Vol. 110, No.5
Letters to the Journal
bocytopenia, agranulocytosis, and aplastic anemia.' Although the mechanisms for these toxicities are unknown, agranulocytosis and thrombocytopenia are considered to have an acute onset and are thought to be reversible after discontinuing the drug.! However, carbonic anhydrase inhibitor-induced aplastic anemia has an insidious onset, appears to be independent of dose, and is rarely reversible after medication is stopped." We treated a patient with primary open-angle glaucoma in whom aplastic anemia and platelet autoantibodies were diagnosed after she had used methazolamide for three months. In October 1987, a 74-year-old woman was given methazolamide 50 mg daily, for control of chronic open-angle glaucoma. Two months later she complained of decreased appetite and truncal pruritic rash. By February 1988, the patient noted fatigue and a 31-lb weight loss. The patient discontinued taking the methazolamide at this time. In May 1988, she was hospitalized with a low-grade fever and was found to have pancytopenia (platelet count, 69,000 cellsymm", hemoglobin level, 8.1 g/dl, and leukocyte count, 1,300 cells Zmrn"), pseudomembranous ulcerative colitis, a right pleural effusion, and Candida esophagitis. She had hypertension, which was not being treated, and denied recent exposure to toxic chemicals. During her initial hospitalization, she was treated with antibiotics, digoxin, random platelet transfusions (five times), and packed red blood cells (nine units). The patient was then transferred to Ohio State University Hospital. Physical examination disclosed ecchymotic areas on the arms at venipuncture sites, decreased breath sounds in the right lung base, sinus tachycardia, and a positive guaiac test for occult blood. Ophthalmic examination disclosed visual acuity of R.E.: 20/100 and L.E.: 20/50. Intraocular pressure was R.E.: 25 mm Hg and L.E.: 24 mm Hg. Cup/disk ratios were 0.4 in each eye. Results of laboratory tests performed at admission showed pancytopenia. Bone marrow biopsy specimens showed hypocellularity of less than 15% and no evidence of infiltrative disease. Cytogenetic analysis showed no mitotic figures. Histocompatibility testing disclosed neutrophil autoantibodies by agglutination and bound platelet autoantibodies by immunofluorescence. Additionally, the patient had strong antibody reactivity to several classes of HLA-A and HLA-B antigens, which is consistent with receiving multiple transfusions, and no alloantibodies to platelets.
571
Treatment consisted of reverse isolation, supportive transfusions, and eventually a four-day trial of high-dose immunoglobulin (500 mg/kg of body weight). There was no hematologic response, and a long-term regimen of oxymetholone was initiated. The patient was transferred back to her local hospital. One year later, the patient appeared to have a limited response to oxymetholone, but still requires occasional supportive transfusions. We believe the time course and medication history of this patient are strongly suggestive of methazolamide-induced aplastic anemia. Although the mechanism of carbonic anhydrase inhibitor-induced aplastic anemia is not known, it is thought to be a direct toxic effect on the hematopoietic stem cells by the drug, its metabolites, or both." It is also possible that this process is mediated by an immune mechanism. The membrane glycoproteins, GPIb, GPIlb, GPIlIa, and GPIX, have been implicated as a target for drug-dependent, platelet-specific antibodies." Although the platelet and neutrophil autoantibody status was not known before methazolamide treatment in our patient, the presence of these autoantibodies suggests that an immune-mediated toxic process was involved.
References 1. Fraunfelder, F. T., Meyer, S. M., Bagby, G. c.. [r., and Dreis, M. W.: Hematologic reactions to carbonic anhydrase inhibitors. Am. J. Ophthalmol. 100:79,1985. 2. Zimran, A., and Beutler, E.: Can the risk of acetazolamide-induced aplastic anemia be decreased by periodic monitoring of blood cell counts? Am. J. Ophthalmol. 104:654, 1987. 3. Pfueller, S. L., Bilston, R. A., Logan, B., Gibson, J. M., and Firkin, B. G.: Heterogeneity of drug-dependent platelet antigens and their antibodies in quinine and quinindine-induced thrombocytopenia. Involvement of glycoproteins Ib, Ilb, lIla, and IX. Blood 72:1155, 1988.
Epstein-Barr Virus Keratitis After a Chemical Facial Peel Stephen C. Pflugfelder, M.D., Andrew Huang, M.D., and Cecelia Crouse, Ph.D. Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine.
572
AMERICAN JOURNAL OF OPHTHALMOLOGY
November, 1990
This study was supported in part by Public Health Service grant R03 EY08193-01 (SCP), and National Eye Institute core grant EY02180. Inquiries to Stephen C. Pflugfelder, M.D., Bascom Palmer Eye Institute, 900 N.W. 17th St., Miami, FL 33136. Epstein-Barr virus has been cultured from corneal epithelial dendrites during infectious mononucleosis' and has been implicated as a cause of stromal keratitis." We treated a patient who developed bilateral keratitis after a chemical facial peel. Laboratory analysis suggested that the keratitis was caused by Epstein-Barr virus. A 66-year-old woman underwent a chemical facial peel in March 1988. A solution containing phenol, water, soap, and croton oil was applied to her face and eyelids. Four days after this procedure, the patient developed joint pain, fever, malaise, and blurred vision in the right eye. Several days later, she noted blurred vision in her left eye. Multiple small epithelial dendrites with underlying anterior stromal haze were noted in each eye. A regimen of trifluorothymidine solution eight times daily was begun. The dendrites resolved in four weeks. In June 1988, recurrent multifocal epithelial dendrites with pleomorphic, ringshaped anterior stromal opacities and edema developed in both corneas. A culture of the epithelial lesions was negative for herpes simplex and varicella zoster viruses, and no specific antigens for these viruses were detected by immunofluorescent staining of scraped corneal cells. Prednisolone phosphate 1 % eyedrops were begun, and the epithelial keratitis resolved. Another recurrence of dendritic epithelial keratitis developed in the right eye on Aug. 8, 1989. A culture of this lesion was again negative for herpes Simplex virus. Impression cytology of the lesion was performed. The epithelial cells at the perimeter of the dendrite on the membrane exhibited strong staining by an immunoperoxidase technique with a monoclonal antibody to Epstein-Barr virus early antigen (Fig. 1). Epstein-Barr virus DNA was detected in cells from this lesion by polymerase chain reaction using Epstein-Barr virus-specific primers and probes as previously described! (Fig. 1). Epstein-Barr virus serologic tests were consistent with previous exposure. The patient was treated with oral acyclovir (1 g per day) for six months. No further epithelial lesions have developed over a two-year follow-up period. Visual acuity decreased to R.E.: 20/100 and L.E.: 20/50 because of corneal stromal scarring and irregular astigmatism (Fig. 2).
Fig. 1 (Pflugfelder, Huang, and Crouse). Top, Autoradiogram of polymerase chain reaction products of DNA obtained from an Epstein-Barr virus-positive Burkitt's lymphoma cell line (Narnalwa, lane 1), scraping of the patient's corneal epithelial dendrite (lane 2), and an Epstein-Barr virus-negative cell line (BL-3, lane 3). Specimens were blotted on a nylon membrane, hybridized with a 32P-labeled probe, and exposed for two hours. Epstein-Barr virus primers and probe sequences from the Bam HI K region were used for polymerase chain reaction." Herpes simplex virus DNA was not amplified from this specimen by polymerase chain reaction. Bottom, Photomicrograph of nitrocellulose acetate membrane impression cytology of corneal epithelial dendrite in the right eye stained with a monoclonal antibody against Epstein-Barr virus anti-early diffuse (R 3.1) antigen (Dupont MEN, Boston, Massachusetts) using an irnmunoperoxidase technique (X 100). Herpes simplexand varicella zoster virus-infected cells did not stain with this antibody, whereas Epstein-Barr virusinfected cells (B95-8) induced to produce lytic antigens were strongly positive.
Facial herpetic infections have been reported after facial peels containing phenol and croton oil.' Our patient developed bilateral epithelial and stromal keratitis with features similar to those previously associated with Epstein-Barr virus! shortly after a facial peel containing these chemicals. Herpes simplex virus was not
Letters to the Journal
Vol. 110, No.5
573
5. Hausen, H. Z., O'Neill, F. J., and Freese, U. K.: Persisting oncogenic herpes virus induced by the tumour promotor TPA. Nature 272:373, 1978.
Conjunctivitis Caused by Thelazia californiensis
Fig. 2 (Pflugfelder, Huang, and Crouse). Irregular ring-shaped anterior stromal opacity that developed in the right eye after resolution of the dendritic epithelial keratitis. Similar lesions developed in the fellow eye.
detected on two separate occasions, and results of further laboratory investigations indicated that Epstein-Barr virus was the causative agent. The croton oil used in the peeling solution contained phorbol esters that have been found to induce Epstein-Barr virus replication in latently infected cells in concentrations less than 20 ng/m1. 5 It is possible that this compound caused corneal reactivation of Epstein-Barr virus, which Crouse and associates" have found to persist in approximately 10% of corneal epithelial specimens obtained from normal eyes from cadavers of patients seropositive for EpsteinBarr virus. Sight-threatening complications, such as those that occurred in our patient, indicate that the use of croton oil in facial peels should be used cautiously and after the patient has been informed of the possibility of activation of herpesviruses.
References 1. Wilhelmus, K. R.: Ocular involvement in infectious mononucleosis (letter to the editor). Am. J. Ophthalmol. 91:117, 1981. 2. Matoba, A. Y., Wilhelmus, K. R., and Jones, D. B.: Epstein-Barr viral stromal keratitis. Ophthalmology 93:746, 1986. 3. Crouse, C. A., Pflugfelder, S. c.. Pereira, I., Cleary, T., Rabinowitz,S., and Atherton, S. 5.: Detection of herpes viral genomes in normal and diseased corneal epithelium. Curro Eye Res. 9:569,1990. 4. Rapaport, M. J., and Kamer, F.: Exacerbation of facial herpes simplex after phenolic face peels. J. Dermatol. Surg. Oncol. 10:57, 1984.
Bruce I. Kirschner, M.D., James P. Dunn, M.D., and H. Bruce Ostler, M.D. Francis I. Proctor Foundation, University of California, San Francisco.
Inquiries to Bruce I. Kirschner, M.D., 1828 El Camino Real, Burlingame, CA 94010.
Thelazia species is a spiruroid nematode that can parasitize the mammalian conjunctival sac. Human thelaziasis is caused by two species, T. californiensis and T. callipaeda. Definitive hosts of T. californiensis include the dog, cat, horse, fox, coyote, sheep, bear, and deer. Flies, including Fannia species, are the intermediate host.' Human infections, which cause pain and watery conjunctivitis, are rare. 2,3 Thelazia callipaeda, which usually parasitizes the dog, is found in the Far East and India and may cause high human infection rates in some areas.' A 60-year-old woman had swelling, tearing, and redness of the right eye that began two weeks after she noted a small fly in that eye while hiking in the Sierra Mountain foothills of California. Treatment with erythromycin ointment and gentamicin eyedrops did not reduce her symptoms. One month after onset of symptoms, an examination disclosed papillary conjunctivitis, lacrimal gland fullness, and moderate bulbar conjunctival injection with 20/20 visual acuity (Fig. 1). Four cream-colored worms were noted on the surface of the eye, including one in the inferior fornix and three near the orifices of the lacrimal gland. These were removed with forceps (Fig. 2). Four days later, a single worm was removed from the lacrimal gland area. Both male and female T. californiensis worms were identified by parasitologists. The patient's symptoms resolved, and no further worms were identified on repeated examinations. Thelaziasis results when embryonated eggs in the ocular secretions of an infected host are ingested by flies, develop into larvae, and are subsequently deposited onto the conjunctiva of a new host. The worms eventually migrate along the ocular surface, which causes a foreign
Letters to the Journal
bocytopenia, agranulocytosis, and aplastic anemia.' Although the mechanisms for these toxicities are unknown, agranulocytosis and thrombocytopenia are considered to have an acute onset and are thought to be reversible after discontinuing the drug.! However, carbonic anhydrase inhibitor-induced aplastic anemia has an insidious onset, appears to be independent of dose, and is rarely reversible after medication is stopped." We treated a patient with primary open-angle glaucoma in whom aplastic anemia and platelet autoantibodies were diagnosed after she had used methazolamide for three months. In October 1987, a 74-year-old woman was given methazolamide 50 mg daily, for control of chronic open-angle glaucoma. Two months later she complained of decreased appetite and truncal pruritic rash. By February 1988, the patient noted fatigue and a 31-lb weight loss. The patient discontinued taking the methazolamide at this time. In May 1988, she was hospitalized with a low-grade fever and was found to have pancytopenia (platelet count, 69,000 cellsymm", hemoglobin level, 8.1 g/dl, and leukocyte count, 1,300 cells Zmrn"), pseudomembranous ulcerative colitis, a right pleural effusion, and Candida esophagitis. She had hypertension, which was not being treated, and denied recent exposure to toxic chemicals. During her initial hospitalization, she was treated with antibiotics, digoxin, random platelet transfusions (five times), and packed red blood cells (nine units). The patient was then transferred to Ohio State University Hospital. Physical examination disclosed ecchymotic areas on the arms at venipuncture sites, decreased breath sounds in the right lung base, sinus tachycardia, and a positive guaiac test for occult blood. Ophthalmic examination disclosed visual acuity of R.E.: 20/100 and L.E.: 20/50. Intraocular pressure was R.E.: 25 mm Hg and L.E.: 24 mm Hg. Cup/disk ratios were 0.4 in each eye. Results of laboratory tests performed at admission showed pancytopenia. Bone marrow biopsy specimens showed hypocellularity of less than 15% and no evidence of infiltrative disease. Cytogenetic analysis showed no mitotic figures. Histocompatibility testing disclosed neutrophil autoantibodies by agglutination and bound platelet autoantibodies by immunofluorescence. Additionally, the patient had strong antibody reactivity to several classes of HLA-A and HLA-B antigens, which is consistent with receiving multiple transfusions, and no alloantibodies to platelets.
571
Treatment consisted of reverse isolation, supportive transfusions, and eventually a four-day trial of high-dose immunoglobulin (500 mg/kg of body weight). There was no hematologic response, and a long-term regimen of oxymetholone was initiated. The patient was transferred back to her local hospital. One year later, the patient appeared to have a limited response to oxymetholone, but still requires occasional supportive transfusions. We believe the time course and medication history of this patient are strongly suggestive of methazolamide-induced aplastic anemia. Although the mechanism of carbonic anhydrase inhibitor-induced aplastic anemia is not known, it is thought to be a direct toxic effect on the hematopoietic stem cells by the drug, its metabolites, or both." It is also possible that this process is mediated by an immune mechanism. The membrane glycoproteins, GPIb, GPIlb, GPIlIa, and GPIX, have been implicated as a target for drug-dependent, platelet-specific antibodies." Although the platelet and neutrophil autoantibody status was not known before methazolamide treatment in our patient, the presence of these autoantibodies suggests that an immune-mediated toxic process was involved.
References 1. Fraunfelder, F. T., Meyer, S. M., Bagby, G. c.. [r., and Dreis, M. W.: Hematologic reactions to carbonic anhydrase inhibitors. Am. J. Ophthalmol. 100:79,1985. 2. Zimran, A., and Beutler, E.: Can the risk of acetazolamide-induced aplastic anemia be decreased by periodic monitoring of blood cell counts? Am. J. Ophthalmol. 104:654, 1987. 3. Pfueller, S. L., Bilston, R. A., Logan, B., Gibson, J. M., and Firkin, B. G.: Heterogeneity of drug-dependent platelet antigens and their antibodies in quinine and quinindine-induced thrombocytopenia. Involvement of glycoproteins Ib, Ilb, lIla, and IX. Blood 72:1155, 1988.
Epstein-Barr Virus Keratitis After a Chemical Facial Peel Stephen C. Pflugfelder, M.D., Andrew Huang, M.D., and Cecelia Crouse, Ph.D. Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine.
572
AMERICAN JOURNAL OF OPHTHALMOLOGY
November, 1990
This study was supported in part by Public Health Service grant R03 EY08193-01 (SCP), and National Eye Institute core grant EY02180. Inquiries to Stephen C. Pflugfelder, M.D., Bascom Palmer Eye Institute, 900 N.W. 17th St., Miami, FL 33136. Epstein-Barr virus has been cultured from corneal epithelial dendrites during infectious mononucleosis' and has been implicated as a cause of stromal keratitis." We treated a patient who developed bilateral keratitis after a chemical facial peel. Laboratory analysis suggested that the keratitis was caused by Epstein-Barr virus. A 66-year-old woman underwent a chemical facial peel in March 1988. A solution containing phenol, water, soap, and croton oil was applied to her face and eyelids. Four days after this procedure, the patient developed joint pain, fever, malaise, and blurred vision in the right eye. Several days later, she noted blurred vision in her left eye. Multiple small epithelial dendrites with underlying anterior stromal haze were noted in each eye. A regimen of trifluorothymidine solution eight times daily was begun. The dendrites resolved in four weeks. In June 1988, recurrent multifocal epithelial dendrites with pleomorphic, ringshaped anterior stromal opacities and edema developed in both corneas. A culture of the epithelial lesions was negative for herpes simplex and varicella zoster viruses, and no specific antigens for these viruses were detected by immunofluorescent staining of scraped corneal cells. Prednisolone phosphate 1 % eyedrops were begun, and the epithelial keratitis resolved. Another recurrence of dendritic epithelial keratitis developed in the right eye on Aug. 8, 1989. A culture of this lesion was again negative for herpes Simplex virus. Impression cytology of the lesion was performed. The epithelial cells at the perimeter of the dendrite on the membrane exhibited strong staining by an immunoperoxidase technique with a monoclonal antibody to Epstein-Barr virus early antigen (Fig. 1). Epstein-Barr virus DNA was detected in cells from this lesion by polymerase chain reaction using Epstein-Barr virus-specific primers and probes as previously described! (Fig. 1). Epstein-Barr virus serologic tests were consistent with previous exposure. The patient was treated with oral acyclovir (1 g per day) for six months. No further epithelial lesions have developed over a two-year follow-up period. Visual acuity decreased to R.E.: 20/100 and L.E.: 20/50 because of corneal stromal scarring and irregular astigmatism (Fig. 2).
Fig. 1 (Pflugfelder, Huang, and Crouse). Top, Autoradiogram of polymerase chain reaction products of DNA obtained from an Epstein-Barr virus-positive Burkitt's lymphoma cell line (Narnalwa, lane 1), scraping of the patient's corneal epithelial dendrite (lane 2), and an Epstein-Barr virus-negative cell line (BL-3, lane 3). Specimens were blotted on a nylon membrane, hybridized with a 32P-labeled probe, and exposed for two hours. Epstein-Barr virus primers and probe sequences from the Bam HI K region were used for polymerase chain reaction." Herpes simplex virus DNA was not amplified from this specimen by polymerase chain reaction. Bottom, Photomicrograph of nitrocellulose acetate membrane impression cytology of corneal epithelial dendrite in the right eye stained with a monoclonal antibody against Epstein-Barr virus anti-early diffuse (R 3.1) antigen (Dupont MEN, Boston, Massachusetts) using an irnmunoperoxidase technique (X 100). Herpes simplexand varicella zoster virus-infected cells did not stain with this antibody, whereas Epstein-Barr virusinfected cells (B95-8) induced to produce lytic antigens were strongly positive.
Facial herpetic infections have been reported after facial peels containing phenol and croton oil.' Our patient developed bilateral epithelial and stromal keratitis with features similar to those previously associated with Epstein-Barr virus! shortly after a facial peel containing these chemicals. Herpes simplex virus was not
Letters to the Journal
Vol. 110, No.5
573
5. Hausen, H. Z., O'Neill, F. J., and Freese, U. K.: Persisting oncogenic herpes virus induced by the tumour promotor TPA. Nature 272:373, 1978.
Conjunctivitis Caused by Thelazia californiensis
Fig. 2 (Pflugfelder, Huang, and Crouse). Irregular ring-shaped anterior stromal opacity that developed in the right eye after resolution of the dendritic epithelial keratitis. Similar lesions developed in the fellow eye.
detected on two separate occasions, and results of further laboratory investigations indicated that Epstein-Barr virus was the causative agent. The croton oil used in the peeling solution contained phorbol esters that have been found to induce Epstein-Barr virus replication in latently infected cells in concentrations less than 20 ng/m1. 5 It is possible that this compound caused corneal reactivation of Epstein-Barr virus, which Crouse and associates" have found to persist in approximately 10% of corneal epithelial specimens obtained from normal eyes from cadavers of patients seropositive for EpsteinBarr virus. Sight-threatening complications, such as those that occurred in our patient, indicate that the use of croton oil in facial peels should be used cautiously and after the patient has been informed of the possibility of activation of herpesviruses.
References 1. Wilhelmus, K. R.: Ocular involvement in infectious mononucleosis (letter to the editor). Am. J. Ophthalmol. 91:117, 1981. 2. Matoba, A. Y., Wilhelmus, K. R., and Jones, D. B.: Epstein-Barr viral stromal keratitis. Ophthalmology 93:746, 1986. 3. Crouse, C. A., Pflugfelder, S. c.. Pereira, I., Cleary, T., Rabinowitz,S., and Atherton, S. 5.: Detection of herpes viral genomes in normal and diseased corneal epithelium. Curro Eye Res. 9:569,1990. 4. Rapaport, M. J., and Kamer, F.: Exacerbation of facial herpes simplex after phenolic face peels. J. Dermatol. Surg. Oncol. 10:57, 1984.
Bruce I. Kirschner, M.D., James P. Dunn, M.D., and H. Bruce Ostler, M.D. Francis I. Proctor Foundation, University of California, San Francisco.
Inquiries to Bruce I. Kirschner, M.D., 1828 El Camino Real, Burlingame, CA 94010.
Thelazia species is a spiruroid nematode that can parasitize the mammalian conjunctival sac. Human thelaziasis is caused by two species, T. californiensis and T. callipaeda. Definitive hosts of T. californiensis include the dog, cat, horse, fox, coyote, sheep, bear, and deer. Flies, including Fannia species, are the intermediate host.' Human infections, which cause pain and watery conjunctivitis, are rare. 2,3 Thelazia callipaeda, which usually parasitizes the dog, is found in the Far East and India and may cause high human infection rates in some areas.' A 60-year-old woman had swelling, tearing, and redness of the right eye that began two weeks after she noted a small fly in that eye while hiking in the Sierra Mountain foothills of California. Treatment with erythromycin ointment and gentamicin eyedrops did not reduce her symptoms. One month after onset of symptoms, an examination disclosed papillary conjunctivitis, lacrimal gland fullness, and moderate bulbar conjunctival injection with 20/20 visual acuity (Fig. 1). Four cream-colored worms were noted on the surface of the eye, including one in the inferior fornix and three near the orifices of the lacrimal gland. These were removed with forceps (Fig. 2). Four days later, a single worm was removed from the lacrimal gland area. Both male and female T. californiensis worms were identified by parasitologists. The patient's symptoms resolved, and no further worms were identified on repeated examinations. Thelaziasis results when embryonated eggs in the ocular secretions of an infected host are ingested by flies, develop into larvae, and are subsequently deposited onto the conjunctiva of a new host. The worms eventually migrate along the ocular surface, which causes a foreign
