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

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

was prominent. Goblet cells were absent. In
one area of prominent conjunctival epider-
midalization, a moderate infiltrate of
lymphocytes and plasma cells accompanied
engorged conjunctival vessels (Fig. 3).
A rim of cornea less than one millimeter in
width marked the edge of the cornea1 perfora-
tion (Fig. 4). The cornea1 epithelium was
thinned and it disappeared completely near
the site of perforation. Inflammatory reaction
around the perforation was nearly nonexis-
tent, despite the presence of numerous
colonies of gram positive bacteria in the
prolapsed intraocular tissue (Fig. 5). Within
the eye, the remaining retina was detached as
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
terchangeably, it is more accurate to specify
xerosis of the conjunctiva or cornea and to
differentiate it from xerophthalmia, which
refers to the entire eye. Keratomalacia, a dif-
fuse, noninflammatory cornea1 melting in
vitamin-protein deficiency, has also been re-
ferred to as discreet colliquative necrosis.‘** I8
In the appropriate geographic setting,
vitamin-protein deficiency represents a While keratomalacia represents a small
significant part of ophthalmic practice. In
1963, nearly seven percent of 44,000 eye
patients at the Madurai Medical College Eye
Department had ocular lesions related to
malnutrition.*’ Estimates of incidence vary
between 20,000 and 80,000 new cases per
year.‘ls *’
One of the earliest clinical findings in
vitamin A deficiency is conjunctival xerosis.
The dry. appearance of the conjunctiva is in
part a sign of early epidermidalization and in
part a sign of failure of mucus production by
the goblet cells.‘~ l6 As xerosis progresses, the
conjunctiva becomes wrinkled, red, opaque
and pigmented, and may develop a Bitot’s
spot.18 Although aqueous tears are adequate,
there is immediate tearfilm breakdown and
inadequate wetting of the cornea1 surface. As
Dohlman’ points out, cornea1 and conjunc-
tival keratinization in vitamin A deficiency is
not due to evaporation, since keratin forma-
tion occurs in epithelia of the gastrointestinal,
genitourinary and respiratory tracts. The oc-
currence of xerosis and xerophthalmia in
vitamin-protein deficiency is not universal. In
a series” of 1116 cases of malnutrition in
South America, 108 individuals showed
ocular lesions of malnutrition. The
seriousness of the malnutrition is indicated by
the fact that 30% of these 108 patients died
FIG. 5. Bacterial colonies (arrows) are evident
within the necrotic, prolapsed intraocular tissue.
(Hematoxylin and eosin X 250)
217
despite strenuous medical efforts.
Xerophthalmia without cornea1 ulceration
was present in 10%. Xerophthalmia was ac-
companied by cornea1 ulceration of varying
degrees in 78%. Keratomalacia occurred in
8% of the patients and the remainder had cor-
neal scarring suggestive of a prior episode of
xerophthalmia.
percentage of reported cases,” its visual con-
sequences are serious. In a patient with es-
tablished xerophthalmia, the cornea un-
dergoes swelling, followed by melting and
perforation with loss of intraocular con-
tents.‘, I6 Dohlman’ suggests that a
collagenase mechanism may account for the
cornea1 melting. Since most patients with
vitamin A deficiency also have severe protein
malnutrition, lower serum levels of the
natural collagenase inhibitors, alpha-2
macroglobulin and alpha-l antitrypsin, may
play a role.’
The serum levels of Vitamin A and
carotenes documented in patients with
xerophthalmia and keratomalacia are
decreased at least 50% from normal levels
and often more.2ov*l In our patient both
serum vitamin A and serum carotene were
20% of normal levels. Since there is a con-
siderable range of normal values for vitamin
A and carotenes, the importance of these
serum levels is open to question. There is no
regular correlation between serum vitamin A
concentration and the presence of Bitot’s
SpOtS.‘a’*O
In addition to the anterior segment changes
it is well established that vitamin A-deficient
diets in man and animals cause night
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
play a role, protein and vitamin A deficiency
in children are prominent features of
kwashiorkor.5* l’ The precise clinical findings
218 Surv Ophthalmol 20 (3) November-December,
depend on the diet and tend to vary in
different parts of the world. Our patient’s
dietary history, which included negligible pro-
tein intake, explains the low serum protein
and marked hypoalbuminemia. While the
vitamin A deficit was documented in the
laboratory, her clinical findings are those
described in starvation with protein and mul-
tiple vitamin deficiency.12* la, 26
Despite the multiple etiologic factors which
interact in patients such as ours, it is useful to
review some experimental studies. MorP5
produced xerophthalmia in rats maintained
on vitamin A deficient diets. The rat cornea1
epithelium showed thickening and keratiniza-
tion which was followed after some weeks by
vascularization and stromal necrosis. Mellan-
by13 confirmed these results in rabbits. Both
authors overlooked the early changes
described by Wolbach and Howe,2s in a
carefully controlled study in rats. Keratiniza-
tion followed epithelial atrophy and preceded
disappearance of goblet cells. It was thought
that infection did not play a primary role and
that vascularization of the cornea1 epithelium
was a late change. 26The hypothesis of initial
atrophy of the cornea1 epithelium is sup-
ported by the work of Friedenwald,8 who
found a 30% decrease in mitotic activity and
prolongation of the mitotic cycle in vitamin A
deficient rats. Similar findings were described
by Beaver’ in germ-free rats, where secondary
infections were not a factor. Ultrastructural
studies23 ‘* tend to confirm the light
microscopic picture. There is a possibility
that structural alterations in the mitochon-
drial matrix may give rise to keratohyalin
granules described in cells of keratinizing
epithelium.‘*
Despite the abundant clinical and ex-
perimental literature, studies of the human
ocular pathology of xerophthalmia and
keratomalacia are rare. Kreiker’O found
goblet cell atrophy and hyaline degeneration
of the cornea1 epithelium before keratiniza-
tion in a vitamin A deficient patient. Sweet
and K’ang” described concurrent loss of
goblet cells and cornea1 keratinization in 17
Chinese children. More advanced cases
showed stromal necrosis and ulceration..
Vascularization and secondary infection were
prominent. In a young child with
keratomalacia, ZaubermatP found necrosis,
keratinization and vascularization in a cor-
neal button removed at surgery. Sfuphylococ-
1975 SMITH, FARRELL, 8AlLEY
cus aureu.s was cultured from the conjunctival
sac. Conjunctival biopsies of Bitot’s spots3
showed ballooning of the epithelial cells as
well as thinning and keratinization of the
epithelium. Although infection may play a
role, all of the changes described above may
be accompanied by a very minimal inflam-
matory response.” In our patient, despite
massive cornea1 necrosis and prolapse of the
intraocular contents, there was surprisingly
little inflammation. The principal ocular
changes included cornea1 necrosis, conjunc-
tival epidermidalization and goblet cell
atrophy.
Although our patient gave a clear history
of night blindness, the pathologic changes
seen in the detached, prolapsed retina must be
interpreted with caution. The absence of
photoreceptor outer segments under these cir-
cumstances is meaningless. The decrease in
nuclei in the outer nuclear layer is suggestive
of chronic avitaminosis A.
In the generally well fed population of
developed countries, xerophthalmia and
keratomalacia are extremely rare and usually
suggest bizzare dietary habits or systemic dis-
ease. Fells and BorsB describe an unusual case
of self-induced avitaminosis A in a 25-year-
old male who subsisted for five years on a diet
limited to brown bread, lime juice and B
vitamin supplements. The patient had an ex-
tinguished electroretinogram and marked
mucus deficiency with xerophthalmia and
cornea1 ulceration. Bitot’s spots were absent.
His serum vitamin A and carotene levels were
less than 10% of normal. Cystic fibrosis
patients may develop protein deficiency
because of malabsorption with consequent
xerophthalmia and night blindness.‘” Boniuk
has observed xerophthalmia and night
blindness in several patients following in-
testinal resection for obesity which produced
a malabsorption syndrome (personal com-
munication). The diet-induced vitamin A
deficiency in our patient was complicated by
severe protein malnutrition and multiple
vitamin deficits which led to her death.
Acknowledgments
We would like to thank C.V.Z. Hawn, M.D. for
sharing the pathologic materia! with us and J.N.P.
Davies, M.D. for his advice and assistance in
reviewing the case.

CLINICAL PATHOLOGICAL REVIEW
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Supported by a grant from the Sight Conserva-
tion Society of Northeastern New York.
Reprint requests should be addressed to Richard
S. Smith, M.D., Department of Ophthalmology,
Albany Medical College, Albany, New York
12208