OCULAR ABNORMALITIES OCCURRING WITH VITILIGO DANIEL M. ALBERT, MD BOSTON, MASSACHUSETTS and
JAMES J. NORDLUND, MD AARON B. LERNER, MD NEW HAVEN, CONNECTICUT BOTH BY INVITATION
One hundred twelve patients with vitiligo were examined for ocular abnormalities. Discrete areas of depigmentation with associated pigment hyperplasia clinically appearing to involve the choroid and retinal pigment epithelium were observed in 44 patients, and active uveitis was seen in nine patients. The changes o-bserved suggest that the spectrum of diseases that includes Harada's disease and the Vogt-Koyanagi syndrome may be broader than previously appreciated. Patients with these syndromes may represent the most severe examples of vitiligo and uveal inflammation. The occurrence of symptoms of night blindness in 12 patients and a family history of retinitis pigmentosa in two of these may signify a possible malfunction of the retinal pigment epithelium. Further evidence for a pigment epithelium disorder is suggested by the high incidence of an unusually prominent choroidal pattern in these patients.
Submitted for publication Oct 19, 1978. From the Harvard Medical School, Massachusetts Eye and Ear Infirmary, Howe Laboratory of Ophthalmology, Boston (Dr Albert), and the Yale University School of Medicine, Yale-New Haven Hospital, Department of Dermatology, New Haven, Conn (Drs Nordlund and Lerner). Presented in combination with the National Society for the Prevention of Blindness at the 1978 Annual Meeting of the American Academy ofOphthalmology, Kansas City, Mo, Oct 22-26. Reprint requests to Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114 (Dr Albert).
INTRODUCTION
VITILIGO is defined as "an idiopathic, probably autoimmune, condition characterized by destruction of the melanocytes in small or large circumscribed areas of the skin, resulting in patches of depigmentation, often having a hyperpigmented border, or often enlarging slowly."! As described in this definition, vitiligo affects approximately 1% of the general population. 2 Vitiligo has become of increasing concern as recognition of the number of syndromes consisting of vitiligo and other serious diseases increases. It has a significantly higher incidence in patients with certain endocrine disorders, such as hyperthyroidism, thyroiditis, adrenal insufficiency, and diabetes mellitus, as well as pernicious anemia and melanoma. 2 -4 No matter how extensive the pigment loss and how great the duration of loss, under ordinary observation, the color of the irides in most patients has not been observed to change. 2 ,5 A few instances of depigmentation of the iris occurring with vitiligo have been described, presumably as a result of iris infiammation. 6 -!O
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The association of generalized vitiligo with depigmentation of the lids and the occurrence of white hairs in the brow and eyelashes is extremely common. 3 In addition, the occurrence of vitiligo with inflammation of the uveal tract is well established. l l •12 Involvement of the central nervous system with associated papilledema, papillitis, or optic neuritis has frequently been described. 1l- 15 In isolated reports, vitiligo has been reported occurring with exophthalmos,16 abnormalities of conjunctival pigmentation,9,17 corneal vascularization,18 achromatopsia,16 macular degeneration,16 and chorioretinal heredodegenerations. 19-24 In the present study, systematic ophthalmologic examinations were carried out in a series of patients with cutaneous vitiligo to determine the range of ocular changes occurring in patients with vitiligo.
were examined with the slit-lamp biomicroscope. Intraocular pressure was measured with an applanation tonometer. The pupils were then dilated with tropic amide (Mydriacyl) 1% and phenylephrine hydrochloride (Neo-Synephrine) 10%. The ocular fundi were examined in all patients by direct and indirect ophthalmoscopy and, where indicated, by fundus contact lens. In selected cases, visual fields were carried out.
METHODS
Because of the nature of the skin change in vitiligo, it is almost impossible to carry out a "double masked" controlled study. To provide an initial control group, identical eye examinations were carried out by the same observer (D.M.A.) on patients serially examined at a chemical plant in the Ohio Valley. A possibly more meaningful control group is being collected using psoriasis patients who are undergoing treatment similar to the vitiligo patients. "Masking" these patients, again, poses a difficult problem.
One hundred twelve patients with previously diagnosed cutaneous vitiligo were examined for ocular abnormalities. The patients were selected from the Pigment Clinic at Yale-New Haven Hospital. Initially, an effort was made to examine patients with vitiligo of long duration or unusual severity. Subsequently, "routine" vitiligo patients were examined. All patients had a standard complete ophthalmologic examination. The patients were questioned regarding their past medical history, review of systems, family history, social history, and occupational history. The best correctable visual acuity was obtained for each eye, and a complete external examination of the eyes was carried out. The anterior segments of the eye
The age range of the patients examined was 10 to 78 years; the average age was 42 years. The study group consisted of 72 female patients and 40 male patients. One hundred two patients were white and ten were black. The duration of vitiligo since time of diagnosis ranged from five months to 57 years, with an average of 18 years of known vitiligo.
RESULTS Ocular findings in patients with vitiligo will be described according to the following categories: (1) changes in the fundus oculi, (2) changes in the iris and anterior
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segments of the eye, (3) other changes in the external eye examination, (4) alterations in visual function, and (5) related diseases occurring in these patients. Results are summarized in Tables 1 and 2. TABLE 1
VITILIGO STUDY
Total No. Patients with discrete areas of depigmentation Unilateral 25 Bilateral 19 Uveitis (active) Iridocyclitis 3 Chorioretinitis 5 Combined 1 Atrophy of iris pigment epithelial layer Atrophy of retinal pigment epithelium Pigment clumping in periphery Peripapillary atrophy Papilledema Optic atrophy Depigmentation of lid Poliosis Whitening of brow Severe symptoms of night blindness
112 44
9
7
40 14 11 2 1 54 18 15 12
CHANGES IN THE FUNDUS OCULI
The .most common ocular abnormality found in these patients was the presence of discrete areas of depigmentation involving the choroid and retinal pigment epithelium. These lesions varied considerably with regard to size, shape, and location. A total of 44 patients (39%) showed these lesions. They were unilateral in 25 patients and bilateral in 19. The involved areas
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ranged in size from several disc diameters to small lesions of approximately 0.25 DD. The larger areas tended to show increased pigmentation at their periphery and often pigment clumping or dispersion centrally and conformed to lesions usually diagnosed as healed chorioretinitis. The smaller lesions often showed only an absence of pigmentation and were usually multiple. Many of the small areas resembled the lesions associated with the peripheral changes seen in the entity of presumed histoplasmosis retinochoroiditis. The location of the lesions was variable. In five patients, an active posterior chorioretinitis was observed, with subretinal exudates, retinal edema, and haziness of the overlying retina (Fig 1 and 2). Of the various changes observed in the eyes of patients with vitiligo, the discrete areas of depigmentation are the lesion that most nearly approaches that "characteristic" for the ophthalmic change in patients with vitiligo (Fig 3 and 4). These areas of depigmentation were observed in patients between the ages of 12 and 78 years. The average age of patients having this change was 45 years. The sexual and racial predominance of affeeted patients would appear to reflect the bias of the general group: 33 female patients showed discrete depigmented lesions of the fundus, and 11 males were affected; 41 of these patients were white and three were black. The duration of vitiligo ranged in these patients from five months to 57 years, with an average duration of 18 years since diagnOSIS.
Forty of the patients examined (36%) had a prominent choroidal pattern (Fig 5). In 16 of these pa-
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TABLE 2 OTHER DISORDERS OCCURRING IN VITILIGO PATIENTS STUDIED FOR OCULAR ABNORMALITIES PATIENTS HAVING ONE OR MORE OF THE FOLLOWING: (1) DISCRETE AREAS OF DEPIGMENTATION OR PIGMENTARY DISTURBANCE OF THE CHOROID AND RETINAL PIGMENT EPITHELIUM; (2) ATROPHY OF IRIS PIGMENT EPITHELIUM; OTHER (3) AC'l'IVE UVEITIS PATIENTS Thyroid disease (hyperthyroidism, hypothyroidism, Hashimoto's thyroid) Hypoadrenalism Diabetes mellitus Endometriosis Cholecystitis Meniere's disease and vertigo Cerebral aneurysm Migraine Glomerulonephritis Renal calculi Thrombophlebitis Myocardial infarction Cardiac arrhythmias Pericarditis Severe food or drug allergies Arthritis Osteochondritis Emphysema Mastoiditis Duodenal ulcer Colitis Metastatic cutaneous melanoma Carcinoma of ovary Multiple myeloma Gaucher's disease Hypercholesterolemia Multiple verucca Herpes zoster Mycosis fungoides
tients, discrete areas of chorioretinal change were observed as well. It is difficult to determine the significance of the prominent choroidal pattern, as it is commonly encoun-
TOTAL
10
5
15
2 1
2
4
2 1
1 5 2 1
3
2
1
1 5 2 1 1
5 1
1 1 2 1 1 1 10 3
1 2 1 1 1
1 1
7
3
5
12
1 1 1 1
1
tered in normal persons, particularly those with lightly pigmented eyes. In seven patients, however, the prominent choroidal pattern had a plaque-like or geographic dis-
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Fig I.-Top, Right eye of pa tient with vitiligo (compl ete) a nd a ctive uveitis . There is a s trong fa milial his tory o f r teinitis pigm entosa (brother , two nieces). Bottom , Progres sion of uveitis in right eye, two years la ter.
tribution, alternating with darker areas of pigmentation. It is likely that the lightly pigmented areas of prominent choroidal pattern represent atrophy of the retinal pigment epithelium. In most instances, considerable choroidal pigmentation could be recognized. In six patients, however, the appearance of the fundus was suggestive of "ocular albinism." The prominence of the choroidal pattern when present was usually bilateral and symmetrical.
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Fig 2. -Top, Left eye of same pa tien t in Fig 1. Bottom, Appearance of left fundus two years later ; n ote progression of ch or ioretinal ch a nges.
In 14 patients (8%), marked pigment clumping in the periphery of the fundus was seen . Again, this is commonly encountered in normal eyes, and its significance is difficult to evaluate. The relative frequency and severity of this change in the present group of patients may be noteworthy. Atrophy of the choroid and retinal pigment epithelium around the optic nerve (peripapillary atrophy) is, likewise, a nonspecific change, often seen in older persons. This was present in an exaggerated
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Fig 3.-Area resembling h ealed chorioretinitis seen in patient with vitiligo.
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Fig 5.-Apparent atrophy of retinal pigment epi· thelium in pa tient with vitiligo and night blind· ness.
ation of papilledema, diplopia, and left hyperreflexia. An elevated CSF pressure had been documented, but the cause had not been determined. No other ocular abnormalities were observed in this patient. Another patient showed evidence of optic atrophy that, by history, followed bilateral optic neuritis, the cause of which had not been determined. Papilledema was also observed in a patient with cutaneous melanoma and vitiligo, presumably on the basis of brain metastases from the melanoma. Fig 4.-Multifocal areas of apparently healed ch orioretinitis in patient with marked vitiligo.
form in 11 patients (10%) present study.
In
the
Chronic papilledema was observed in one patient, a 20-year-old black woman. A review of the patient's history revealed that she had been admitted to a university medical center three years earlier for evalu-
Changes in the Iris and Anterior Segment of the Eye Transmission of light through the iris (transillumination of the iris) was seen in seven patients, indicating a defect in the iris pigment epithelial layer. Although these changes were discernible with the slit-lamp biomicroscope, they were not observable by routine inspection of the iris. These changes
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were bilateral in both cases. Three additional patients were observed to have active iritis, as indicated by the presence of cells and flare in the anterior chamber. In two of these patients, the iris color was lighter in the right eye (heterochromia). Marked pigment disposition was noted on the corneal endothelium of another patient; the source was presumed to be the pigment epithelium. Two patients with no apparent ocular abnormalities volunteered that their irides had become lighter over the period of years during which they had had vitiligo. In both instances, relatives concurred in this observation. Unfortunately, neither patient had adequate color photographs to confirm or refute his impression. Although lens changes of various type and severity were noted in a number of the older patients examined, three patients (a 34-yearold man, 36-year-old man, and a 36-year-old woman) had posterior subcapsular cataracts with no evident cause, suggesting perhaps previous intraocular inflammation.
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A 24-year-old white woman had horizontal nystagmus that was congenital by history. This patient also had atrophy of the iris pigment epithelium, a strikingly prominent choroidal pattern, discrete depigmented lesions of the choroid and retinal pigment epithelium, and marked pigmentary dispersion at the periphery. One instance of bilateral congenital ptosis and one patient with Horner's syndrome were observed. In spite of the high incidence of thyroid disease, no problem with ocular motility was observed in these patients, and only one of the vitiligo group was seen with exophthalmos. Visual Function
In 107 of the 112 patients examined, the best corrected visual acuity was 20/30 or better in each eye. In three of the five patients with more severely decreased visual acuity, the chorioretinitis-like lesions appeared to be a factor in the deficit (Fig 6). In the remaining
Other External Eye Changes
Fifty-four patients were observed to have involvement of the lids by vitiligo. Twenty-two of these patients were also affected with one or more of the following: (1) discrete atrophic areas in the fundus, (2) atrophy of the iris pigment epithelium, and (3) iritis. Poliosis was present in 18 patients, and in 15 there was partial or total involvement of the brow by vitiligo. Seven patients were seen with strabismus, and four additional patients had been operated on earlier in life for strabismus. Five other patients gave a history of a sibling, parent, or child with strabismus.
Fig 6.-Unilateral macular lesion in 42.year-old patient with cutaneous melanoma and vitiligo.
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two patients, one had decreased vision as the result of diabetic retinopathy and the other amblyopia ex anopsia. Twelve patients had complaints of severe night blindness. Two of these patients had relatives with proven retinitis pigmentosa. One of these was a woman with a borderline normal amplitude on her electroretinogram who was suspected of being a carrier of the sex-linked type of retinitis pigmentosa. Another patient has a fundus picture consistent with fundus albipunctatus. Other Related Diseases
In Table 2, other diseases and abnormalities affecting the patients included in this study are listed. Those involving patients with pigmentary ocular changes are noted. Control Population
Three hundred seventy-one patients were seen consecutively at a chemical plant in the Ohio Valley. The a verage age of the patients examined was 56 years. The patients were predominantly white (95%). Examinations were carried out by the same observer and in an identical manner to those given in the vitiligo study. Pertinent findings are listed in Table 3. DISCUSSION
Most of the present understanding of vitiligo stems from studies regarding changes in the skin.2-4 In addition to the "typical" form of vitiligo, many variations can occur involving the skin and hair,
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TABLE
3
CONTROL STUDY
Total No. 371 Patients with discrete areas of 20 depigmentation and pigment hyperplasia of choroid and retinal pigment epithelium Atrophy of iris pigment epithelial 3 layer (excluding aphakic patients) Active uveitis 0 Prominent choroidal pattern 7 Pigment clumping in periphery 5 Peripapillary atrophy 5 Depigmented skin of lids 0 Poliosis 0 Fundus albipunctatus 1 Papilledema 0 1 Optic neuritis Optic atrophy 1
and these are considered in detail elsewhere. 2-4 The disorders in the noncutaneous structures involved in the syndromes associated with vitiligo may share some common disorder of autoimmunity with the skin changes. For the most part, these syndromes involve organs bearing little morphologic relation to the skin. Involvement of the eye in vitiligo is intriguing, in contrast, because the ocular structures share certain common morphologic and developmental relationships to the skin, particularly with regard to pigmented cells. The uvea of the eye (ie, the iris, ciliary body, and choroid) contains dendritic melanocytes morphologically similar to those seen in the dermis. However, certain differences exist that must be borne in mind. Unlike the skin, a second population of pigmented cells exists in the eye: the pigment
OCULAR ABNORMALITIES 1153 1979 epithelium. These are generally of meningeal irritation. This synbasal or cuboidal cells that, when drome reflects the integration of seen in flat section, have a hex- Vogt-Koyanagi syndrome37 .38 with agonal appearance and are among Harada's disease. 39 The Vogt-Koythe earliest cells in the body to anagi syndrome was originally debecome pigmented. The proper func- scribed as a severe, acute anterior tioning of the outer retina is de- uveitis associated with alopecia, pendent upon these cells. They are vitiligo, poliosis, and dysacousia. in many respects undifferentiated Harada's disease was described as cells and, in pathologic conditions, a posterior uveitis occurring with appear to be multipotential with signs of meningeal irritation, inregard to their ability to differen- creased protein level, and pleocytotiate into other tissues. This pop- sis of the CSF. In the relatively ulation of cells comprises the retinal "pure" form of these disorders, pigment epithelium, the pigment vitiligo occurs in more than 50% epithelium of the ciliary body, and of the Vogt-Koyanagi syndrome, the pigment epithelium of the iris. but in less than 10% of Harada's Thus, in considering pigment ab- disease.!l A review of reports of normalities in the eye, both the these disorders, however, reveals uveal melanocytes and pigment that many cases show considerable epithelial cells must be kept in overlap of the associated finding mind. of the Vogt-Koyanagi syndrome with Harada's disease.ll.l2.4o.43 A Disorders of the eye have been recent study of nine cases on file at reported in association with vitiligo the Armed Forces Institute of Pafor more than a century.12.l5.23-32 thology confirmed histopathologiSince vitiligo in these earlier years cally as well as clinically the lack was assumed to be the result of of a clear distinction between these syphilis, nervous and infectious disorders.H Histopathologically, indiseases, and malignancy, 33 the stances of granulomatous and nonchanges in the eye were attributed granulomatous uveitis were found to similar causes. Gradually it under each designation. The study became clear that these syndromes concluded that the term "uveoof vitiligo with ocular changes fell meningoencephalitic syndrome" into certain general categories. At- was a more useful term in categorophy of the iris pigment ("vitiligo rizing these disorders, as it disiridis") with associated depigmen- tinguished those cases which, in tation of the skin around the eye addition to uveal involvement, was recognized to be largely the showed evidence of meningoenresult of herpes zoster ophthal- cephalitic irritation; this appears to be the major differentiating micus. 34-36 point. The most widely studied association of vitiligo with eye disease From the standpoint of the ophis in the Vogt-Koyanagi-Harada thalmologic changes, sympathetic syndrome.! 2 This diagnosis has ophthalmia bears a close clinical generally come to be applied to and histopathologic relationship to patients with a chronic, bilateral, the Vogt-Koyanagi-Harada synexudate uveitis associated with drome, and an overlap between whitening of the eyes, hair, and these entities exists.26.28.30-32.37.44-48 eyelashes and with varying signs Instances of vitiligo occurring with VOLUME JUNE
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clear-cut sympathetic ophthalmia do occur. 12 .49 Differentiating features between sympathetic ophthalmia and the Vogt-Koyanagi-Harada syndrome include (1) the occurrence of ocular trauma that is always present in sympathetic ophthalmia but infrequent in the Vogt-KoyanagiHarada syndrome; (2) the racial incidence, with sympathetic ophthalmia being reported predominantly in white patients, whereas the Vogt-Koyanagi-Harada syndrome is frequent in Orientals, blacks, and deeply pigmented whites; and (3) sympathetic ophthalmia is always a granulomatous inflammation and shows other specific histopathologic distinctions as well. In the Vogt-Koyanagi syndrome, even in the eyes that retain normal vision, areas of depigmentation and clumping of pigment in the retina occur. These areas, described as a "sunset glow fundus" appear to bear a similarity to the pigmentary changes seen in the present study.4o.50-52 The presence of "albinotic fundi" developing in eyes with chorioretinitis and vitiligo, also similar to findings in the present case, have been observed. 27 .53 Aside from the Vogt-KoyanagiHarada group and sympathetic ophthalmia, uveitis and vitiligo have occurred in the absence of any predisposing conditions or in association with dysacousia or signs of meningeal irritation l l •12 ; in patients with cutaneous melanoma following bacille Calmette-Guerin (BCG) administration 54 ; in patients with cutaneous and ocular melanoma prior to or in the absence of BCG treatment2-4; and following the apparent introduction of cobaltous aluminate into the skin. 55 In patients with cutaneous melanoma, vitiligo may occur spontane-
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ously2.3 or follow immunostimulation with BCG54 or vaccinia. 56 The association of vitiligo with melanoma is important. Lerner and Nordlund 2 found that 20% of patients with melanomas have vitiligo and speculate that if patients with metastases could be kept alive for several years, vitiligo would develop in nearly all cases. It has been well demonstrated that the immune system plays an important role in the natural history of malignant melanoma and that both cellular and humoral factors directed against melanoma cells can be detected. 57- 59 It is probable that vitiligo in these cases is an immunologically mediated melanocyte destruction, which apparently can affect the ocular pigmented cells as well in certain cases. The chorioretinal heredodegenerations (tapetoretinal degenerations, neuroretinal degenerations) form an important class of visual disorders. Their cause and pathogensis is unknown, but pigmentary disturbances, particularly of the retinal pigment epithelium, may play a prominent role. Few of the reported cases of these disorders have shown an association with cutaneous vitiligo,20-24.6o-62 although how carefully this has been sought is questionable. Depigmentation of the eye or absence of pigmentation of the eye may occur without skin changes being present. The occurrence of ocular albinism is well known. 63 This is, however, not a well-defined condition, and it is difficult to draw the line between an extremely "blonde" iris and fundus and true albinism. Ocular albinism has also been described as complete, incomplete, and localized. Ocular albinism may be associated with various syndromes, including the Chediak-Higashi syndrome. 64 .65
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Although in most normal persons the irides are usually the same color, simple heterochromia has been found in many human populations, but is a relatively rare finding. 66 .67 It has not been possible to assess the incidence because slight differences in eye color are often overlooked, especially in lighteyed people. Absence of normal pigmentation may result from interruption of the normal adrenergic innervation to the eye. 68 A light iris color is seen in Waardenberg's syndrome. 69 Loss of iris pigment also occurs in Fuch's heterochromic iridocyclitis, which consists of a unilateral, chronic, mild iridocyclitis; heterochromia with the involved iris becoming the lighter iris; and cataract and glaucoma developing in the hypochromic eye.66.67.70 As a sequela of uveitis, endophthalmitis, and panophthalmitis, the iris may undergo atrophy and necrosis and have a lighter color as a result of the loss of pigment cells from the stroma and pigment epithelium. Various other conditions may result in atrophy of the iris and subsequent loss of pigment. These include chronic glaucoma, essential progressive atrophy of the iris, and senile change. Loss or alteration of the choroidal melanocytes and retinal pigment epithelium may occur in a number of primary and secondary degenerations and dystrophies, from toxic degeneration resulting from a variety of drugs, irra.diation and trauma, senile change, ischemia, and hemorrhage and inflammation often associated with systemic disease. The present study indicates that pigmentary changes of the eye may
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occur more commonly in association with vitiligo than the previous literature would indicate. Active uveitis (iritis and choroiditis) is undeniably an abnormal finding. Discrete areas of loss of choroidal pigmentation and retinal pigment epithelium with associated pigment clumping, as well as the finding of transillumination of the iris, may represent the sequelae of previous inflammation. It is possible that this inflammation occurs insidiously, and its activity and progression may be difficult to distinguish by routine clinical examination. The striking prominence of a choroidal pattern as well as the finding of patients with night blindness suggests a widespread defect in the retinal pigment epithelium that may have a genetic basis. Many of the patients showing ocular changes have received various forms of treatment for vitiligo. 3 Although numerous studies indicate no relation between administration of psoralen compounds or hydroquinone and ocular abnormalities, their possible role in inducing the changes presently described must be considered. One recent study has, however, demonstrated the development of a severe pigmentary retinopathy in birds following the combined oral administration of 8-methoxypsoralen given in conjunction with exposure to sunlight. 71 In the study of the eyes of patients with psoriasis receiving psoralen-ultraviolet light treatment, a high incidence of various pigmentary fundus changes has also been observed (T. Spivak, personal communication, August 1978). In summary, this study demonstrates the need for further ocular evaluation of patients with vitiligo
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as well as dermatologic evaluation of patients with uveitis and ocular diseases involving degeneration of the retinal pigment epithelium. Such information would permit a better understanding of the mechanism and relationships of the pigmentary changes in the skin and eye.
REFERENCES 1. Friel JP (ed): Dorland's Illustrated Medical Dictionary, ed 25. Philadelphia, WB Saunders Co, 1974. 2. Lerner AB, Nordlund JJ: Vitiligo: What is it? Is it important? JAMA 239:11831187, 1978. 3. Lerner AB: Vitiligo: Its relationship to systemic disease. Curr Top Dermatol, to be published. 4. . On the etiology of vitiligo and grey hair. Am J Med 51:141-147, 1971. 5. Lerner AB, Nordlund JJ, Albert DM: Pigment cells of the eyes in people with vitiligo. N Engl J Med 296:232, 1977. 6. Maguire A, Moynahan EJ: Acquired albinism with intraocular depigmentation. Proc R Soc Med 54:696-697, 1961. 7. Moynahan EJ: Pigment cells in eyes of people with vitiligo. N Engl J Med 296: 824, 1977. 8. Hoff F: Akuter totaler Pigmentverlust. Dtsch Med Wochenschr 79:284-287, 1954. 9. Wexler D: Ocular depigmentation accompanying generalized vitiligo. Arch Ophthalmol 57:393-396, 1928. 10. Haye MC, Guyot-Sionnest M, Coulon MG: Association de retinite pigmentaire erde vitiligo. Bull Soc Ophtalmol Fr 73:1155-1158, 1973.
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14. Corcelle L, Verin P, Cohadon F: Sur un cas de maladie de Harada. Rev Neurol 108:813-814, 1963. 15. Gilbert W: Vitiligo und Auge, ein Beitrag zur Kenntnis der herpetischen Augenerkran kungen. Klin Monatsbl Augen· heilkd 48:24-31, 1910. 16. Cremona AC, Alezzandrini AA, Casala AM: Vitiligo, poliosis y degeneracion macular unilateral. Arch Oftalmol Buenos Aires 36:102-106, 1963. 17. Hanssen R: Uber Vitiligo. Z Augenheilkd 56:35-37, 1925. 18. Gastgeiger H: tiber fruhzeitiges Ergrauen von Zilien. Arch Augenheilkd 45: 261-266, 1925. 19. Jutte A: Uber Augenhintergrundsveranderungen beim akuten Lupus erythematodes visceralis. Klin Monatsbl Augenheilkd 137:765-772, 1960. 20. Franceschetti A, Francois J, Babel J: Chorioretinal Heredodegenerations. Springfield, Ill, Charles C Thomas Publisher, 1974, pp 1184-1186. 21. Alezzandrini AA: Manifestation unilaterale de degenerescence tapeto-retinienne, de vitiligo, de poliose, de cheveaux blancs et d'hypoacousie. Ophthalmologica 147:409419, 1964. 22. Casala AM, Alezzandrini AA: Vitiligo y poliosis unilateral con retinitis pigmentoria e hipoacusia. Arch Agent Derm 9:449456, 1959. 23. Merz M, Szmigielski M, Ladncucki J: Unilateral sectorial pigmentary degeneration and vitiligo. Ophthalmologica 157:357361, 1969. 24. Preste E: Vitiligo monolatrale dell iride. Pathologica 65:241-242, 1973. 25. Korting GW, Curth W, Curth HO, et al: The Skin and Eye. Philadelphia, WB Saunders Co, 1973, pp 95-101. 26. Cramer E: Abriss d. Unfall-u. In· validitiitskunde d. Schapparats. Stuttgart, lEnke, 1912.
11. Perry HD, Font RL: Clinical and histopathologic observations in severe VogtKoyanagi-Harada syndrome. Am J Ophthalmol 83:242-254, 1977.
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28. Bock E: Ueber fruhzeitiges ergrauen der Urmpern. Klin Monatsbl Augenheilkd 28:484-492, 1880.
13. Vladykova J, Singer G: Harada's disease. Cesk Oftalmol 20:369-373, 1964.
29. Hutchinson J: A case of blanched eyelashes. Arch Surg 4:357-358, 1892/1893.
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30. Nettleship E: A case of sympathetic ophthalmitis with whitening of the eyelashes. Trans Ophthalmol Soc UK 4:83-84, 1883/1884.
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31. Tay W: L. Diseases of the Eyelids 1. A case of symmetrical whitening of the eyelashes and eyebrows with sympathetic ophthalmia. Trans Ophthalmol Soc UK 12:2930, 1892.
46. Wilson P: Sympathetic ophthalmitis simulating Harada's disease. Br J Ophthalmol 46:626-628, 1962.
32. Schenkl A: Ein Fall von plotzlich aufgetretenel' Poliosis circumscipta der Wimperno Arch Dermatol Syph 5:136-319, 1873. 33. Ormsby OS: Diseases of the Skin. Philadelphia, Lea & Febiger, 1927. 34. Lowenstein A: Iritis herpetica. Klin Monatsbl Augenheilkd 71:313-322, 1923. 35. Baldino S: Irido-corioidite di origine endocrino simpatica. Arch Oftalmol 27:244260, 1920. 36. Wyss 0: Beitrag zur Kenntuiss des herpes zoster. Arch Heilkd 12:261-293, 1871. 37. Vogt A: Friihzeitiges Ergrauen der Zilien und Bemerkungen uber den sogenannten plotzlichen Eintritt dieser Veranderung. Klin Monatsbl Augenheilkd 44:228242, 1906. 38. Koyanagi Y: Dysakusis, Alopecia und Poliosis bei schwerer Uveitis nicht traumatischen Ursprungs. Klin Monatsbl Augenheilkd 82:194-211, 1929.
47. Ikui H, Furuyoshi Y. Nakamizo K, et al: Histopathological studies on cutaneous lesions in sympathetic ophthalmia and Vogt-Koyanagi-Harada syndrome. Acta Soc Ophthalmol Jpn 65:1057-1059, 1961. 48. Fine , BS, Gilligan JH: The VogtKoyanagi syndrome. A variant of sympathetic ophthalmia: Report of two cases. Am J Ophthalmol 43:433-440, 1957. 49. Stankovic I: Electro-encephalography and audiometry in sympathetic ophthalmia. Acta 18th Inti Cong Ophthalmol 2:1276, 1958. 50. Reed H, Lindsay A, Speakman J, et al: The uveoencephalitis syndrome or VogtKoyanagi-Harada disease. Can Med J 79: 451-459, 1958. 51. Cordes FC: Harada's disease treated with cortisone. Am J Ophthalmol 39:499510, 1955. 52. Parker WR: Severe uveitis with associated alopecia, poliosis, vitiligo and deafness. Arch Ophthalmol 24:43g.446, 1940.
39. Harada E: Clinical study of non-suppurative choroiditis. A report of acute diffuse choroiditis. Acta Soc Ophthalmol Jpn 30:356, 1926.
53. Erdman NP: Zur Frage eines Zusammenhanges zwischen Vitiligo und Augenleiden. Klin Monatsbl Augenheilkd 49:129-138, 1911.
40. Cowper AR: Harada's disease and Vogt-Koyanagi syndrome: Uveoencephalitis. Arch Ophthalmol 45:367-376, 1951.
54. Donaldson RC, Canaan SA, McLean RB, et al: Uveitis and vitiligo associated with BCG treatment for malignant melanoma. Surgery 76:771-778, 1974.
41. Brunno MG, McPherson SD Jr: Harada's disease. Am J Ophthalmol32:513-522, 1949. 42. Rosen E: Uveitis, with poliosis, vitiligo, alopecia and dysacousia (Vogt-Koyanagi syndrome). Arch Ophthalmol33:281-292, 1945. 43. Davies WS: Uveitis with associated alopecia, poliosis, vitiligo and deafness. Arch Ophthalmol 14:23g.243, 1935. 44. Soriano FJ: Tautheit, Ausfallen und Ergrauen der Haare bei den schweren doppelseitigen sympatheischen und nichsympathischen uveitiden. Arch Oftalmol Buenos Aires 4:537-543, 1929.
55. Rorsman H, Dahlquist I, Jacobsson S, et al: Tattoo granuloma and uveitis. Lancet, July 5, 1969. 56. Nairn RC, Guili EP, Nind AP: Antitumor immunoreactivity in patients with malignant melanoma. Med J Aust 1:397-403, 1972. 57. Hellstrom I, Sjogren HO, Warner G, et al: Blocking of cell-mediated tumor immunity by sera from patients with growing neoplasms. Int J Cancer 7:226-237, 1971. 58. Lewis MG, Ikonopisov RL, Nairn RC, et al: Tumor-specific antibodies in human malignant melanoma and their relationship
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to the extent of the disease. Br Med J 3:547552, 1969.
Higashi syndrome. Arch Ophthalmol 75:8488, 1966.
59. Burdick KH, Hawk W: Vitiligo in a case of vaccinia virus-treated melanoma. Cancer 17:708-712, 1964.
66. Lowenstein IE, Thompson HS: Fuchs' heterochromic cyclitis: A critical review of the literature. I. Clinical characteristics of the syndrome. Surv OphthalmoI17:394-457, 1973.
60. Landers MB III, Wolbarsht ML, Dowling JE, et al: Retinitis Pigmentosa: Clinical Implications of Current Research in Ad· vances in Experimental Medicine and Biology. New York, Plenum Press, 1977, pp 3942.
67. _ _ _. Fuchs' heterochromic cyclitis: A critical review of the literature. II. Etiology and mechanisms. Surv Ophthalmol 18:2-61, 1973.
61. Vinken PJ, Bruyn GVV: Handbook of Clinical Neurology. New York American Elsevier Publishing Co, 1972, vol 13, pp 2443.
68. Laties AM: Ocular melanin and the adrenergic innervation to the eye. Trans Am Ophthalmol Soc 72:560-605, 1974.
62. Bell J: Anomalies and Diseases of the Eyes, Nettleship Memorial Volume. Cambridge, Cambridge University Press, 1922.
69. Waardenberg PJ: A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root, with the pigmentary defects of the iris and head hair, and with congenital deafness. Am J Hum Genet 3:195-253, 1951.
63. Duke-Elder S: System of Ophthalmology. St Louis, CV Mosby Co, 1963, vol 3, pp 804-809. 64. Blume RS, Wolff SM: The ChediakHigashi syndrome: Studies in four patients and a review of the literature. Medicine 51: 247-280, 1972. 65. Johnson DL, Jacobson LW, Toyama R, et al: Histopathology of eyes in Chediak-
70. Perry H, Yanoff M, Scheie HG: Rubeosis in Fuchs' heterochromic iridocyclitis. Arch Ophthalmol 93:337-339, 1975. 71. Singer L, Romem M, Egyed MN, et al: Methoxsalen-induced ocular lesions in ducks. Ophthalmic Res 8:329-334, 1976.
JAMES J. NORDLUND, MD AARON B. LERNER, MD NEW HAVEN, CONNECTICUT BOTH BY INVITATION
One hundred twelve patients with vitiligo were examined for ocular abnormalities. Discrete areas of depigmentation with associated pigment hyperplasia clinically appearing to involve the choroid and retinal pigment epithelium were observed in 44 patients, and active uveitis was seen in nine patients. The changes o-bserved suggest that the spectrum of diseases that includes Harada's disease and the Vogt-Koyanagi syndrome may be broader than previously appreciated. Patients with these syndromes may represent the most severe examples of vitiligo and uveal inflammation. The occurrence of symptoms of night blindness in 12 patients and a family history of retinitis pigmentosa in two of these may signify a possible malfunction of the retinal pigment epithelium. Further evidence for a pigment epithelium disorder is suggested by the high incidence of an unusually prominent choroidal pattern in these patients.
Submitted for publication Oct 19, 1978. From the Harvard Medical School, Massachusetts Eye and Ear Infirmary, Howe Laboratory of Ophthalmology, Boston (Dr Albert), and the Yale University School of Medicine, Yale-New Haven Hospital, Department of Dermatology, New Haven, Conn (Drs Nordlund and Lerner). Presented in combination with the National Society for the Prevention of Blindness at the 1978 Annual Meeting of the American Academy ofOphthalmology, Kansas City, Mo, Oct 22-26. Reprint requests to Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114 (Dr Albert).
INTRODUCTION
VITILIGO is defined as "an idiopathic, probably autoimmune, condition characterized by destruction of the melanocytes in small or large circumscribed areas of the skin, resulting in patches of depigmentation, often having a hyperpigmented border, or often enlarging slowly."! As described in this definition, vitiligo affects approximately 1% of the general population. 2 Vitiligo has become of increasing concern as recognition of the number of syndromes consisting of vitiligo and other serious diseases increases. It has a significantly higher incidence in patients with certain endocrine disorders, such as hyperthyroidism, thyroiditis, adrenal insufficiency, and diabetes mellitus, as well as pernicious anemia and melanoma. 2 -4 No matter how extensive the pigment loss and how great the duration of loss, under ordinary observation, the color of the irides in most patients has not been observed to change. 2 ,5 A few instances of depigmentation of the iris occurring with vitiligo have been described, presumably as a result of iris infiammation. 6 -!O
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The association of generalized vitiligo with depigmentation of the lids and the occurrence of white hairs in the brow and eyelashes is extremely common. 3 In addition, the occurrence of vitiligo with inflammation of the uveal tract is well established. l l •12 Involvement of the central nervous system with associated papilledema, papillitis, or optic neuritis has frequently been described. 1l- 15 In isolated reports, vitiligo has been reported occurring with exophthalmos,16 abnormalities of conjunctival pigmentation,9,17 corneal vascularization,18 achromatopsia,16 macular degeneration,16 and chorioretinal heredodegenerations. 19-24 In the present study, systematic ophthalmologic examinations were carried out in a series of patients with cutaneous vitiligo to determine the range of ocular changes occurring in patients with vitiligo.
were examined with the slit-lamp biomicroscope. Intraocular pressure was measured with an applanation tonometer. The pupils were then dilated with tropic amide (Mydriacyl) 1% and phenylephrine hydrochloride (Neo-Synephrine) 10%. The ocular fundi were examined in all patients by direct and indirect ophthalmoscopy and, where indicated, by fundus contact lens. In selected cases, visual fields were carried out.
METHODS
Because of the nature of the skin change in vitiligo, it is almost impossible to carry out a "double masked" controlled study. To provide an initial control group, identical eye examinations were carried out by the same observer (D.M.A.) on patients serially examined at a chemical plant in the Ohio Valley. A possibly more meaningful control group is being collected using psoriasis patients who are undergoing treatment similar to the vitiligo patients. "Masking" these patients, again, poses a difficult problem.
One hundred twelve patients with previously diagnosed cutaneous vitiligo were examined for ocular abnormalities. The patients were selected from the Pigment Clinic at Yale-New Haven Hospital. Initially, an effort was made to examine patients with vitiligo of long duration or unusual severity. Subsequently, "routine" vitiligo patients were examined. All patients had a standard complete ophthalmologic examination. The patients were questioned regarding their past medical history, review of systems, family history, social history, and occupational history. The best correctable visual acuity was obtained for each eye, and a complete external examination of the eyes was carried out. The anterior segments of the eye
The age range of the patients examined was 10 to 78 years; the average age was 42 years. The study group consisted of 72 female patients and 40 male patients. One hundred two patients were white and ten were black. The duration of vitiligo since time of diagnosis ranged from five months to 57 years, with an average of 18 years of known vitiligo.
RESULTS Ocular findings in patients with vitiligo will be described according to the following categories: (1) changes in the fundus oculi, (2) changes in the iris and anterior
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segments of the eye, (3) other changes in the external eye examination, (4) alterations in visual function, and (5) related diseases occurring in these patients. Results are summarized in Tables 1 and 2. TABLE 1
VITILIGO STUDY
Total No. Patients with discrete areas of depigmentation Unilateral 25 Bilateral 19 Uveitis (active) Iridocyclitis 3 Chorioretinitis 5 Combined 1 Atrophy of iris pigment epithelial layer Atrophy of retinal pigment epithelium Pigment clumping in periphery Peripapillary atrophy Papilledema Optic atrophy Depigmentation of lid Poliosis Whitening of brow Severe symptoms of night blindness
112 44
9
7
40 14 11 2 1 54 18 15 12
CHANGES IN THE FUNDUS OCULI
The .most common ocular abnormality found in these patients was the presence of discrete areas of depigmentation involving the choroid and retinal pigment epithelium. These lesions varied considerably with regard to size, shape, and location. A total of 44 patients (39%) showed these lesions. They were unilateral in 25 patients and bilateral in 19. The involved areas
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ranged in size from several disc diameters to small lesions of approximately 0.25 DD. The larger areas tended to show increased pigmentation at their periphery and often pigment clumping or dispersion centrally and conformed to lesions usually diagnosed as healed chorioretinitis. The smaller lesions often showed only an absence of pigmentation and were usually multiple. Many of the small areas resembled the lesions associated with the peripheral changes seen in the entity of presumed histoplasmosis retinochoroiditis. The location of the lesions was variable. In five patients, an active posterior chorioretinitis was observed, with subretinal exudates, retinal edema, and haziness of the overlying retina (Fig 1 and 2). Of the various changes observed in the eyes of patients with vitiligo, the discrete areas of depigmentation are the lesion that most nearly approaches that "characteristic" for the ophthalmic change in patients with vitiligo (Fig 3 and 4). These areas of depigmentation were observed in patients between the ages of 12 and 78 years. The average age of patients having this change was 45 years. The sexual and racial predominance of affeeted patients would appear to reflect the bias of the general group: 33 female patients showed discrete depigmented lesions of the fundus, and 11 males were affected; 41 of these patients were white and three were black. The duration of vitiligo ranged in these patients from five months to 57 years, with an average duration of 18 years since diagnOSIS.
Forty of the patients examined (36%) had a prominent choroidal pattern (Fig 5). In 16 of these pa-
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TABLE 2 OTHER DISORDERS OCCURRING IN VITILIGO PATIENTS STUDIED FOR OCULAR ABNORMALITIES PATIENTS HAVING ONE OR MORE OF THE FOLLOWING: (1) DISCRETE AREAS OF DEPIGMENTATION OR PIGMENTARY DISTURBANCE OF THE CHOROID AND RETINAL PIGMENT EPITHELIUM; (2) ATROPHY OF IRIS PIGMENT EPITHELIUM; OTHER (3) AC'l'IVE UVEITIS PATIENTS Thyroid disease (hyperthyroidism, hypothyroidism, Hashimoto's thyroid) Hypoadrenalism Diabetes mellitus Endometriosis Cholecystitis Meniere's disease and vertigo Cerebral aneurysm Migraine Glomerulonephritis Renal calculi Thrombophlebitis Myocardial infarction Cardiac arrhythmias Pericarditis Severe food or drug allergies Arthritis Osteochondritis Emphysema Mastoiditis Duodenal ulcer Colitis Metastatic cutaneous melanoma Carcinoma of ovary Multiple myeloma Gaucher's disease Hypercholesterolemia Multiple verucca Herpes zoster Mycosis fungoides
tients, discrete areas of chorioretinal change were observed as well. It is difficult to determine the significance of the prominent choroidal pattern, as it is commonly encoun-
TOTAL
10
5
15
2 1
2
4
2 1
1 5 2 1
3
2
1
1 5 2 1 1
5 1
1 1 2 1 1 1 10 3
1 2 1 1 1
1 1
7
3
5
12
1 1 1 1
1
tered in normal persons, particularly those with lightly pigmented eyes. In seven patients, however, the prominent choroidal pattern had a plaque-like or geographic dis-
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Fig I.-Top, Right eye of pa tient with vitiligo (compl ete) a nd a ctive uveitis . There is a s trong fa milial his tory o f r teinitis pigm entosa (brother , two nieces). Bottom , Progres sion of uveitis in right eye, two years la ter.
tribution, alternating with darker areas of pigmentation. It is likely that the lightly pigmented areas of prominent choroidal pattern represent atrophy of the retinal pigment epithelium. In most instances, considerable choroidal pigmentation could be recognized. In six patients, however, the appearance of the fundus was suggestive of "ocular albinism." The prominence of the choroidal pattern when present was usually bilateral and symmetrical.
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Fig 2. -Top, Left eye of same pa tien t in Fig 1. Bottom, Appearance of left fundus two years later ; n ote progression of ch or ioretinal ch a nges.
In 14 patients (8%), marked pigment clumping in the periphery of the fundus was seen . Again, this is commonly encountered in normal eyes, and its significance is difficult to evaluate. The relative frequency and severity of this change in the present group of patients may be noteworthy. Atrophy of the choroid and retinal pigment epithelium around the optic nerve (peripapillary atrophy) is, likewise, a nonspecific change, often seen in older persons. This was present in an exaggerated
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Fig 3.-Area resembling h ealed chorioretinitis seen in patient with vitiligo.
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Fig 5.-Apparent atrophy of retinal pigment epi· thelium in pa tient with vitiligo and night blind· ness.
ation of papilledema, diplopia, and left hyperreflexia. An elevated CSF pressure had been documented, but the cause had not been determined. No other ocular abnormalities were observed in this patient. Another patient showed evidence of optic atrophy that, by history, followed bilateral optic neuritis, the cause of which had not been determined. Papilledema was also observed in a patient with cutaneous melanoma and vitiligo, presumably on the basis of brain metastases from the melanoma. Fig 4.-Multifocal areas of apparently healed ch orioretinitis in patient with marked vitiligo.
form in 11 patients (10%) present study.
In
the
Chronic papilledema was observed in one patient, a 20-year-old black woman. A review of the patient's history revealed that she had been admitted to a university medical center three years earlier for evalu-
Changes in the Iris and Anterior Segment of the Eye Transmission of light through the iris (transillumination of the iris) was seen in seven patients, indicating a defect in the iris pigment epithelial layer. Although these changes were discernible with the slit-lamp biomicroscope, they were not observable by routine inspection of the iris. These changes
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were bilateral in both cases. Three additional patients were observed to have active iritis, as indicated by the presence of cells and flare in the anterior chamber. In two of these patients, the iris color was lighter in the right eye (heterochromia). Marked pigment disposition was noted on the corneal endothelium of another patient; the source was presumed to be the pigment epithelium. Two patients with no apparent ocular abnormalities volunteered that their irides had become lighter over the period of years during which they had had vitiligo. In both instances, relatives concurred in this observation. Unfortunately, neither patient had adequate color photographs to confirm or refute his impression. Although lens changes of various type and severity were noted in a number of the older patients examined, three patients (a 34-yearold man, 36-year-old man, and a 36-year-old woman) had posterior subcapsular cataracts with no evident cause, suggesting perhaps previous intraocular inflammation.
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A 24-year-old white woman had horizontal nystagmus that was congenital by history. This patient also had atrophy of the iris pigment epithelium, a strikingly prominent choroidal pattern, discrete depigmented lesions of the choroid and retinal pigment epithelium, and marked pigmentary dispersion at the periphery. One instance of bilateral congenital ptosis and one patient with Horner's syndrome were observed. In spite of the high incidence of thyroid disease, no problem with ocular motility was observed in these patients, and only one of the vitiligo group was seen with exophthalmos. Visual Function
In 107 of the 112 patients examined, the best corrected visual acuity was 20/30 or better in each eye. In three of the five patients with more severely decreased visual acuity, the chorioretinitis-like lesions appeared to be a factor in the deficit (Fig 6). In the remaining
Other External Eye Changes
Fifty-four patients were observed to have involvement of the lids by vitiligo. Twenty-two of these patients were also affected with one or more of the following: (1) discrete atrophic areas in the fundus, (2) atrophy of the iris pigment epithelium, and (3) iritis. Poliosis was present in 18 patients, and in 15 there was partial or total involvement of the brow by vitiligo. Seven patients were seen with strabismus, and four additional patients had been operated on earlier in life for strabismus. Five other patients gave a history of a sibling, parent, or child with strabismus.
Fig 6.-Unilateral macular lesion in 42.year-old patient with cutaneous melanoma and vitiligo.
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two patients, one had decreased vision as the result of diabetic retinopathy and the other amblyopia ex anopsia. Twelve patients had complaints of severe night blindness. Two of these patients had relatives with proven retinitis pigmentosa. One of these was a woman with a borderline normal amplitude on her electroretinogram who was suspected of being a carrier of the sex-linked type of retinitis pigmentosa. Another patient has a fundus picture consistent with fundus albipunctatus. Other Related Diseases
In Table 2, other diseases and abnormalities affecting the patients included in this study are listed. Those involving patients with pigmentary ocular changes are noted. Control Population
Three hundred seventy-one patients were seen consecutively at a chemical plant in the Ohio Valley. The a verage age of the patients examined was 56 years. The patients were predominantly white (95%). Examinations were carried out by the same observer and in an identical manner to those given in the vitiligo study. Pertinent findings are listed in Table 3. DISCUSSION
Most of the present understanding of vitiligo stems from studies regarding changes in the skin.2-4 In addition to the "typical" form of vitiligo, many variations can occur involving the skin and hair,
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TABLE
3
CONTROL STUDY
Total No. 371 Patients with discrete areas of 20 depigmentation and pigment hyperplasia of choroid and retinal pigment epithelium Atrophy of iris pigment epithelial 3 layer (excluding aphakic patients) Active uveitis 0 Prominent choroidal pattern 7 Pigment clumping in periphery 5 Peripapillary atrophy 5 Depigmented skin of lids 0 Poliosis 0 Fundus albipunctatus 1 Papilledema 0 1 Optic neuritis Optic atrophy 1
and these are considered in detail elsewhere. 2-4 The disorders in the noncutaneous structures involved in the syndromes associated with vitiligo may share some common disorder of autoimmunity with the skin changes. For the most part, these syndromes involve organs bearing little morphologic relation to the skin. Involvement of the eye in vitiligo is intriguing, in contrast, because the ocular structures share certain common morphologic and developmental relationships to the skin, particularly with regard to pigmented cells. The uvea of the eye (ie, the iris, ciliary body, and choroid) contains dendritic melanocytes morphologically similar to those seen in the dermis. However, certain differences exist that must be borne in mind. Unlike the skin, a second population of pigmented cells exists in the eye: the pigment
OCULAR ABNORMALITIES 1153 1979 epithelium. These are generally of meningeal irritation. This synbasal or cuboidal cells that, when drome reflects the integration of seen in flat section, have a hex- Vogt-Koyanagi syndrome37 .38 with agonal appearance and are among Harada's disease. 39 The Vogt-Koythe earliest cells in the body to anagi syndrome was originally debecome pigmented. The proper func- scribed as a severe, acute anterior tioning of the outer retina is de- uveitis associated with alopecia, pendent upon these cells. They are vitiligo, poliosis, and dysacousia. in many respects undifferentiated Harada's disease was described as cells and, in pathologic conditions, a posterior uveitis occurring with appear to be multipotential with signs of meningeal irritation, inregard to their ability to differen- creased protein level, and pleocytotiate into other tissues. This pop- sis of the CSF. In the relatively ulation of cells comprises the retinal "pure" form of these disorders, pigment epithelium, the pigment vitiligo occurs in more than 50% epithelium of the ciliary body, and of the Vogt-Koyanagi syndrome, the pigment epithelium of the iris. but in less than 10% of Harada's Thus, in considering pigment ab- disease.!l A review of reports of normalities in the eye, both the these disorders, however, reveals uveal melanocytes and pigment that many cases show considerable epithelial cells must be kept in overlap of the associated finding mind. of the Vogt-Koyanagi syndrome with Harada's disease.ll.l2.4o.43 A Disorders of the eye have been recent study of nine cases on file at reported in association with vitiligo the Armed Forces Institute of Pafor more than a century.12.l5.23-32 thology confirmed histopathologiSince vitiligo in these earlier years cally as well as clinically the lack was assumed to be the result of of a clear distinction between these syphilis, nervous and infectious disorders.H Histopathologically, indiseases, and malignancy, 33 the stances of granulomatous and nonchanges in the eye were attributed granulomatous uveitis were found to similar causes. Gradually it under each designation. The study became clear that these syndromes concluded that the term "uveoof vitiligo with ocular changes fell meningoencephalitic syndrome" into certain general categories. At- was a more useful term in categorophy of the iris pigment ("vitiligo rizing these disorders, as it disiridis") with associated depigmen- tinguished those cases which, in tation of the skin around the eye addition to uveal involvement, was recognized to be largely the showed evidence of meningoenresult of herpes zoster ophthal- cephalitic irritation; this appears to be the major differentiating micus. 34-36 point. The most widely studied association of vitiligo with eye disease From the standpoint of the ophis in the Vogt-Koyanagi-Harada thalmologic changes, sympathetic syndrome.! 2 This diagnosis has ophthalmia bears a close clinical generally come to be applied to and histopathologic relationship to patients with a chronic, bilateral, the Vogt-Koyanagi-Harada synexudate uveitis associated with drome, and an overlap between whitening of the eyes, hair, and these entities exists.26.28.30-32.37.44-48 eyelashes and with varying signs Instances of vitiligo occurring with VOLUME JUNE
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clear-cut sympathetic ophthalmia do occur. 12 .49 Differentiating features between sympathetic ophthalmia and the Vogt-Koyanagi-Harada syndrome include (1) the occurrence of ocular trauma that is always present in sympathetic ophthalmia but infrequent in the Vogt-KoyanagiHarada syndrome; (2) the racial incidence, with sympathetic ophthalmia being reported predominantly in white patients, whereas the Vogt-Koyanagi-Harada syndrome is frequent in Orientals, blacks, and deeply pigmented whites; and (3) sympathetic ophthalmia is always a granulomatous inflammation and shows other specific histopathologic distinctions as well. In the Vogt-Koyanagi syndrome, even in the eyes that retain normal vision, areas of depigmentation and clumping of pigment in the retina occur. These areas, described as a "sunset glow fundus" appear to bear a similarity to the pigmentary changes seen in the present study.4o.50-52 The presence of "albinotic fundi" developing in eyes with chorioretinitis and vitiligo, also similar to findings in the present case, have been observed. 27 .53 Aside from the Vogt-KoyanagiHarada group and sympathetic ophthalmia, uveitis and vitiligo have occurred in the absence of any predisposing conditions or in association with dysacousia or signs of meningeal irritation l l •12 ; in patients with cutaneous melanoma following bacille Calmette-Guerin (BCG) administration 54 ; in patients with cutaneous and ocular melanoma prior to or in the absence of BCG treatment2-4; and following the apparent introduction of cobaltous aluminate into the skin. 55 In patients with cutaneous melanoma, vitiligo may occur spontane-
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ously2.3 or follow immunostimulation with BCG54 or vaccinia. 56 The association of vitiligo with melanoma is important. Lerner and Nordlund 2 found that 20% of patients with melanomas have vitiligo and speculate that if patients with metastases could be kept alive for several years, vitiligo would develop in nearly all cases. It has been well demonstrated that the immune system plays an important role in the natural history of malignant melanoma and that both cellular and humoral factors directed against melanoma cells can be detected. 57- 59 It is probable that vitiligo in these cases is an immunologically mediated melanocyte destruction, which apparently can affect the ocular pigmented cells as well in certain cases. The chorioretinal heredodegenerations (tapetoretinal degenerations, neuroretinal degenerations) form an important class of visual disorders. Their cause and pathogensis is unknown, but pigmentary disturbances, particularly of the retinal pigment epithelium, may play a prominent role. Few of the reported cases of these disorders have shown an association with cutaneous vitiligo,20-24.6o-62 although how carefully this has been sought is questionable. Depigmentation of the eye or absence of pigmentation of the eye may occur without skin changes being present. The occurrence of ocular albinism is well known. 63 This is, however, not a well-defined condition, and it is difficult to draw the line between an extremely "blonde" iris and fundus and true albinism. Ocular albinism has also been described as complete, incomplete, and localized. Ocular albinism may be associated with various syndromes, including the Chediak-Higashi syndrome. 64 .65
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Although in most normal persons the irides are usually the same color, simple heterochromia has been found in many human populations, but is a relatively rare finding. 66 .67 It has not been possible to assess the incidence because slight differences in eye color are often overlooked, especially in lighteyed people. Absence of normal pigmentation may result from interruption of the normal adrenergic innervation to the eye. 68 A light iris color is seen in Waardenberg's syndrome. 69 Loss of iris pigment also occurs in Fuch's heterochromic iridocyclitis, which consists of a unilateral, chronic, mild iridocyclitis; heterochromia with the involved iris becoming the lighter iris; and cataract and glaucoma developing in the hypochromic eye.66.67.70 As a sequela of uveitis, endophthalmitis, and panophthalmitis, the iris may undergo atrophy and necrosis and have a lighter color as a result of the loss of pigment cells from the stroma and pigment epithelium. Various other conditions may result in atrophy of the iris and subsequent loss of pigment. These include chronic glaucoma, essential progressive atrophy of the iris, and senile change. Loss or alteration of the choroidal melanocytes and retinal pigment epithelium may occur in a number of primary and secondary degenerations and dystrophies, from toxic degeneration resulting from a variety of drugs, irra.diation and trauma, senile change, ischemia, and hemorrhage and inflammation often associated with systemic disease. The present study indicates that pigmentary changes of the eye may
1155
occur more commonly in association with vitiligo than the previous literature would indicate. Active uveitis (iritis and choroiditis) is undeniably an abnormal finding. Discrete areas of loss of choroidal pigmentation and retinal pigment epithelium with associated pigment clumping, as well as the finding of transillumination of the iris, may represent the sequelae of previous inflammation. It is possible that this inflammation occurs insidiously, and its activity and progression may be difficult to distinguish by routine clinical examination. The striking prominence of a choroidal pattern as well as the finding of patients with night blindness suggests a widespread defect in the retinal pigment epithelium that may have a genetic basis. Many of the patients showing ocular changes have received various forms of treatment for vitiligo. 3 Although numerous studies indicate no relation between administration of psoralen compounds or hydroquinone and ocular abnormalities, their possible role in inducing the changes presently described must be considered. One recent study has, however, demonstrated the development of a severe pigmentary retinopathy in birds following the combined oral administration of 8-methoxypsoralen given in conjunction with exposure to sunlight. 71 In the study of the eyes of patients with psoriasis receiving psoralen-ultraviolet light treatment, a high incidence of various pigmentary fundus changes has also been observed (T. Spivak, personal communication, August 1978). In summary, this study demonstrates the need for further ocular evaluation of patients with vitiligo
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as well as dermatologic evaluation of patients with uveitis and ocular diseases involving degeneration of the retinal pigment epithelium. Such information would permit a better understanding of the mechanism and relationships of the pigmentary changes in the skin and eye.
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