Suramin Keratopathy
Edward J. Holland, M.D., Cy A. Stein, M.D., Alan G. Palestine, M.D., Renato LaRocca, M.D., Chi-Chao Chan, M.D., Toichiro Kuwabara, M.D., Charles E. Myers, M.D., Rose Thomas, R.N., Nanette McAtee, R.N., and Robert N. Nussenblatt, M.D.
Vortex keratopathy occurred in six patients given high-dose intravenous suramin for adre- nocortical carcinoma. The corneal findings were bilateral and symmetric. Two patients complained of foreign-body sensation. One patient developed opacities of the anterior lens epithelium. Histopathologic studies of the eyes in one patient showed intraepithelial apical deposits in the cornea, conjunctiva, and lens epithelia. By electron microscopy, these deposits were found to be membranous lamel- lar inclusion bodies. These findings, as dem- onstrated by osmium-PAS staining and elec- tron microscopy, were similar to those in other drug-induced lipid storage diseases.
SURAMIN was originally developed as an antitrypanosomal agent. It inhibits many lysosomal enzymes and induces systemic mucopolysaccharidosis in animals when given in high doses. There have been few reports of ocular toxicity in dosages used for parasitic infections. Recently, however, toxic keratop- athy was reported in five AIDS patients treated with high-dose suramin.1 Three of these pa- tients had vortex keratopathy and two had epithelial and subepithelial opacities. The total dose of suramin in these patients ranged from 3.2 to 17.2 g.
Herein we report the clinical findings of vor- tex keratopathy in six patients treated with high-dose intravenous suramin for adrenocor- tical carcinoma. The corneal findings were simi-
From the Department of Ophthalmology, University of Minnesota, Minneapolis (Dr. Holland); and the Na- tional Cancer Institute (Drs. Stein, LaRocca, and Myers, and Ms. Thomas and Ms. McAtee) and the National Eye Institute (Drs. Palestine, Chan, Kuwabara, and Nussenblatt), National Institutes of Health, Bethesda.
Reprint requests to Edward J. Holland, M.D., Depart- ment of Ophthalmology, University of Minnesota, Box 493, 516 Delaware St. S.E., Minneapolis, MN 55455.
lar to those in Fabry’s disease or the drug- induced keratopathies of chloroquine, amiodarone, and chlorpromazine. The histo- pathologic, including osmium-PAS staining, and electron microscopic findings in one case are also described.
Patients and Methods
All patients (Table) were participants in a clinical trial conducted at the National Insti- tutes of Health of high-dose intravenous sura- min for the treatment of unresectable adreno- cortical carcinoma. Each patient had a pretreatment ophthalmic examination, includ- ing visual acuity, color vision, slit-lamp biomi- croscopy, tonometry, ophthalmoscopy with a dilated pupil, electroretinography, and electro- oculography. After initiation of treatment, each patient was seen weekly for measurement of visual acuity and slit-lamp biomicroscopy. Ophthalmoscopy with a dilated pupil, electroretinography, and electro-oculography were repeated at four to eight weeks.
Case Reports
Case 4
A 44-year-old man received suramin for adre- nocortical carcinoma; results of the pretreat- ment ophthalmic examination were normal. After three weeks of treatment, the patient developed vortex keratopathy in both eyes. During the fifth week, he experienced pain and photophobia in the left eye. Corneal findings included vortex keratopathy and a superficial punctate keratopathy, as well as a concentric ring of partially eroded epithelium 3 mm from the corneoscleral limbus in the left eye. Treat- ment with topical lubricants resulted in resolu-
| PATIENT NO., AGE (YRS), SEX | WEEKLY DOSE OF SURAMIN | SURAMIN SERUM LEVEL AT ONSET OF KERATOPATHY (MG/ML) | TOTAL DOSE AT ONSET OF KERATOPATHY (G) | CLINICAL FINDINGS |
|---|---|---|---|---|
| 1, 27, F | 1,400 mg/m2 | 185 | 10.9 | Vortex keratopathy and inferior superficial punctate kera- topathy in both eyes |
| 2, 45, M | 1,400 mg/m2 (3rd-wk dose not given) | 200 | 10.2 | Vortex keratopathy in both eyes |
| 3,31, F | 1,400 mg/m2 | 154 | 8.1 | Vortex keratopathy in both eyes |
| 4, 44, M | 1,400 mg/m2 (3rd-wk | 128 | 5.2 | Vortex keratopathy in both eyes |
| dose not given; 4th-wk dose, 800 mg/m2) | 170 | 9.0 | Peripheral epithelial erosions in left eye | |
| 5, 28, F | 1,400 mg/m2 (7th- and | 169 | 9.8 | Vortex keratopathy in both eyes |
| 8th-wk doses, 700 mg/m2) | 244 | 14.6 | Diffuse superficial punctate keratopathy and conjunctival injection in both eyes | |
| 164 | 15.8 | Stellate pattern of opacities in anterior lens epithelium in both eyes | ||
| 6,31, F | 1,400 mg/m2 every 4 days | 150 | 5.6 | Vortex keratopathy in both eyes |
tion of both the erosions and the superficial punctate keratopathy.
Case 5
A 28-year-old woman with normal results on a pretreatment ophthalmic examination was first noted to have epithelial deposits on both corneas one day after her fourth dose of sura- min. Over the next two weeks, the corneal epithelial pigmentation progressed and had the typical vortex appearance, similar to the other patients. After six weekly doses, the patient noticed foreign-body sensation and photopho- bia. On examination, conjunctival injection and superficial punctate keratopathy were noted as well as the vortex keratopathy. Her serum drug level was 244 ug/ml and the total dose was 14.6 g. Over the next two weeks, her dose was halved because of systemic side ef- fects and her ocular symptoms resolved. At eight weeks, fine pigment opacities in a stellate configuration were noted in the anterior lens capsules of both eyes. Over the next several weeks, the vortex keratopathy and anterior lens capsule opacities became more prominent. Results of color vision, ophthalmoscopy, elec- troretinogram, and electro-oculogram testing remained normal. During week 22, the patient died of hepatic complications secondary to tumor extension. Her eyes were obtained for light and electron microscopy.
Histopathologic examination-The left eye was immediately opened. No gross abnormalities were observed. The cornea was sectioned. One portion was immediately embedded in O.C.T. compound and frozen at -70 C, and the other portion was fixed in glutaraldehyde for one hour, then transferred to formalin. After fixa- tion, the eye was sectioned into three portions. One section underwent graded dehydration and methacrylate embedding of 2-um sections for routine light microscopic examination, the second was exposed to osmium for one hour, then graded dehydration and methacrylate em- bedding of 2-um sections for PAS staining was performed, and the third section underwent graded dehydration and was postfixed in osmi- um tetroxide and was then dehydrated and embedded in epoxy resin. Thin sections were stained with uranyl acetate and lead citrate for electron microscopic examination.
Results
All six patients receiving high-dose intrave- nous suramin developed a vortex epithelial keratopathy in both eyes. Initially, light golden deposits of the epithelium in the inferior one third of the cornea were seen. Progression to a darker brown pigmentation extending over the
entire cornea in a whorl-like pattern occurred in all patients (Fig. 1).
Two patients complained of mild pain and photophobia. One of these patients (Patient 4) developed a concentric ring of partially eroded epithelium in the periphery of the left cornea. The other symptomatic patient (Patient 5) de- veloped superficial punctate keratopathy. One other patient had clinical findings of superficial punctate keratopathy but was asymptomatic. Patient 5 also developed opacities of the ante- rior lens epithelium. This patient had the high- est peak serum level of suramin, 244 µg/ml, which was obtained two weeks before the lens changes. The total dose of suramin in this patient at the onset of lens opacities was 15.8 g, which was 4.9 g higher than any other patient in the study. The earliest onset of vortex kera- topathy was seen in Patient 4 who had a serum level of 129 µg/ml and a total dose of 5.2 g at the time the corneal changes were detected. The mean total dose at onset for all patients was 8.3 g.
In Patients 4 and 5, visual acuity decreased only while the epithelium was abnormal. Upon resolution of the irregular epithelium, vision returned to normal in both patients. Intraocu- lar pressure remained normal in all cases. None of the patients had any visible retinopathy, and no changes in color vision, electroretinogram, or electro-oculogram were detected.
Histopathologic examination of the eyes from Patient 5 disclosed small clusters of parti- cles in the paranuclear zone of the epithelial cells of the cornea (Fig. 2). These apical depos- its were also seen in the perivascular and epi-
thelial cells of the conjunctiva and lens epitheli- um (Fig. 3). These findings were best seen with osmium-PAS staining. Thickening of the base- ment membrane was noted in the retinal pig- ment epithelia at the fovea, but other retinal layers did not demonstrate any abnormalities. Small numbers of large cells (tumor cells) were seen in some choroidal vessels and stroma. Electron microscopic examination of the corne- al and conjunctival epithelial cells showed nu- merous lamellar inclusion bodies measuring 0.1 × 0.25 um, located mainly in the supranuclear zone of basal cells and wing cells (Fig. 4). Small numbers of lamellar inclusion bodies were also noted in the lens epithelium. The lens capsule had a multilaminar structure.
Discussion
Suramin has been used clinically since 1920 to treat trypanosomiasis and later to kill the adult onchocerciasis worm. It has recently been found to be an inhibitor of reverse transcriptase of the human immunodeficiency virus2 and a trial of suramin to treat AIDS patients was instituted.
One of the effects of suramin is adrenal toxic- ity.3 Therefore, this medication has also been under trial as a new therapy for conditions of adrenal cortical hyperfunction, specifically
unresectable adrenocortical carcinoma. In the present study, six patients with adrenocortical carcinoma were treated with high-dose intrave- nous suramin. All patients had pretreatment ophthalmic examinations that showed no ab- normalities; the patients were then examined weekly. Each patient developed bilateral vortex keratopathy similar to that seen in Fabry’s dis- ease and drug-induced lipid storage toxicity.
Three of the patients had additional findings of corneal epithelial toxicity: superficial punc- tate keratopathy in two patients and peripheral epithelial erosions in another. One patient de- veloped stellate opacities of the anterior lens capsule. This patient had the highest serum level and total dose of suramin. None of the patients developed subepithelial opacities as was described in three of five patients with AIDS who were treated with suramin.1 Addi- tionally, none of the patients in the AIDS study1 were reported to have superficial punc- tate keratopathy, corneal erosions, or lens opacities.
Side effects of suramin include nephrotoxic- ity, hepatotoxicity, pruritus, exfoliative derma- titis, arthralgias, and, rarely, anaphylaxis.4,5 Ocular findings in patients with onchocerciasis and trypanosoma treated with intravenous and oral suramin include blepharitis, conjunctivi- tis, photophobia, and lacrimation.6 The corneal findings described in our study have not been reported in the patients treated with suramin for parasitic disease. One explanation is that the total dose of suramin was higher and the rate of peak serum drug level was faster in both the adrenocortical carcinoma and AIDS pa-
tients than is typically seen in the treatment of onchocerciasis or trypanosomiasis. Other pa- tients receiving suramin might also develop
2
N
keratopathy and lens changes if the dose and rate of drug delivery were similar to that in our patients. Indeed, the severity of the keratop- athy appeared to be related to the total dose in both the adrenocortical carcinoma and the AIDS patients treated with suramin.
Suramin binds strongly to proteins and is concentrated within lysosomes, probably as a result of endocytosis of the suramin-protein complexes.7 It causes glycosaminoglycan and sphingolipid accumulation when given intrave- nously to the rat. Histopathologically, the findings simulate a lipid storage disease.8 The histopathologic and electron microscopic findings in the corneas from Patient 5 appeared similar to those seen in drug-related vortex keratopathy and Fabry’s disease. Methacrylate sections that have been PAS-stained after expo- sure to osmium demonstrate lipid deposition particles in the cornea, conjunctiva, and lens epithelia. These particles are lamellar inclusion bodies that have a lipid inclusion configuration in the cytoplasma. Similarly, electron microsco- py of the cornea in patients taking chloroquine and amiodarone, and patients with Fabry’s dis- ease demonstrates lipid-bearing, concentrically arranged intralysosomal inclusions in the cor- neal epithelium.9
Although not detected clinically, amiodarone has been found to induce lamellar inclusion bodies in the choroid and retina.10,11 In the present study clinical retinopathy was not de- tected. However, mild localized degeneration of the retinal pigment epithelium at the foveal zone was found histopathologically. As sura- min is used more frequently, long-term follow- up examinations will be needed to evaluate possible retinal toxicity.
References
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