VITAMIN A-RESPONSIVE PUNCTATE KERATOPATHY IN XEROPHTHALMIA A L F R E D SOMMER, M.D.,
N A N I E M R A N , M.D., Bandung,
Xerophthalmia remains a major cause of corneal destruction and blindness in many developing countries. The widely used clinical classification (Table 1) sug gests a sharp distinction between cases with and without corneal disease. 1 But few if any cases of mild xerophthalmia (night blindness, conjunctiva! xerosis, or Bitot's spots) have undergone careful slit-lamp examination; consequently, lit tle is known of the earliest manifestations of corneal involvement. The Indonesian Nutritional Blindness Prevention Project is presently conduc ting detailed clinical examinations on large numbers of xerophthalmic children. Results indicate punctate epithelial keratopathy is the earliest corneal manifes tation of xerophthalmia and is already present in the majority of cases classically considered free of corneal disease. METHODS
Between July and December 1977, 78 consecutive patients with xerophthalmia without corneal ulceration were exam ined at the Cicendo Eye Hospital, Ban dung, with a.handlight and a slit lamp (with and without fluorescein). An addi tional 29 controls of cases of corneal xerophthalmia, matched for age, sex, and From the Nutritional Blindness Prevention Proj ect, Bandung, Indonesia (Drs. Sommer, Emran, and Tamba), and the Wilmer Institute, Johns Hopkins Hospital, Baltimore, Maryland (Dr. Sommer). The Nutritional Blindness Prevention Project is a joint undertaking of the Ministry of Health, Government of Indonesia, and Helen Keller International, New York, N.Y., with substantial funding from the United States Agency for International Develop ment, Washington, D.C. This study was presented at the International Symposium on Cornea Research, Kyoto, Japan, May 13, 1978. Reprint requests to Alfred Sommer, M.D., Wilmer Institute, Johns Hopkins Hospital, 601 N. Broad way, Baltimore, MD 21205. 330
AND T I E N TAMBA,
M.D.
Indonesia TABLE 1 C L A S S I F I C A T I O N O F ACTIVE X E R O P H T H A L M I A
Classification
Description
XN* X1A X1B
Night blindness Conjunctival xerosis Conjunctival xerosis with Bitot's spot Corneal xerosis Corneal xerosis with ulceration Keratomalacia
X2 X3A X3B
*XN is considered a secondary sign.
neighborhood, without night blindness and normal on handlight examination, were similarly studied. Additional ophthalmologic, pediatric, bacteriologic, biochemical, and histopathologic investi gations were performed but are not ger mane to the present discussion. Xerophthalmic patients were enrolled in one of several treatment regimens de pending on the severity of disease. As part of a concurrently running protocol to de termine the proportion of cases of con junctival xerosis and Bitot's spots caused by active vitamin A deficiency, those with clear corneas by handlight examina tion were randomly allocated to receive either low doses (700 IU) or high doses (200,000 IU) of vitamin A orally. Every attempt was made to reexamine all pa tients at frequent intervals, and low-dose recipients received high-dose therapy after three months, or sooner if their con dition deteriorated. Informed consent was obtained from every child's parent or guardian. RESULTS
Obvious corneal involvement on handlight examination was associated with ex-
AMERICAN JOURNAL O F OPHTHALMOLOGY 87:330-333, 1979
VOL. 87, NO. 3
PUNCTATE KERATOPATHY IN XEROPHTHALMIA
331
•ZmVStm*
«£«««•?••/ Svv-v.vK.":
'•as
Figure (Sommer, Emran, and Tamba). Xerophthalmia associated punctate keratopathy has a strong predilection for the inferonasal quadrant, the first area involved and the last to clear.
tensive punctate keratopathy: myriads of densely packed, tiny, brightly staining specks covering the entire corneal sur face. Where the distribution was less uni form, as in cases of milder disease, there was a striking predilection for the inferior half of the cornea, especially the infero nasal quadrant (Figure). For conve nience, we graded the distribution of lesions 1 through 4, representing involve ment of the inferonasal quadrant, inferior half, inferior three fourths, and the entire surface of the cornea, respectively. Inten sity was graded 1 through 3, indicating mild, moderate, and heavy concentrations of lesions. If punctate keratopathy is an early man ifestation of xerophthalmia, the propor tion of individuals affected, and the ex tent and intensity of corneal involvement might be expected to increase with in
creasing evidence and severity of disease (Table 2). Controls—Both eyes of 29 controls of corneal cases matched for age, sex, and locale were normal by handlight exami nation. Only two controls (four eyes) had definite punctate keratopathy (7%), in each instance minimal and limited to the periphery of the inferonasal quadrant. Noncorneal xerophthalmia (XN, X1A, XIB)—All corneas appeared crystal clear by handlight examination, the basis for their clinical classification. 2 Children with a history of night blind ness-unconfirmed by clinical examination were assumed to have the mildest form of xerophthalmia. Of nine cases (18 eyes), 4 eyes (22%) had punctate keratopathy. Among affected corneas, the average dis tribution and density of lesions was 1.0. In five children (ten eyes), clinical ex-
TABLE 2 F L U O R E S C E I N - P O S I T I V E P U N C T A T E KERATOPATHY
Clinical Classification
No. of Eyes
Controls XN: History contributory; examination negative XN: History contributory; examination positive X1A, IB X2
58
Positive,
Average Extent*
Average Density!
7
1.0
1.0
18
22
1.0
1.0
10 63 47
60 75 100
1.3 1.9 3.5
1.7 1.9 2.2
%
*1 signifies inferonasal quadrant; 2, inferior one-half of cornea; 3, inferior three-fourths of cornea; 4, entire corneal surface. t l signifies mild; 2, moderate; 3, heavy.
332
AMERICAN JOURNAL OF OPHTHALMOLOGY
amination confirmed the presence of night blindness. Sixty percent of cases (three) and eyes (six) had punctate kerathopathy, with an average distribution of 1.33 and density of 1.67. Thirty-four children had conjunctival xerosis (X1A, X1B) in at least one eye. Of 63 involved eyes, 75% (47) had punctate keratopathy, with an average distribution and intensity of 1.9. Comeal xerosis (X2)—Corneal xerosis (X2) was the severest lesion in 30 cases. All 47 eyes with corneal xerosis had ex tensive punctate keratopathy, with an av erage distribution of 3.5 and intensity of 2.2. Therapeutic trial—The importance of vitamin A deficiency in the genesis of these lesions is confirmed by their re sponse to therapy. Follow-up examina tions were available on 18 patients (26 eyes) with punctate keratopathy who were treated with a single oral dose of 200,000 IU of vitamin A. The lesions healed in a definite pattern. Improvement began with loss of staining, leaving an early mixture of staining and nonstaining white specks. By the second week, many of the nonstaining specks had become lightly pigmented, and by the fourth week all staining had ceased, leaving residually pigmented epithelial or subepithelial specks, most apparent inferiorly. Superior and temporal aspects of the cornea healed and cleared first, the inferonasal last. Between one and three days after treat ment 40% of involved corneas (four of ten) improved (Table 3). After four to seven days, all showed improvement and 25% (three of 12) were entirely free of punctate staining (cured). The proportion free of staining rose to 80% (eight of ten) at two weeks and 100% at one month. Conversely the course of the disease in ten low-dose recipients (18 involved eyes) with punctate keratopathy was markedly different. By the end of the first month
MARCH, 1979 TABLE 3
P U N C T A T E KERATOPATHY AMONG X1A, X1B PA T I E N T S * : R E S P O N S E T O 200,000 IU VITAMIN A
Duration Total Since Improved, Cured, I m p r c ved or Cured, Treatment % % % 1-3 4-7 2 1
days days wks mo
40 75 20
0 25 80 100
40 100 100 100
* Twenty-six eyes were' available for at least one follow-up examination.
none of the corneas showed improve ment, whereas 6 1 % had actually deterio rated at some time in the interval (four of them alarmingly so). All four were treated with 200,000 IU of vitamin A with subse quent improvement or cure within nine days. Both eyes of one low-dose recipient eventually healed spontaneously, at 65 days. DISCUSSION
Our observations leave little doubt that punctate epithelial keratopathy is an early manifestation of xerophthalmia, and al ready present in most eyes usually con sidered free of corneal involvement. Sixty percent of confirmed cases of night blind ness (XN) and 75% of eyes classified X1A or X1B (conjunctival xerosis) were affect ed. Because only 7% of normal controls were similarly affected, it is unlikely the high prevalence of punctate keratopathy among xerophthalmic children was due to other causes, a supposition confirmed by the therapeutic trial. The positive controls might indeed represent instances of in cipient xerophthalmia. Serum vitamin A levels among locale-matched controls were considerably below random sample norms (unpublished data). Pathogenesis of the lesions and reasons for their predilection for the inferonasal quadrant remain uncertain. Impaired me-
VOL. 87, NO. 3
PUNCTATE KERATOPATHY IN XEROPHTHALMIA
tabolism of the corneal epithelium could be the direct result of vitamin A deficien cy per se, or secondary to instability of the tear film with local drying. But sugges tions that they are the result of loss of conjunctival mucous-producing goblet cells 3 seem unlikely. All corneas im proved within seven days of therapy and 80% ceased to stain by two weeks, long before goblet cells reappear (unpublished data). 4 - 5 Both eyes of one low-dose recipient healed spontaneously at 65 days, proba bly from improved diet or treatment out side the study. Preliminary results of our longitudinal field study indicate almost 50% of children with noncorneal xerophthalmia improved spontaneously over a four-month period (unpublished data). The presently accepted xerophthalmia classification, 1 primarily derived from handlight examinations, is insufficiently precise for research purposes. Nonethe less, it is a useful clinical tool. Medical workers encountering the disease are un likely to have more than a handlight available, and any child suspected of hav ing active xerophthalmia deserves imme diate treatment, whether or not subtle slit-lamp evidence of early corneal in volvement is already present. But field surveys based on handlight examinations will grossly underestimate the prevalence of corneal involvement. SUMMARY
Slit-lamp examination of 78 cases of xerophthalmia and 29 controls matched
333
for age, sex, and locale indicated a direct correlation between the presence, densi ty, and extent of punctate epithelial keratopathy and the severity,of corneal and noncorneal involvement. Only 7% (four of 58) of control eyes but 60% (six of ten) of cases with confirmed night blindness, 75% (47 of 63) of eyes with conjunctival xerosis, and all eyes with corneal xerosis (47) were affected. Within one week of high-dose systemic vitamin A therapy all affected corneas had improved. None of ten patients receiving low-dose systemic therapy showed any improvement over a two-month period, whereas 6 1 % of in volved corneas actually deteriorated in the interim. Punctate epithelial keratopathy appears to be the earliest corneal manifestation of xerophthalmia, and is already present in the vast majority of cases classically con sidered free of corneal involvement. REFERENCES 1. Vitamin A Deficiency and Xerophthalmia. Re port of a Joint WHO/USAID Meeting. Technical Report Series 590. Geneva, Switzerland, World Health Organization, 1976. 2. Sornmer, A.: Field Guide to the Detection and Control of Xerophthalmia. Geneva, Switzerland, World Health Organization, 1978. 3. Dohlman, C. H., and Kalevar, V.: Cornea in hypovitaminosis A and protein deficiency. Isr. J. Med. Sci. 8:1179, 1972. 4. Sommer, A., Sugana, T., Edi, D., and Green, W. R.: Vitamin A responsive pan-ocular xerophthal mia in a healthy adult. Arch. Ophthalmol. 96:1630, 1978. 5. Sullivan, W. R., Mc Culley, J. P., and Dohl man, C. H.: Return of goblet cells after vitamin A therapy in xerosis of the conjunctiva. Am. J. Ophthalmol. 75:720, 1973.
N A N I E M R A N , M.D., Bandung,
Xerophthalmia remains a major cause of corneal destruction and blindness in many developing countries. The widely used clinical classification (Table 1) sug gests a sharp distinction between cases with and without corneal disease. 1 But few if any cases of mild xerophthalmia (night blindness, conjunctiva! xerosis, or Bitot's spots) have undergone careful slit-lamp examination; consequently, lit tle is known of the earliest manifestations of corneal involvement. The Indonesian Nutritional Blindness Prevention Project is presently conduc ting detailed clinical examinations on large numbers of xerophthalmic children. Results indicate punctate epithelial keratopathy is the earliest corneal manifes tation of xerophthalmia and is already present in the majority of cases classically considered free of corneal disease. METHODS
Between July and December 1977, 78 consecutive patients with xerophthalmia without corneal ulceration were exam ined at the Cicendo Eye Hospital, Ban dung, with a.handlight and a slit lamp (with and without fluorescein). An addi tional 29 controls of cases of corneal xerophthalmia, matched for age, sex, and From the Nutritional Blindness Prevention Proj ect, Bandung, Indonesia (Drs. Sommer, Emran, and Tamba), and the Wilmer Institute, Johns Hopkins Hospital, Baltimore, Maryland (Dr. Sommer). The Nutritional Blindness Prevention Project is a joint undertaking of the Ministry of Health, Government of Indonesia, and Helen Keller International, New York, N.Y., with substantial funding from the United States Agency for International Develop ment, Washington, D.C. This study was presented at the International Symposium on Cornea Research, Kyoto, Japan, May 13, 1978. Reprint requests to Alfred Sommer, M.D., Wilmer Institute, Johns Hopkins Hospital, 601 N. Broad way, Baltimore, MD 21205. 330
AND T I E N TAMBA,
M.D.
Indonesia TABLE 1 C L A S S I F I C A T I O N O F ACTIVE X E R O P H T H A L M I A
Classification
Description
XN* X1A X1B
Night blindness Conjunctival xerosis Conjunctival xerosis with Bitot's spot Corneal xerosis Corneal xerosis with ulceration Keratomalacia
X2 X3A X3B
*XN is considered a secondary sign.
neighborhood, without night blindness and normal on handlight examination, were similarly studied. Additional ophthalmologic, pediatric, bacteriologic, biochemical, and histopathologic investi gations were performed but are not ger mane to the present discussion. Xerophthalmic patients were enrolled in one of several treatment regimens de pending on the severity of disease. As part of a concurrently running protocol to de termine the proportion of cases of con junctival xerosis and Bitot's spots caused by active vitamin A deficiency, those with clear corneas by handlight examina tion were randomly allocated to receive either low doses (700 IU) or high doses (200,000 IU) of vitamin A orally. Every attempt was made to reexamine all pa tients at frequent intervals, and low-dose recipients received high-dose therapy after three months, or sooner if their con dition deteriorated. Informed consent was obtained from every child's parent or guardian. RESULTS
Obvious corneal involvement on handlight examination was associated with ex-
AMERICAN JOURNAL O F OPHTHALMOLOGY 87:330-333, 1979
VOL. 87, NO. 3
PUNCTATE KERATOPATHY IN XEROPHTHALMIA
331
•ZmVStm*
«£«««•?••/ Svv-v.vK.":
'•as
Figure (Sommer, Emran, and Tamba). Xerophthalmia associated punctate keratopathy has a strong predilection for the inferonasal quadrant, the first area involved and the last to clear.
tensive punctate keratopathy: myriads of densely packed, tiny, brightly staining specks covering the entire corneal sur face. Where the distribution was less uni form, as in cases of milder disease, there was a striking predilection for the inferior half of the cornea, especially the infero nasal quadrant (Figure). For conve nience, we graded the distribution of lesions 1 through 4, representing involve ment of the inferonasal quadrant, inferior half, inferior three fourths, and the entire surface of the cornea, respectively. Inten sity was graded 1 through 3, indicating mild, moderate, and heavy concentrations of lesions. If punctate keratopathy is an early man ifestation of xerophthalmia, the propor tion of individuals affected, and the ex tent and intensity of corneal involvement might be expected to increase with in
creasing evidence and severity of disease (Table 2). Controls—Both eyes of 29 controls of corneal cases matched for age, sex, and locale were normal by handlight exami nation. Only two controls (four eyes) had definite punctate keratopathy (7%), in each instance minimal and limited to the periphery of the inferonasal quadrant. Noncorneal xerophthalmia (XN, X1A, XIB)—All corneas appeared crystal clear by handlight examination, the basis for their clinical classification. 2 Children with a history of night blind ness-unconfirmed by clinical examination were assumed to have the mildest form of xerophthalmia. Of nine cases (18 eyes), 4 eyes (22%) had punctate keratopathy. Among affected corneas, the average dis tribution and density of lesions was 1.0. In five children (ten eyes), clinical ex-
TABLE 2 F L U O R E S C E I N - P O S I T I V E P U N C T A T E KERATOPATHY
Clinical Classification
No. of Eyes
Controls XN: History contributory; examination negative XN: History contributory; examination positive X1A, IB X2
58
Positive,
Average Extent*
Average Density!
7
1.0
1.0
18
22
1.0
1.0
10 63 47
60 75 100
1.3 1.9 3.5
1.7 1.9 2.2
%
*1 signifies inferonasal quadrant; 2, inferior one-half of cornea; 3, inferior three-fourths of cornea; 4, entire corneal surface. t l signifies mild; 2, moderate; 3, heavy.
332
AMERICAN JOURNAL OF OPHTHALMOLOGY
amination confirmed the presence of night blindness. Sixty percent of cases (three) and eyes (six) had punctate kerathopathy, with an average distribution of 1.33 and density of 1.67. Thirty-four children had conjunctival xerosis (X1A, X1B) in at least one eye. Of 63 involved eyes, 75% (47) had punctate keratopathy, with an average distribution and intensity of 1.9. Comeal xerosis (X2)—Corneal xerosis (X2) was the severest lesion in 30 cases. All 47 eyes with corneal xerosis had ex tensive punctate keratopathy, with an av erage distribution of 3.5 and intensity of 2.2. Therapeutic trial—The importance of vitamin A deficiency in the genesis of these lesions is confirmed by their re sponse to therapy. Follow-up examina tions were available on 18 patients (26 eyes) with punctate keratopathy who were treated with a single oral dose of 200,000 IU of vitamin A. The lesions healed in a definite pattern. Improvement began with loss of staining, leaving an early mixture of staining and nonstaining white specks. By the second week, many of the nonstaining specks had become lightly pigmented, and by the fourth week all staining had ceased, leaving residually pigmented epithelial or subepithelial specks, most apparent inferiorly. Superior and temporal aspects of the cornea healed and cleared first, the inferonasal last. Between one and three days after treat ment 40% of involved corneas (four of ten) improved (Table 3). After four to seven days, all showed improvement and 25% (three of 12) were entirely free of punctate staining (cured). The proportion free of staining rose to 80% (eight of ten) at two weeks and 100% at one month. Conversely the course of the disease in ten low-dose recipients (18 involved eyes) with punctate keratopathy was markedly different. By the end of the first month
MARCH, 1979 TABLE 3
P U N C T A T E KERATOPATHY AMONG X1A, X1B PA T I E N T S * : R E S P O N S E T O 200,000 IU VITAMIN A
Duration Total Since Improved, Cured, I m p r c ved or Cured, Treatment % % % 1-3 4-7 2 1
days days wks mo
40 75 20
0 25 80 100
40 100 100 100
* Twenty-six eyes were' available for at least one follow-up examination.
none of the corneas showed improve ment, whereas 6 1 % had actually deterio rated at some time in the interval (four of them alarmingly so). All four were treated with 200,000 IU of vitamin A with subse quent improvement or cure within nine days. Both eyes of one low-dose recipient eventually healed spontaneously, at 65 days. DISCUSSION
Our observations leave little doubt that punctate epithelial keratopathy is an early manifestation of xerophthalmia, and al ready present in most eyes usually con sidered free of corneal involvement. Sixty percent of confirmed cases of night blind ness (XN) and 75% of eyes classified X1A or X1B (conjunctival xerosis) were affect ed. Because only 7% of normal controls were similarly affected, it is unlikely the high prevalence of punctate keratopathy among xerophthalmic children was due to other causes, a supposition confirmed by the therapeutic trial. The positive controls might indeed represent instances of in cipient xerophthalmia. Serum vitamin A levels among locale-matched controls were considerably below random sample norms (unpublished data). Pathogenesis of the lesions and reasons for their predilection for the inferonasal quadrant remain uncertain. Impaired me-
VOL. 87, NO. 3
PUNCTATE KERATOPATHY IN XEROPHTHALMIA
tabolism of the corneal epithelium could be the direct result of vitamin A deficien cy per se, or secondary to instability of the tear film with local drying. But sugges tions that they are the result of loss of conjunctival mucous-producing goblet cells 3 seem unlikely. All corneas im proved within seven days of therapy and 80% ceased to stain by two weeks, long before goblet cells reappear (unpublished data). 4 - 5 Both eyes of one low-dose recipient healed spontaneously at 65 days, proba bly from improved diet or treatment out side the study. Preliminary results of our longitudinal field study indicate almost 50% of children with noncorneal xerophthalmia improved spontaneously over a four-month period (unpublished data). The presently accepted xerophthalmia classification, 1 primarily derived from handlight examinations, is insufficiently precise for research purposes. Nonethe less, it is a useful clinical tool. Medical workers encountering the disease are un likely to have more than a handlight available, and any child suspected of hav ing active xerophthalmia deserves imme diate treatment, whether or not subtle slit-lamp evidence of early corneal in volvement is already present. But field surveys based on handlight examinations will grossly underestimate the prevalence of corneal involvement. SUMMARY
Slit-lamp examination of 78 cases of xerophthalmia and 29 controls matched
333
for age, sex, and locale indicated a direct correlation between the presence, densi ty, and extent of punctate epithelial keratopathy and the severity,of corneal and noncorneal involvement. Only 7% (four of 58) of control eyes but 60% (six of ten) of cases with confirmed night blindness, 75% (47 of 63) of eyes with conjunctival xerosis, and all eyes with corneal xerosis (47) were affected. Within one week of high-dose systemic vitamin A therapy all affected corneas had improved. None of ten patients receiving low-dose systemic therapy showed any improvement over a two-month period, whereas 6 1 % of in volved corneas actually deteriorated in the interim. Punctate epithelial keratopathy appears to be the earliest corneal manifestation of xerophthalmia, and is already present in the vast majority of cases classically con sidered free of corneal involvement. REFERENCES 1. Vitamin A Deficiency and Xerophthalmia. Re port of a Joint WHO/USAID Meeting. Technical Report Series 590. Geneva, Switzerland, World Health Organization, 1976. 2. Sornmer, A.: Field Guide to the Detection and Control of Xerophthalmia. Geneva, Switzerland, World Health Organization, 1978. 3. Dohlman, C. H., and Kalevar, V.: Cornea in hypovitaminosis A and protein deficiency. Isr. J. Med. Sci. 8:1179, 1972. 4. Sommer, A., Sugana, T., Edi, D., and Green, W. R.: Vitamin A responsive pan-ocular xerophthal mia in a healthy adult. Arch. Ophthalmol. 96:1630, 1978. 5. Sullivan, W. R., Mc Culley, J. P., and Dohl man, C. H.: Return of goblet cells after vitamin A therapy in xerosis of the conjunctiva. Am. J. Ophthalmol. 75:720, 1973.
