POSTGRAD. MED. J. (1964), 40, 711

THE OCULAR MANIFESTATIONS OFNUTRITIONAL DISEASE

D. S. MCLAREN, M.D. (Edin.), Ph.D. (Lond.), A. HALASA, M.D. (Beirut), M.S. (Iowa).D.T.M. & H. (Eng.). Assistant Professor of Ophthalmology,

Research Professor of Clinical Nutrition. Department of Ophthalmology.School of Medicine, American University of Beirut, Beirut, Lebanon.

MALNUTRITION as a cause of blindness has beenand still is, much underestimated. In manycountries it is the chief cause of blindness inyoung children. The onset is insidious anddifficult to diagnose and the later stages pro-ceed rapidly to irreversible damage. Opthal-mologists have tended not to be particularlyinterested in conditions that do not makedemands on their diagnostic or surgical skilland nutritionists have fought shy of such aspecialized organ as the eye. It is however, ofgreat importance that doctors trained inEurope and North America and going to workabroad should be prepared to deal with themedical problems as they exist there. They willfind malnutrition rife in all its forms with eyeinvolvement meriting their close attention.Furthermore, in all spheres of medical prac-tice, it should be realised that on occasionmalnutrition may be the cause of visual symp-toms as for example in states of malabsorption,chronic alcoholism and when vitamins areinadvertently omitted from anti-allergenic infantformulae.The association of visual impairment and

poor diet has long been recognised. Accountsof prolonged sieges, sea voyages, religious fastsand severe seasonal shortage of food andfamines record the frequent occurrence ofoutbreaks of night blindness under these con-ditions. Among the earliest of all medicalwritings such as the Ebers papyrus (circa 1600B.C.) and Chinese treatises of a similar periodare to be found the well-known prescriptionsof liver for night blindness and other eyediseases. The approach in these times, however,appears to have been a purely empirical oneas the part played by poor diet was not known.It was not until the 19th century that xeroph-thalmia began to emerge as a clinical entitywith its characteristic pathology, symptomat-ology and aetiological relationship to dietarydeficiency. In the first quarter of the 20th cen-tury reports of the frequent occurrence ofxerophthalmia and keratomalacia in Japan,

Indonesia, India and elsewhere showed it tobe a serious problem in many parts of theworld. The discovery of fat-soluble vitamin Aand the demonstration of its efficacy in theDanish outbreak during the first world war aswell as in induced deficiency in experimentalanimals proved that the early retinal dysfunc-tion and later corneal damage were bothcaused by vitamin A deficiency.

In all probability another nutritional con-dition affecting the eyes lies inseparable fromvitamin A deficiency among the early accounts.Nutritional amblyopia or retrobulbar neuro-pathy, resulting from deficiency of vitamins ofthe B complex, now appears to form a featureof some early accounts of pellagra and beriberiand reached epidemic proportions in some FarEastern prisoner-of-war camps during WorldWar II.Both these nutritional diseases causing blind-

ness are serious problems in many parts of theworld at the present time. They will be con-sidered in more detail now, together with therole of malnutrition in certain other eyediseases. Detailed treatment of the historicalaspects of this subject may be found elsewhere(Oomen, 1961, McLaren, 1963).Vitamin A Deficiency

All too often the physician tends to forgetthat severe vitamin A deficiency is a generalizeddisease, affecting especially epithelial tissuesthroughout the body. Recent work suggeststhat, outside the retina, vitamin A is chieflyconcerned with mucopolysaccharide synthesisand stability of lysozome membranes. Childrenaged three months to four years are mostcommonly affected. Thousands continue to goblind every year throughout the world fromthis cause alone. (Oomen, McLaren, Escapini,1964). The problem is especially serious inmost of the countries of South and East Asia,and in some countries in the Near East, NorthAfrica, Central and South America. The term"xerophthalmia" has been adopted by WHO

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712 POSTGRADUATE MEDICAL JOURNAL December, 1964

TABLE I

THE AGE SPECTRUM OF VITAMIN A DEFICIENCY

Stage Pathogenic factors ManifestationsPregnancy Basic diet low in vitamin A Low plasma vitamin A

(mostly carotene) Low liver storesIncreased requirements Bitot's spots (occasional)Food taboos Xerophthalmia (rare)Strain of repeated pregnancies

Fetus Low liver storesXerophthalmia (rare)? Abortion? Congenital malformations

1st year Breast milk: low concentration, Lowering of plasma vitamin Aof life diminished volume Depletion of liver stores

Artificial feeding Xerophthalmia and keratomalaciaMaternal neglect (relatively common)Infections Xerosis conjunctivae and Bitot's

spots (rare)2-5 years Prolonged breast feeding Peak incidence of xerophthalmia

Supplementation with foods low and keratomalaciam vitamin A Xerosis conjunctivae and Bitot's

Deposed child situation spots (not uncommon)Infections Fundus changes

School age Diet 'low in vitamin A (mostly Xerosis conjunctivae and Bitot'scarotene), fat, and protein spots predominate

Infections Night blindnessFundus changes

Adult As above plus special privation Night blindness predominates(famine, prison) Bitot's spots (occasional)

Keratomalacia (rare)From McLaren, D. S. Malnutrition and the Eye, New York, Academic Press, 1963 p. 196.

as the most convenient one available to denotethe severe deficiency state. Many patients donot survive but succumb to such infections asgastroenteritis, measles and other respiratoryconditions which play an integral part in thecausation of xerophthalmia, together with theeverpresent protein malnutrition, of kwashior-kor or marasmic type. In a detailed study inJordan of 18 hospitalized cases of xerophthal-mia we had a mortality of more than 80%despite large doses of promptly administeredvitamin A and attention to dehydration andaccompanying infections. In a similar group ofmalnourished children but with no clinical orbiochemical evidence of vitamin A deficiencythe mortality was only 15%. (McLaren,Tchalian and Shirajian, 1964).The accompanying table shows how various

factors play a part in the pathogenesis of thedisease at different ages and how the mostsevere eye lesions are found in the youngestgroups.

Night blindnessIn co-operative subjects impairment of scoto-

pic vision due to vitamin A deficiency can bedetected by rod scotometry or dark adaptome-

try before the subject is aware that he is nightblind. The electroretinogram may also showchanges at this stage. There is unfortunately atpresent no practical visual test that might beapplied to young children in the susceptibleperiod to diagnose the condition at this earlystage before the anterior segment of the eyeundergoes the changes of xerosis. Plasma levelsof the circulating vitamin are not of help inearly diagnosis as there is poor correlationbetween them and the eye signs except in themost advanced stage. For instance, we found(Halasa and McLaren 1964) low blood levelsof vitamin A (below 20 tg./100 ml.) in 39 outof 58 marasmic children examined in Beirutalthough in none was there any conjunctival,corneal or fundus change attributable to vitaminA deficiency.

It has been claimed that certain changes inthe fundus accompanying night blindness andconjunctival xerosis respond to vitamin A,(Teng-Khoen-Hing, 1959). Their existence is notin doubt; they have been carefully photo-graphed, and resemble closely the appearanceof the fundus in retinitis punctata albescensand fundus albi punctatus, but their precise

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December, 1964 McLAREN and HALASA: Ocular Manifestations o[ Nutritional Disease 1.: . :..,~·'~.::...:-::;~::~;::':.·:.:..:...·'! ::,:i...~,.~'!..'.:i ...

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relationship to vitamin A deficiency still re-mains to be elucidated.

Night blindness, per se, is not pathognomonicof vitamin A deficiency, being also a featureof various eye diseases e.g. retinitis pigmentosa,Oguchi's disease, choroideremia, gyrate atrophyof the choroid and retina, onchocerciasis andoccasionally congenital. If nutritional in originthe symptom will disappear after consumptionof about 30,000 I.U. of vitamin A dailyadministered as cod or halibut liver oil.Conjunctival xerosis and Bitot's spot

If vitamin A deficiency persists the anterior,as well as the posterior, segment of the eyebecomes affected. The bulbar conjunctivabecomes dry, thickened and wrinkled with lossof normal transparency, increase in pigmenta-tion and failure of the surface to be wetted bytears. These changes result from keratinizationof the epithelial cells and are usually mostmarked in the area situated in the interpal-pebral fissure where exposure and trauma un-doubtedly play some part. It is not possiblefrom a study of the conjunctival changes aloneto know whether vitamin A deficiency hascaused them.

Bitot's spot (Fig. 1) has long been associatedwith night blindness and vitamin A deficiency.It consists of a whitish or grayish plaque ofdesquamated epithelial cells with a foamy sur-face usually situated close to the limbus onthe exposed part of the bulbar conjunctivamore commonly temporal than nasal. Broadlyspeaking there appear to be two types of

Bitot's spot from the point of view of causa-tion. Small isolated spots, in older children andadults with good dietary histories, no com-plaints and normal plasma levels of vitamin A,do not respond to vitamin A therapy andappear to result chiefly from local factors. Onthe other hand, more diffuse spots or patchesof material, in young children with otherevidence of xerophthalmia and low levels ofvitamin A in the plasma, usually respond totreatment together with the other signs ofdeficiency.Corneal xerosis and keratomalacia

Xerosis of the cornea has the same charac-teristics as xerosis of the conjunctiva and isindicative of a more advanced stage of thedeficiency. In addition there is infiltration of thestroma, the whole cornea taking on a bluishhazy appearance, and there may be minimalvascularization.

Before long loss of substance of the corneaand deformity commence. At this advancedstage a characteristic liquefactive process,known as "colliquative necrosis" is responsiblefor the irreversible corneal damage that resultsin varying degrees of visual impairment. Atfirst an excavation, what may be called an"ulcer" for want of a better term, occurs inthe central part of the cornea and results inany degree of loss in depth of corneal tissue. Inadvanced cases corneal perforations, iris pro-lapse and even loss of vitreous and extrusionof the lens may result. When this processinvolves the whole cornea it is called kerato-malacia (Fig. 2).

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714 POSTGRADUATE MEDICAL JOURNAL December, 1964

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:,iiir~:i-;j:;'.'??~i " ?' *:.~d .. . .,'iiii·:i:::l: ::i~ :b

iii :'l

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FIG. 2.-K-eratomalacia with complete liquefac-ivenecrosis of the cornea in a Jordanian ,infant offive months.

It proceeds very rapidly, often without anyreaction or inflammation, the corneal structuremelting into a cloudy gelatinous mass whichmay be dead white or dirty yellowish in colour.

In untreated cases endophthalmitis not in-frequently supervenes. If the patient survivesthere may be a combination in the two eyesof a whole range of residual damage from thefinest nebulae through dense, partial, totalleucomata, to phthisis bulbi or anterior staphy-loma. The minimal vascularization of thecorneal scar is usually a striking feature ofthose resulting from uncomplicated vitamin Adeficiency. Fortunately the two eyes are fre-quently affected to a widely differing degree soit is often possible to save sight, at least inone eye. From our experience in Jordan werecommend that vitamin A be given to thesevere case by mtouth, by intra-gastric tube ifnecessary, as absorption is best by this routeand by intramuscular injection also, to ensurethat the child does get the vitamin. By bothroutes aqueous dispersions are better utilizedbut are, unfortunately, not generally available,the palmitate in oil being the usual form. Byeach route the dose should be calculated on thebasis of actual body weight and 5,000 I.U./Kg./day be given by each route for three days,thereafter continuing with cod liver oil bymouth.

Hypervitaminosis AAmong the rather bizarre collection of symp-toms resulting from toxic doses of vitamin A

some are ocular. In acute toxicity, diplopia andlights before the eyes in adults and papil-loedema accompanying an increase of intra-cranial pressure in children and adults havebeen the most frequent. Fear of inducing thiscondition by the vigorous treatment of xero-phthalmia is unfounded.More and more cases of chronic hyper-vitaminosis A are being reported, usuallyoccuring in young children given 100,000 I.U.or more daily for many months. Papillcedema,extra-ocular paralyses, diplopia, exophthalmosand superficial retinal haemorrhages are amongthe ocular features reported.Physicians and public alike, in this vitamin-

conscious era, need to be made aware of thedangers of excessive dosage of vitamin A.

Nutritional Retrobulbar NeuropathyThis condition has been endemic in certain

parts of the West Indies, West Africa and Indiafor many years and also occurred in epidemicproportions in the Far Eastern prisoner-of-warcamps during the second world war (Smith andWoodruff, 1951). The precise cause is notknown but most investigators are agreed thatit is nutritional and usually responds to someof the B complex of vitamins. Thiamine,riboflavin and vitamin B,2 have all beenclaimed to be effective. Frequently the bestresults are obtained with multi-B complextherapy and this is reasonable as these vitaminsfrequently occur together in nature.

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December, 1964 McLAREN and HALASA: Ocular Manifestations of Nutritional Disease 715

The amblyopia that occurs in chronic alco-holism and tobacco addiction is identical insymptomatology and the pathological changesit produces. (Victor, Mancall and Dreyfus,1960). Vitamin Ba1 appears to be especiallyeffective (Heaton, McCormick and Freeman,1958). This type of amblyopia is also due tomalnutrition, but secondary to the anorexia,chronic gastritis and other metabolic effects ofthe addiction.

Nutritional amblyopia produces blurring ofvision for both near and distant objects, fre-quently accompanied by photophobia andretrobulbar pain. Examination of the visualfields reveals central or centrocaecal scotomatawith little or no contraction at the periphery.Based on the experience of the many hundredsof cases followed up after the last war itappears that all degrees of visual disabilityresult, short of complete blindness. Othercranial nerves, especially the auditory andoculo-motor are often involved. Exaggeratedreflexes, muscles wasting and sensory losses inlimbs are frequent. Skin and mucous mem-brane changes suggestive of vitamin B com-plex deficiency may be found in the samepatients.Other Eye Conditions Attributed to Vitamin BComplex Deficiency

There has been described a superficialkeratitis which has been termed "cornealepithelial dystrophy". It was reported in someprisoner-of-war camps and was apparentlyidentical with an endemic disease of the corneafound in Trinidad and the Philippines. One ofus (McLaren, 1963) has suggested that this isnot a nutritional condition but indistinguish-able from epidemic keratoconjunctivitides ofviral aetiology.The eyes are commonly affected in

Wernicke's encephalopathy due to acutedeficiency of thiamine (de Wardener andLennox, 1947). Like nutritional amblyopia, thishas occurred under conditions of privation, asin prison camps, and is also seen in the ter-minal stages of chronic alcoholism. Nystagmusis an invariable and helpful diagnostic feature,being also one of the earliest manifestations.Other eye signs include fatigue and paralysisof the external rectus muscles, paralysis ofconjugate horizontal gaze, loss of visual acuityand papillcedema. A similar state has alsobeen attributed to deficiency of nicotinic acid.

Other conditions that have been reportedinclude fundus changes in infantile beriberi,riboflavin-responsive impairment of dark adap-

tation, a disturbance of vitamin B,, metabo-lism in diabetic retinopathy, and widespreadhaemorrhages in the retina in megaloblasticanemias of nutritional origin.Inanition and starvation

In comparison with other organs of the bodythe eye appears to be remarkably well pro-tected against the adverse effects of generalundernutrition. This may well have somethingto do with the advanced stage of developmentreached by the eye at even the time of birthand to the great functional significance of theeye for survival. Most of the studies carriedout on starved individuals immediately afterthe second world war did not reveal muchevidence of eye involvement. Notable excep-tions however are the condition attributed tostarvation in the civilian population of Athenstermed "superficial polymorphous keratopathy"(Djacos, 1949) and certain changes in thefundus such as narrowing of the retinal arteries,cedema of the optic disc and white or yellowishspots on the retina reported in prisoners ofwar in Germany and Russia.

Other nutrientsThere is little evidence that imbalance of

nutrients, other than those dealt with above,plays any part in the causation of human eyedisease. However, attention may be drawn tothe association of zonular cataract and thehypocalcaemia of tetany, the possible relation-ship of retinal haemorrhages in the newborninfant and maternal deficiency of vitamin K,the defect in dark adaptation reported in somepatients with zinc deficiency secondary to liverdisease, and the occurrence of bright orange-coloured plaques, possibly of cholesterol, atthe bifurcation of retinal arterioles in somepatients with atherosclerosis in which dietary fatis thought to play some aetiological role.

Malnutrition and Certain Eye DiseasesDiscrete colliquative keratopathy

This is the name given by one of us (McLaren,1963) to a mysterious disease of the corneadescribed originally in malnourished childrenin South Africa. In the typical case there is aquiet and discrete dissolution of one smallpart of the cornea frequently followed byprolapse of the iris. Although it has hithertobeen maintained that this is a separate entityand distinct from the keratomalacia of vitaminA deficiency one is left wondering whether theymight not after all turn out to be one and thesame condition once a thorough nutritional and

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biochemical evaluation were made of theAfrican cases. The poor dietary background andgenerally malnourished condition is certainlysuggestive of this.TrachomaWhile it is true that trachoma is common

among communities that are malnourishedthere is no proof that nutritional factors per seplay any part. From purely clinical evidenceit seems that the corneal complications oftrachoma progress more rapidly in the mal-nourished but on the other hand it has alsobeen suggested that marasmic children areoften not affected in communities wheretrachoma is rife among the more healthymembers. It is possible that certain enzymesystems essential for the virus are lacking inthe malnourished conjunctiva. In Jordan,where both vitamin A deficiency and trachomaco-exist among many of the poorer sectionsof the population, follicle formation in thepalpebral conjunctiva has been noted in as-sociation with xerosis and Bitot's spots on thecontiguous bulbar conjunctiva, making thesignificance of these latter signs difficult tointerpret.Cataract

In experimental animals cataract has beeninduced by diets deficient in protein, individualamino-acids and riboflavin. There is a gooddeal of circumstantial evidence that senilecataract has a high incidence, an early age ofonset and possibly tending rather commonlyto be nuclear in origin in places like Indiawhere the above-mentioned nutrients are inshort supply. Children who have recoveredfrom severe protein malnutrition (kwashiorkor)do not have evidence of early cataract but it ispossible, although difficult to prove that theymight be candidates for cataract later in life.(McLaren, 1963).

Refractive errorsAlthough the refractive state of the eye

appears to be very largely under genetic con-trol (Sorsby, Sheridan and Leary, 1962) thereis evidence that environmental factors mayhave some influence. We have shown thatmarasmic infants tend to be myopic and thatafter recovery their refraction returns to morenormal levels (Halasa and McLaren, 1964).Premature infants are more myopic than thoseborn at full term (Graham and Gray, 1963).One of us (McLaren, 1960, Johnstone andMcLaren, 1963) reported a high incidence ofmyopia in school children who had passedthrough a severe famine in Tanganyika al-though the refraction of similar tribes in otherparts of the country where there had been nofamine was normal. All these results pointin the same direction but need further carefulinvestigation.Summary

Xerophthalmia is still a major cause ofblindness in many parts of Asia, Africa andLatin America. In the most susceptible agegroup, the young child, it accounts for themajor proportion of blindness in these areasand the underlying vitamin A deficiency con-tributes considerably to the high childhoodmortality.

Nutritional retrobulbar neuropathy, tobacco-alcohol amblyopia, certain encephalopathiesand some diseases affecting the cornea aredue to deficiency of B vitamins. Under con-ditions of special privation and in certain en-demic foci they are of considerable importance.Much remains to be learned about the role

of malnutrition in the pathogenesis of othereye conditions.The original work referred to in this paper was

supported by U.S. Public Health Service GrantsAM 05285 and 06735 from the Institute of Arthritisand Metabolic Diseases.

REFERENCESDE WARDENER, H. E., and LENNOX, B. (1947): Cerebral Beriberi (Wernicke's enoephalopathy) Review of 52

Cases in Singapore Prisoner of War Hospital. Lancet, i, 11.DJACOS, C. (1949): Les Alt6rations Oculaires dans les Oedemes de Carence, Arch. Opthal. (Paris), 9, 421.GRAHAM, M. V., and GRAY, 0. P. (1963): Refraction of Premature Babies' Eyes, Brit. med. J., i, 1452.HALASA, A., and MCLAREN, D. S. (1954): The Refractive State of Malnourished Children, Arch. Ophthal., 71, 827.HEATON, J. M., MOCORMICK, A. J. A., and FREEMAN, A. G. (1958): Tobacco Amblyopia: A Clinical Mani-

festation of Vitamin Bi1 Deficiency, Lancet, ii, 286.JOHNSTONE, W. W., and MCLAREN, D. S. '(1963): Refraction Anomalies in Tanganyikan Children, Brit. . Oph-thal., 47,, 95.MCLAREN, D. S.S(1960): Nutrition and Eye Disease in East Africa: Experience in Lake and Central Prov-

inces, Tanganyika, J. trop. Med. Hyg., 63, 101.MCLAREN, D. S. (1963): Malnutrition and the Eye, p. 162, New York: Academic Press.MCLAREN, D. S., TCHALIAN, M., and SHIRAJIAN, E. (1964): Xerophthalmia in Jordan. Amer. J. clin. Nutr., in

the press.OOMEN, H. A. P. C. (1961): An Outline of Xerophthalmia, Int. Rev. trop. Med., 1, 132.OOMEN, H. A. P. C., MCLAREN, D. S., and ESCAPINI, U. (1964): Xerophthalmia: the Public Health Aspects of

Vitamin A Deficiency. W.H.O.-limited circulation report in the press.SMITH, D. A., and WOODRUFF, M. F. A. (1951): Deficiency Diseases in Japanese Prison Camps, Spec. Rep. Ser.

Med. Res. Coun. (Lond.), No. 274.SORSBY, A., SHERIDAN, M., and LEARY, G. A. (1962): Refraction and its Components in Twins, ibid, No. 303.TENG-KHOEN-HING (1959): Fundus Changes in Hypovitaminosis A. Ophalmologica (Basel), 137, 81.VICTOR, M., MANCALL, E. L., and DREYFUS, P. M. (1960): Deficiency Amblyopia in the Alcoholic Patient-

a Clinicopathologic Study, Arch Opthal, 64, 1.

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