Erik Linnér

Ocular hypertension. A prospective twenty-year follow-up study.

Abstract In a prospective study of 41 persons with ocular hypertension followed for 20 years, 14 individuals (34 per cent) developed glaucoma. Of 38 persons who 20 years ago were normotensive, 2 (5 per cent), developed glaucoma. This difference is significant. The mean IOP of the remaining untreated ocular hypertensives was about 7 mmHg higher than the mean tension in the control group.

Ocular hypertension. I. The clinical course during ten years without therapy. Aqueous humour dynamics.

An initial group of 152 subjects with moderate ocular hypertension constituted the basic material of the present study. Antiglaucoma treatment was started in 8 men and in 6 women. A remaining group of 92 subjects were kept under clinical observation for ten years without antiglaucomatous therapy and without any evidence of progressive disc cuppping or field defects. The intraocular pressure as well as the outflow facility showed a tendency to decrease with time, which was assumed to indicate a reduction in aqueous flow with increasing age. The tonographic findings support the view that the moderately elevated intraocular pressure is mainly due to an increased rate of aqueous flow.

EFFECTS OF LONG-TERM SYSTEMIC STEROIDS ON CATARACT FORMATION AND ON AQUEOUS HUMOUR DYNAMICS

The occurrence of posterior subcapsular cataracts in some patients with rheumatoid arthritis treated with corticosteroid hormones in high doses over a long period of time was reported by Black et al. 1960 (6). This paper was later followed by more detailed reports by the same authors ( 7 ) . Afterwards subsequent papers have appeared in the literature, with diverging opinions concerning the relationship between corticosteroid treatment and cataract. In a recent paper by Sundmark where 3 cases of subcapsular cataracts were found among 48 patients, the literature is reviewed (17 ) . One of the objections is that many of the patients in the previous reports suffered from rheumatoid arthritis, and such a generalized disease might in itself play a r81e for the development of a cataract. The problem of a possible relationship between the development of a cataract and the intake of corticosteroids over a long period of time is also of a great interest because it might throw some new light on the physiology of the lens. Observations in cases of senile cataract indicating a reduction in blood flow through the secretory part of the eye and in aqueous flow has been demonstrated (9, 13). Topical application of steroids was found to increase the rate of aqueous flow in human eyes and the normal variations in flow during day and night were reduced in patients without normal adrenocortical activity (10, 12, 14). Recently a marked elevation of the intraocular pressure and an increased outflow resistance following topical application of steroids were reported (2, 8). A group of patients on long-term systemic steroid therapy showed an increased applanation pressure and a decreased water provocative facility of out-

The course of untreated ocular hypertension. A tonographic study.

It is still not certain what happens when ocular hypertension is left alone, despite the great amount of research that has been done on the subject. Nearly every case is treated as soon as it is discovered, and no one has been able tc study the development over a long period of time in a representative sample of untreated cases. Leydhecker (8) studied the development over three years in a group of whom 40 per cent had not been treated, but he only reported what happened to the ocular function during these years, nothing about the ocular tension. Chandler (4) reported that he had observed cases in which a tension of 30 mm. had not risen {though the patient had not been treated for years. In 1958 Armaly began an investigation of a representative sample (altogether 679 persons) of the population, which was planned to take five years: so far he has “dealt with the simultaneous presence of tonometric predictors and a defined arcuate scotoma” (1 , 2). The general opinion, dating back to Donders according to Haffmans in 1862 (5), is that ocular hypertension nearly always gets worse and worse, at any rate glaucoma simplex; Sugar (13) said that the tension rose gradually from a little over 24 mm. Hg up to 40 mm. Hg, sometimes to as high as 60 mm. Hg (Schiotz 1955 scale). Ballintine (3), on the other hand, observed that the intraocular pressure was only moderately elevated in persons who had grown blind from glaucoma after having refused treatment for religious reasons. In 1962 one of us (Stromberg (12)) reported the results of a mass survey of the ocular tension in the population over 40 years of age of a (town where

THE INITIAL DROP OF THE INTRAOCULAR PRESSURE FOLLOWING INTRAVENOUS ADMINISTRATION OF ACETAZOLAMIDE IN MAN

Following the intravenous administration of acetazolamide a drop of the intraocular pressure has been reported to occur within two to three minutes in the rabbit, cat and dog (Gloster and Perkins 1955; Langham and Lee 1957; W i strand 1957) and to reach its maximum [about 60 O/o of the outflow pressure) after ten to fifteen minutes. In the shcep no measurable pressure drop was observed within 60 minutes (Wistrand 1958). The initial pressure drop following an intravenous administration in man does not seem to have been studied before. The sheep and the human eye fall within the same category, having an excess (relative to plasma water) of chloride and a deficit of bicarbonate. This is opposite to the situation in the rabbit, cat and dog, where an excess of bicarbonate is found. In the cat and dog there is also an excess of chloride but in the rabbit a deficit of this ion has been reported (Dawson 1956; Davson and Luck 1957). I t was therefore considered to be of interest to investigate the speed with which the eye pressure response to carbonic anhydrase inhibition occurs in the human eye. Normal human eyes were examined during day time and in some additional experiments during night time when the rate of aqueous flow is reduced. Because a greater pressure-response is possible at an elevated intraocular pressure a few glaucomatous eyes were also examined.

ADRENOCORTICAL HORMONES AND GLAUCOMA

As an introduction to this short survey, which cannot be complete, I should like to say a few words about the hormones formed in the adrenal cortex as well as about some of the synthetic analogues. A great number of different steroids are known to be synthezised by the adrenal cortex : so far more than 40 different corticosteroids have been isolated. There are also a great number of precursors and metabolic products making it difficult to establish clearly which are the true adrenocortical hormones. The hormones have been classified into three different groups : 1. Gluco-corticosteroids 2. Mineralo-corticosteroids 3. Sex-hormones The third group, which includes androgens, esterogens and progesteron has the number of C-atoms varying between 18 and 2 1. The sex hormones will no1 be further discussed here. The glucoand mineralo-corticosteroids all have a skeleton consisting of three six-membered rings and one five-membered ring with a total number of 21 carbon atoms in the molecule. The distinction between glucoand mineralocorticosteroids is not quite valid, since there are only quantitative differences in their actions on the mineral and carbohydrate metabolism. The adrenocortical hormones are of vital importance and their action is essential for maintaining a constant internal environment, homeostasis. The composition of the corticosteroids varies among different species. In the human being cortisol (hydrocortisone) dominates quantitatively and it is possible to substitute an adrenalectomized patient by means of this compound alone. The activity of corticosteroids is concerned with the metabolism of both carbohydrate, fat and proteins, but there is a considerable difference in the intensity of the action of the various hormones. The hormones cause an increase in the blood sugar level, which is counteracted by an increased production of insulin. The breakdown of protein is stimulated by large doses of corticosteroids.

THE INITIAL CHANGE IN INTRAOCULAR PRESSURE INDUCED THE SUCTION CUP

A method for clinical determination of the inflow of aqueous humor into the human eye by means of a suction cup has been described by Rosengren (5, 6, 7 ) . The method has been developed further and the sources of error discussed by Ericson (2). The principle is that a suction cup is placed on the eye so that its contacting surface exerts a pressure against the sclera around the limbus. In this way the episcleral veins are compressed so that the drainage of aqueous humor from the eye is blocked, producing an increased pressure in the eye. With the help of tables (3) which show the relationship between intraocular pressure and volume, it can be calculated how much of a volume increase is required in order to raise the pressure to a certain level. This estimated increase in volume has been used as a measure of the inflow of aqueous humor during the time the suction cup is placed on the eye. The method has been found useful for comparative clinical studies on the aqueous flow. The estimation of aqueous flow by means of the suction cup produces different values depending on how long the outflow channels are blocked by the suction cup (2). Lower flow values per minute are obtained with longer application. A conceiirable explanation for this discrepancy could be that the aqueous inflow is sensitive to increase in pressure; this inhibition becoming more significant at the higher pressure which is produced by a longer period of suction. Other causes such as leakage of aqueous humor under the contact surface of the suction cup and the presence of unidentified outflow channels can not be excluded. These studies were made on eyes with an intraocular pressure inside the normal limits. Later investigations (10) made on eyes with different intraocular pressures

Electromyographic study of the eye muscles in endocrine exophthalmos.

Opinions diverge as to whether or not a single basic mechanism underlies the syndrome of endocrine exophthalmos (Rose, 1952; Lamberg, 1954; Falconer & Alexander, 1951 ; Mulvany, 1944; Cordes, 1954; Rundle, FinlayJones & Noad, 1953). According to Mulvany a distinction can be made between a thyrotoxic and a thyrotrophic type of exophthalmos. I t is possible, however, that combinations of these forms exist (Copper, 1948; Dayton, 1953). All except three of our 17 patients either acquired exophthalmos or had exacerbation of existing exophthalmos following various types of antithyroid therapy. Though, in the opinion of Mulvany, this type of exophthalmos should be classified as thyrotrophic, it seems more plausible to regard it as a mixed form. In the three exceptions exophthalmos developed spontaneously without previous signs of thyroid dysfunction or previous antithyroid therapy, but in those cases too, a thyroid-pituitary disorder was detected. Weakness of the extraocular muscles, or ophthalmoplegia, is known to be a common symptom of endocrine exophthalmos (Brain). Many different theories have been propounded to account for this phenomenon. Kappis (1910) suggested a neurogenic etiology, but the consensus today is that the eye-muscle changes are primary and located in the muscle tissue itself. Their nature, however, remains obscure. Brain attributed the ophthalmoplegia to increased tension within the muscle cone, but this view seems to be invalidated by the fact that in many cases ophthalmoplegia preceded the protrusion. The changes in the interstitial connective tissue, with an increase of the mucopolysaccharide content as well as metachromatic semilunar structures beneath the sarcolemma, as demonstrated by Asboe-Hansen, Iversen & Wichman (1952), could well account for the loss of muscle function. The effect of thyrotrophic hormone

CONNECTIVE TISSUE PROBLEMS IN OPHTHALMOLOGY

During the last decades much interest has been focused on the physiology and pathology of connective tissue. Only 20 years ago this tissue was looked upon as an almost inactive framework of the body. Now, however, new biochemical methods and advanced physical techniques are yielding much information about different aspects of connective tissue such as transport of different compounds between cells and metabolic changes. Connective tissue consists of a variety of cells such as fibroblasts, mast cells, and histocytes, a network of fibers both collagenous and elastic, the whole surrounded by amorphous groundsubstance. The connective tissue ground substance is a physiological substrate through which water, electrolytes, and other essential compounds are transported to the various cells of the body. The capacity to accumulate and bind water is one of the most important functions of the ground substance, a characteristic which depends upon its specific chemical and physical properties. The groundsubstance contains both proteins and different mucopolysaccharides. Many of the mucopolysaccharides are sulphated, however, hyaluronic acid is an exception. Among the cell components the mast cells have taken on a special interest. These cells, which were described first by Ehrlich have cytoplasmic granules which stain metachromatically with certain basic dyes, such as toluidin blue. The mast cell is supposed to produce heparin (Jorpes, Holmgren and Wilander 1937), hyaluronic acid (Asboe-Hansen 1950) and histamine (Ridley 1958). The functions of the mast cell, however, are not clear; they are probably different in different tissues and in different species. The fibroblasts are of great importance in tissue repair and are probably stimulated by the mucopolysaccharides within the surrounding groundsubstance (Sylvkn 1941, Balazs & Holmgren 1950). The acid mucopolysaccharides also seem to be necessary for the formation of different collagen fibers (Kramer 1953, Jackson & Randall 1953, Bowes, Elliot 8c Moss 1953), especially the sulphated mucopolysaccharides. The mucopolysaccharides also play a role during inflammatory processes where their water binding capacity is important; here the hyaluronic acid plays a part.

Facility of outflow in shallow anterior chamber.

The shallow anterior chamber has been found to be an essential factor for the type of primary glaucoma characterized by attacks of increased intra-ocular pressure. It is generally accepted that these episodes are caused by a contact between the iris and the cornea blocking the passage through the angle. Therefore it is not surprising that the outflow facility is found to be decreased during these attacks. During the free intervals between the attacks, however, the outflow facility was found to be within normal limits if the angle is re-opened (Grant 1951, and others). These reports seem to indicate that the narrowness of the angle in itself is not a facility-reducing factor. In patients with unilateral attacks of acute glaucoma a study of the other eye is of special interest because the structure of the anterior chamber is very similar in both eyes (Rosengren 1931, Tornquist 1956). Consistently Grant (1951) found normal outflow facilities. During the hypertensive phase of the glaucomatous eye Weekers and Prijot (1952) sometimes found a decreased facility in the other eye. In an extensive study of aqueous humour dynamics Goldmann (1951) among other data reported the outflow resistance and the volume of the anterior chamber in 24 normal human eyes. The figures suggest a tendency towards higher resistance at smaller volume of the anterior chamber, but is seems impossible to draw any definite conclusions from this material. In perfusion experiments of enucleated human eyes Frangois, Rabaey and Neetens (1956 a, b) studied the outflow facility during varying depths of the anterior chamber. The changes in chamber depth were obtained by an adjustable pressure applied to the equator of the globe. The outflow facility was found to decrease at decreasing chamber depth. A similar trend was demonstrated by Bhrhny.