss or impairment of central vision, oedematous reactions to treatment spreading to involve the macula, haemorrhage from damage to the large tributary veins, and increasing vitreous traction from coagulation in the area of established retinitis proliferans which may lead to retinal detachment. At a later stage, new vessels closed by photocoagulation may reopen or new proliferations develop at the margin of treated areas. This occurrence is illustrated, together with the appearances after photocoagulation, in Figures 3 to 5, and the differing approaches to photocoagulation which have been discussed are set out in a diagram of the fundus oculi, Figure 6.

Figure 6. Methods of photocoagulafion. This diagram summarises the current concepts of treatments. 1. 'Pattern bombing' of the whole fundus (quadrant only shown). 2. Treatment of new vessels and specific lesions. 3. Treatment of the centres of hard exudate rings. 4. Treatment of lesions in the vascular raphe (in macular oedema). 5. Annular treatment around the macula (for macular oedema and hard exudates).


Clofibrate

Cullen, Ireland and Oliver (1964) reported a controlled trial in exudative retinopathy, in which there was a significant reduction in hard exudates in the treated group, but no significant improvement in vision. However, when the series was extended to 5 years (Nolan and Cullen, 1969), the treated patients showed a slightly greater visual improvement than the untreated (17 per cent improved, as compared to 3 per cent). They maintain that not only does clofibrate clear established exudates but that it may prevent the deposition of fresh ones, a point as yet incompletely proven. If this contention is true, then clofibrate may have therapeutic value in those cases where hard exudates are forming in quantity in the macula area but vision is not yet seriously impaired. Its ultimate status in treatment will depend on the resolution of uncertainty about the deposition of hard exudates, in particular the extent to which they represent either the debris left after neuroretinal degeneration, or part of an exudative process leading to the degeneration. It has been established that the resolution of a large patch of hard exudate leaves behind a detectable scotoma at the same site (King et al, 1963).

CONCLUSIONS AND CHOICE OF TREATMENT IN DIABETIC RETINOPATHY

Diabetic control

No discussion of the treatment of diabetic retinopathy would be complete without mention of the relationship between the strictness of control of carbohydrate metabolism and the onset and progress of retinopathy. The subject is difficult to study and the pitfalls of interpretation are many. A good review is given by Caird, Pirie and Ramsell (1969b); their main conclusions are that definite evidence exists, particularly in the older age groups of a correlation between good diabetic control in the early years of the disease, and lower incidence of retinopathy. The value of continuing good control, or later establishment of good control, is less sure, as is the effect of good control on the progress of established retinopathy, though proliferative retinopathy is less common in patients with good diabetic control.

The present status of treatment

The fact that so much space has been devoted to the treatment of diabetic retinopathy must be ample evidence that the subject is obscure. Were there one really effective treatment no problem would exist; were the pathogenesis of diabetic retinopathy better understood then the search for treatment would be informed and the pageant of ephemeral fashions ended. In approaching the aetiology of diabetic retinopathy two lines of enquiry seem necessary; firstly to understand the nature of the circulatory disturbance in the retina so that local palliative treatment may be more effective; secondly, to unravel the biochemical abnormalities which underlie the complication, with the hope of finding a fundamental treatment.

Xenon arc and laser photocoagulation offer the best hope at present of local palliative treatment, but much remains to be learned about the extent

806 D . W . HILL

and timing of treatment and the appropriate areas of retinopathy to coagulate. The present steps are largely empirical and punctuated by the acclamation of poorly validated results on one side, and the call for controlled trials on the other, at a stage when the real matters to be tested are scarcely grasped. Both pituitary ablation and photocoagulation produce, when effective, a remission in the diabetic retinopathy similar to the change which may be seen spontaneously, but the duration of that remission is uncertain. Recurrence ofret inopathy after pituitary ablation has been reported in relation to return- ing pituitary function (Joplin et al, 1967), but it is not always certain that this is necessarily the cause. Recurrences after photocoagulation are well documented; they are more easily treated as the photocoagulation can be repeated provided that the lesions are accessible and do not involve an area of retina vital to visual function.

Indications for, and choice of treatment

As no binding rules can be laid down, and different opinions may be equally valid, it follows that this statement carries a personal bias. There is no compelling reason for the treatment of diabetic retinopathy unless, either proliferative retinopathy or exudative retinopathy affecting the macula, develop. In either event, the early stages of this established change should be the signal for considering photocoagulation, which should be directed towards new vessels, exudative rings and leaking vessels in the first instance, more generalised treatment of the 'pattern bombing' type being reserved for patients with more advanced disease and those whose retinopathy progresses after treatment. In exudative retinopathy, coagulation often has to be placed close to the macula which entails additional risk; this has to be balanced against the severity of disease and the expected improvement.

Pituitary ablation is indicated as a primary line of treatment in patients presenting with rapidly advancing proliferative retinopathy, when neo- vascularisation is unsuitable for photocoagulation on account of extent or site (e.g. papillomacular area), and before fibrotic secondary changes occur. The general medical criteria already discussed must also be satisfied.

Clofibrate can usefully be given as an adjunct to treatment in those patients with marked deposits of hard exudates in the macular region, provided useful vision remains.

In my opinion, none of these indications, except perhaps that for primary pituitary ablation, is so strong as to exclude a controlled clinical trial, provided adequate safeguards are incorporated for withdrawal if the retinopathy deteriorates beyond a defined limit.

General Bibliography Caird, F. I., Pirie, A. & Ramsell, T. G. (1969) Diabetes and the Eye. Oxford: Blackwell.

REFERENCES

Becker, B. et al (1954) Adrenal cortex and B-vitamins in diabetic retinopathy. Diabetes, 3, 175-187.

Becker, B. (1967) In Vascular Complications of Diabetes Mellitus, ed. Kimara, S. & Caygill, W, M., pp. 43-47. St. Louis: C. V. Mosby Co.


Beetham, W. P. (1963) Visual prognosis of proliferating diabetic retinopathy. British Journal of Ophthalmology, 47) 611-619.

Caird, F. I. (1965) Prognosis for vision in diabetic retinopathy. In On the Nature and Treat- ment of Diabetes, ed. Leibel, B. S. & Wrenshall, G. A., p. 465. Amsterdam: Excerpta Medica.

Caird, F. I. & Garrett, C. J. (1963) The prognosis for vision in diabetic retinopathy. Diabetes, 12; 389-397.

Caird, F. I., Pirie, A. & Ramsell, T. G. (1969a) Diabetes and The Eye. p. 115. Oxford: Blackwell.

Caird, F. I., Pirie, A. & Ramsell, T. G. (1969b) Diabetes and the Eye. pp. 81-87. Oxford: Blackwell.

Cullen, J. F., Ireland, J. T. & Oliver, M. F. (1964) A controlled trial of atromid therapy in exudative diabetic retinopathy. Transactions of the Ophthalmological Society of the United Kingdom, 84, 281-295.

Hunter, P. R. et al (1967) Controlled trial of Methandienone in treatment of diabetic retinopathy. British Medical Journal, ii, 651-653.

Joplin, G. F. et al (1965) Pituitary ablation for diabetic retinopathy. Quarterly Journal of Medicine, 34) 443-462.

Joplin, G. F. et al (1967) Diabetic retinopathy II: comparison of disease remission induced by various degrees of pituitary ablation by y90. Diabetologia, 3, 406-412.

King, R. C. et al (1963) Exudative diabetic retinopathy, spontaneous changes and effects of a corn oil diet. British Journal of Ophthalmology, 47, 666-672.

Kxill, A. E. et al (1971) Photocoagulation in diabetic retinopathy. American Journal of Ophthalmology, 72, 299-320.

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Luft, R. et al (1955) Hypophysectomy in man. Further experiences in severe diabetes mellitus. British Medical Journal, ii, 752-756.

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Meyer-Schwickerath, G. R. E., Schott, K. (1968) Diabetic retinopathy and photocoagulation. American Journal of Ophthalmology, 66, 597-603.

Nolan, J. & Cullen, J. F. (1969) Present status of Clofibrate therapy in ophthalmology. British Journal of Ophthalmology, 53, 9-15.

Oakley, N. et al (1967) Diabetic retinopathy. I. The assessment of severity and progress by comparison with a set of standard fundus photographs. Diabetologia, 3, 402-405.

Okun, E. & Cibis, P. A. (1966) The role of photocoagulation in the therapy of proliferative diabetic retinopathy. Archives of Ophthalmology, 75, 337-352.

Poulsen, J. E. (1953) Houssay phenomenon in man; recovery frorrt retinopathy in a case of diabetes with Simonds' Disease. Diabetes, 2, 7-12.

Root, H. F., Mirsky, S. & Ditzel, J. (1959) Proliferative retinopathy in diabetes mellitus. Journal of the American Medical Association, 169, 903-909.

Rubinstein, K. & Myska, V. (1972) Treatment of diabetic maculopathy. British Journal of Ophthalmology, 56, 1-5.

Saskin, E., Waldman, S. & Pelner, L. (1951) Diabetic retinopathy. A new approach to therapy with a steroid hormone testosterone proprionate. American Journal o f Ophthalmology, 34) 613-617.

Taylor, E. (1970) Proliferative diabetic retinopathy, regression of optic disc neovascularisa- tion after retinal photocoagulation. British Journal of Ophthalmology, 54) 535-539.

Zweng, H. C., Little, H. L. & Peabody, R. R. (1971) Argon laser photocoagulation of diabetic retinopathy. Archives o f Ophthalmology, 84) 395-400.

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