SURVEY OF OPHTHALMOLOGY
MAJOR
VOLUME 36 - NUMBER 4. JANUARY-FEBRUARY 1992
REVIEW
Climatic Droplet Keratopathy RH. GRAY, M.RC.P., F.RC.S., F.C.OPHTH., AND A. FREEDMAN, F.RC.S., F.C.OPHTH.
G.J. JOHNSON,
M.D., F.RC.S.(C),
F.C.OPHTH.,
Oxford Eye Hospital, Walton Street, Oxford, United Kingdom
Abstract. Climatic droplet keratopathy (CDK) is a degenerative condition characterized by the accumulation of translucent material in the superficial cornea1 stroma within the interpalpebral strip, beginning peripherally and spreading centrally. Progressive accumulation in later life can lead to significant visual disability, and people leading an outdoor life are particularly at risk. The translucent cornea1 deposits are composed of protein, but although they share some of the staining characteristics of degenerated protein, such as that found in pingueculae, their exact histochemical nature remains uncertain. The cornea1 deposits are thought to be derived from plasma proteins, which diffuse into the normal cornea, and may be photochemically degraded by excessive exposure to ultra-violet light (UV). The degraded protein material may then be deposited in the superficial stroma. UV light is now widely accepted to be the main etiological factor in the pathogenesis of CDK. Sector iridectomy, cornea1 epithelial debridement, lamellar keratoplasty, and penetrating keratoplasty have all been employed in the treatment ofvisually incapacitating CDK. (Surv Ophthalmol 36:241-253, 1992)
Key words. climatic droplet keratopathy l cornea1 degeneration l environmental effects l Labraddr keratopathy l spheroid degeneration l ultraviolet light
In 1955, Bietti et al9 described a degenerative cornea1 condition occurring in the male population of the Persian Gulf and Red Sea area. He recognized the similarity of his cases to those in previous reports, and the condition came to bear his name. Bietti was convinced that the cornea1 degeneration was due to an external environmental factor. Ten years later, Freedman described similar findings among the lnuit (Eskimo), Indian, and white settlers living along the coastline of Labrador and northern Newfoundland. He called the condition “Labrador keratopathy. “34 Since that time it has become increasingly apparent that this distinctive degenerative cornea1 condition occurs in many different parts of the world. The degenerative changes are characterized by the accumulation of translucent particles in the superficial cornea within the interpalpebral strip, beginning peripherally and spreading centrally (Fig.
1). Progressive accumulation in later life leads to significant visual disability, and those leading an outdoor life are particularly at risk. Reports have now been made from widely separated geographical areas, and a variety of names have been applied. It is now almost certain that all these descriptions are of the same disease process, which finds its extreme development in the Dahlak Islands of the Red Sea, Somalia, and India. The various names given to this entity, and our choice of the term, “climatic droplet keratopathy,“35 are discussed in Section II.
I.
Historical Aspects
The early references changes similar to CDK literature, and described ation with other ocular The earliest reference 241
to cornea1 degenerative appeared in the German cornea1 deposits in associpathology. may be that of Wedlgo in
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Fig. 1. Painting of the cornea of a Newfoundland sea captain with Grade 3 CDK. (Courtesy of Dr. J.S. Speakman and medical artist, Eila Hopper Ross, AOCA, University of Toronto, Canada).
186 1, whose drawing of a traumatized cornea from an eye suffering panophthalmitis showed globular deposits in the stroma and epithelium. In 1886 Beselin’ described the cornea1 pathology of an eye enucleated for a large staphyloma, and demonstrated globular material with a staining reaction of amyloid. Kamocki” commented on the presence of numerous refractile spheres in the cornea1 scar of a young man, which he called “colloid.” Von Hippels’ added two similar cases in 1895, though he concluded the material was not amyloid, but rather the transformed products of red blood cells. Baquis’ provided a review of colloid degeneration of the cornea in 1898. In the following year Birch-Hirschfeld’O described four cases. He regarded the abnormal material as hyaline rather than colloid, and agreed that its origin was from the blood. Best,’ describing a series of nine patients in 1900, found the deposits to be chemically similar to tyrosine, and regarded albumin as their principal component. Duke-Elder and Leigh” reviewed the subject in 1935, and distinguished primary and secondary cases on clinical grounds. Early reports from the area of the Red Sea (including the Dahlak Islands), Somalia, and the Persian Gulf described the primary degeneration as almost exclusively confined to males. A comprehensive review was provided by Bietti et al9 in 1955, who described both the clinical and histopathological features. The condition has come to be known as “Bietti’s nodular cornea1 dystrophy.” Bietti was convinced that the lesions were due to external agents, and he favored pronounced evaporation due to the dry heat, although he also considered
GRAY
ET AL
wind-borne dust causing microtrauma, and chemical effects consequent upon the common occupation of diving for pearls without wearing face masks. In 1973, Rodger72 visited the Dahlak islands and found this keratopathy to account for 57% of all cases of blindness. He also examined salt-mine workers in Eritrea, and concluded that ultraviolet (UV) light was the principal etiological factor. Freedman reported cases resembling CDK in Kuwait and Iran.32 In 1935, Lugl?’ described cases in Italy that were similar both clinically and histologically to CDK, and he likened the deposits to droplets of oil. He thought they were hyaline in origin. Similar reports followed from Italy and North Africa.2,3s,6’*70,76 In 1964, Etzine and Kaufmann21 described three affected Blacks from the Transvaal, and in 1973 Freedman’* described similar findings in six Bantu. At the same time, Freedman35,36 (unrelated to the present author) described affected females as well as maIes, and postulated that poor nutrition might be an etiological factor. He also described one patient in whom CDK co-existed with xeroderma pigmentosum,” a condition in which the skin is unusually sensitive to UV light. In North Cameroon, Anderson and Fuglsang4 reported that over 50% of the male population had CDK. Similar cornea1 lesions have been documented in the white and aboriginal population of Australia 32,60,82as have cases from India,“g~77 the Seychelles,67 and New Guinea.20 In Labrador and Newfoundland, the first definitive description was provided by Freedman,34 but Faye24 had earlier ( 1962) distinguished the lesions from cornea1 edema, which was the usual diagnosis made in earlier years. Extended clinical descriptions of cases from several parts of the world were given by Freedman in 1973,92 and accompanied by histological findings reported by Garner, Morgan and Tripathi4’ UV radiation for the first time was considered the most likely etiological agent. Gillan4’ positively correlated disease severity with frequency of snow-blindness. Patients with CDK have also been reported from Baffin Island,33 Northern Canada,26,g’ Greenland,63*64 Iceland,” Finland,” and northwestern Russia.28 Reports of this degeneration first appeared from the United States in 1972. Fraunfelder and Hanna30s3’ distinguished not only primary and secondary types, but also a conjunctival form, which did not always coexist with the cornea1 degeneration. Klintworth5’ provided the biggest series in 1972, and he studied the histochemical and electron microscopic findings from corneas of thirtylive affected patients. Three other papers dealt exclusively with histopathological findings.‘2*‘5*73
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CLIMATIC DROPLET KRRATOPATHY TABLE
1
The Varkd Nomenclature of CDK According to race, geography or occupation: I Ciechi delle Isole Dahlac.
La Distrofia corneale dei tropici. Tropical dystrophy. La dystrophie cormWe nodulaire en ceinture des pays tropicaux a sol aride. Fisherman’s keratitis. Labrador keratopathy. Nama keratopathy. La keratite du Labrador. Eskimo keratopathy.
By eponym: Bietti’s nodular dystrophy. Bietti’s nodular cornea1 dystrophy. According to clinical appearance: Degeneratio corneae sphaerularis elaioides. Degeneratio primaria oleoguttata centrale et superficiale. Band shaped nodular dystrophy. Nodular band shaped hyaline keratopathy. Spheroidal degeneration. Gelatinous dystrophy. Droplet keratopathy. Droplet degeneration of the cornea. According to presumed nature of deposits: Die Colloide Degeneration der Cornea. Die Hyaline Degeneration der Cornea. A special type of hyaline degeneration. Degeneratio hyaloidea granuliformis corneae. Keratinoid cornea1 degeneration. Proteinaceous cornea1 degeneration. Elastotic degeneration of cornea. Cornea1 elastosis. According to presumed aetiology:
Chronic actinic keratopathy. Band shaped climatological degeneration. Climatic droplet keratopathy.
II. Nomenclature A profusion of names have been applied to the different manifestations of what is likely to be a single pathological response in the cornea. These have included Bietti’s band-shaped nodular dystrophy, spheroid(a1) degeneration, chronic actinic keratopathy, oil droplet degeneration, elastoid degeneration, keratinoid cornea1 degeneration, hyaline degeneration, Nama keratopathy, and climatic droplet keratopathy (Table 1). These names have been based on race, geography, occupation, clinical appearance, presumed etiology, or presumed nature of the cornea1 deposits. Eponyms have also been used. Objections can and have been raised to most of them, and the appropriate nomenclature is controversial. Klintworth (1972) suggested the term “chronic actinic keratopathy,” and this does have
Zanettin. Falcone C. Falcone G. Bietti. Prasadrao. Freedman A. Freedman J . Tremblay. English.
19379s 19542s 195422 1956g
Etzine. Freedman J .
19642’ 197332
Lugli. Alajmo. Etzine. Duke Elder. Fraunfelder. Freedman J. Garner. Anderson.
19355s 1953s 19642’ 196518
Baquis. Sachsalber. Parsons. Kozlowski. Garner. Christensen. Brownstein. Rodrigues.
1 8986
Klintworth. Forsius. Freedman A.
197252 197228 197332
1961fig 196534 19733s 197486 197520
;;;;:: 19763g 19764
1901’5 1904% 195355 19704’ 1973’3 ;;;;::
the merit of scientific accuracy. However, it has not gained widespread popularity. In 1973 Freedman proposed the term “climatic droplet ketatopathy” (CDK),35 and this has gained some measure of international acceptance. 19B,%4Ys'Oa,7',8MSuv light is now widely accepted as the main etiological factor, but there is still considerable uncertainty regarding the precise nature of the proteinaceous cornea1 deposits. The term CDK, therefore, seems reasonable since it emphasizes the major importance of external environmental factors. Although UV light is not part of the climate in the strictest sense, the term “climatic” recognizes the possible synergistic effect of wind velocity and wind-blown particles. It is also the case that the geographical regions where reflected UV light is intense are also those where extreme climatic conditions apply. It is appreciated that the word “droplet” is purely descriptive, and may imply fluid filled spaces where none are found,
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GRAY ET AL
Fig. 2. Left: Early CDK is present in the peripheral cornea, but hard to see at this magnification (X 10). Right: It is best seen at higher magnification ( x 16) by iris retroillumination. (Courtesy of Mr. N. Phelps Brown).
but better alternatives await definitive pathological descriptions. We feel that adopting uniform nomenclature may help to increase understanding and awareness of the basic similarities of the primary condition throughout the world.
III. Classification In 1970, Garner41 drew attention to the histopathological similarities of cornea1 deposits in CDK and those found in a wide variety of ocular diseases featuring cornea1 damage, such as lattice cornea1 dystrophy and perforating injury. He divided the degeneration into primary and secondary because of these histopathological similarities. Fraunfelder and Hanna” introduced the term “spheroid degeneration” in 1973, and divided patients into three clinical categories. In type 1, the cornea1 deposits occurred bilaterally with increasing age and without evidence of previous ocular disease. In type 2, cornea1 deposits were associated with significant preexisting ocular pathology. In type 3, conjunctival deposits were prominent, with or without cornea1 involvement. Taylor’” recommended using the term “spheroidal droplet degeneration” only for secondary deposition, and included in this category elderly patients without excessive UV exposure or previous cornea1 pathology, and with minimal cornea1 deposition. He felt this category to be etiologically distinct from (primary) CDK.
IV. Clinical Findings A. PBIMABY
CDK
Patients with primary CDK have bilateral involvement, with translucent or golden yellow de-
posits interpalpebrally, and without evidence of other cornea1 pathology. In their earliest stages, these deposits may be difficult to see, and are best detected by iris retroillumination (Fig. 2). The deposits can also be seen to autofluoresce in UV light. As the condition advances, deposits extend across the visual axis, and vision may be reduced (Fig. 3). Eventually, large deposits elevate the cornea1 epithelium and can spontaneously flake off. They may appear reddish brown (Fig. 4). Freedman introduced a three-tier grading system in 1965 (Table 2), based on the distribution and severity of the globular deposits and their visual consequences. Johnson suggested a modified grading system in 197548 (Table 3). Cornea1 sensation is unaffected in the early stages, but some patients with Grade 3 or 4 disease tested by Johnson with an anaesthesiometer showed moderate reduction in sensitivity. Freedman34 reported a reduction in stromal thickness in some patients with Grade 3 disease, but this has not been a consistent finding. B. SECONDARY
CDK
The cornea1 findings reflect those of the responsi-
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CLIMATIC DROPLET KERATOPATHY
Fig. 3. CDK deposits have extended
across the pupil,
affecting visual acuity.
Fig. 4. In advanced CDK, the deposits can form nodules, which elevate the cornea1 epithelium, and can spontaneously flake off.
ble pathology. Golden yellow deposits may surround areas of cornea1 vascularization, but are separated from the vessels by a narrow clear zone. The deposits accumulate in the superficial cornea1 stroma. They do not generally assume a bandshaped configuration, and the findings are usually unilateral (Fig. 5). C. CONJUNCTIVAL
FORM
As proposed by Fraunfelder,31 this category of patients includes those in whom conjunctival deposits are more pronounced than those of the cornea, which may be normal. The deposits may be seen nasally and temporally in the interpalpebral area, and may be associated with pingueculae. The deposits may be seen either on the surface of or within the pinguecula itself. Norn63 found that 75% of affected Inuit in south west Greenland had conjunctival involvement alone.
V. Pathological Globular “hyaline-like” perficial cornea1 stroma
Findings
deposits within the suwere demonstrated by
TABLE
Fig. 5. Secondary CDK. The vascularization of the cornea in the region of the deposits distinguish it from primary CDK. (Courtesy of Mr. J.D.C. Anderson).
Wedlgo as long ago as 186 1, yet their histochemical nature is still uncertain. Parsons@j concluded in 1904 that the material resulted from a special form of hyaline degeneration, being formed extracellularly and subsequently invading the cornea1 epithe-
2
Freedman’s Clinical Grading System Grade 1: The keratopathy begins as a grey haze immediately beneath the epithelium. Its distribution is interpalpebral, and it fades towards the central cornea. A narrow clear zone usually demarcates it from the limbus, and this peripheral zone may have an irregular border, described as a “rugged coastline” appearance. At this early stage the deposits are best seen by iris retroillumination. The appearance has been likened to that of moisture condensing on glass. Grade 2: Globular deposits extend into the interpupillary area, and vision is reduced to 6/24 or better. Globule size becomes more variable, and the peripheral clear zone may be filled in with smaller deposits. Also commonly seen at this stage are large golden deposits subconjunctivally, and these overlie a pinguecula if present. Grade 3: Vision reduced to 6/36 or worse. By this stage, clear areas may be found within affected cornea, suggesting a flaking of involved cornea1 epithelium and Bowman’s layer. The epithelium nevertheless remains normal until the condition is very severe, when orange or brownish nodules can form, which elevate the epithelium. Iris and lens detail become urocrressivelv obscured bv the denosition.
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Surv 0phthalmo136 TABLE
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GRAY ET AL
3
Johnson’s Modified Grading System
Trace: Deposits seen in very small numbers. One eye only affected, or only one end of interpalpebral strip in each eye if bilateral.
Grade 1: Involvement of medial and lateral interpalpebra1 strips, with sparing of central cornea. Grade 2: Central cornea affected, but not enough to affect visual acuity. Grade 3: Central cornea affected, and vision reduced. Grade 4: Elevated nodules present in addition to findings of Grade 3.
lium. Duke-Elder and Leigh” proposed in 1965 that the globules were produced by aggregation of smaller deposits, and they noted the relationship of climatic conditions to a primary bilateral form. A. LIGHT MICROSCOPIC HISTOCHEMISTRY
Fig. 6. Grade 1 CDK, peripheral cornea. Numerous deposits are demonstrated at the level of Bowmans layer, and in the superficial stroma. (Hematoxylin and Eosin, X 160) (Reprinted from Johnson GJ, Overall M4’ with permission of the Editor, BritishJournal of Ophthalmology).
FEATURES AND
Hematoxylin-eosin stained sections of the cornea show homogenous globular deposits of variable size located in the superficial cornea1 stroma, Bowman’s layer, and subepithelial space (Fig. 6). The deposits disrupt Bowman’s membrane, and, when advanced, can elevate and thin the cornea1 epitheliurn. Other histochemical stains taken up by the deposits include Toluidine blue and basic fuchsin, and this is not altered by prior treatment with fat solvents such as acetone. The deposits also stain positively (red) with Martius-Scarlet-Blue (MSB) (Fig. 7). Red staining with MSB is frequently taken to imply the presence of fibrin, and although it is clear that CDK deposits are not themselves composed simply of fibrin, positive MSB staining may indicate the presence of similar material. CDK deposits stain weakly or negatively with eosin, PASAlcian blue, congo red, or Sudan black B. The histochemical staining characteristics are similar to those of degenerate connective tissue, such as is found in pingueculae, and the terms “elastosis” and “elastotic degeneration” have been used by some authors to draw attention to this similarity. 14V73 Nevertheless, Garner et al” found that the deposits fail to stain with orcein or aldehyde fuchsin, in contrast to elastotic material from pingueculae. There is general agreement that the deposits contain protein rich in tryptophan, tyrosine, cystine, and cysteine. Tabbara*’ has analyzed two specimens of cornea1 deposits using sodium dodecyl sulfatepolyacrylamide gel electrophoresis. He found them to be largely protein, with molecular weights rang-
Fig. 7. Grade 3 CDK, central cornea. The deposits stain with Martius Scarlet Blue, indicating the presence of material similar to fibrin. (Martius Scarlet Blue, x 160).
from 20,000 to 300,000 Daltons. However, CDK deposits are extremely insoluble and, therefore, difficult to isolate, and it is possible that the protein analyzed was not from these deposits alone. Klintworth53 has pointed out that the amino acids of which the deposits are at least partly composed (tryptophan, tyrosine, arginine) are not detectable in similar quantities in normal type 1 cornea1 collagen. He emphasized the association of CDK and pingueculae, and postulated that degenerate elastotic subconjunctival material diffused into the cornea to form the deposits. The clinical observation that deposits are largest in the peripheral cornea supports the concept of limbal diffusion. In his studies in Labrador,45 Johnson found eight patients with CDK and lattice cornea1 dystrophy, but histochemical stains showed little similarity of ing
.
CLIMATIC DROPLET KERATOPATIIY the CDK deposits with amyloid. While CDK deposits have some of the staining characteristics of fibrin,56 they cannot consist entirely of this material because of their consistent autofluorescence. Also, MSB staining of CDK deposits demarcates them clearly from adjacent cornea1 collagen, and this would not be expected if the deposits were derived from breakdown of the collagen. The term “fibrinoid” has been used to describe material derived from collagen in a rheumatic nodule.49 CDK droplets are unlikely to be of this nature because of their high content of tryptophan. However, Lendrum% has pointed out that fibrinogen escaping from the lumen of an artery and precipitated intramurally as fibrin forms a spongework or filter, which traps other substances leaking from the vessel wall. CDK deposits do not stain consistently for fibrin, and this so-called “vascular fibrinoid” might account for some of the staining differences. B. ELECTRON
MICROSCOPIC
Fig. 8. Grade 3 CDK, central cornea. Numerous well circumscribed deposits are present within and beneath Bowman’s layer. Their size is variable. (Transmission electron micrograph, x 7000).
FINDINGS
Klintworth ( 1972)52 was the first to study the electron microscopic (EM) characteristics of the CDK deposits in 35 corneas from patients in USA. Round, electron dense, featureless material was consistently demonstrated in Bowman’s layer and superficial stroma. D’Alena and Wood (1972)16 studied a lamellar keratoplasty specimen of a 79-year-old Mexican laborer with CDK. The electron microwere similar to those of graph appearances Klintworth. Brownstein et al (1973)” reported EM findings on five secondary cases of CDK. The droplet appearances were similar, but although they were distributed mostly in the superficial stroma, they were also found in the cornea1 epithelium itself. Tremblay and Dube ( 1974)84 described similar EM findings on three corneas from Inuit hunters on the shores of the Hudson Bay. Johnson and Ghosh ( 1975)48 studied CDK deposits from patients in Labrador and again found them to be similar (Fig. 8). Sometimes the basal epithelial cells were indented, but the deposits were always surrounded by basement membrane material (Fig. 9). Their size was variable, but the edges were always smooth and clearcut. Collagen fibrils adjacent to the deposits were disorganized. All droplets were extracellular, and no evidence of secretory activity was seen in epithelial or stromal cells.
VI. Source of Abnormal
Material
Klintworth5’ studied the electron microscopic characteristics of “chronic actinic keratopathy.” He found the deposits to be electron-dense and extracellular, and saw no evidence of epithelial or stroma1 cell secretory activity. He felt that the material was derived from pericorneal connective tissue,
Fig. 9. Grade 3 CDK. Deposits may appear intraepithelial, but are always surrounded by thickened basement membrane. (Transmission electron micrograph, x 10,000).
and emphasized the histochemical similarities between CDK deposits and those of conjunctival elastosis. Hanna and Fraunfelder,3’V44 on the other hand, suggested that the deposits were derived from secretory activity in abnormal cornea1 or conjunctival fibrocytic cells. Their EM material showed the smaller cornea1 deposits to be surrounded by granular material, suggesting the deposits were derived from the granular material. In turn, the larger deposits were often found to be surrounded by smaller ones, suggesting that they had been formed by aggregation of the latter. It has been observed that the margins of deeper deposits appear less well defined than those in the superficial stroma, and this has been taken as evidence of their stromal origin. Johnson suggested, however, that this ap-
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1992
pearance may simply be due to looser packing of cornea1 collagen in the deeper part of the stroma. Cursino and Fine” have been alone in suggesting that the deposits develop by degeneration of corneal collagen. The EM findings outlined above, particularly the smooth margins of the deposits and apparently normal adjacent cornea1 collagen, argue against this as the source of the deposits. Furthermore, stains such as MSB or Mallory’s PTAH show a sharp demarcation between deposits and stroma, which would not be expected if they were derived from stromal degeneration. Garner studied five cases of secondary CDK,41 and favored an epithelial origin for the deposits because of their proximity to a disordered cornea1 epithelium, their amino acid content, and positive performic acid-Schiff staining characteristics. However, this proposition has not been supported by EM findings. Johnson has studied in detail the possibility of deposits being formed by plasma protein diffusion into the cornea.45,50 Both albumin5g and immunoglobulins’ are present in the normal cornea, and radiolabelling experiments” have shown the latter to move across the center of the cornea. Using immunoperoxidase and immunolluorescent markers, Johnson45 found that albumin, fibrinogen, and immunoglobulin G and A are present in maximum concentration around the deposits of affected corneas. Although the deposits themselves do not take up the markers, they are surrounded by positively reacting protein. He suggested that the plasma proteins diffusing through the cornea may be acted upon by an external agent and become precipitated in the stroma at the level of Bowman’s layer. Some of the apparently contradictory staining properties of the deposits might be explicable on the basis of their diverse biochemistry. The presence of “secondary” deposits in corneas of eyes affected by other diseases may similarly reflect altered plasma protein diffusion into the cornea.
VII. Prevalence Johnson45 found the overall prevalence to be 60.1% for males and 13.5% for females in the population of Labrador over 40 years old. These figures are closely in accord with those of Young and Finlay. ‘* Norn’j3 found an ove r a 11p revalence of 12.5% in the Inuit population of southwest Greenland, and 4.1% for Danes in Copenhagen. Anderson and Fuglsang’s figures4 from North Cameroon showed the overall prevalence for both sexes aged 40 to 49 years was 40.3%, rising to 60.6% for those over 50. A countrywide survey in the Republic of Djibouti has recently found the overall prevalence for both sexes (of all ages) to be 2.8% for the rural population, and
GRAY ET AL 0.5% for urban dwellers.“” Johnson4’ has recently estimated CDK to be the third most common cause of blindness in Somalia, after cataract and glaucoma. In Australia, Taylora found the prevalence to be 41% in male aborigines over the age of 45, while only 8% of females were affected. In Arkansas, USA, Fraunfelder and Hanna3’ found the prevalence of histologically detectable CDK (cornea1 or conjunctival) to be over 40% for males. Taylor et als5 studied 838 male watermen over the age of 30 years from Chesapeake Bay in Maryland (USA), and found the prevalence of CDK was 19%. In contrast, Garner et a13’ found a prevalence of 6% in England, including all conjunctival cases. When only cornea1 cases were included, the prevalence fell to approximately 1%. Cornea1 lesions indistinguishable from CDK have been described in people as young as 16 years of age.’
VIII. Differential Diagnosis The diagnosis can be made with confidence when characteristic yellow globules in the superficial cornea of both eyes occur in an aging male patient who has worked outdoors most of his life in an area of high UV exposure. Earlier this century a frequent diagnosis for patients in Labrador manifesting stage 1 CDK was early (epithelial) cornea1 edema. This can now easily be distinguished from CDK by slit-lamp biomicroscopy. Band keratopathy65 occurs in a similar age group, but the cornea1 haze is diffuse and whiter, due to calcium deposition. Scattered lacunae of clear cornea, and absence of limbal sparing also serve to distinguish it clinically from CDK. The latter is also distinguished histopathologically by absence of calcium. Salzmann’s nodular degenerationa occurs secondary to cornea1 inflammation, especially trachoma and phlyctenular keratitis. It is characterized by discrete, elevated grey or blue-grey superficial stromal opacities, which form nodules and elevate the corneal epithelium. The size and distribution of the nodules, as well as evidence of previous cornea1 pathology, distinguish them from primary CDK. However, in some cases the EM findings have been strikingly similar to those of CDK,88 and it is possible that Salzmann’s nodular degeneration and secondary CDK share common etiological factors. Vogt’s limbal girdle (type 2),‘s is a frequent finding in older patients, and, like CDK, it involves the interpalpebral cornea. However, it has a chalky white appearance, may merge with the limbus without an intervening clear zone, and does not spread centrally. These features all distinguish it from the early changes of CDK.
CLIMATIC DROPLET RERATOPATIIY In primary lipoidal degeneration of the cornea,‘5 glistening refractile bodies are seen predominantly in the posterior stroma, and their distribution is not interpalpebral. A prominent arcus senilis may be present and, if so, the refractile cornea1 deposits may merge with it.
IX. Etiological
Factors
From his early observations in Labrador, Freedman emphasized that only those whose working lives were spent outdoors were affected. Furthermore, the degree of severity correlated closely with the length of time spent outside. Women were affected to a significant degree only if they too had adopted an outdoor working life. Johnson” found that CDK existed asymetrically only when strabismus, ptosis, or prolonged voluntary eye closure were present in the less affected eye. Furthermore, the restriction of the lesions to the exposed interpalpebral area of cornea argues strongly in favor of an environmental factor. Finally, neither in Freedman’s study34 nor in subsequent observations from the Labrador region has there been any evidence for a racial or genetic predisposition to the condition. A variety of factors have been suggested in the etiology of CDK, and these will be considered below. A. AGE AND SEX The association between CDK and increasing age is clear. Also, males are more severely affected than females, particularly those whose working lives are Bietti com_ spent outdoors. 4,9,22,26,27,28,31,39,42,77.91,92 mented particularly on the protection from exposure afforded to women in Muslim countries. Three publications from the Dahlak islands,72 southwest Greenland@ and southwest Africa35 have failed to show any sex difference, but it is likely that the women in these series had climatic exposure similar to that of males. B. NUTRITION Nutritional status has steadily improved in recent years in Labrador, but in the past, deficiency diseases such as beri-beri and vitamin A deficiency were a common problem. The geographic variation of nutritional deficiencies that had been documented in the past did not correspond to the distribution of CDK as studied by Johnson,” and furthermore, young men who have grown up in improved nutritional circumstances have been affected. Freedman35*36 suggested a nutritional component in the etiology of CDK, based on his study of the Nama people of south-west Africa. He found severe disease to correlate with malnutrition, and found
249 females to be affected as commonly as males. He did not however comment on the lifestyle of involved females. C. LOW HUMIDITY When low humidity has been proposed as the agent responsible for the cornea1 degeneration, it has been implied that the mechanism of action is by rapid evaporation of the tear film and dessication of the cornea, possibly with concentration of the tear salts. However, it is the relative humidity which determines the rate of evaporation from a surface such as the cornea, and although in Labrador the total water content of the air in winter is low, it is, in fact, well saturated (70-80%). It is only indoors, when the air temperature rises by many degrees, that relative humidity drops to low levels. Similarly, in the Dahlak islands, the relative humidity is high despite the heat and strong winds. Tear film abnormalities in CDK patients are not usually seen,83 and trappers and hunters in Labrador report that tear secretion becomes copious when outdoors in the cold. A dessication keratitis has been described5 in Eighth Army personnel fighting in the western desert of North Africa in 1942. The temporary central cornea1 disturbance bears no relation to CDK. Furthermore, the sicca syndromes are not associated with cornea1 lesions similar to CDK, as might be expected if cornea1 drying was a major etiological factor. D. LOW TEMPERATURE It had seemed unlikely that low temperature was a factor in the etiology of CDK once similar lesions were described in temperate and tropical climates, and, in fact, Bietti and Gandolfi suggested that high temperatures might be important. Kohlstad and Opsah154 detected transient cornea1 epithelial damage among cross-country skiiers: the lesions described were not similar to those seen in CDK. Liddy5’ reported a trial of soft contact lens wear in members of the Canadian armed forces on winter exercises in the Arctic. The lenses remained comfortable, pliant, and well lubricated throughout, implying that the unprotected cornea is not at risk from damage by severe cold. The incidence of CDK falls in the very northernmost parts of Labrador, further indicating that low temperatures are not a significant etiological factor. E. MICROTRAUMA The acute effects of windborne ice particles on the cornea have been described by Forsius et a1.26 Epithelial erosions, stainable with fluorescein, were seen in people who had been driving snowmobiles in temperatures of - 30 to - 40 degrees centigrade.
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1992
The erosions healed within 24 hours, leaving no permanent changes. As noted previously, cornea1 epithelial changes are conspicuously absent in CDK. Furthermore, CDK can develop in an environment free of significant airborne particulate matter, such as snow or dust. These areas in which CDK have been reported include South Africa, southeastern USA, and England. Johnson studied Canadian meteorology charts for average wind speeds over Labrador, and found the highest prevalence of CDK (latitude 55 degrees) occurred in an area of relatively low wind speeds. This may be explicable if it is assumed that lower average wind speeds allow greater time to be spent outdoors. Snowstorms are most frequent in northern Labrador; yet, as already noted, the prevalence of CDK falls in these regions. F. ULTRAVIOLET
RADIATION
The sensitivity of biological tissues to UV radiation (190400 nm) depends on several factors such as wavelength, exposure time, and specific properties of the tissue. In general, the shorter wavelengths produce the most acute damage, and wavelengths below 290 nm are known to cause acute and dramatic effects on the skin6’ and cornea.14 (These wavelengths are produced artificially because the atmosphere absorbs UV light below approximately 290 nm). Pathologic effects have been documented through the full thickness of rabbit corneas after acute experimental exposure to UV light.” However, in contrast to acute UV damage, chronic exposure and damage has not been so well recognized. The human cornea absorbs all UV light below a wavelength of approximately 295 nm, and the peak sensitivity of absorption occurs at 288 nanometers. Along with skin, the cornea is directly exposed to UV radiation, and, indeed, Klintworth5’ has demonstrated an association of CDK and basal cell carcinomas, the latter known to be related to excessive UV exposure. It is also almost certainly significant that the acute UV damage of snow blindness is reported more commonly by people in Labrador with CDK. In a series of elegant experiments using dummy heads (or mannikins), Urbach” showed that the eyes are well protected from overhead UV light by the supraorbital ridges, and only received a high dose of UV when the light from above was reflected from ground cover such as snow or sand. A shade such as a peaked cap has been shown to reduce ocular UV exposure in some circumstances by up to 50%.74 However, exposure measurements were made for fishermen, landscape workers and construction workers only, and it is likely that the de-
GRAY ET AL gree of protection afforded by brimmed hats is considerably less in the presence of snow or sand. The severity of CDK tends to diminish north of Labrador, and by studying large numbers of patients,5”‘Johnson was able to define the peak of prevalence‘occurring between 55 and 56 degrees latitude. He then calculated the total reflected UV flux throughout Labrador, and found it to reach a peak almost exactly in the same latitude, establishing a link between UV and disease severity. The increasing obliquity of the sun’s rays in the northern parts of Labrador (and even more in the Arctic) causes more of the UV to be filtered out by the ozone layer. This may explain why the prevalence of CDK falls in the north of Labrador despite increasing snow cover. Klintworth’” has pointed out the opportunities for excessive UV radiation that exist in all areas where a high prevalence of CDK has been reported. Direct correlation with UV levels, however, has been made in only three areas other than Eastern Canada. In the Dahlak islands, Rodgers” measured the total integrated short UV radiation with UV sensors, including in his measurements the UV reflected from the white coral sand. He documented a three- to eightfold increase in UV levels compared to those in England. Of 838 watermen from the Chesapeake Bay area in Maryland, USA, Taylor et aIs5 found evidence of CDK in 162 (19%). By combining field and laboratory derived data and published ambient UV-B data with personal exposure histories, he found a significant association between CDK and broadband UV exposure (290-400 nm). In Australia, however, Taylora’ studied UV maps over the country, but could not confirm a correlation with the varying prevalence of CDK in that country. Indirect evidence for the importance of UV comes from a fascinating report” of “band-shaped nodular dystrophy” occurring in an African family with xeroderma pigmentosum (XP). In XP patients, the normal DNA repair mechanisms to UV damage are missing, and they develop multiple skin cancers at an early age. The nodular cornea1 dystrophy described was present in members of the family as young as eight years, and in one patient with unilateral ptosis the covered cornea was not affected. Histology in one case showed multiple hyaline deposits in the superficial cornea1 stroma. The immediate effects of UV light on organic molecules are at least partly understood, and its clinical effects on tissues such as the skin and corneal epithelium are well recognized. Studying the isolated human crystalline lens, Pirie”’ has shown that the amino acids tryptophan, tyrosine, methionine, cysteine, and histidine are the most sensitive to pho-
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CLIMATIC DROPLET KERATOPATHY totoxic damage. It is interesting that recent work by Johnson et a14’ has demonstrated a significant association between CDK and anterior lens capsular changes within the pupillary area, while Resnikoff et alfoa have indicated an association between CDK, cataract, and the exfoliation syndrome. The aging cornea absorbs more light in both the UV and visible spectrum, ” the increased UV absorption resulting from the build-up of fluorescent chromophores derived from the photochemical degradation of tryptophan. CDK deposits fluoresce strongly in UV light, suggesting that they are photochemically active. The explanation of the characteristic clear zone at the limbus is not immediately apparent if UV light is acting on plasma proteins derived from the limbal circulation. However, it is possible that at this site the rate of diffusion is too rapid for the proteins to be altered and precipitated. Additionally, altered protein may be reabsorbed into the limbal circulation before the stage of precipitation. Freedmans felt that the clear zone demarcated the peripheral termination of Bowmans layer, but EM has shown deposits to occur beyond, and independently of, Bowmans layer. It is interesting to speculate that Iimbal hyperemia due to acute snow blindness might allow increased protein access to the cornea, accelerating the rate of formation of CDK deposits. Cornea1 micro-trauma may also cause limbal hyperemia, and could in this way contribute to the development of CDK in some parts of the world.
X. Treatment and Prognosis If UV light is the major etiological factor, then longterm protection from it is likely to be effective. Dahan et al” have documented regression of CDK following cataract surgery on 17 patients in South Africa. They felt that the aphakic state caused photophobia, and consequent avoidance of bright light protected the cornea from further damage. No comment was made on the correction of the aphakia, and it is possible that if aphakic glasses were being worn these would filter out at least some UV light. As previously discussed, the reflection of UV light from surfaces such as sand or ice make preventive measures like hats or peaked caps only partially effective. UV filtering glasses are logical; the practical difficulties of wearing them in the arctic climate have been stressed by Johnson. In fact, the Inuit have long used goggles made of caribou antler (ikka), with narrow slits carved in them, to avoid snow blindness. TO the best of our knowledge there are no re-
Fig. 10. Grade 4 CDK. This patient from Somalia has undergone cataract extraction, and a broad iridectomy has also been carried out for visual benefit. (Courtesy of Dr. S. Franken).
ports specifically addressing the question of treatment and its results. CDK deposits may spontaneously flake off when they are advanced, and scraping of the cornea1 epithelium has been used as a temporary measure to improve vision. Superficial keratectomy without grafting has also been performed successfully (Leith A, personal communication). For longer term improvement, lamellar or penetrating keratoplasty remain the accepted surgical procedures for visually incapacitating CDK. However, cataract is usually present in severe cases, and it is often difficult to estimate the relative contributions of cornea and lens to the visual deficit. Finally, cataract surgery can be combined with sector iridectomy (Fig. 10) if cornea1 surgery is felt to be inappropriate (Franken S, personal communication).
XI. Conclusion Climatic droplet keratopathy is a distinctive corneal degenerative condition occurring world-wide and with specific clinical features. These characteristic features can be recognized in many reports from around the world over many years, although a variety of different names have been introduced. The features in common include the deposition of droplets in the interpalpebral region of the superficial cornea1 stroma, increasing deposition with age, male preponderance, and greater prevalence in areas of higher UV levels. The exact protein nature of the cornea1 deposits remains unknown, but it is likely that they represent photochemically degraded protein material. The circumstantial evidence for UV radiation as the major etiological factor is overwhelming. While it is possible that the cornea itself may be the source of the protein depos-
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Surv Ophthalmol36
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1992
its, we believe the evidence indicates that the mate-
rial is derived from plasma proteins, which diffuse into the cornea from the limbal vascular arcades. As concern over damage to the ozone layer increases, the destructive effects of chronic excessive LJV exposure on the skin have been emphasized. We feel that the vulnerability of the cornea also requires emphasis. Acknowledgements We are most grateful to Dr. J.S. Speakman and Mrs.
Eileen Hopper Ross for permission to reproduce the anterior segment painting (Fig. l), and to Dr. S. Franken for permission to reproduce Fig. 10. We also thank the Editor of the British Journal of Ophthalmology for allowing us to reproduce Fig. 6, and Mr. Nicholas Phelps Brown for his expert help in photographing the early stages of CDK (Fig. 2).
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Outline I. Historical aspects II. Nomenclature III. Classification IV. Clinical findings A. Primary CDK B. Secondary CDK C. Conjunctival form V. Pathological findings A. Light microscopic features and histochemistry B. Electron microscopic findings VI. Source of abnormal material VII. Prevalence VIII. Differential diagnosis IX. Etiological factors A. Age and sex B. Nutrition C. Low humidity D. Low temperature E. Microtrauma F. Ultraviolet radiation X. Treatment and prognosis XI. Conclusion
Reprint address: Mr. R.H. Gray, Oxford Eye Hospital, Walton St, Oxford, OX2 6AN.