ACTA OPHTHALMOLOGICA VOL. 39 1961

From the Ophthnlmological Department, Central Hospital, University of Helsinki (Chief: Professor Matcno Vannas, M . D.)

LIPID KERATOPATHY*)

A clinical and serum lifiid chemical study of sixteen cases

BY

Henrik Forsius

Deposits of fat in the cornea may be of differing origin and occur in amorphous or crystalline form. Lipid dystrophies originate partly secondarily as the sequel of a universal disorder of fat metabolism, i. e. gargoylism, partly without de- monstrable cause.

A disease group in which an excess of fat may be established in the serum in combination with a local factor in the cornea is lipid keratopathy. This paper reviews a series of cases of this disease which is called by different names in the literature. e. g. Fettentartung der Hornhaut, dystrophia adiposa corneae, keratitis interstitialis lipina, lipoidosis corneae, lipid keratitis and lipid keratopathy.

The following forms were distinguished, according to e. g. Bussaca: (a) an- nular dystrophy which differs from marked senile arcus e. g. in its yellow colour; (b) discoid fatty dystrophy revealing in the parenchyma a round greyish white or yellow disk which contains numerous needle-shaped crystals and fat; (c) other forms including fatty infiltration in keratitis and secondary adiposis of old corneal scars.

According to Heath, the commonest causes of secondary fat deposition are parenchymatous keratitis, ulcerative keratitis, corneal herpes and tuberculous iridocyclitis.

Annular lifiid keratofiathy

Fat is normally deposited in the corneal periphery with advancing age. This sudanophilic fat deposition - arcus senilis - can be demonstrated microscopical- ly in a certain degree in all old and middle-aged people (Rohrschneider) and even biomicroscopically in most persons past middle age (Meyer, Forsius 1). A

*) Received February 18th 1961.

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distinct correlation with the blood fat level is seen in persons under 40 while other factors, probably a local factor in the cornea, predominate in older sub- jects (Forsius 1). While in arcus senilis there is no intracellular deposition of fat. necrosis or vascularity in the cornea are demonstrable in lipid kerato- pathy (Cogan). There is, however, no sharp dividing line between these forms. Vannas e. g. considered that a reported case of annular fatty dystrophy derived from arcus senilis. Another worker, Heath, was of the opinion that senile marginal atrophy and arcus are related to the deposition of fat in the cornea. Potvin draw a parallel between arcus senilis and corneal ulceration. In the discussion following a paper read by Cogan (Cogan), Franceschetti referred to the connection between lipid arcus and marginal ulcerations and even marginal ectasia. Cogan replied that he had not observed any such correlation. I have reported on 2 cases of marked arcus (or lipid keratopathy) with reduced corneal sensitivity and fatty dystrophy in the fellow eye (Forsius 2). One patient sub- sequently had an ulceration in the lipid ring. These 2 cases are included in the present report (as Nos. 4 and 6). Palich-Szbnt6 has recently reported 65 cases of infiltration in the vicinity of the arcus in persons over 50.

Discoid lifiid keratofiathy

Disk-shaped fatty dystrophy occurs without the reactivation of the original disease. In its typical form, a greyish-yellow round disk is seen in the middle of the cornea which is vascularized by isolated deep and superficial blood vessels. On the margin of the inflammation, birefringent crystals are seen pre- dominantly extracellularly in the necrotic areas. Spotty calcification is seen sometimes (Cogan). The changes are greatest in the deep layers (Thomas). Aplastic uveitis is sometimes present. Fat can also be deposited during the current disease process and can then be reversible. Caspar noted even spon- taneous remission of a yellow focus of many years standing in a young man. The persons affected are usually of later middle age or older, but the con- dition can occur also in children. Fatty degeneration was established by Orzalesi in a child of 8 who had had trachoma.

Fatty degeneration is called primary if the cornea shows fat deposition un- connected with an earlier eye disease. Primary fatty degeneration is very rare. Remembering how frequently corneal scars are demonstrated without the patient’s knowledge of any earlier eye disease or injury, it is not surprising that many researchers do not accept primary lipid keratopathy with certainty. According to Thomas (1955), only 16 published cases fulfil the criteria for primary lipid keratopathy.

As a great number of the reported cases have hypercholesterolemia in con- jugation with lipid keratopathy the former has been regarded as a contributory factor.

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An extreme form of lipid keratopathy is represented by the cases called xanthomatosis bulbi by v. Zsily. In these the deposition of fat occurs in the anterior chamber, too, in the form of e. g. cholesterol crystals.

There is probably a correlation to atherosclerosis and to other medical diseases. The literature, which consists mostly of individual case histories, sometimes provides information on the general condition of the patients. Bachstez considered that Basedow’s disease was involved in the case reported by him. Corneal disease was established by Meesmann in a diabetic with hyper- cholesterolemia; he considered that the foci resembled atheromatous foci in the blood vessels. Satanowsky diagnosed latent diabetes in one of her 3 cases, Michon and Bretagne nephritis, hypertension and hypercholesterolemia. Heath suggested that it is usually women, often very fat, who eat much fatty food. Xanthelasma is sometimes established.

Genet and Martin reported 5 cases of cholesterol deposition in the cornea, one of them a patient with left-sided heart failure and yellow fatty deposition which broke up into crystals as time went on. Conway and Loewenstein established nephrosis in a man with corneal deposition of fat in the form of greyish-white spots throughout the parenchyma. Hypertensive cardiovascular disease accompanied by arteriosclerosis was established by Davidson in a patient. Snydacker noted annular lipid keratitis with hypercholesterolemia. A case with hypothyroidism and overweight was reported by Kronfeld. Zeeman and Groen studied 12 cases of lipid keratitis, partly of crystalline structure. Nearly all the patients were fat, 6 had hypertension, 4 severe arteriosclerosis. One patient had diabetes and xanthelasma and another had myxedema. Eleven of the patients had hypercholesterolemia. Franceschetti, Klein and Babel studied a case of xanthomatosis in the cornea with high blood cholesterol levels by paper electrophoresis. and found low alphalipoproteins and low albumin and alpha-1-proteins. Fatty depositions in the cornea in the form of arcus juvenilis are common in xanthomatoses which are correlated with athero- sclerosis (Kornerup). An extreme case of bilateral central fat deposition in the cornea in xanthoma tuberosum (cholesterol concentration up to 1450 mg per cent) was reported by Davidson, Pilz and Zeller. Cogan studied the cholesterol content in 10 patients with lipid keratopathy of the cornea. Four of them had a cholesterol content of over 300 mg per cent and one had 500 mg per cent with a fatty acid concentration of 627 mg per cent. The corneal foci of fat resembled atherosclerotic foci and the accumulation of fat demonstrated in the cornea in experimental rabbit xanthomatosis.

OWN INVESTIGATIONS

The present series consisted of 16 patients with lipid keratopathy collected in 1954-1960 at the Ophthalmological Department, University of Helsinki. The examination findings are given in Table 1. There are photographs of

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Fig. I . Right eye of a woman of 47 with uremia (Case No. 1). A discoid fatty degeneration has developed in the cornea in the course of 2-3 years. No previous corneal lesion.

Fig. 2. Left eye of a woman of 50 (Cases No. 2). A discoid lipid dystrophy.

Phlyctenular keratitis in childhood.

cases 1, 2, 4, 5, 6, 8, and 13 (Figs. 1-9). Arcus senilis was classified as follows: marked arcus in which fatty infiltration occurs throughout the parenchyma in at least some place; weak arcus in which the ring of fat can be seen on gross examination, but is not throughout the parenchyma; and only biomicroscopically visible arcus. The chemical methods used in the investiga- tion were reviewed in an earlier work (Forsius 1). The blood chemistry of 165 patients with different degrees of arcus senilis was compared in that work.

A medical examination was performed on all patients complaining of distress and in the majority of the other cases. The majority of the patients were

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women; only 3 men. The mean age was 60.2 years. The subjects affected by lipid keratopathy were predominantly from the older age groups. The youngest was 38. In the majority of the cases the patient had had keratitis (9 cases) or a perforating corneal lesion (2 cases) in childhood or adolescence. In later years, fat deposition occurred in the scars and the patient’s vision was impaired, usually slowly but in 3 cases relatively rapidly during the last few years. The lipid keratitis had originated from keratitis in 4 cases; three of them had

Fig. 3. Same person as in Fig. 2. In this eye, serpiginous ulcer in a cornea

with fatty degeneration.

Fig. 4. F. J., Case No. 4. Annular fatty degeneration with marginal ulceration

in a man of 74.

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Fig. 5. The fellow eye of the one in Fig. 4. Deep diffuse fatty degeneration. An eye disease

in childhood. Fifteen years ago a central 4 mm corneal macula.

Fig. 6. M. B., Case No. 5. A woman of 49 with a white swollen area from which radial rays

depart. Deep and superficial vessels. Sequela of herpetic keratitis 11 months ago.

hypercholesterolemia. In one case (No. 1) the patient had no knowledge of an earlier condition and it might perhaps be regarded as primary disk-shaped lipid keratopathy. Four other patients had discoid keratitis (Nos. 2 , 3 , 5 and 13). The other patients had more or less well defined white or yellowish leukomas. Two of them (Nos. 4 and 6) had an extremely yellow, broad arcus (= annular fatty dystrophy) in the other eye. The patient’s vision was usually sharply reduced. Occasional large blood vessels, starting from the conjunctiva and gradually invading the parenchyma, generally led to the fatty region. The fellow eye was also often damaged, the clearest evidence of which was the fact that vision was normal in only 5 cases. Ten cases showed parenchymal opacities, and in 4 of them they could be designated as lipid keratitis. There

277 Acta Ophthalmol. Vol. 39, I1 20

were 4 cases in which the better eye revealed infiltrates or ulcers during the period of observation. Corneal sensitivity was measured with nylon thread in 5 cases (according to Boberg-Ans). It was moderately or sharply reduced, as in the eyes with annular lipid degeneration. Pressure was elevated in 9 eyes, 4 of them the more affected eye. It was of secondary type in 5 cases and simplex type in 1 case. Three of these eyes had glaucoma capsulare, and 1 eye with normal intraocular pressure also revealed lens exfoliation. Increased pressure with lens exfoliation is common in Finland. Arcus senilis is registered in the better eye. Where the condition of the cornea permitted classification

Fig. 7 . H. K., Case No. 8. A woman of 47 with corneal ulcer. Phlyctenular keratitis in

childhood. Increasing central and peripheral fat deposition in the cornea for the last 15 years.

Fig. 8. A. F., Case No. IS. A woman of 72 who had a corneal ulcer 10 years earlier. Marked

arcus senilis of the cornea. Slowly progressing parenchymal fat deposition.

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Fig. 9. A. T., Case No. 6. The eye of a woman of 70; perforated with a knife a t the age of 4. Extremely yellow arcus in both eyes (annular lipid keratitis). The lesion was infiltrated

by fat as the arcus developed.

Males

(14 cases), arcus senilis was marked in 10 and weak in 4 cases of which one case (No. 7) was on the verge of microscopic.

Females

Age h Micro- I Weak1 Marked i No I Micro- I Weak1 Marked I arcus I scopic I I I arcus I scopic I I

30-39 12 20 18 1 4 0 4 9 2 39 38 7 9 35 14 4 50-59 6 15 9 1 17 24 14 60-69 1 14 17 3 21 12 > 70 2 4 14 1 15 25

14 persons with lipid keratopathy 30-39 1 40-49 50-59 1 60-69 > 70 1

3 1 2

1 4

The serum cholesterol content was less than 300 mg per cent in 2 cases, mean 353 mg per cent. The total serum lipid value was determined in 8 cases and averaged 11.9 per mille.

Table 3. Serum proteins and lipids were studied by paper electrophoresis. The results were compared with the values obtained by the same method in the earlier investigation.

Serum proteins I Serum lipids

L. N. 21.9 R. F. 22.9 F. J. 22.7 M. D. 19.9 H. K. 14.7 S. R. 16.5 U. K. 25.5 A. S. 25.0

11.1 14.1 11.6 9.6 9.5

12.8 12.2 18.2

6.9 10.3 8.0 9.1 7.1

10.6 5.6

15.3

60.1 52.7 57.7 61.5 68.7 60.1 57.6 41.5

35.9 22.9 29.6 30.2 10.4 32.6 22.4 10.3

64.1 77.1 70.4 69.8 89.6 67.4 77.6 89.7

Mean 21.1 12.3 9.1 57.5 24.3 75.7

General condition

The table shows many divergences from normal in the health status. Four patients suffered from cardiac failure and 2 from high blood pressure. One . person had uremia as the consequence of 10 years of chronic nephritis. Two patients had xanthelasma and 1 had psoriasis. Three persons revealed roent- genological evidence of old hilar adenites or pleurisy. One patient had been operated on for thyreotoxicosis.

To obtain a suitable grnup for comparison the first 60 case reports for 1960 in the same age classes were studied. Where indicated, a medical examination was performed on these patients. Glaucoma and cataract were the predominant diagnoses in the older age classes on admission. Of these 60 patients, 13 had roentgenologically or clinically demonstrable dilatation of the heart. The blood pressure was 170 mm Hg or more in 10 patients 6 of whom had no dilatation of the heart. Two patients had senile.diabetes, 1 had gallstone trouble, another had been operated on for goitre, 2 had emphysema and 4 post-pleuretic scars. Only 24 of the patients were completely healthy. A careful examination of those 24 even would perhaps have resulted in the discovery of some fault - one had a sedimentation rate of 63 and another had a serum cholesterol content of 370 mg per cent. The average SR was 18.0 mm during the first hour. The majority of the patients with heart disease were over 60. These gloomy

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statistics suggest that caution is necessary in assessing the significance of me- dical diseases for the genesis of lipid keratitis. Even when the uremic patient was omitted, the sedimentation rate was considerably higher in the lipid keratitis series.

DISCUSSION

The clinical picture varied slightly in the different cases. Disk-shaped degenera- tion occurred in 5 cases and secondary fat deposition 9f irregular shape in the other 1 1 cases of which 2 had annular lipid degeneration in the contralateral eye. The history of the patients was similar, usually involving keratitis or an injury in childhood which had accumulated fat slowly in the last few years. Direct fat deposition had occurred in 4 cases in connection with keratitis of long duration. Why, then, do the scars fill with lipids? Most workers suggest hypercholesterolemia. In the present series there was generally both hyper- cholesterolemia and an increase in total fat in the blood. According to Cogan, the histological picture is similar to that seen in atherosclerosis. As in the series of Zeeman and Groen, a striking number of the cases had diseases of the heart and blood vessels, xanthelasma and thyreotoxicosis. Both patients in the present series with a serum cholesterol content of less than 300 mg per cent had myodegeneration of the heart. One of them also had psoriasis which is often accompanied by hypercholesterolemia. Only one blood sample was taken from each of them.

The comparison of this series with persons affected with different degree of arcus senilis was specially interesting. In earlier investigations of persons with arcus of different degrees the present author found that young persons (under 40) with marked arcus generally showed high serum lipid values. The correlation was less good in persons between 40 and 59 years of age and non- existent in older persons who always have arcus. Table 2 includes the cases of lipid keratopathy, and they follow the same lines. There were no cases without arcus or only biomicroscopically demonstrable arcus. I t would thus seem as if the persons who developed marked arcus were also most susceptible to lipid keratitis. The fat values have a greater and the corneal factor less importance for the accumulation of lipids in the cornea in the younger patients. Among persons over 60 both the arcus and lipid keratitis are more dependent on local senile processes in the cornea.

SUMMARY

The material consisted of 16 persons with lipid keratopathy of the cornea. Their mean age was 60.2 years, the youngest patient was 38. There was a childhood history of keratitis in 9 and perforating corneal trauma in 2 cases.

28 1

The scars were gradually infiltrated with fat in old age except in 4 of these cases in which the fat deposition originated in connection with keratitis. One patient - a woman of 47 with uremia - knew nothing of an earlier eye injury, i. e. had primarily ? lipid dystrophy. Besides this case, 4 other cases had discoid keratitis. The other patients had more or less well defined white or yellowish leukoma. Two of these cases had an extremely yellow arcus senilis, i. e. annular dystrophy in the contralateral eye. There were 10 cases in which the fellow eye was damaged by parenchymal opacities, 4 of which could be described as lipid keratitis. Corneal ulcers were common in both eyes. Arcus senilis was more marked than in a control material of the same age.

Heart failure and other diseases were present in numerous cases. Comparison with 60 persons of the same age showed, however. that the importance of such complications must not be exaggerated.

The serum cholesterol content was under 300 nig per cent in only 2 cases (mean 353 mg per cent). The serum cholesterol, total serum lipids and paper electrophoretic protein and lipoprotein values of persons with different degrees of arcus senilis were compared in an earlier work. I t appeared that persons with lipid keratopathy are most closely comparable with persons affected by marked arcus senilis. The conclusion to be drawn is that persons predisposed to marked arcus senilis are most liable to develop lipid keratitis. The earlier investigation had established a good correlation in young and middle-aged persons between arcus senilis and high serum cholesterol values. By contrast. a corneal factor was predominant in older people. The same observation seemed to be true of the development of lipid keratopathy in the cornea.

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