SURVEY OF OPHTHALMOLOGY VOLUME 20. NUMBER 3.

NOVEMBER-DECEMBER 1975

CLINICAL PATHOLOGICAL REVIEW

MILTON M. BONIUK, EDITOR

Keratomalacia
RICHARD S. SMITH, M.D., THOMAS FARRELL, M.D., AND THOMAS BAILEY, M.D.

Department of Ophthalmology, Albany Medical College, Albany, and the Division of

Ophthalmology, Mary Imogene Bassett Hospital, Cooperstown, New York

Abstract. Xerophthalmia and keratomalacia are public health problems of great

magnitude which are usually associated with multiple vitamin and protein deticien-
ties. The authors report the case of a 27-year-old commune member who subjected
herself to a bizarre protein and vitamin deficient diet for many months. This ul-
timately produced nyctalopia, xerophthalmia and keratomalacia with bilateral cor-
neal perforation. Despite therapy, she remained comatose and expired shortly after
admission. Ocular pathological changes included bilateral cornea1 melting with
prolapse of intraocular contents, conjunctival epidermidalization, goblet cell atrophy
and thinning of the outer nuclear layer of the retina. It is noted that ocular findings in
pure avitaminosis A produced experimentally include epithelial atrophy followed by
keratinization. (Surv Ophthalmol 20:213-219, 1975)

Key .Words: cornea keratomalacia

l l night blindness l vitamin A
. xerophthalmia * xerosis

V
itamin A deficiency is a public health Case Report
problem of great magnitude in un-
CLINICAL SUMMARY
developed countries.‘* Estimates of in-
cidence range from 20,000 to 80,000 new A 27-year-old Caucasian female was
cases per year. I’*25Bilateral blindness conse- admitted in a semicomatose condition to the
quent to keratomalacia is a frequent sequel. intensive care unit of the Mary Imogene
Vitamin A deficiency by itself, or in associa- Bassett Hospital. She had lived with her hus-
tion with kwashiorkor,2’ protein deficiency9 band in a communal group for the preceding
or multiple vitamin deficiency9 may result in five years. During that period she had
death unless prompt treatment is instituted. followed a “cult” vegetable and grain diet of
The clinical aspects”* 16-18
and experimental uncertain composition. Six weeks prior to ad-
induction of vitamin A deficiency are the sub- mission she limited her diet to brown rice,
jects of numerous studies.lm2s13*l5 Despite the water and herbal tea. In the preceding month
importance of the eye in avitaminosis A, the she complained of poor night vision, followed
ocular histopathologic changes have received by gradual loss of all vision. Concomitantly,
little attention.3v 5. 23 The clinical and her husband noted the development of crusts
histopathologic findings in a case of self- on her eyes and lids. During this latter period,
induced nyctalopia and bilateral keratoma- she became anorexic, confused and
lacia and a review of the literature are the progressively lethargic. She had collapsed on
subjects of this report. the day of admission, and for the first time
213
214 Surv Ophthalmol 20 (3) November-December, 1975 SMITH, FARRELL, BAILEY

medical attention was sought. According to gentamicin drops, and bilateral patching.
her husband, there was no history of prior ill- Six hours after admission, both eyes
ness or drug habits. developed a serosanquinous discharge. Ex-
Physical examination on admission showed amination showed complete melting of the
a pale, semicomatose, moderately wasted cornea1 stroma with prolapse of the in-
female who responded only to painful stimuli. traocular contents of both eyes. Specimens
Her blood pressure was unobtainable, the excised from the surface of the lids consisted
apical pulse rate was 100, rectal temperature of retinal tissue.
was 315°C respirations were 40 and labored, The patient did not regain consciousness.
and her weight was 41.5 kg. Other significant Despite intravenous isoproteronal and
physical findings included dry, crusted mucous levoarteronal, her systolic blood pressure
membranes, coarse breath sounds with in- remained below 100 mm Hg. Pulmonary
spiratory and expiratory rhonchi, dry skin, edema returned even with a total negative
and bilateral Babinski reflexes. fluid balance of six liters in her last 24 hours
Ocular examination showed dry, gritty, of hospitalization. She died in intractable
yellow crusts on the lid margin, conjunctiva pulmonary failure 65 hours after admission.
and corneas of both eyes. The conjunctiva
had a dry, lusterless appearance. The corneas AUTOPSY FINDINGS
were thickened and opaque. All other por-
Generalized interstitial pulmonary edema
tions of the anterior and posterior segments
and hemorrhagic bronchopneumonia were
were obscured by the cornea1 changes.
present. There was diffuse hemorrhagic esoph-
Laboratory data obtained at admission
ageal and gastric ulceration. Gram positive
showed an hematocrit of 24% and a white cell
cocci and fungal organisms resembling
count of 5700. Blood chemistries were:
Mucor sp. were seen in gastric, esophageal,
sodium 181 meq/L, potassium 3.5 meq/L,
and pulmonary inflammatory lesions.
chloride 139 meq/L, serum glucose 366 mg%,
Metaplastic changes in epithelia were
creatine 5.2 mg%. Her prothrombin time was
minimal. Death was attributed to sepsis and
20.3 with a control of 11.4. The vitamin A
respiratory failure with associated pulmonary
level was 10 meq/lOO ml (normal 40-100);
edema and hemorrhage. It was assumed that
serum carotene was 20 meq/lOO ml (normal
multiple vitamin and protein deficiencies
100-150); .vitamin B,, level was normal; and
precipitated the chain of events leading to
serum folate was less than 0.10 mg/ml. Total
death.
serum protein was 3.4 gm/lOO ml with only
1.4 gm of albumin. Arterial blood showed a
OCULAR PATHOLOGY
pH of 7.28 with a PO2of 25.2 and bicarbonate
of 11.6. An admission chest x-ray showed a The material excised in the intensive care
streaky infiltrate in the right lower lobe, unit prior to death included retina and red
possibly an early pneumonia. Cultures of blood cells (Fig. 1). The retinal tissue showed
material from the conjunctiva grew Proteus mild edema, loss of photoreceptor outer
vulgaris and diphtheroids. segments and minimal decrease in thickness
The admitting diagnoses included of the outer nuclear layer. The remainder of
hypovolemic shock, dehydration, acidosis, the retina was well preserved. No
malnutrition and xerophthalmia. The shock microorganisms were identified.
and dehydration were treated with prompt in- The gross and microscopic appearance of
travenous whole blood transfusions and ap- both eyes was similar. The globes were soft
propriate fluid replacement. Intramuscular and collapsed. Except for a one millimeter
vitamin A and K was given as well as in- rim of tissue, the corneas were absent. Fresh
travenous B-complex vitamins (Berocca). hemorrhage and intraocular contents
Systemic antibiotics were also administered. protruded through the 9 millimeter perfora-
On the afternoon of admission the patient tion. There was massive intraocular
developed pulmonary edema which was hemorrhage with detachment of retina,
successfully treated with intravenous choroid and ciliary body. The lens could not
furosemide, endotracheal intubation and the be identified on gross examination.
use of a volume limited respirator. Her The attached conjunctiva showed
xerophthalmia was treated topically with acanthosis, epidermidalization and early
half-hourly methylcellulose drops, hourly keratinization (Fig. 2). Rete ridge formation
CLINICAL PATHOLOGICAL REVIEW 215

was prominent. Goblet cells were absent. In thinned and it disappeared completely near
one area of prominent conjunctival epider- the site of perforation. Inflammatory reaction
midalization, a moderate infiltrate of around the perforation was nearly nonexis-
lymphocytes and plasma cells accompanied tent, despite the presence of numerous
engorged conjunctival vessels (Fig. 3). colonies of gram positive bacteria in the
A rim of cornea less than one millimeter in prolapsed intraocular tissue (Fig. 5). Within
width marked the edge of the cornea1 perfora- the eye, the remaining retina was detached as
tion (Fig. 4). The cornea1 epithelium was was the choroid. The inner retinal layers were

FIG. 1. Prolapsed ocular tissue excised in emergency room. Fresh hemorrhage (H) and retina (R) are
presen It. In some areas (arrows) photoreceptor outer segments are absent. (Hematoxylin and eosin X 100)

FIG. 2. The conjunctiva (C) shows epidermidalization. rete ridge formation (arrows) and patchy
keratinization (inset, arrowheads). (Hematoxylin and eosin X 150)
216 SurvOphthalmol 20 (3) November-December, 1975 SMITH, FARRELL, BAILEY

well preserved. The outer nuclear layer and Discussion

photoreceptors resembled the material
removed before death (Fig. 1). The sclera and The Greek root xeros (= dry) is used in the
optic nerve were normal and showed no signs terms “xerosis” and “xerophthalmia.”
of inflammation. Although these terms are used in-

FIG. 3. Beneath epidermidalized conjunctiva (C), dilated conjunctival vessels (arrows) are a ssociated
with a lymphocytic infiltrate (L). (Hematoxylin and eosin X 100)

FIG. 4. A narrow rim of cornea (C) is present at the edge of the perforation. Iris (I) and a fralgment of
Desc:elnet’s membrane (D) prolapse through the wound. Iris, cornea and sclera (S) show only aLminimal
infla .mmatory reaction. (Hematoxylin and eosin X 120)
CLINICAL PATWOLOGICAL REVIEW 217

terchangeably, it is more accurate to specify despite strenuous medical efforts.

xerosis of the conjunctiva or cornea and to Xerophthalmia without cornea1 ulceration
differentiate it from xerophthalmia, which was present in 10%. Xerophthalmia was ac-
refers to the entire eye. Keratomalacia, a dif- companied by cornea1 ulceration of varying
fuse, noninflammatory cornea1 melting in degrees in 78%. Keratomalacia occurred in
vitamin-protein deficiency, has also been re- 8% of the patients and the remainder had cor-
ferred to as discreet colliquative necrosis.‘** I8 neal scarring suggestive of a prior episode of
In the appropriate geographic setting, xerophthalmia.
vitamin-protein deficiency represents a While keratomalacia represents a small
significant part of ophthalmic practice. In percentage of reported cases,” its visual con-
1963, nearly seven percent of 44,000 eye sequences are serious. In a patient with es-
patients at the Madurai Medical College Eye tablished xerophthalmia, the cornea un-
Department had ocular lesions related to dergoes swelling, followed by melting and
malnutrition.*’ Estimates of incidence vary perforation with loss of intraocular con-
between 20,000 and 80,000 new cases per tents.‘, I6 Dohlman’ suggests that a
year.‘ls *’ collagenase mechanism may account for the
One of the earliest clinical findings in cornea1 melting. Since most patients with
vitamin A deficiency is conjunctival xerosis. vitamin A deficiency also have severe protein
The dry. appearance of the conjunctiva is in malnutrition, lower serum levels of the
part a sign of early epidermidalization and in natural collagenase inhibitors, alpha-2
part a sign of failure of mucus production by macroglobulin and alpha-l antitrypsin, may
the goblet cells.‘~ l6 As xerosis progresses, the play a role.’
conjunctiva becomes wrinkled, red, opaque The serum levels of Vitamin A and
and pigmented, and may develop a Bitot’s carotenes documented in patients with
spot.18 Although aqueous tears are adequate, xerophthalmia and keratomalacia are
there is immediate tearfilm breakdown and decreased at least 50% from normal levels
inadequate wetting of the cornea1 surface. As and often more.2ov*l In our patient both
Dohlman’ points out, cornea1 and conjunc- serum vitamin A and serum carotene were
tival keratinization in vitamin A deficiency is 20% of normal levels. Since there is a con-
not due to evaporation, since keratin forma- siderable range of normal values for vitamin
tion occurs in epithelia of the gastrointestinal, A and carotenes, the importance of these
genitourinary and respiratory tracts. The oc- serum levels is open to question. There is no
currence of xerosis and xerophthalmia in regular correlation between serum vitamin A
vitamin-protein deficiency is not universal. In concentration and the presence of Bitot’s
a series” of 1116 cases of malnutrition in SpOtS.‘a’*O
South America, 108 individuals showed In addition to the anterior segment changes
ocular lesions of malnutrition. The it is well established that vitamin A-deficient
seriousness of the malnutrition is indicated by diets in man and animals cause night
the fact that 30% of these 108 patients died blindness.“, *OIn our patient, poor night vi-
sion was noted in the month prior to admis-
sion. Since her brown rice diet was started
only six weeks before admission, it seems
likely that her earlier diet had been markedly
deficient in vitamin A. Her moribund condi-
tion did not permit electrophysiologic testing.
Although pure vitamin A deficiency can be
produced in the laboratory, in clinical
situations the picture is always complicated
by dietary deficits of proteins and other
vitamins. In fact, low serum albumin levels
nearly always accompany xerophthalmia and
keratomalacia.5* 9, I1 Although other factors7
FIG. 5. Bacterial colonies (arrows) are evident play a role, protein and vitamin A deficiency
within the necrotic, prolapsed intraocular tissue. in children are prominent features of
(Hematoxylin and eosin X 250) kwashiorkor.5* l’ The precise clinical findings
218 Surv Ophthalmol 20 (3) November-December, 1975 SMITH, FARRELL, 8AlLEY

depend on the diet and tend to vary in cus aureu.s was cultured from the conjunctival
different parts of the world. Our patient’s sac. Conjunctival biopsies of Bitot’s spots3
dietary history, which included negligible pro- showed ballooning of the epithelial cells as
tein intake, explains the low serum protein well as thinning and keratinization of the
and marked hypoalbuminemia. While the epithelium. Although infection may play a
vitamin A deficit was documented in the role, all of the changes described above may
laboratory, her clinical findings are those be accompanied by a very minimal inflam-
described in starvation with protein and mul- matory response.” In our patient, despite
tiple vitamin deficiency.12* la, 26 massive cornea1 necrosis and prolapse of the
Despite the multiple etiologic factors which intraocular contents, there was surprisingly
interact in patients such as ours, it is useful to little inflammation. The principal ocular
review some experimental studies. MorP5 changes included cornea1 necrosis, conjunc-
produced xerophthalmia in rats maintained tival epidermidalization and goblet cell
on vitamin A deficient diets. The rat cornea1 atrophy.
epithelium showed thickening and keratiniza- Although our patient gave a clear history
tion which was followed after some weeks by of night blindness, the pathologic changes
vascularization and stromal necrosis. Mellan- seen in the detached, prolapsed retina must be
by13 confirmed these results in rabbits. Both interpreted with caution. The absence of
authors overlooked the early changes photoreceptor outer segments under these cir-
described by Wolbach and Howe,2s in a cumstances is meaningless. The decrease in
carefully controlled study in rats. Keratiniza- nuclei in the outer nuclear layer is suggestive
tion followed epithelial atrophy and preceded of chronic avitaminosis A.
disappearance of goblet cells. It was thought In the generally well fed population of
that infection did not play a primary role and developed countries, xerophthalmia and
that vascularization of the cornea1 epithelium keratomalacia are extremely rare and usually
was a late change. 26The hypothesis of initial suggest bizzare dietary habits or systemic dis-
atrophy of the cornea1 epithelium is sup- ease. Fells and BorsB describe an unusual case
ported by the work of Friedenwald,8 who of self-induced avitaminosis A in a 25-year-
found a 30% decrease in mitotic activity and old male who subsisted for five years on a diet
prolongation of the mitotic cycle in vitamin A limited to brown bread, lime juice and B
deficient rats. Similar findings were described vitamin supplements. The patient had an ex-
by Beaver’ in germ-free rats, where secondary tinguished electroretinogram and marked
infections were not a factor. Ultrastructural mucus deficiency with xerophthalmia and
studies23 ‘* tend to confirm the light cornea1 ulceration. Bitot’s spots were absent.
microscopic picture. There is a possibility His serum vitamin A and carotene levels were
that structural alterations in the mitochon- less than 10% of normal. Cystic fibrosis
drial matrix may give rise to keratohyalin patients may develop protein deficiency
granules described in cells of keratinizing because of malabsorption with consequent
epithelium.‘* xerophthalmia and night blindness.‘” Boniuk
Despite the abundant clinical and ex- has observed xerophthalmia and night
perimental literature, studies of the human blindness in several patients following in-
ocular pathology of xerophthalmia and testinal resection for obesity which produced
keratomalacia are rare. Kreiker’O found a malabsorption syndrome (personal com-
goblet cell atrophy and hyaline degeneration munication). The diet-induced vitamin A
of the cornea1 epithelium before keratiniza- deficiency in our patient was complicated by
tion in a vitamin A deficient patient. Sweet severe protein malnutrition and multiple
and K’ang” described concurrent loss of vitamin deficits which led to her death.
goblet cells and cornea1 keratinization in 17
Chinese children. More advanced cases
showed stromal necrosis and ulceration..
Acknowledgments
Vascularization and secondary infection were
prominent. In a young child with We would like to thank C.V.Z. Hawn, M.D. for
keratomalacia, ZaubermatP found necrosis, sharing the pathologic materia! with us and J.N.P.
keratinization and vascularization in a cor- Davies, M.D. for his advice and assistance in
neal button removed at surgery. Sfuphylococ- reviewing the case.
 219
CLINICAL PATHOLOGICAL REVIEW

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