U N U S U A L S U P E R F I C I A L V A R I A N T O F G R A N U L A R

D Y S T R O P H Y O F T H E C O R N E A

R A J A H A D D A D , M . D . , R A M O N L . F O N T , M . D . ,

AND B E N S . F I N E , M . D .

Washington, D.C.

Granular dystrophy of the cornea

(Groenouw type I ) 1 is a dominantly inher-

ited condition that usually becomes man-

ifest in the first decade of life or around

puberty. The characteristic clinical pic-

ture is generally that of bilateral discrete,

grayish-white opacities that involve the

superficial stromal layers in the axial re-

gion of the cornea. 2 The lesions tend to

aggregate, enlarge, and increase in num-

ber, leading to destruction of Bowman's

membrane (with resulting epithelial ele-

vation and secondary changes), as well as

spreading both pejcipheiaily and more

deeply. 3 After the third or fourth decade,

a central disk-shaped area of opacities is

formed, and a 2- to 3-mm clear zone

around the corneoscleral limbus remains

characteristically present . 2 , 4 ' 5

Patients with granular dystrophy of the

cornea experience only gradual decrease

in their visual acuity and may maintain

useful vision for a long t ime . 2 , 6 We report

two cases of granular dystrophy of the

cornea that have unusual clinical presen-

tations and histopathologic appearances.

From the Registry of Ophthalmic Pathology, Armed Forces Institute of Pathology, Washington, D.C. This study was supported in part by a research grant from the Max Kade Foundation, Inc., New York, New York, and in part by training grant EY-00032 and research grant EY-00133 from the National Eye Institute, National Institutes of Health.

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of De-fense.

Reprint requests to Ramon L. Font, M.D., Oph-thalmic Pathology Division, Armed Forces Institute of Pathology, Washington, DC 20306.

C A S E R E P O R T S

Case 1—A 7-year-old boy was first seen by an ophthalmologist at the age of 6 years because of reduced vision and irritation in both eyes. His vision at that time was 6/9 (20/30) in each eye. On examina-tion, bilateral corneal opacities were observed and described as "coalescence of macular lesions in the anterior one fifth of the cornea, chiefly in Bowman's area." The corneal periphery was clear. Family history was noncontributory. Findings from oph-thalmologic examinations of the patient's parents and two brothers were normal.

Within the following nine months, visual acuity decreased to 6/30 (20/100) in both eyes. A diagnosis of superficial corneal dystrophy, not further classi-fied, was made. Subsequently, a penetrating corneal graft was performed on the right eye, followed by improvement of acuity to 6/12 (20/40). We evaluated the corneal button, fixed in 10% buffered formalin.

Sections from the paraffin-embedded tissue were stained with hematoxylin and eosin, PAS, Masson's trichrome, Congo red, Alcian blue, colloidal iron, and Wilder's reticulin stains. Congo red stains were examined for birefringence and dichroism with po-larized light.

HISTOPATHOLOGIC FINDINGS—In routine hema-toxylin and eosin-stained sections, the epithelium was irregularly thick, with focal areas of separation from the underlying stroma and irregularities of the basement membrane. The main pathologic finding, however, was the presence of eosinophilic, sheetlike deposits located immediately beneath the epitheli-um and completely replacing Bowman's membrane and the subjacent superficial corneal lamellae (Fig. 1, A). On higher magnification the deposits that had appeared amorphous displayed a slight granularity (Fig. 1, B). The remainder of the stroma, Descemet's membrane, and the endothelium were unremark-able. The abnormal areas stained red with Masson's trichrome (Fig. 1, C) and showed argyrophilia with Wilder's reticulin stain but stained negatively with PAS, Alcian blue, colloidal iron, and Congo red stains. They also showed less birefringence when compared with that of the normal stroma. An initial histopathologic diagnosis of Reis-Bücklers dystro-phy was made.

ELECTRON MICROSCOPIC FINDINGS—Electron microscopic studies performed on formalin-fixed, paraffin-embedded tissue disclosed the characteris-tic electron-dense, rod-shaped, crystalline structures of granular dystrophy (Fig. 2) described by various authors. 7 - 9 We did not observe granules with "aper-tures" 1 0 or spongy appearance11 in our sampling.

213

214 AMERICAN JOURNAL OF OPHTHALMOLOGY FEBRUARY, 1977

Fig. 1 (Haddad, Font, and Fine). Case 1. A, Superficial location of lesions of granular dystrophy con-fined only to the plane of Bowman's membrane and subjacent corneal stroma (hematoxylin and eosin, x60). B, Higher magnification showing the granular composition of lesions (hematoxylin and eosin, x305). C, Same specimen (Mas-son's trichrome method, x305).

Fig. 2 (Haddad, Font, and Fine). Case 1. Densely homogeneous rod-shaped structures characteristic of granular dystrophy as seen by transmission electron microscopy (x36,000).

Case 2—An 18-year-old woman had "corneal dys-trophy" in both eyes for several years. She had many episodes of irritation, as well as progressive de-creased acuity in both eyes. According to her oph-thalmologist, no other member of her family was known to have any history of corneal disease.

The patient underwent a corneal transplantation in the left eye and visual acuity improved to 6/7.5 (20/25). No histopathologic examination of the kera-tectomy specimen was undertaken. When seen by her ophthalmologist less than one year later, her right eye had visual acuity of 6/24 (20/80), numerous

VOL. 83, NO. 2 GRANULAR DYSTROPHY OF THE CORNEA 215

opacities involved the superficial corneal stroma and subepithelial layers, and a clear area was present peripherally. A penetrating corneal graft procedure was performed on this eye one year after that on the left eye, and the paraffin-embedded tissue was sent' here for consultation. The clinical diagnosis at the time of surgery was "superficial corneal dystrophy, type undetermined." Sections and special stains were prepared as in Case 1.

HISTOPATHOLOGIC FINDINGS—The histologic features (Fig. 3) were almost identical to those observed in Case 1, except for more pronounced epithelial changes including thinning, irregularities, and buckling over the abnormal subepithelial de-posits. Examination of sections with special stains led to observations identical to those described in Case 1. Histologically the lesion was thought to represent Reis-Bücklers dystrophy, but we could not establish an unequivocal diagnosis.

Electron microscopic studies from the paraffin-embedded tissue displayed the characteristic fea-tures of granular dystrophy (Fig. 4).

DISCUSSION

These two cases of granular dystrophy of the cornea are unusual for several rea-

Fig. 3 (Haddad, Font, and Fine). Case 2. Top, Subepithelial location of deposits in granular dys-trophy, sparing the remainder of the corneal stroma (Masson's trichrome, x80). Bottom, Similar deposits at higher magnification (Masson's trichrome, x300).

sons: (1) a noncontributory family history in both cases; (2) an atypical clinical presentation characterized by a rapid pro-gression of the lesion, repeated episodes of irritation, and early deterioration of visual acuity; and (3) unusual histopatho-logic findings localized to a plane in and near Bowman's membrane that we con-fused initially (in both cases) with Reis-Bücklers dystrophy. Although granular dystrophy is characterized by an autosomal-dominant pattern of inheri-tance, several case reports have demon-strated that a dominant pattern of inheri-tance was not always es tabl ished. 2 , 8 , 1 2 In 1938, Bücklers 4 described (in several members of one family) a special variety of granular dystrophy that differed from the usual type of granular dystrophy be-cause of the presence of finger-shaped as well as ring-shaped opacities clinically localized to the "most anterior corneal stroma and subepithelial layers." These patients also suffered repeated violent in-flammatory attacks. In a second paper published in 1949, Bücklers 1 3 pointed out that this "dystrophia corneae anularis" was more likely to be related to lattice and Reis-Bücklers dystrophies than to the usual granular dystrophy. Unfortunately, no histopathologic studies were made in those cases.

The lesions in granular dystrophy of the cornea progress slowly and insidious-ly until the third or fourth decade, 6 and patients occasionally maintain good vi-sion for even longer periods.2 Therefore, we assume that the rapid progression of the clinical manifestations, which in turn led to early keratoplasty, in our cases is probably caused by diffuse spreading along the plane of Bowman's membrane and subjacent corneal lamellae, leading to early secondary epithelial changes— alterations that are not generally encoun-tered in the early stages of this disorder. The early epithelial alterations are more typical of Reis-Bücklers dystrophy, in which recurrent attacks of pain and irrita-

216 AMERICAN JOURNAL OF OPHTHALMOLOGY FEBRUARY, 1977

Fig. 4 (Haddad, Font, and Fine). Case 2. Typical lesions of granular dystro-phy as seen by transmis-sion electron microscopy (X45,000).

tion from corneal epithelial erosions usu-ally appear in early childhood or in infan-c y . 1 4 The primary site of involvement in granular dystrophy lies within the super-ficial corneal stroma, either in the plane of Bowman's membrane 3 , 1 5 or, more fre-quently, immediately beneath i t . 2 - 4 , 6 , 1 6

With aging, the deposits become larger, invade Bowman's membrane, and extend more deeply into the stroma. This se-quence represents the usual histopatho-logic findings seen in advanced cases, an observation that has already been docu-m e n t e d , 1 7 - 1 9 and supports the findings in our two c a s e s . 2 0 , 2 1 Histologically, there-fore, the unusual superficial formation of deposits in our cases and the lack of deeper stromal involvement must be dif-ferentiated from the various dystrophies involving the anterior cornea, 2 2 such as Reis-Bücklers dystrophy, which bears the closest resemblance to that in our cases. The histopathologic findings in our two cases, which were reviewed by several members of the staff here, initially were thought to represent Reis-Bücklers dys-trophy.

In his paper dealing with the histo-chemistry of granular dystrophy, Gar-ne r 2 3 stated that one case which had "pre-sented a clinical diagnostic problem as

well, was unusual in that, while there were widespread deposits within and im-mediately deep to the epithelium, there was total absence of granular material in the substantia propria." Similar corneal involvement limited to the superficial corneal layers has been noted in some cases of recurring granular dystrophies in grafted e y e s . 2 4 , 2 5 These generally formed within a pannus lying anterior to Bow-man's membrane.

Corneal granular dystrophy is usually identified with histochemical techniques, as shown by Jones and Zimmerman 2 6

and Smith and Zimmerman. 2 7 In Reis-Bücklers dystrophy, however, the stain-ing results, as shown by some investiga-t o r s , 1 4 , 2 8 - 3 0 may be similar to those of granular dystrophy, while others may be inconstant and variable. In some cases, therefore, the histologic similarity of the Reis-Bücklers dystrophy and the superfi-cial form of granular dystrophy makes differentiation by light microscopy diffi-cult.

In their study on members of two fami-lies with Reis-Bücklers dystrophy, Win-kelmann and Del leman 2 8 reported that the lesions stained a brilliant red with Masson's trichrome and Mallory meth-ods. Some of those lesions bear a striking

VOL. 83, NO. 2 GRANULAR DYSTROPHY OF THE CORNEA 217

resemblance to those seen in our cases. In routine hematoxylin and eosin-stained sections it may be possible to differenti-ate between the lesions of these two dys-trophies on the basis of their morphologic features alone. Lesions in Reis-Bücklers dystrophy may appear homogeneous, fi-br i l la ry , 1 4 , 2 9 or scar l ike . 2 1 , 3 1 In granular dystrophy of the cornea one may see on higher magnification some "granularity" of the deposits, especially at the edges. This sharp-edged morphologic appear-ance of the granules under high magnifi-cation proved, in retrospect, to be a most useful criterion for identifying the granu-lar nature of the lesion. Granules involv-ing the plane of Bowman's membrane, as seen in both calcific and noncalcific band keratopathies, 3 2 stain basophilic with hematoxylin-eosin methods and should not be confused with superficial granular dystrophy. In our two patients the granu-larity of the lesions (especially in Case 2) was not marked, and electron microscopic examination showed the granules to be slightly smaller than in the conventional types of granular dystrophy. Electron mi-croscopic examination remains the most helpful method to establish a definite diagnosis of the various types of corneal dystrophies in which confusion in differ-ential diagnosis might occur.

S U M M A R Y

Two patients with a superficial variant of granular dystrophy of the cornea oc-curring primarily in nongrafted eyes de-veloped rapid progression of clinical manifestations and visual deterioration at an early age. No other members of their family were known to be affected. A clini-cal diagnosis of superficial corneal dys-trophy, type undetermined, was made. The histopathologic features of the cor-neas resembled thejmdings seen in Reis-Bücklers dystrophy and led to some con-fusion in the differential diagnosis. Elec-tron microscopic studies in both cases

unequivocally established the diagnosis of granular dystrophy.

R E F E R E N C E S

1. Groenouw, A.: Knötchenförmige Hornhaut-trübungen. Arch. Augenheilkd. 21:281, 1890.

2. Duke-Elder, S., and Leigh, A. C : Diseases of the Outer Eye. Cornea and Sclera. In Duke-Elder, S. (ed.): System of Ophthalmology, vol. 8, pt. 2. St. Louis, C. V. Mosby, 1965, p. 927.

3. Goldberg, M. F.: Corneal disorders. In Gold-berg, M. F. (ed.): Genetic and Metabolic Eye Dis-ease. Boston, Little Brown and Co., 1974, p. 290.

4. Bücklers, M.: Die erblichen Hornhautdystro-phien. Klin. Monatsbl. Augenheilkd. 3 (Suppl.):l, 1938.

5. François, J . : Die erblichen Hornhautdystroph-ien. Ber. Dtsch. Ophthalmol. Ges. 71:171, 1972.

6. Von der Heydt, R.: Corneal dystrophies. Am. J. Ophthalmol. 28:55, 1945.

7. McTigue, J . W.: The electron microscope in corneal pathology. In King, J. H., Jr., and McTigue, J . W. (eds.): The Cornea World Congress. Washing-ton, D.C., Butterworths, 1965, p. 49.

8. McTigue, J. W.: The human cornea. A light and electron microscopic study of the normal cornea and its alterations in various dystrophies. Trans. Am. Ophthalmol. Soc. 65:591, 1967.

9. Akiya, S., and Brown, S. I.: Granular dystrophy of the cornea. Characteristic electron microscopic lesion. Arch. Ophthalmol. 84:179, 1970.

10. Brownstein, S., Fine, B. S., Sherman, M. E., and Zimmerman, L. E.: Granular dystrophy of the cornea. Light and electron microscopic confirma-tion of recurrence in a graft. Am. J . Ophthalmol. 77:701, 1974.

11. Iwamoto, T., Stuart, J. C , Srinivasan, B. D., Mund, M. L., Farris, R. L., Donn, A., and DeVoe, A. G.: Ultrastructural variation in granular dystrophy of the cornea. Albrecht von Graefe's Arch. Klin. Ophthalmol. 194:1,1975.

12. Grayson, M., and Keates, R. H.: Stromal dys-trophies. In Manual of Diseases of the Cornea. Boston, Little Brown and Co., 1969, p. 57.

13. Bücklers, M.: Uber eine weitere familiäre Hornhautdystrophie (Reis). Klin. Monatsbl. Augen-heilkd. 114:386, 1949.

14. Rice, N. S. C , Ashton, N., Jay, B., and Blach, R. K.: Reis-Bücklers dystrophy. A clinico-pathological study. Br. J . Ophthalmol. 52:577,1968.

15. Clark, W. B.: Hereditary and constitutional dystrophies of the cornea. Am. J. Ophthalmol. 33: 692, 1950.

16. Franceschetti, A., and Babel, J.: Heredofamil-ial degenerations of the cornea. Pathological anato-my. In the 16th International Ophthalmological Congress, London, 1950. London, British Medical Association, 1951, vol. 1, p. 245.

17. Groenouw, A.: Knötchenförmige Horn-hauttrübungen. Graefe's Arch. Ophthalmol. 46:85, 1898.

18. Fuchs, A.: Uber Knötchenförmige Hornhaut-

218 AMERICAN JOURNAL O F OPHTHALMOLOGY FEBRUARY, 1977

trübungen. Graefe's Arch. Ophthalmol. 53:423, 1901.

19. Bücklers, M.: Das histologische Bild der bröckligen Hornhautdystrophie. Klin. Monatsbl. Augenheilkd. 101:111, 1938.

20. Hogan, M. J . , and Zimmerman, L. E.: Oph-thalmie Pathology. An Atlas and Textbook. Phila-delphia, W. B. Saunders, 1962, p. 323.

21. Yanoff, M., and Fine, B. S.: Ocular Pathology. A Text and Atlas. Hagerstown, Maryland, Harper and Row, 1975, p. 297.

22. Fogle, J. A., Green, W. R., and Kenyon, K. R.: Anterior corneal dystrophy. Am. J. Ophthalmol. 77:529, 1974.

23. Garner, A.: Histochemistry of corneal granu-lar dystrophy. Br. J. Ophthalmol. 53:799, 1969.

24. Tripathi, R. C., and Garner, A.: Corneal gran-ular dystrophy. A light and electron microscopic study of its recurrence in a graft. Br. J. Ophthalmol. 54:361, 1970.

25. Stuart, J. C , Mund, M. L., Iwamoto, T., Troutman, R. C , White, H., and DeVoe, A. G.: Recurrent granular corneal dystrophy. Am. J. Oph-thalmol. 79:18, 1975.

26. Jones, S. T., and Zimmerman, L. E.: Histo-pathologic differentiation of granular, macular and lattice dystrophies of the cornea. Am. J. Ophthalmol. 51:394, 1961.

27. Smith, M. E., and Zimmerman, L. E.: Amy-loid in corneal dystrophies. Differentiation of lattice from granular and macular dystrophies. Arch. Oph-thalmol. 79:407, 1968.

28. Winkelmann, J. E., and Delleman, J. W.: Reis-Bücklers Hornhautdystrophie und die Rolle der Bowmannschen Membran. Klib. Monatsbl. Aug-enheilkd. 155:380, 1969.

29. Jones, S. M., and Stauffer, L. K.: Reis-Bücklers corneal dystrophy. Trans. Am. Acad. Oph-thalmol. Otolaryngol. 74:417, 1970.

30. Hall, P.: Reis-Bücklers dystrophy. Arch. Oph-thalmol. 91:170, 1974.

31. Griffith, D. G., and Fine, B. S.: Light and electron microscopic observations in a superficial corneal dystrophy. Probable early Reis-Bücklers' type. Am. J. Ophthalmol. 63:1659, 1967.

32. Cursino, J. W., and Fine, B. S.: A histologic study of calcific and noncalcific band keratopathies. Am. J. Ophthalmol. 82:395, 1976.

O P H T H A L M I C MINIATURE

The Controlled Clinical Trial with Statistical Assessment—1835 It appears to me to be one of the most important desiderata in practical

medicine, to ascertain, in regard to each doubtful disease, how far its cases are really self-limited, and how far they are controllable by any treatment. This question can be satisfactorily settled only by instituting, in a large number of cases, which are well identified and nearly similar, a fair experimental comparison of the different active and expectant modes of practice, with their varieties in regard to time, order, and degree. This experiment is vast, considering the number of combinations which it must involve; and even much more extensive than a corresponding series of pathological observations; yet every honest and intelligent observer may contribute to it his mite. Opportunities for such observations, and especially for monographs of diseas-es, are found in the practice of most physicians, yet hospitals and other public charities afford the most appropriate field for instituting them upon a large scale. The aggregate of results, successful and unsuccessful, circumstantially and impartially reported by competent observers, will give us a near approxi-mation to truth, in regard to the diseases of the time and place in which the experiments are instituted. The numerical method employed by Louis in his extensive pathological researches, and now adopted by his most distinguished contemporaries in France, affords the means of as near an approach to certainty on this head, as the subject itself admits.

J A C O B B I G E L O W

Self-Limited Diseases: A Discourse Delivered before The Massachusetts Medical Society, at Their Annual Meeting, May 27th, 1835 (As published in Nature in Disease, 2nd ed., enlarged. By Jacob Bigelow. Boston, Phillips, Sampson, and Co., 1859)