June 19371 AFFECTIONS OF THE EYE : WRIGHT 363^ affections of the eye in the

malarial FEVERS AND KALA-AZAR j

By R. E. WRIGHT, c.i.e.

LIEUTENANT-COLONEL, I.M.S.

Professor of Ophthalmology, Madras, India It must not be assumed from the title tnat

fliy intention is to give a sort of key to various pathological conditions occurring in the eye, either in association with, or academically still wore important, actually due to an infection with the various types of parasites responsible

/for the diseases named. This article is intended i to be, on the contrary, rather of a general nature, offering negative rather than positive information, in the hope that it will provoke those who have the time and. opportunity for clinical research to produce something more

definite, supported by figures of statistical value, and associated with a careful review of the literature.

My own impression after a long experience of ophthalmological work in a part of the country where malaria is fairly common, kala-azar much less so, is that we are very rarely entitled to

speak of conjunctivitis, keratitis, uveitis, iritis, neuritis, or any other

' itis' connected with the

eye, as due to these affections. In the Government Ophthalmic Hospital,

Madras, we have not made a diagnosis of a

malarial origin in eye affections more often than once in 50,000 times. I do not deny that one may meet with retinal haemorrhages and vitreous opacities more frequently than this in malaria and kala-azar. These, on rare occasions, may be very extensive if associated with a severe

infection and a heavy parasite count so that it is almost safe to assume that the small retinal vessels are actually injured by the presence of the parasites and their toxins, and that endo-

thelial damage, capillary embolism, and rupture of smaller vessels occur; although apart altogether from this mode of causation the

hemorrhage may be the result of anaemia

induced by the infection. At times we have

looked.with hopeful suspicion on the malaria

associated with an ophthalmic lesion?when we felt we must blame some agent and had not

enough evidence to blame any?but have had sufficient honesty to avoid labelling the eye

condition malarial, realizing that the wish was father to the thought. In holding the views expressed above, I may

be making a mistake, but the onus of proof lies with those who regard malaria as a condition

which should be seriously considered by the eye specialist as productive of ocular diseases. One

is familiar with a suffusion of the conjunctival and sub-conjunctival tissues in the fever of

these affections, but it is hardly reasonable to refer to it as conjunctivitis of malarial or kala- azar origin. Such congestion of the membrane is met with in many fevers. Herpes febrilis is

met with in association with malaria?more

particularly in Europeans?but it is an inde-

pendent disease. Some of the varieties of keratitis supposed to

be due to malaria have probably been diagnosed in complete ignorance of the existence of other potential causes. The keratitis disciformis referred to by writers in connection with malaria, is just as likely to be a variety of the disease which I have labelled elsewhere, ' kerato- conjunctivitis diversiformis et uveitis anterior' (this embraces the superficial punctate keratitis group of the textbooks). It is a world-wide

364 THE INDIAN MEDICAL GAZETTE [June, 1937

affection occurring sporadically and epidemi- cally, but for the most part misdiagnosed in

many of its phases. Inside the last ten years, we have seen over 13,000 cases in Madras city and districts. It is a disease sui generis into the

aetiology of which we need not go now, but

neither the existence of this condition, as such, nor the aetiology of herpes febrilis were known

to Elliot when he published his Tropical Ophthalmology in 1920 in which he discusses

keratitis in malaria. I hesitate to deny the

existence of iritis in malaria and kala-azar, but in view of the fact that many of the observa-

tions on which its existence were founded pre- ceded the use of the corneal microscope, the matter needs careful investigation under the

conditions of a modern experimental enquiry. No doubt iritis has been observed in patients suffering from malarial fever, but the records on which the aetiological role of the malarial para- site is assumed can hardly bear critical investi- gation. Cyclitis and cyclitic pain in this con- nection must be distinguished from ciliary congestion, and the pain associated therewith, and minor attacks of increased tension. The

optic 1 neuritis' said to be due to these fevers

no doubt may appear to exist at times, but hardly as an inflammatory condition. Here our

poor terminology helps out the individual anxious to add malaria and kala-azar to the several dumps into which we gladly throw a

diagnosis of neuritis, when we know nothing about its aetiology, but get the lead of a clinical association. It would be foolish to deny that a haemorrhage into the nerve may take place in malaria or kala-azar, or that a localized ischaemia in the nerve may give rise to retro-

bulbar-group signs and symptoms. It is obvious that the nerve may look red and swollen in an acute attack of ague; it may even do so after

homatropin instillation to an extent sufficient to deceive anyone but an expert. A real neuritis with evidences of the various criteria of inflam-

mation?e.g., a drop in the vision and sub-

sequent healing by scar tissue with partial atrophy of the nerve fibres?is so uncommon in association with active malaria and kala-azar as to afford a reasonable presumption that these diseases are either not a cause of neuritis or only so on very rare occasions.

The line of thought which I have tried to

develop above is reversed by Goldfeder (1936), who diagnoses latent and chronic malaria by means of the distribution of peculiar conjunc- tival vessels. He considers that the presence of certain types of vessels are as pathognomonic of malaria as Hutchinson's teeth are for con- genital syphilis. I can hardly subscribe to his views, as vessels so similar as to be indistin- guishable are to be seen in persons who have never had malaria, but of this more below. There are of course numbers of observers who believe that malaria is a cause of eye disease. Dedimos (1932) suggests that malaria attacks

practically all the structures of the eye and the nerves connected therewith. In the acute form lesions of the cornea predominate, whereas in the more chronic form lesions of the retina and choroid predominate. He is careful to add that it is not always easy to prove the relationship between the ocular lesion and malaria. The

co-existence of the two is not sufficient. In

general, the ocular lesion can be attributed to

malaria only under certain conditions :?

(1) The periodic appearance or aggravation of the condition.

(2) The therapeutic influence of quinine. (3) The presence in the blood of plasmodium-

fragmented red cells or pigment-containing leucocytes, an increase in the mononuclear

lymphocytes during the chronic stages, and

enlargement of the spleen. The severe forms of malaria with ocular com-

plications are in the majority of instances due to the malignant tertian species and almost

always with involvement of the nervous system. Prognosis is, as a rule, favourable. Treatment

depends wholly on the use of quinine. Pereyra (1922) considers that three types of

corneal affection, dendritic, herpetic, and inter- stitial keratitis, as well as conjunctivitis, iritis and choroiditis, may be due to malaria. The nerve may also show a number of changes the most common of which are (1) simple hyperce- mia, (2) papillitis, (3) retrobulbar neuritis, (4) acute endocular neuritis, (5) neuro-retinitis, and (6) atrophy, which in all cases is secondary to inflammatory process. The retina may show

pigmentary changes, the result of chorio-retinitis and endarteritis of small vessels and may even be ruptured by pathologic adhesion between retina and vitreous. The author is specially interested in retinal lmnorrhages on account of having seen a number of cases and having had the opportunity to examine the eyes of one

post mortem.

Kiep (1922) attributes the following to malaria. ' Dendritic or herpetic keratitis, deep- seated central parenchymatous keratitis, retinal and pre-retinal haemorrhages, optic neuritis

generally accompanied by retinal htemorrhages and paresis or paralysis of the seventh cranial nerve. He has not been able to decide that neuritis is caused by malaria. Of 63 cases of

herpetic keratitis 43 gave no history of previous ocular trouble. The ocular conditions might arise the same day as the initial malarial attack or long afterwards. In his experience, it was

invariably unilateral and arose from various forms of the Plasmodium. In all four cases of

parenchymatous keratitis, the Wassermann was negative. There was no other evidence of

syphilis and the keratitis was always unilateral. In each case the benign tertian fever was found. The progress of keratitis was slow, its duration

averaging three months, and central permanent opacity of the cornea was left. With reference

June, 1937] AFFECTIONS OF THE EYE : WRIGHT 365

to retinal haemorrhage, his experience agreed

with that of Fischer who found the cause 01

the haemorrhage to be the blocking of \ essoin

with malarial parasites'. Four of his cases also showed optic

neuiitis.

He had seen seven cases of optic neuritis

without

haemorrhage and two cases of post-neuntic

atrophy which both gave a negative AVasser-

ttiann reaction. Villard (1930) reports conjunctivitis, deep

keratitis, true malarial iritis in haemorrhages

of

the vitreous rare, choroiditis not uncommon,

spasm of the retinal vessels and retinal haemoi-

^&es, and neuritis not so rare.

Krol (1931) in an analysis of 404 optic

atrophies gives the following figures :

Among 42,980 patients who were

examined

r?m 1925 to 1929 inclusive, 404 or 0.94 per

cent

^ ere suffering from optic nerve atrophies.

The

Prevalent causes of these atrophies

were syphilis

'?4 per cent, meningitis 11.1 Pcr c611^ an^

trauma 9.8 per cent. Of interest is the rela-

funcly _ liigh incidence of optic

nerve atrophies

ollowing acute infectious diseases; malaria

in

?2 per cent, recurrent fever 1.2 per cent,

and

> phoid fever in 0.95 per cent \

.^steban (1932) records 2,000 cases

of malaria

^Jth one instance of neuritis.

inn egi (1934) describes the eye

changes in

}uu eases of malaria. In this series,

54 presented undus changes (small haemorrhages

in 11).

Barg (1935) records sub-hyaloid haemorrhages

n 'Our cases of severe tropical malaria,

^ulach's report (1936) deals with an epidemic

, malaria in Dagesban in 1933, which was

j"'aracterized by frequent ocular complications.

J} ,S1* weeks, he observed 20 cases of keratitis

J ,

retinal haemorrhages (three of these

'V neuritis). Two showed metastatic ophthal-

Ja, one of which ended in panophthalmitis. .

hese are a few references taken at random

|j?m ophthalmological journals. In contrast to

i -iS. ^ lGw expressed therein, Kirkpatrick in the

iseases of the optic nerve' and

' Diseases of

[!?+, choroid and retina ' published in connection

1 the Government Ophthalmic Hospital,

* adras, 1919, does not mention malaria as a

aipir suc^ conditions. Writing in 1920 found

' the greatest

!, Clllty in satisfying himself that malaria

attacks the eye at all '. ? ,

.

Recently, an opportunity occurred of making

' c mical investigation in the Madras Agency

tracts said to have a case incidence per

mille of

?Vef 75. In 1934, a member of my staff Dr

P.

1 ^ arayana Iver was posted there. He undei-

l0?k the task of making careful observations

?n the condition of the eyes in malaria. It was

course impossible for him to pursue his

study

o the exclusion of other aetiological agents, but

Vs Endings are of interest. He had considei-

f.ble difficulty in persuading many of the primi-

]^e types he examined to permit an ophthal-

moscopic examination under a mydriatic, but

eventually 75 cases of well-marked chronic malaria were dealt with. The diagnosis was not always confirmed by blood examination but the enlarged spleen (in a district where kala- azar is rare), the cachexia, the history, the type of fever, and the response to quinine therapy left little doubt in the observer's mind as to the nature of the patient's ailment. In these 75 cases, he

' could not detect any pathological conditions of the external eye or fundus, except in two '. One of these showed lenticular opa- cities, the other a choroiditis. In the latter, there were many septic conditions present and syphilis could not be excluded. Dr. Narayana Iyer doubts?and I think rightly?if the condi- tions present in these two were directly related to the malaria.

In 1936, Dr. N. Sakharam Rao, another member of the staff of this hospital, carried out a similar investigation in the Agency Tracts. In this heavily-infected population, only those with undoubted clinical evidences were selected. He examined in all 178 cases and at the time of his first report was not able to attribute any of the pathological eye conditions found to malaria. He says

' In two cases old haemor- rhages were seen; one was Kahn positive, the other Kahn negative. Three cases showed post- neuritic atrophy; 'all were Kahn positive. Corneal complications were seen in eight cases; all had trachoma. Five cases had retinitis pig- mentosa and 33 keratomalacia (with xerosis, night blindness, etc.)'. He uses the term kera- tomalacia as we always do in the Government Ophthalmic Hospital, Madras, as synonymous with a clinically-predominant avitaminosis

' A '. Later on, Dr. Sakharam Rao made a special

investigation in connection with Goldfeder's sign (see above). He writes 'I have been able to examine 82 cases of chronic malaria for the

symptom of malarial eye blood vessels des- cribed by Goldfeder. For this purpose I have selected cases with a history of malaria for three years and over and enlargement of spleen of two fingers or more '.

His observations show that, in chronic malaria, vessels such as Goldfeder describes arc met with, but since they are also met with in some eyes unassociated with malaria, the sign cannot logically be considered as evidence of malaria. In this connection, the following figures by Dr. Narayanaswami Naidu of the staff of the Government Ophthalmic Hospital, Madras, are of interest:?

March, 1937. One hundred cases examined in which there was no evidence or history of malaria. Sixty males and forty females. Two males and one female showed vessels such as Goldfeder describes.

It is well known that the angiospasm due to quinine hypersensitivity and its sequelae have frequently been mistaken for a manifestation of malaria.

366 THE INDIAN MEDICAL GAZETTE [June, 1937

Males Females Children below 10 years

Total number examined

45 22 15

Total .. | 82

Both eyes

Goldfeder's sign +

Remarks

12 3

One eye

19 5

15 24

Total

31 8

39

Not observed in

any case below 10 years.

Quinine amblyopia J. Sedan (1929) describes a case of tem-

porary blindness from retinal angiospasm of malarial origin. (In this report, there is a

strong suggestion that the etiological agent was quinine.) The case recorded is probably one of mistaken diagnosis and is typical of the confu- sion which has existed in the minds of observers in connection with eye disease and malaria, where the post hoc fallacy has been freely exploited. Ghosh (1936) reports a case of cerebral

malaria causing persistent loss of sight in which a quinine aetiology cannot be excluded. This quinine amaurosis is so well recognized

in India and elsewhere that it is unnecessary to detail its features. The number of cases re-

corded in the literature rather tends to give one an exaggerated idea of its incidence, e.g., Duggan and Nanavati (1931).

Scardapane (1930) reports 7 cases of quinine amblyopia.

In 1931, I corresponded with my late friend and colleague Lieut.-Col. H. Acton on this

subject and now see from his letters that he had not observed an instance in 900 European cases treated in 1918-19 by quinine salts

(using at least 20 grains daily), nor had he seen an instance in any case under his treat- ment up to the date of his letter, January 1931 (by which time his experience was much larger). Drs. Narayana Iyer and Sakharam Rao did

not observe any case of quinine amaurosis in

1,961 Indian patients treated by quinine in the

Agency Tracts. Since 1920, the year of publication of Elliot's

Tropical Ophthalmology, I have not seen more than 20 cases. It is met with as an idiosyn- crasy. I have seen it occur after the ingestion of seven grains of the sulphate, whereas it may not occur after 60 grains. Whether massive doses would always produce a quinine amaurosis, we have no opportunity of knowing. I once saw a case in consultation with Dr. W. T. Lawrence of the s.s.

' Orama' in which 405

grains of the bisulphate was taken at a single dose by a female patient. The following is a

brief extract from his notes :?? ' The onset was with coma, passing into

delirium; complete loss of vision, hearing almost nil, vomiting, urine loaded with albumin. A

diagnosis was made of acute nephritis; then the

discovery of quinine ingestion. Loss of vision complete for seven days, subsequent improve- ment to the extent of seeing outlines, then to seeing shadows of persons moving. She could not focus, or take hold of any article or avoid objects when walking. At this stage you saw her, approximately ten days after the onset. She returned to work in 26 days, but even then had to be assisted about the ship. The pupils were still dilated and the eyes could not follow

quick movements of the hand. A full ten days after we got home (under two months from the date of onset), she still clung to her friends' arms, but she could then write a letter success-

fully \ Duggan and Nanavati (1929) have drawn

attention to more cases in ophthalmic literature than other Indian observers, but the condition is probably no more common in the Bombay Presidency than elsewhere. The ophthalmic specialist naturally has a greater opportunity of seeing cases and his experience doe? not

represent the true incidence. If we take into consideration the enormous number of instances in which quinine is exhibited in India, year in, year out, and remember that except possibly in enormous doses (a single dose of over 1

drachm) it is a matter of idiosyncrasy, the incidence is very low. Even so, it must be

infinitely more common than malarial ischaemia, if such a condition actually does exist. Pre-

sumably, nowadays the condition would be best treated by nitroscleran like other ischaemic conditions of the retina and optic nerve since

acetylcholine does not appear to be as valuable as was anticipated. Turning for a moment to kala-azar, we do not

see many cases of kala-azar in Madras, but in those I have examined there were no patho- logical eye changes. Presumably the position is very similar to that in the case of malaria? but there is much less information available- Ling (1924) and Lee (1924) described retinal haemorrhages in kala-azar in Peking and Central China. The latter author saw four instances in

140 cases. In 1931, I asked for Dr. Napier's opinion in this connection. He kindly wrote and told me that there did not appear to be

any constant lesions and that retinal haemor-

rhage?the most frequent finding?was rela- tively uncommon, occurring in only about 2 or 3 per cent of cases. Kirwan examined his cases

June, 1937] PYREXIA SIMULATING ENTERIC : CHAKRAVARTI & TYAGI 367

so that expert opinion supported his view. As a great deal of work has been done on kala-azar in Calcutta since then, we may expect further detail on the subject. Meantime we are led to assume that kala-azar is not of greater aetio-

Ipgical importance than malaria in the produc- tion of eye affections. The position to-day in India as regards the

ophthalmological importance of these two

diseases does not seem to be very different to that in 1920 when Elliot published his Tropical Ophthalmology. Retinal haemorrhages are met with in both, in fact haemorrhage into the

posterior segment of the eye appears to be the only associated pathological condition which is not viewed with scepticism by observers who nave had considerable opportunity of judging. Other conditions described require considerably more scientific support in order to confirm their existence. Even the posterior-segment haemor- rhages are possibly rather more dependent on the severity of the anemia than the severity of the toxaemia, although there is some evidence that a heavy crescent invasion is more likely to

associated with retinal haemorrhages apart loin the degree of anaemia. Malarial keratitis, which was regarded as a distinct possibility in -India years ago, is now looked upon much more

doubtfully. We have learnt a great deal about corneal diseases in the last 16 years and now know enough to place some of the varieties of keratitis, formerly called malarial, in their correct aetiological position.

References

Barg, Z. (1935). Sovietskii Viestnik Opht., Vol VI p. 100. (Abstract?Amer. Journ. Ophth., Aug. 1935.)

'

Bulach, X. 0. (1936). Amer. J (rum. Ophth. Vol XIX p. 450.

Dedimos, P. (1932). Arch. d'Opht., Vol. XLIX. p. 249. (Abstract?Arch. Ophth., Aug. 1933, p. 259.) Duggan, J. N., and Nanavati, B. P. (1929). Trans.

Internat. Ophth. Congress. Duggan, J. N., and Nanavati, B. P. (1931). Brit.

Journ. Ophth., Vol. XV, p. 160.

Elliot, R. H. (1920). Tropical Ophthalmology. Oxford University Press, New York.

Esteban, M. (1932). Rev. Cubana Oto-neuro-ojtal., Vol. I, p. 120. (Abstract?Amer. Journ. Ophth., Dec. 1933.)

Goldfeder, A. E. (1936). Arch. Schiffs- u. Trop.-Hyg., Vol. XL, p. 207.

Ghosh, A. K. (1936). Indian Med. Gaz., Vol. LXXI, p. 403.

Kiep (1922). Proc. Opt. Soc. Egypt. (Abstract? Amer. Journ'. Ophth., Vol. V, p. 977.)

Ivrol, A.' (1931). Arch. Ojtalmologii, Vol. VI, p. 163. (Abstract?Amer. Journ. Ophth., Vol. XIV, p. 980.) Leet F. H. v(1924). Amer. Journ. Ophth., Vol. VII,

p. 838.

Ling, W. P. (1924). Ibid., Vol. VII, p. 829.

Motegi (1934). (Abstract?Arch. Ophth., Vol. XII, Oct.)

Pereyra (1922). Arch. d. Oft., p. 49. (Abstract?/< Amer. Journ. Ophth., Vol. V, p. 929.)

Scardapane (1930). Sagii de Oph. (Abstractr-Arch.

Ophth., p. 575.) Sedan, J. (1929). Ann. d'Ocul., Vol. CLXVI, p. 705.

(Abstract?Arch. Ophth., April 1930, p. 471.)

Villard, H. (1930). Arch. d'Opht., Vol. XLVII, p. 200.

(Abstract?Amer. Journ. Ophth., Oct. 1930.)