Bull. Org. mond. Sante 1966, 34, 357-361Bull. Wld Hitha Org.

Ocular Manifestations of Vitamin-A Deficiencyin Man*

D. S. McLAREN,1 H. A. P. C. OOMEN 2 & H. ESCAPINI 3

Vitamin-A deficiency continues to be one of the most widely prevalent and devastatingnutritional diseases of man. This is in spite of the discovery of vitamin A more than halfa century ago and its now ready availability in inexpensive concentrated form. Lack ofknowledge at many levels is the basis of this tragic situation, which may result in needlessblindness and loss of life, especially among young children.

As a contribution to the alleviation of the problem, the present paper has as its objectthe provision, for the general and hospital physician in those countries where xerophthalmiais endemic, of adequate descriptive and pictorial information to enable him to make anaccurate diagnosis ofvitamin-A deficiency when he is presented with any stage of the ocularmanifestations.

In recent years there has been increasing recog-nition of the widespread occurrence of vitamin-Adeficiency in man (Oomen, 1961; McLaren, 1963).In its most serious form not only is sight threatened,frequently resulting in total blindness, but there isalso a high mortality (McLaren et al., 1965). Thepre-school child, more particularly between theages of nine months and four years, is especially atrisk. In many countries vitamin-A deficiency is themajor cause of blindness in this age-group.The ocular manifestations of vitamin-A deficiency

merit special attention, not only because the de-structive corneal lesions lead to permanent impair-ment of vision, but also because they afford, in man,the only reliable clinical evidence of the deficiencystate. Moreover, serum levels of the vitamin inindividuals do not correlate well with eye changesindicative of early vitamin-A deficiency.When a single descriptive clinical term was sought

for this disease entity it seemed that " xeroph-

* This investigation was supported by the World HealthOrganization and by United States Public Health ServiceResearch Grants NIH AM 06735 to the World HealthOrganization and AM 05285 to the Institute of Nutrition.Sciences, Columbia University, New York.

1 Professor of Clinical Nutrition and Director of theColumbia University-American University Nutrition Re-search Program, American University of Beirut, Beirut,Lebanon.

' Director, Institute of Tropical Hygiene, Amsterdam,Netherlands.

' Professor of Ophthalmology, University of San Sal-vador, El Salvador.

thalmia" was the best available. This word hasthe advantages of long and general usage togetherwith the implication of a serious affection of theeyes. Although etymologically only eye involvementis implied, in common medical parlance an advancedstate of generalized hypovitaminosis A is under-stood. It is therefore suggested that the more specificterms " conjunctival xerosis " and " corneal xerosis "be used in describing the actual state of the eyeitself and that " xerophthalmia " be reserved for thesyndrome.

There are several reasons why xerophthalmia hashitherto not received the attention it merits. It isonly in the past 30 years or so that protein malnutri-tion, with which xerophthalmia is more commonlythan not associated, has come to be recognized asone of the most prevalent and serious of all diseases.Concentration on protein malnutrition has led tothe neglect of other aspects of malnutrition in thechild, and xerophthalmia has suffered particularlyin this regard. In the countries where xerophthalmiais common-all of them having few doctors andmost of them over-populated-there are but ahandful of physicians who have received specialtraining in the examination of the eye. After all,physicians in general feel diffident about passing anopinion on a lesion affecting such a specialized organas the eye. Unfortunately ophthalmologists tend tobe preoccupied with surgery and feel, perhaps notaltogether unnaturally, that a condition that is oftenalmost hopeless when they first see the case lies

1725 357

D. S. MCLAREN, H. A. P. C. OOMEN & H. ESCAPINI

outside their province. Even the parents may nothave their attention attracted to the condition untilit is too late and the corneas are dissolving awaybehind the closed eyelids of the young child. Finallythe high mortality, even in xerophthalmia casestreated in hospital, reduces the social consequencesof blindness and further contributes to the neglect ofthe problem.During 1962-63, WHO implemented recommen-

dations that had been made by several Joint FAO/WHO Expert Committees and undertook a globalsurvey of xerophthalmia. The epidemiological andpublic health aspects were surveyed in nearly 50countries in South and East Asia, the EasternMediterranean, North Africa, and Central and SouthAmerica (Oomen, McLaren & Escapini, 1964).The present paper is the result of many years'

experience of each one of the authors in countrieswhere the xerophthalmia problem exists, togetherwith the accumulated knowledge of many otherphysicians in all these countries. Our objective is toprovide the practising physician with clear de-scriptions and illustrations of the eye lesions ofvitamin-A deficiency so that he may recognize thecondition in all its stages.

In view of the common occurrence of eye involve-ment in malnourished children, it needs to bereiterated that the eyes should always be fullyexamined and their condition carefully noted inreports of protein malnutrition (McLaren, 1958).Furthermore, there is now evidence to show that,even in the absence of overt physical changes in theeye, the liver stores of vitamin A in the protein-malnourished child are usually very low (McLarenet al., 1965). Consequently, restoration of thesestores should be part of any regime of rehabilitationof these children.

TH1E POSTERIOR SEGMENT OF THE EYE

RodfunctionDiminution in the supply of vitamin A in the

form of the aldehyde (retinene, retinal) to the rodcells of the retina results in impairment of thefunction of dark adaptation. This may be detectedby rod scotometry (Livingston, 1944), dark adapto-metry (Hume & Krebs, 1949), and electroretino-graphy (Dhanda, 1955) long before the subjectcomplains of night-blindness. Unfortunately, allthese methods are not applicable to the susceptibleage-group-the pre-school child-because a fullyco-operative and intelligent subject is essential.

They also require expensive and delicate equipmentnot suitable for field studies. The development of asimple yet sensitive objective biophysical test of rodfunction applicable to population groups susceptibleto vitamin-A deficiency would be a distinct advancein measuring the extent of the problem.The symptom of night-blindness should always

suggest the possibility of vitamin-A deficiency, butit may result from non-nutritional causes, such ascongenital night-blindness and retinitis pigmentosa.

The optic fundusSeveral reports from East Asia have described

changes in the fundus resembling those seen inretinitis punctata albescens and which, it is claimed,respond to vitamin-A therapy. Teng Khoen Hing(1959, 1964) has reported many cases in Indonesiaand has published fundus photographs. The possi-bility that factors other than nutrition are responsiblehas to be entertained, for such changes have notbeen found associated with vitamin-A deficiencyelsewhere (Halasa & McLaren, 1964).

THE ANTERIOR SEGMENT OF THE EYE

Conjunctival appearancesThe changes characteristic of vitamin-A deficiency

are usually confined to the bulbar conjunctiva, butoccasionally in long-standing cases the conjunctiva ofthe lower lid and adjacent lower fornix may be roughand wrinkled.

Conjunctival xerosis (Plate IA, D and Plate IIA,B, C). This may be generalized throughout theexposed part of the bulbar conjunctiva or localizedto a small part or parts of the same. Whatever theextent of the changes, their nature is the same andhas the following characteristics:

(a) Dryness-the literal meaning of "xerosis".Dryness is judged by lack of the normal lustre orbrilliance of the bulbar conjunctiva. The appearancehas been likened to that of wax or dry paint.

(b) " Unwettability". This occurs regardless ofthe presence or absence of tears. Patches of xerosisemerge from their surroundings " like sandbanks atreceding tide" when the child stops crying. Thisprobably results from the disruption of the continuityof the preconjunctival film by the xerotic process inthe epithelium.

(c) Loss of transparency. The ability of the con-junctiva to transmit light is impaired, leading todecreased visibility of the conjunctival vessels. On

358

OCULAR MANIFESTATIONS OF VITAMIN-A DEFICIENCY

inspection with the slit-lamp, the translucent con-junctiva, which normally looks clear (" like anaquarium") and crossed by blood vessels, appearsto be milky owing to fine droplets. Soon the vascularpattern, apart from the large arterioles, becomesobscured.

(d) Thickening. There is a tendency to generalizedthickening and stiffness of the conjunctiva.

(e) Wrinkling. There are small, more or lessvertical folds in the conjunctiva best demonstratedby rucking up the loose temporal conjunctiva againstthe outer canthus on maximal lateral movement ofthe eyeball.

(f) Pigmentation. In dark-skinned races there is afine, diffuse smoky pigmentation, which is not to beconfused with the patchy and coarser pigmentationthat is frequently observed in healthy subjects ofthese races. In prolonged xerosis, the lower fornixfirst becomes yellowish, then light grey and finallydark brown owing to the presence ofchromatophoresin the basal cell layer of the epithelium. This charac-teristic "gutter" pigmentation responds slowly,over a period of weeks or months, to treatment.

Bitot's spot (Plate IB, Plate IIA, B, C, andPlate IV). The usual form taken by a Bitot's spot is asmall plaque of a silvery-grey hue with a foamysurface. It is quite superficial and is raised abovethe general level of the conjunctiva; it is more or lessreadily removed by manipulation of the lids ordirect wiping, revealing a xerotic conjunctival bedwith a rough surface.

Bitot's spot is invariably situated on the bulbarconjunctiva, frequently bilateral and temporal andless commonly nasal, and is usually confined to theinterpalpebral fissure close to the limbus. Thistypical location of the spot would seem to beexplained by the protection of the material here fromthe wiping movements of the lids, close to theprotruding limbus. The shape varies considerably,being often irregularly circular or oval with the longaxis horizontal. The classical triangular form withthe base to the limbus is less common.

Exceptionally, the following variations may befound. Bitot's spot material may be scattered widelyover the conjunctiva, sometimes having a verticallycorrugated arrangement. Not all spots are foamy;some have a cheese-like or grease-like surface. Someaccumulations are quite exuberant and not flat likea plaque. The significance of these differences inappearance is not known. The spots may be black inchildren whose eyelids are smeared with mascara

(e.g., kajal in India, a mixture of carbon and grease).If an unusual part of the conjunctiva is permanentlyexposed, as in strabismus, coloboma of the eyelid,or ectropion, a Bitot's spot may develop in relationto such an area, illustrating the etiological import-ance of exposure.

Bitot's spot may or may not be associated withgeneralized conjunctival xerosis. When so associated,the subjects are usually young children and may alsohave night blindness. These spots, together withthe accompanying generalized xerosis, usuallyrespond to vitamin-A therapy. Bitot's spots arealso encountered in some parts of the world withoutgeneralized xerosis or evidence of retinal dysfunction,usually in older children and adults. These are oftenminimal lesions; evidence of vitamin-A deficiencymay be lacking (Plate IID), and there may be noresponse to therapy (Darby et al., 1960; Paton &McLaren, 1960).Accumulation of debris (Plate IC and Plate IIIA).

In some cases ofadvanced xerosis, debris accumulateson the surface of the bulbar conjunctiva and mayspread on to the adjacent part of the cornea. Thismaterial is creamy white, glistening, non-foamy andeasily becomes detached to lie in the canthi, thelower fornix, or on the eyelid borders. This is aquite unusual appearance, Bitot's spot being muchmore common. The material of the latter adheresmore tenaciously to the eye.Any one, or even several, of these appearances

may not be taken as diagnostic of conjunctivalxerosis due to vitamin-A deficiency. The presenceof most or all of them is highly suggestive of such adiagnosis, which will be confirmed by a return tothe normal appearance under adequate therapy.Bitot's spot is a useful indicator of vitamin-Adeficiency, especially in young children, but it is notpathognomonic.

Corneal changesActive stages. These lead on from the appearances

of conjunctival xerosis, which are in evidence by thetime the cornea has become affected. Both corneasusually show changes but to widely varying degrees.Photophobia and inflammatory changes are notregarded as essential features. In the uncomplicatedcase, the mildness of congestion in the eye is trulyremarkable.

Reversible changes (Plate ID) are characterizedby generalized corneal xerosis, dryness, " un-wettability" and loss of transparency, which leadto an early haziness of the cornea. These appearances

359

D. S. MCLAREN, H. A. P. C. OOMEN & H. ESCAPINI

may be demonstrated by holding the lids apart for15 seconds. Slit-lamp examination at this early stagemay reveal an increase of fine pigment in the para-limbal portions of the cornea, although it must beremembered that pigment in this area is common inhealthy members of darkly pigmented races. Theremay also be a loss of continuity of the surfaceepithelium and diminished tactile sensitivity. Later,cellular infiltration of the corneal stroma contributesto the intensity of the haziness of the cornea, whichfrequently has a bluish, milky appearance, usuallymost marked in the lower central part. In some casesthere is a cellular exudate in the lower part of theanterior chamber.

Irreversible changes are characterized by thefollowing signs:

(a) " Ulceration ", (Plate IE) which involves aloss of substance of a part or the whole of thecorneal thickness. This phenomenon is designated" ulceration " for lack of a more specific term, butit is characterized by mild signs of reaction orinflammation. Advanced degrees of stromal lossresult in descemetocele and complete perforationwith iris prolapse. These lesions are more commonin the lower central cornea.

(b) Keratomalacia (Plate IF and Plate IIIB),which consists of a characteristic softening (colliqua-tive necrosis) of the entire thickness of a part, or

more often the whole, of the cornea, invariablyleading to deformation or destruction of the eyeball.The process is a rapid one, the corneal structuremelting into a cloudy gelatinous mass which may bedead-white or dirty-yellowish in colour. Extrusionof the lens and loss of vitreous may occur. Inuntreated cases, endophthalmitis not infrequentlysupervenes. Particularly in very young children,keratomalacia may rapidly develop in the absenceof the characteristic changes, described earlier, in theconjunctiva.

Sequelae (Plate IIIC). These result from thespontaneous or therapy-assisted healing of theirreversible changes mentioned above. The leastserious as to vision are nebulae and small leucomatasituated away from the pupillary area, usually in thelower central part of the cornea. If the iris hasprolapsed there will be leucoma adherens withdistortion of the pupil. Large, often heavily vascula-rized and pigmented, total or subtotal leucomatacause loss of vision, fortunately often affecting onlyone eye with minimal changes in the other.

Keratomalacia, on healing, results in anteriorstaphyloma composed of the scarred remnant of thecornea and incorporated elements of uvea bulgingforwards under the influence of raised intra-ocularpressure. If the damaged cornea ruptures ratherthan bulges then the contents are extruded, and ashrunken globe, phthisis bulbi, is the end result.

ACKNOWLEDGEMENT

We are grateful to members of Nutrition and of Communicable Diseases, WHO, Geneva, for helpfuldiscussions.

RtSUMIt

Les manifestations oculaires de l'hypovitaminose Arevetent une importance particuliere en raison de leurfrequente gravite et aussi parce qu'elles sont le seulindice clinique sOr d'une telle carence.Un apport insuffisant de vitamine A aux tissus retiniens

entraine une deterioration de la fonction d'adaptation al'obscurite. Les differentes methodes destinees ai objectiverces troubles requierent malheureusement la collaborationdu sujet examine et ne peuvent servir au depistage de lacarence dans le groupe, specialement vulnerable, desenfants d'age prescolaire.

Les premiers signes cliniques apparaissent au niveaudu segment anterieur de I'aeil et consistent generalementen lesions de la conjonctive bulbaire. Celle-ci perd sonfilm protecteur, devient seche, moins transparente; elle

s'epaissit, se plisse et presente une legere pigmentation.L'existence eventuelle d'une tache de Bitot, de forme etd'etendue tres variables, peut poser un probleme etio-logique: souvent associee 'a d'autres signes d'hypo-vitaminose A, elle peut cependant exister en 1'absence detoute carence et de toute atteinte retinienne et resister autraitement par la vitamine A.Au niveau de la cornee, les lesions sont de deux ordres.

Certaines, reversibles en cas de traitement precoce, ont uncaractere nettement evolutif. Elles succedent aux altera-tions pathologiques de la conjonctive et sont du memetype. Si la carence est notable, l'evolution s'accelere et leslesions irreversibles apparaissent rapidement, surtoutchez les jeunes enfants: ulceration grave de la cornee,perte de substance suivie de cicatrisation ou de perfora-

360

PLATE I

B

D

_- _~~~~~~~~~~~~~~~~~~~~-

-.' ; F

A. Extensive xerosis of the conjunctiva with oedematous folds in the lower conjunctival sac. Distorted Bitot's spot visible. MaleIndonesian child aged 4 years, right eye. Tests revealed blood-plasma vitamin-A level of 3 MgI100 ml, and a trace of carotene.

B. Bitot's spot, striated, with hyperpigmentation and dryness of surrounding conjunctiva. Male Indonesian child aged 3 years,right eye.

C. Accumulation of debris in a 9-month-old Jordanian male infant. The material has extended from the lower fornix on to thegreater part of the cornea. Tests revealed blood-plasma vitamin-A level of 2 MAgIl00 ml and liver vitamin-A level of 0 t&g/g liver.

D. Haziness and infiltration of the cornea, with early neovascularization. Xerosis conjunctivae is also well shown. Male Jordanianchild aged 2 years 3 months. Tests revealed blood-plasma vitamin-A level of 3,4g/100 ml and liver vitamin-A level of 0 ,.g/g liver.

E. Eye of Guatemalan infant showing central softening with ulcer formation. Reaction is minimal; scarring inevitable.F. Perforation of the cornea and extrusion of the lens in an 18-month-old Jordanian male child. Tests revealed blood-plasma

vitamin-A level of 2 A&gIlO0 ml.Comparative values for healthy children: plasma vitamin A 20-50 tig/100 ml; liver vitamin A 50,4.g/g.

PLATE II

A. Generalized xerosis of the bulbar conjunctiva in a maleJordanian child aged 1 year 3 months before treatment. Theconjunctiva is dry, thickened and wrinkled and lacks lustre.Centrally there is increased pigmentation and flecks offoamy Bitot's spot material. There is considerable con-junctival injection. Tests revealed blood-plasma vitamin-Alevel of 7 ,g/100 ml and liver vitamin-A level of 5 ,.g/g liver.

B. Same eye as Plate IIA, 16 days later, after commencement oftreatment with 10 000 international units of water-dispersiblevitamin-A palmitate per kilogram of body weight daily for fivedays. There were no local applications. The peripheralconjunctiva is now clear, transparent and no longer wrinkled,and the injection has disappeared. The central pigmentedarea with Bitot's spot material now stands out in contrast.Tests showed blood-plasma vitamin-A level of 25 ,g/100 ml.

C. Same eye as Plate IIA and IIB, 29 days after commencementof treatment. No additional vitamin A was given apart fromthat in the regular hospital diet. Bulbar conjunctiva is nowcompletely clear. Tests showed blood-plasma vitamin-Alevel of 7 Ag/100 ml and liver vitamin-A level of 136 iig/gliver.

D. Bitot's spot in an Ethiopian male aged 10 years. This andmany other similar cases have been studied carefully forevidence of vitamin-A deficiency and response to therapy.All results have been negative (Darby et al., 1960; Paton &McLaren, 1960). The Bitot spot is confined to the exposedpart of the bulbar conjunctiva, the rest of the conjunctivabeing normal.

PLATE III

A. Same eye as in Plate IC, seven days after treat-ment with an intramuscular administration of50000 international units of vitamin-A palmitatein oil per kilogram of body weight, given in onedose. Plasma vitamin-A level rose to 11 t.g/100 ml. Debris completely cleared, revealingnormal cornea.

B. Keratomalacia affecting entire cornea of Egyptianchild aged 2 years. Absence of reaction andsecondary infection is striking. Such eyes arenot acutely painful, and consequently they arefrequently neglected by the parents.

C. Bilateral scars of cornea in El Salvadorian childrecovering in hospital from xerophthalmia andkwashiorkor. The situation of the scars in thelower central part of the cornea is characteristic.More advanced changes lead to phthisis bulbi oranterior staphyloma.

PLATE IV

BITOT'S SPOTS IN JAVANESE CHILDRENInk drawings by H. Sterkman after colour macrophotographs

A. Circumscribed triangular lateral spot on a xerotic con-~ i ajunctival patch in a 9-year-old girl.

BS-

u ~~~~~~~B.Striated lateral spot in a 3-year-old boy.

I r

C. Large lateral spot overflowing the limbus in a 22-month-oldboy. The spot leaves only part of the exposed bulbar Lcon-junctiva visible.

? ) N\ T

D. Large fluid lateral spot and four small medial spots in a3-year-old boy.

[ f

4 N_

..- .MFZL_

OCULAR MANIFESTATIONS OF VITAMIN-A DEFICIENCY 361

tion avec iridocele. Frequemment, la corn6e tout entierese n6crose et se liquefie, presentant le tableau clinique de lak6ratomalacie.

Les s6quelles, succedant aux lesions irreversibles, n'ontque peu d'importance fonctionnelle en cas de taie ou deleucome benin n'interessant pas l'aire pupillaire. Lesleucomes plus etendus ou adh6rents entrainent la pertede la vision de l'aeil atteint. La keratomalacie, apres

guerison, laissera persister un staphylome anterieur ou unglobe oculaire atrophie avec perte complete de la fonc-tion.En depit de son etymologie, les auteurs preferent

reserver le terme . x6rophtalmie * a 1'ensemble desmanifestations cliniques dues aux formes graves de1'hypovitaminose A et utiliser, pour la description desl6sions oculaires, une terminologie plus specifique.

REFERENCES

Darby, W. J., McGanity, W. J., McLaren, D. S., Paton,D., Alemu, Z. & Medhen, M. G. (1960) Publ. HlthRep. (Wash.), 75, 738

Dhanda, R. P. (1955) Arch. Ophthal., 54, 841Halasa, A. & McLaren, D. S. (1964) Arch. Ophthal., 71,

827Hume, E. M. & Krebs, H. A. (1949) Spec. Rep. Ser. med.

Res. Coun. (Lond.), No. 264Livingston, P. C. (1944) Lancet, 2, 33McLaren, D. S. (1958) Bull. Wld Hlth Org., 19, 303-314McLaren, D. S. (1963) Malnutrition and the eye, NewYork Academic Press

McLaren, D. S., Shirajian, E., Tchalian, M. & Khoury, G.(1965) Amer. J. clin. Nutr., 17, 117

Oomen, H. A. P. C. (1961) Int. Rev. trop. Med., 1,132

Oomen, H. A. P. C., McLaren, D. S. & Escapini, H.(1964) Trop. geogr. Med., 16, 271

Paton, D. & McLaren, D. S. (1960) Amer. J. Ophthal.,50, 568

Teng Khoen Hing (1959) Ophthalmologica (Basel),137, 81

Teng Khoen Hing (1964) Ocular fundus changes inhypovitaminosis A, Djakarta (Thesis)