Brief Reports

LIGHTNINGINDUCED CATARACT AND NEURORETINOPATHY CHANGXIAN YI, MD, YUANGBO LIANG, MD, OU JIEXIONG, MD, HONG YAN, MD From the Zhongshan Ophthalmic Center, Sun Yat-sen University of Medical Science, Guangzhou, China. The mechanism of injury from lightning strike is not exactly understood, although heating, direct strike, blunt injuries, voltage, resistance, pathway, and duration1 have been considered the most important factors. Various mechanisms may lead to different types of damage. We report here a case with a special neuroretinopathy that caused retinal edema around the papilla and not prominently on the macula. The damage may also involve the optic nerve, which may explain the unfavorable visual recovery. Case Report
A 32-year-old man was struck by lightning while working in a eld. He lost consciousness and woke up a few hours later with no vision, which lasted for several days. Ten days later, he was transferred to our department with visual acuity of hand motions at 10 cm in the right eye and 20/200 in the left. Intraocular pressure was 17 mmHg in the right and 20 mmHg in the left eye. There was some slight opacity both in subanterior and subposterior capsule of lens in both eyes (Figure 1). The conjunctiva, cornea, and anterior chamber were unremarkable. The posterior vitreous seemed to have more cells and the right eye was particularly hazy. The right fundus was vague (Figure 2A), but it was still possible to observe the change of the retina. The boundary of the papilla was clear and peripapillary retina was clearly white, indicating retinal edema. The ratio of diameters of the arteriole and vein at the optic disk border was 2:3. No exudate or bleeding was observed. The left fundus was clearly better with no obvious edema (Figure 2B). Some mild retinal folds similar to the macular retinoschisis could be recognized. Peripheral retina and vessels were ophthalmoscopically normal in both eyes. Findings of scotopic and photopic electroretinography (ERG) were abnormal in both eyes (Figure 3). In the right eye, the The authors have no proprietary interest in the contents of this article. Reprint requests: Changxian Yi, MD, Zhongshan Ophthalmic Center, Sun Yat-sen University of Medical Science, 510060 Guangzhou, PR China; e-mail: yichang@public.guangzhou.gd.cn scotopic blue icker ERG was extinguished and the scotopic white 30-Hz icker ERG was reduced in amplitude. In the left eye, both the photopic and scotopic ERG were reduced in amplitude. Pattern visual evoked response (PVER) was normal on the left side but of reduced amplitude on the right side (Figure 4). Examination with ERG, visual evoked potentials, and the unfavorable visual recovery indicated a combined injury of retina and optic nerve. There were no previous ocular diseases recorded and the patient believes that he had good vision until this happened. The systemic and laboratory examinations were unremarkable. After admission to the hospital, 50 mg of prednisone per day was given for 4 days. The adjunctive therapy included vitamins E and C; injection of vitamin B complex solution, which contains vitamins B1, B6, and B12; adenosine triphosphate; and inosine, together with some Chinese traditional medicine, such as panax notoginsang saponins, which was deemed to enhance the microcirculation of optic nerve. Two days after treatment, vision was hand motions at 20 cm in the right eye and 20/100 in the left eye. Three days later, the right eye had a vision of 20/200 and the left 20/100, which remained unchanged until discharge from hospital 17 days later.

Discussion Lightning injury has been associated with cataract, uveitis, punctate keratitis, cystic macular edema, and macular hole,1 but to our knowledge retinal lesions centered in the optic nerve with an obvious discrepancy between the eyes has not been reported. Several points drew our attention. First, the cataract was formed in both eyes, whereas the lesion on the two fundi was very different, which may imply that the direction of the lightning strike could play an important role in fundus pathologic change. The retinal lesion was prominent on the right side but minimal on the left eye. Second, the lesion that showed retinal edema surrounding the optic disk was obvious; however, the papilla had no swelling. It is difcult to evaluate ophthalmoscopically the damage to the optic nerve; however, according to the ERG, PVER, and the unfavorable visual recovery, we may conclude that the optic nerve was severely injured, in addition to the retinal damage. Third, with such heavy injury of the optic nerve and surrounding retina, the macula seemingly was spared. There have been several reports of macular lesions caused by lightning.2,3 Because of the high content of melanin granules of retinal pigment

RETINA, The Journal of Retinal and Vitreous Diseases, encourages authors to submit Brief Reports describing unusual ndings, new techniques, and new instruments. Material submitted for consideration in this section of the journal is done so with the assumption that the data provided do not duplicate previously published material and that the material has not been submitted for consideration elsewhere. Each author must sign a disclosure to this effect (see Instructions to Authors for complete wording of transfer letter). Brief Reports submitted for this section of the journal may be subjected to the standard review process that is applied to other material submitted to RETINA. Brief Reports should follow the requirements listed in the Instructions to Authors, with the following caveats: Brief Reports should not exceed 4 pages in length; no more than 5 references should be cited; and each Brief Report should include no more than 4 gures.

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Fig. 1. Color photograph of the lens, right eye. A, Mild opacity at subanterior capsule. B, Subposterior capsule opacity.

Fig. 2. Color photograph of the fundus. A, Vague appearance of the fundus owing to cataract and slightly hazy vitreous. Marked retinal edema surrounds the optic disk. Macular foveal reex was not visible; however, there was no obvious edema, hole, or other severe damage in the fovea. B, The left fundus was clearly visible. No edema was observed; however, mild macular fold was visible.

Fig. 3. Scotopic and photopic electroretinography (ERG) were abnormal in both eyes. A, The scotopic blue icker ERG was extinguished in the right eye. B, The scotopic white 30-Hz icker ERG was reduced in amplitude in the right eye. The photopic (C) and scotopic (D) ERG were reduced in amplitude in the left eye.

epithelium, macula injury was much more frequently observed. The changes include macular edema, macular hole, and retinal pigment epithelium damage. In this patient, however, the retinal injury is not centered in macula but optic nerve. Therefore the mechanism that occurred in this patient might be different from the thermal damage as proposed in the previous reports.1 4 The exact mechanism is unclear. There could be various explanations. There may have been retinal whitening that extended around the macular region and was absorbing 10 days later. There may have been an occlusion of the vessels owing to acute swelling in the optic head or for other reasons, such as transient vascular incompetence leading to the accumulation of extracellular uid in the macula or a kind of blunt injury or blunt injuryassociated mechanism such as shake wave. The retina surrounding the optic nerve is

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is well documented,1 4 and has also been reported with car travel.5 Here we report on a patient with intraocular gas who experienced ocular pain and vision loss while traveling via high-speed train in rapid ascent. Case Report
A 17-year-old man presented with a serous macula detachment associated with optic disk pit in the right eye. Vitrectomy with 14% peruoropropane gas injection was performed in Tokyo, roughly at sea level. One week postoperatively, visual acuity (VA) was count ngers, IOP was 21 mmHg, and a 60% intraocular gas ll was noted. The patient returned that day via Shinkansen (high-speed bullet train) to his home in Nagano (elevation 575 m). Approximately 80 minutes into the trip, after passing through a tunnel near Karuizawa (elevation 1025 m, roughly the highest point on the train route), the patient suddenly experienced sharp pain and blackout of vision in the operated eye, which resolved after 5 6 minutes. For his 2-week postoperative visit, the patient made an uneventful reverse journey from Nagano to Tokyo by Shinkansen. Examination revealed a VA of 20/100 and an IOP of 10 mmHg. The retina was reattached with a 50% gas ll. The patient returned that day to Nagano by Shinkansen and again experienced several minutes of transient amaurosis and ocular pain near Karuizawa. The next follow-up examination in Tokyo, 3 weeks postoperatively, revealed a 30% gas ll and a normal IOP. That day, returning home to Nagano by Shinkansen, the patient experienced a third and nal episode of transient amaurosis and ocular pain near Karuizawa. Four months postoperatively, the VA was 20/20 with a normal IOP.

Fig. 4. A, Pattern visual evoked response shows reduced amplitude on the right side. B, Pattern visual evoked response was normal on the left.

relatively thicker than other parts of the fundus, which is more subject to contusion-like damage. However, there also may be combined strong voltage, which insulted the optic nerve; therefore, visual recovery was uncertain. This case of lightning injury on fundus demonstrates that lightning damage could predominantly happen on the peripapillary retina. Besides thermal injury, other mechanisms could lead to retinal damage, which may be involved in this process. The visual prognosis may be poor in the form of retinal shock surrounding optic nerve even though the macula was free from severe damage. References
1. 2. 3. Bullock J. Was Saint Paul struck blind and converted by lightning? Surv Ophthalmol 1994;39:151160. Lagreze WD, Bomer TG, Aiello LP. Lightning induced ocular injury. Arch Ophthalmol 1995;113:1076 1077. Espaillat A, Janigian R, To K. Cataracts, bilateral macular hole, and rhegmatogenous retinal detachment induced by lightning. Am J Ophthalmol 1999;127:216 217. Juffe GJ, Handa JT. Lightning maculopathy. Retina 1994;14:169 172.

Discussion According to Boyles Law, the absolute IOP (AIOP atmospheric pressure IOP) decreases with the ambient atmospheric pressure, leading to an increase in intraocular gas volume. However, the drop in AIOP lags behind the drop in ambient atmospheric pressure, causing a relative increase in IOP.2 In our patient, pain consistently occurred when ascending from sea level to 1025 m over 80 minutes. By Lincoffs analysis, the gas volume would have expanded by the AIOP ratio (760 IOP)/(672.5 IOP).2 In the rst episode, this would translate to a 13% expansion, changing a 60% gas ll (2.40 mL) to a 68% gas ll (2.70 mL), assuming a 4 mL vitreous cavity volume in a phakic eye. Theoretically, the sudden 0.30 mL increase in intraocular volume could not be compensated for by choroidal compression, scleral expansion, and/or aqueous outow,2 and therefore increased IOP and pain resulted. Similar calculations for the second and third episodes show that the intraocular volume increased 0.26 mL and 0.15 mL, respectively. Interestingly, the rst time the reverse trip was taken, involving an asymptomatic ascent from 575 m to 1025 m, the trip would have been associated with only a 0.11 mL increase in intraocular volume. In summary, symptomatic increases in IOP can occur with high-speed train travel when ascending

4.

TRANSIENT AMAUROSIS ASSOCIATED WITH INTRAOCULAR GAS DURING ASCENDING HIGHSPEED TRAIN TRAVEL KEVIN M. SHIRAMIZU, MD, ANNABELLE A. OKADA, MD, AKITO HIRAKATA, MD From the Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan. Pain associated with elevated intraocular pressure (IOP) in patients with intraocular gas during air travel
Reprint requests: Akito Hirakata, MD, Department of Ophthalmology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan; e-mail: akito-h@t3.rim.or.jp

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rapidly. With intraocular gas use, it is important to ask patients about travel plans that include a signicant ascent in elevation, whether by airplane, train, or car. References
1. 2. Dieckert JP, OConnor PS, Schacklett DE, et al. Air travel and intraocular gas. Ophthalmology 1986;93:642 645. Lincoff H, Weinberger D, Reppucci V, Lincoff A. Air travel with intraocular gas I. The mechanisms for compensation. Arch Ophthalmol 1989;107:902906. Lincoff H, Weinberger D, Stergiu P. Air travel with intraocular gas II. Clinical considerations. Arch Ophthalmol 1989;107: 907910. Kokame GT, Ing MR. Intraocular gas and low-altitude air ight. Retina 1994;14:356 358. Gandorfer A, Kampik A. [Expansion of intraocular gas due to reduced atmospheric pressure. Case report and review of the literature.] Ophthalmologe 2000;97:367370.

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HUMIDIFIED AIR EFFECT ON PUPIL SIZE DURING FLUIDAIR EXCHANGE , MD, MASAHITO OHJI, MD, OSMAN EKI ATSUSHI HAYASHI, MD, XIAO Y. FANG, MD, SHUNJI KUSAKA, MD, YASUO TANO, MD From the Department of Ophthalmology, Osaka University Medical School, Suita, Osaka, Japan. Perioperative management of the pupil has long been a subject of considerable interest because adequate visualization of the retina during vitrectomy is vital for a successful outcome.1 Various methods have been suggested to manage small pupils that cannot be adequately dilated before surgery despite the best efforts with pharmacologic means or pupils that constrict during surgery because of ocular hypotony or manipulation of the iris.2 4 Conversely, it is a common observation that initially well dilated pupils become smaller during uidair exchange although the surgeon has avoided hypotony or direct trauma to the iris. We hereby report that the use of a humidier and exposure time are possible factors that affect pupil size in aphakic eyes during uidair exchange. Materials and Methods All Dutch pigmented rabbits used in the study were maintained in accordance with the Statement for the
The authors have no proprietary interest in any instruments or drugs used in the study. Reprint requests: Masahito Ohji, MD, Department of Ophthalmology, Osaka University Medical School, 2-2 Yamadaoka, E7 Suita, Osaka 565-0871, Japan; e-mail: ohji@ophthal.med. osaka-u.ac.jp

Use of Animals in Ophthalmic and Vision Research by the Association for Research in Vision and Ophthalmology. Fourteen pigmented rabbits underwent two-port pars plana lensectomy and vitrectomy after intramuscular injection of ketamine hydrochloride (35 mg/kg) (Ketalar, Parke-Davis, Tokyo, Japan) and xylazine hydrochloride (5 mg/kg) (Selektal, Bayer, Tokyo, Japan). One eye of each rabbit was randomly assigned to be used in the study. Pupils were dilated with four drops of 0.5% tropicamide and 0.5% phenylephrine hydrochloride (Mydrin-P, Santen, Osaka, Japan). Pars plana lensectomy was performed with a lens fragmentor. Removal of the lens cortex was accomplished by means of the vitrector keeping the anterior capsule intact initially. After vitrectomy, the anterior capsule was removed just before the standard uidair exchange. Total operative time was approximately 15 minutes until uidair exchange. Seven eyes (Group 1) were insufated with dry air with 50 mmHg air pump (Ten Thousand Posterior Segment System, Alcon Surgical, Irvine, CA) pressure. Dry air was generated by passing the normal room air through a silica gel contained closed system. Humidied air was used in the other seven eyes (Group 2) with 57 mmHg infusion pressure. Humidied air was obtained by passing the room air through clean, nonsterile water before it was instilled in the eye as described previously.6 The order of treating rabbits with humidied versus desiccated air was randomized. Because passing air through water causes a decrease in air pressure proportional to the height of water in the bottle6 (75 mm in this study), we set a preliminary experiment and obtained air owinfusion pressure curves for dry and humidied air. Based on this preliminary experiment, whereas in Group 1, the air insufator was set to 50 mmHg, air pump pressure was adjusted to 57 mmHg in Group 2 to get the same air ow. Thus, air insufated into the eye in dry and humidied air groups was equalized also in terms of actual infusion pressure. In both groups, infused air was allowed to ow out from the sclerotomy site opposite the infusion cannula through the backush needle. The surgeries were recorded with a videotape recorder (model SLV-9 9; Sony, Tokyo, Japan) at one standard illumination and a constant magnication of the operation microscope. Pupillary areas were computed in pixel units with a software program (NIH image version 1.61) from the videotapes and expressed as a percentage of the initial pupil area. Calculations were started immediately after taking out the uid from the vitreous cavity and from the anterior

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pupillary areas against time during uidair exchange in the groups. The pupils remained larger in the eyes exposed to humidied air compared with dry air (Group 2 versus Group 1) over the rst 7 minutes during uidair exchange (P 0.018). After that time, pupil sizes did not show any statistical difference throughout 20 minutes of uidair exchange (P 0.532). Figure 2 shows the pupil sizes in the groups at the third minute during uidair exchange (P 0.003). Discussion
Fig. 1. Comparison of pupillary areas against time during uidair exchange in Group 1 (eyes exposed to dry air with 50 mmHg infusion pressure) and Group 2 (eyes exposed to humidied air with 57 mmHg infusion pressure).

chamber by using a backush needle during uidair exchange. Each animal was killed with an intracardiac injection of 3 mL of pentobarbital sodium (Abbott Laboratories, North Chicago, IL) at the end of the operation. During the experiment, the humidity of the operating room air was 30%; that of dry air after passing through silica gel was 19%; and that of humidied air after passing through water was 73%. Mann-Whitney U tests were used to compare the data. Results Collapse of the anterior chamber or globe was not observed in any eye during surgery. Figure 1 shows

Recently, some adverse effects of normal room air used during uidair exchange have been reported.57 It is postulated that visual eld defects after vitrectomy may result from desiccation of the retina by room air during uidair exchange.5,6 Harlan et al7 have shown that posterior lens desiccation during uidair exchange may be the initiating factor in the pathogenesis of posterior lens changes after vitrectomy. Although we developed, in 1983, an automatic insufation regulator that can generate humidied air before instilling to the eye, we stopped using it because any adverse effect on visual outcome from using room air without humidication was not noted at that time.8 Because we thought the desiccation of the iris would also accelerate pupillary miosis during uidair exchange, we tested the effects of humidied and dry air on pupil size by setting all other conditions similar in this study. We used maximal dry and humidied air we could obtain to simulate every possible room air

Fig. 2. Pupil sizes at the third minute during uidair exchange. Dry air in an eye with 50 mmHg infusion pressure (left). Humidied air in an eye with 57 mmHg infusion pressure (right).

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condition. Additionally, because the infused air would rapidly become hydrated by residual uid in the eye,9 we let the infused air ow through an open backush needle. Pupils exposed to dry air started to constrict earlier than did those exposed to the humidied air. The difference was signicant during the rst 7 minutes of uidair exchange. In the humidier system we used, water molecules are distributed to the airstream.10 In this way, humidied air probably creates more of a physiologic environment for the iris structure in vitrectomized eyes. After 7 minutes, pupils of eyes receiving humidied air also began to constrict and the two groups did not show any difference. It seems that allowing the infused air to leave from the sclerotomy site through a backush needle could not maintain humidity of the iris any longer. From Figure 1, one can also interpret that air exposure time is another factor affecting pupil size. The desiccated air and humidied air caused miosis as time elapsed, but the humidied air constricted pupils to a size comparable to that of pupils exposed to desiccated air approximately 2 minutes more slowly, giving the surgeon approximately 2 extra minutes of pupillary dilation. Based on the data obtained from the current study, we can conclude that humidication of air infusion during vitrectomy slows the rate of miosis in an aphakic rabbit model.

10.

Peterson BD. Heated humidiers: structure and function. Respir Care Clin N Am 1998;4:243259.

HYPOPYON UVEITIS IN IMMUNOCOMPETENT PATIENTS TREATED FOR MYCOBACTERIUM AVIUM COMPLEX PULMONARY INFECTION WITH RIFABUTIN MITCHELL S. FINEMAN, MD,* JAMES VANDER, MD, CARL D. REGILLO, MD, STEVEN W. FINEMAN, MD, GARY C. BROWN, MD From the *Retina Vitreous Consultants, Pittsburgh, Pennsylvania; Retina Service, Wills Eye Hospital, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Although human immunodeciency virus (HIV)negative patients are increasingly being diagnosed with Mycobacterium avium complex (MAC) pulmonary infection and treated with multidrug regimens that include rifabutin and clarithromycin, there are few data regarding the development and clinical manifestations of iridocyclitis in these patients. We report the clinical ndings in two HIV-negative patients who developed acute hypopyon uveitis while being treated with rifabutin for MAC pulmonary infection and review the current literature. Case Reports Case 1
A 57-year-old woman weighing 57 kilograms with a 2-year history of pulmonary infection with MAC was started on a multiple drug regimen including ethambutol 400 mg per oral twice daily, clarithromycin 500 mg per oral twice daily, and rifabutin 300 mg per oral daily 2 months before presentation. One week before presentation, the patient noted symptoms consistent with a diffuse polyarthralgia syndrome but did not seek medical evaluation. One day before presentation, she noted the acute onset of pain, redness, and decreased visual acuity (VA) in the right eye. Evaluation by her general ophthalmologist revealed a VA of 20/40. The anterior Supported in part by the Vitreoretinal Research and Education Foundation, Philadelphia, Pennsylvania. None of the authors has a proprietary interest in any of the products mentioned in this article. Reprint requests: Mitchell S. Fineman, MD, Retina Vitreous Consultants, 3501 Forbes Avenue, Ste 500, Pittsburgh, PA 15213.

References
1. 2. 3. 4. 5. de Juan E. Management of pupil. In: Ryan SJ, Glaser BM, eds. Retina. St Louis: CV Mosby, 1994:22432246. Stern WH. Argon laser photomydriasis during vitrectomy surgery. Am J Ophthalmol 1985;99:366 367. Eckardt C. Pupillary stretching: a new procedure in vitreous surgery. Retina 1985;5:235238. de Juan E, Hickingbotham D. Flexible iris retractors. Am J Ophthalmol 1991;111:776 777. Welch JC. Dehydration injury as a possible cause of visual eld defect after pars plana vitrectomy for macular hole. Am J Ophthalmol 1997;124:698 699. Ohji M, Nao-i N, Saito Y, et al. Prevention of visual eld defect after macular hole surgery by passing air used for uid-air exchange through water. Am J Ophthalmol 1999; 127:62 66. Harlan JB, Lee ET, Jensen PS, et al. Effect of humidity on posterior lens opacication during uid-air exchange. Arch Ophthalmol 1999;117:802 804. Tano Y, Ueno N, Nishikawa N, et al. Automatic insufation regulator. Folia Ophthalmologica Japonica 1983;34:1880 1882. Rubin JS, Thompson JT, Sjaarda RN, et al. Efcacy of uid-air exchange during pars plana vitrectomy. Retina 1995; 15:291295.

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7.

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9.

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chamber revealed moderate brinoid inammation. Fundus examination was signicant for moderate vitreous cell and no focal areas of retinitis. Treatment with topical prednisolone acetate 1% in the right eye hourly and a topical cycloplegic agent was initiated. The following day, VA in the right eye had worsened to 20/60. Slit-lamp examination revealed marked conjunctival injection, signicant brin, and a 2-mm hypopyon in the deep anterior chamber. No fundus details were discernible owing to the anterior segment inammation. The patient was referred for B-scan ultrasonography, and this revealed moderate vitreous debris without evidence of retinal detachment. Liver function studies performed at this time were normal. Because the working clinical diagnosis at this time was possible bacterial endogenous endophthalmitis, a diagnostic vitreous tap followed by intravitreal injection of vancomycin 1 mg/0.1 mL and amikacin 400 mcg/0.1 mL was performed. Treatment with topical fortied vancomycin 50 mg/mL and tobramycin 15 mg/mL was initiated and topical steroids and cycloplegics were continued. The following day, VA was hand motions and the anterior chamber brinoid reaction had increased. The rifabutin was discontinued at this time. Over the next several days, the hypopyon decreased and the anterior segment and vitreous inammation diminished. Four weeks later, VA was 20/20, and the anterior chamber was deep and quiet. The amount of vitreous debris was minimal and the retina was entirely normal appearing. Vitreous cultures failed to grow any bacteria. There remained no evidence of ocular inammation or any systemic bacterial infection through 4 months of additional follow-up.

Case 2
A 72-year-old woman weighing 55 kilograms with chronic culture-proven MAC pulmonary infection was started on a multidrug regimen that included clarithromycin 500 mg per oral twice daily and rifabutin 300 mg per oral daily several weeks before presentation. Three days before presentation, she noted decreased vision and pain in the right eye. Her ocular history was negative. On examination, VA was 20/200 in the right eye and 20/30 in the left eye. Slit-lamp examination of the right eye revealed 3 keratic precipitates, 3 cell and are in the anterior chamber, and a 10% hypopyon. Fundus examination of the right eye revealed trace anterior vitreous cells and was otherwise normal. Slit-lamp biomicroscopy and fundus examination of the left eye had normal ndings. Diagnostic evaluation including rapid plasma reagin and uorescent treponemal antibodyantibody screen, ACE, Lyme titers, antinuclear antibodies, and complete blood count were negative or normal. Liver function studies were not performed. Treatment was initiated with topical prednisolone acetate 1% hourly and scopolamine 0.25% three times a day in the right eye. The rifabutin was continued because it was believed to be essential for treatment of the pulmonary infection. One week later, VA in the right eye had improved to 20/100, the hypopyon was no longer present, and the anterior chamber cells were present in trace amounts. One month later, VA in the right eye had improved to 20/50. The patient continued to use topical prednisolone acetate 1% four times daily while taking rifabutin. Eighteen months later, she was no longer using any oral or topical medications and examination revealed a VA of 20/25 in the right eye without signs of ocular inammation.

Discussion Mycobacterium avium complex, a species of nontuberculous mycobacteria, includes the two species M

avium and M intracellulare. Infection in HIV-positive patients primarily presents as disseminated disease in patients with low CD4 lymphocyte counts and is associated with an increased mortality. Infection in HIV-negative patients occurs less commonly and usually manifests as one of three clinical presentations: elderly men with chronic obstructive pulmonary disease who present with cough, weight loss, and cavitary lesions; patients with underlying bronchiectasis; nonsmoking women over 50 years old with an interstitial pattern on chest x-ray.1 The presence of MAC in this last group was previously thought to represent colonization, but is now recognized as a true infection. The diagnosis of MAC infection is established by clinical and radiologic ndings in conjunction with sputum cultures, smears, bronchial washings, or lung tissue biopsy. Treatment of MAC infection in patients with and without HIV disease is similar and involves multiple drugs, increasing the risk of drug toxicity. Initial treatment in HIV-negative adults consists of a minimum three-drug regimen that includes a macrolide antibiotic (clarithromycin or azithromycin), ethambutol, and a rifamycin agent (rifabutin or rifampin).1 Treatment is continued until the patient is culture-negative on therapy for 1 year. Although treatment with clarithromycin alone is effective, the risk of emergence of drug-resistant bacteria precludes monotherapy.2 Rifabutin is the preferred rifamycin because it is more active in vitro against MAC than rifampin.3 This multidrug treatment regimen is approximately 90% effective in converting consecutive monthly sputum cultures to negative for at least 1 year.1 Most cases of uveitis associated with the use of rifabutin have been reported in HIV-positive patients.4 Grifth and associates5 reported the rst two cases of uveitis in HIV-negative patients in a study involving 26 patients treated for MAC pulmonary disease with a multidrug regimen that included rifabutin in combination with ethambutol, streptomycin, and either clarithromycin or azithromycin. In this series, the most severe adverse effects were diffuse polyarthralgia syndrome in 19% and anterior uveitis in 8% of patients. The uveitis was seen only in those patients randomized to the regimen that included clarithromycin. However, no details regarding the clinical presentation or treatment of the patients with uveitis were reported. Jewelewicz and associates6 reported an 8-year-old boy who developed bilateral uveitis while on a multidrug regimen including rifabutin and clarithromycin after bilateral lung transplantation. Although this patient was not HIV-positive, he was immunosuppressed. Previous studies involving HIVpositive patients treated for MAC infection reported a

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40% incidence of anterior uveitis when doses of clarithromycin higher than 500 mg twice daily were used in combination with doses of rifabutin higher than or equal to 600 mg per day.7 When the rifabutin dose was reduced to 300 mg per day, the incidence of uveitis fell to 6%.8 Clarithromycin is thought to increase rifabutin levels and toxicity by inhibiting the metabolism of rifabutin via the cytochrome P 450 system.9 Based on these ndings, it is recommended that rifabutin doses should not exceed 300 mg/d in regimens that contain clarithromycin.1 Because azithromycin has not been shown to increase rifabutin levels, it may be a safer choice in patients at risk for rifabutin toxicity. Preliminary studies also suggest that azithromycin-containing multidrug regimens for MAC infection may be efcacious when administered intermittently.10 Both patients in our series presented with severe uveitis, and one patients clinical picture prompted treatment for presumed endogenous bacterial endophthalmitis before the association with rifabutin treatment was realized. Most clinicians associate rifabutininduced uveitis with the treatment of MAC infection in HIV-positive patients; therefore, the clinical suspicion may not be as high when evaluating HIV-negative patients. The patients described herein were being treated with the currently recommended multidrug regimens in recommended doses and still developed severe uveitis. Both patients were women and had relatively low body mass, a possible predisposing factor. Liver function was normal in the one patient who was tested, suggesting that abnormal liver function is not a prerequisite for this adverse event. As better clinical recognition and increased culturing lead to higher prevalence rates of MAC infection in HIVnegative patients, more patients will be diagnosed with this condition and treated with rifabutin-containing drug regimens. Therefore, rifabutin-induced uveitis should be considered in any patient who presents with ocular inammation and has a history of MAC infection, regardless of systemic immune status. References
1. Medical Section of the American Lung Association. Diagnosis and treatment of disease caused by nontuberculous mycobacteria (ofcial statement of the American Thoracic Society). Am J Respir Crit Care Med 1997;156:S125. 2. Wallace RJ Jr, Brown BA, Grifth DE, et al. Initial clarithromycin monotherapy for Mycobacterium aviumintracellulare complex lung disease. Am J Respir Crit Care Med 1994;149: 13351341. 3. Skinner MH, Blaschke TF. Clinical pharmacokinetics of rifabutin. Clin Pharmacokinet 1995;28:115125. 4. Saran BR, Maguire AM, Nichols C, et al. Hypopyon uveitis in patients with acquired immunodeciency syndrome treated for systemic Mycobacterium avium complex infection with rifabutin. Arch Ophthalmol 1994;112:1159 1165.

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10.

Grifth DE, Brown BA, Girard WM, et al. Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the treatment of Mycobacterium avium complex lung disease. Clin Infect Dis 1995;21:594 598. Jewelewicz DA, Schiff WM, Brown S, et al. Rifabutinassociated uveitis in an immunosuppressed pediatric patient without acquired immunodeciency syndrome. Am J Ophthalmol 1998;125:872 873. Shafran SD, Deschenes J, Miller M, et al. Uveitis and pseudojaundice during a regimen of clarithromycin, rifabutin, and ethambutol. MAC Study Group of the Canadian HIV Trials Network [letter]. N Engl J Med 1994;330: 438 439. Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprooxacin. Canadian HIV Trials Network Protocol 010 Study Group. N Engl J Med 1996;335:377383. Hafner R, Bethel J, Power M, et al. Tolerance and pharmacokinetic interactions of rifabutin and clarithromycin in human immunodeciency virusinfected volunteers. Antimicrob Agents Chemother 1998;42:631 639. Grifth DE, Brown BA, Murphy DT, et al. Initial (6-month) results of three-times-weekly azithromycin in treatment regimens for Mycobacterium avium complex lung disease in human immunodeciency virusnegative patients. J Infect Dis 1998;178:121126.

BACTERIAL GROWTH IN PERFLUOROCARBON LIQUIDS: An in vitro Study CARLOS A. MOREIRA, JR, MD, AGOSTINHO BRYK, JR, MD, MARIA C. KOMATSU, MD, LECIANA C. VANZO, MD From the Department of Ophthalmology, Federal University of Paran, Brazil. The use of peruorocarbon liquids (PFCL) in vitreoretinal surgery was rst reported by Chang et al in 1987.1,2 Since then, it has increasingly been used by retinal surgeons for many purposes.3,4 These substances have proven to be useful in vitreoretinal surgery because of their favorable physical and chemical properties, which provide good surgical performance,5 in that they are easily injected and removed. However, small amounts of PFCL (blisters or droplets) may
Presented at the XXII Club Jules Gonin Meeting, Taormina, Italy, September 2 6, 2000. The authors do not have a proprietary interest in the study. Reprint requests: Carlos Moreira, Jr., MD, Rua Fernando Simas, 1010 Curitiba, Brazil 80430-190.

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Table 1. Quantication of Pseudomonas aeruginosa (ATCC 27853) Growth in Different Culture Media Peruoro-octane Time, h 0 72 168 240 Flask 1 12* 00* 00* 0 Flask 2 36* 00* 00* 0 Number of Colonies Trypticase Soy Broth Abundant Abundant Abundant Abundant /IV /IV /IV /IV 0.9% Saline Abundant Abundant Abundant Abundant /IV /IV /IV /IV

* Colony counting from micropipette inoculation on blood agar plates.

remain in the vitreous cavity or under the retina6 after surgery. The vast use of PFCL in vitreoretinal surgery and the possibility of droplets of this substance remaining in the vitreous cavity called to our attention the possibility of bacterial contamination and risks to patients and surgeons. Therefore, it is important to verify the potential for contamination of PFCL. It has been shown that Staphylococcus aureus and Pseudomonas aeruginosa are common pathogenic agents in intraocular infections.7 The goal of this study was to determine the growth of S aureus and P aeruginosa in peruoro-octane, one of the most widely used PFCL in vitreoretinal sugery.5,8 Materials and Methods Peruoro-octane Peruorocarbon liquids are compounds belonging to a class of puried peruoropropylene oxide oligomers with characteristic physicochemical properties. These compounds are immiscible with water, transparent, colorless, chemically inert, odorless, nonammable, of low viscosity, and insoluble in organic solvents, with high specic gravity.5,8 They are optically transparent and their refraction index is similar to that of the normal vitreous body (i.e., 1.29), a feature that permits their easy intraocular observation during intraoperative maneuvers.2,8 The low viscosity (23 centistokes at 25C) and insolubility in standard organic solvents are other favorable properties.2,8 Procedure Three culture media were used: peruoro-octane (3 M, St. Paul, MN), tryptic soy and casein digestion broth (TSB), and 0.9% saline solution. Five milliliters of peruoro-octane were divided into 1-mL asks numbered 1 through 5. A full colony of P aeruginosa (ATCC 27853) was inoculated into Flasks 1 and 2, and a full colony of S aureus (ATCC 25932) was inoculated into Flasks 3 and 4. Flask 5 served as a control with no contamination. Full bac-

terial colonies were used because peruoro-octane is not miscible with water. To determine the bioavailability of such microorganisms, a colony of each bacteria was inoculated into a ask containing 1 mL TSB, a culture medium rich in nutrients favorable to bacterial proliferation. The same procedure was repeated to contaminate a 0.9% saline solution to compare the results obtained with peruoro-octane with those obtained with another medium devoid of nutrients. All solutions were homogenized in a Vortex apparatus at 1,000 rotations per minute and later kept in an incubator at 37C for 10 days. Replating was performed with a calibrated loop at 1:1000 and with a micropipette (0.05 mL) at time zero and 72 hours, 168 hours, and 240 hours after contamination. The material was manipulated under a laminar ow hood throughout the procedure to prevent external contamination. Bacterial growth was determined by colony counting on blood agar plates 24 hours after each replating.

Results In peruoro-octane, we observed the growth of one colony of P aeruginosa in Flask 1 and of three colonies in Flask 2 at time zero. When a micropipette was used for replating, Flask 1 yielded two colonies and the other ask yielded six. At all other times, however, no growth of the bacteria was observed. In contrast, in TSB and 0.9% saline solution, growth was abundant at all time points (Table 1). At time zero, one colony of S aureus was detected in Flask 3 and 16 colonies were detected in Flask 4. When replating was performed with a micropipette, the results were four and two colonies, respectively. During the subsequent hours, S aureus growth was no longer observed in peruoro-octane. A reduction in S aureus growth occurred in TSB and saline over time, but even so, growth was abundant (Table 2). No bacterial proliferation was observed at any time point in the uncontaminated control ask (Flask 5).

BRIEF REPORTS Table 2. Quantication of Staphylococcus aureus (ATCC 25923) Growth in Different Culture Media Peruoro-octane Time, h 0 72 168 240 Flask 3 14* 00* 00* 00* Flask 4 162* 00* 00* 00* Number of Colonies Trypticase Soy Broth Abundant Abundant Abundant Abundant /IV /IV /IV /IV 0.9% Saline Abundant Abundant Abundant Abundant

535

/IV /IV /IV /IV

* Colony counting from micropipette inoculation on blood agar plates.

Discussion As expected, the highest bacterial growth occurred in soy and casein digestion broth, which is a culture medium favorable to bacterial growth. A calibrated loop and micropipette were used to get peruorooctane samples from Flasks 1 to 5, because of the high specic gravity of peruoro-octane. Replating with a micropipette was added to the procedure to make sure that samples obtained from asks with peruoro-octane were of adequate amount. Although P aeruginosa are highly resistant bacteria capable of developing even in extremely unfavorable media, they did not grow in any of the peruorooctane samples under study, except at time zero, which corresponds to the time of inoculation. Lack of nutrients alone would not be sufcient to explain the absence of growth of these bacteria in an adequate manner because we showed that the bacteria grew abundantly even in 0.9% saline solution. There was no S aureus growth in peruoro-octane except at time zero. The staphylococci grew abundantly in 0.9% saline, although growth was slightly reduced after 168 hours (7 days). No bacterial proliferation occurred in the peruoro-octane sample used as an uncontaminated control, showing that the peruoro-octane being used was a sterile product and that no external contamination had occurred during manipulation of the substance. These in vitro results have shown that peruorooctane is not a favorable medium for bacterial growth and therefore is not prone to bacterial contamination during vitreoretinal surgery. The presence of small droplets of PFCL is relatively frequent after complex vitreoretinal procedures, and it appears that PFCL may not represent a source of infection. References
1. Chang S, Zimmerman NJ, Iwamoto T, et al. Experimental vitreous replacement with peruorotributylamine. Am J Ophthalmol 1987;103:29 37. Chang S. Low viscosity liquid uorochemicals in vitreous surgery. Arch Ophthalmol 1987;103:38 43. Coll GE, Chang S, Sun J, et al. Peruorocarbon liquid in the 4.

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7. 8.

management of retinal detachment with proliferative vitreoretinopathy. Ophthalmology 1989;102:630 639. Moreira CA Jr, Uscocovich CE, Moreira AT. Experimental studies with peruoro-octane for hemostasis during vitreoretinal surgery. Retina 1997;17:530 534. Bourke RD, Cooling RJ, Simpson RN, et al. The stability of peruoro-N-octane during vitreoretinal procedures. Arch Ophthalmol 1996;114:537544. Queiroz JM Jr, zler SA, Moreira CA Jr, et al. Histopathologic evaluation of subretinal peruorocarbon liquids. Invest Ophthalmol Vis Sci 1991;32:881. Abstract. Forster RK. Etiology and diagnosis of bacterial postoperative endophthalmitis. Ophthalmology 1980;87:313319. Queiroz J Jr, zler SA, Liggett P, et al. Experimental intraoperative use of peruorotributylamine, peruorodecaline, and peruorooctane. Arq Bras Oftal 1992;55:112116.

BILATERAL MULTIPLE RETINAL HYPERFLUORESCENT DOTS IN A PRESUMED RICKETTSIA CONORII INFECTION HALUK ESGIN, MD,* FILIZ AKATA, MD From the Departments of *Ophthalmology and Clinical Microbiology and Infectious Disease, University Hospital Trakya, Edirne, Turkey. In rickettsial diseases, various vascular lesions can be seen in the retina and optic disk. Optic nerve head and retinal edema, intraretinal hemorrhages, cotton-wool spots, retinal white inltrates, retinal vasculitis, and vascular occlusions have been previously reported.13 We report a case with small retinal hyperuorescent dots by angiography, which resemble multiple evanescent white dot syndrome (MEWDS), in a Rickettsia conorii infection.
This study has not been published or presented elsewhere. The authors have no proprietary interests related to this study. Reprint requests: Haluk Esgin, MD, Trakya niversitesi Tp Fakltesi, Gz hastalklar, Anabilim dal, 22030 Edirne, Turkey.

2. 3.

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Fig. 1. Fundus photograph of the right eye with cotton-wool spots in the peripapillary region, 12 days after a tick bite.

Fig. 3. Midphase of uorescein angiogram of the left eye shows discrete, punctuate focal areas of leakage in the deep retina at the posterior pole and leakage from the peripapillary capillaries.

Case Report
A 51-year-old man developed shaking chills, shivering, fever, headache, and a sore throat 5 days after a tick bit him while he was working in his garden. Three days after the fever started, a maculopapular skin rash appeared over his body, including his palms and soles. The patient was admitted to a local hospital for 2 days and was treated only with antipyretics. Because of his increasing body temperature (40.5C) and generalized skin rash, he was transferred to our hospital. The patient had a history of taking care of his neighbors dog in the same garden. On physical examination, a tick bite in his left buttock, 1 1 cm in size, and a black lesion associated with eschar (tache noire) were identied. Although the patient had no complaints regarding his eye, he was sent for a routine ophthalmologic examination because of his Type II diabetes mellitus, controlled only by diet. Visual acuity was 20/20 in both eyes. Findings from slit-lamp examination were normal. Fundus examination showed three cotton wool spots in the right eye (Figure 1) and two cotton-wool spots in the left eye. Signs of vasculitis were found in the superotemporal quadrant of the right eye (Figure 2) and inferior quadrant of the left eye periphery. No hemorrhages were seen in the retina or choroid in either eye, and no inammatory vitreous reaction or opacities were found. Fluorescein angiography of both eyes showed leakage from the dilated peripapillary capillaries, uorescein blockage caused by the cotton-wool exudates, and vascular uorescein leakage in the periphery caused by vasculitis. Also, punctuate hyperuorescence in the posterior pole, which was more prominent in the left eye (Figure 3), was seen. No signs of diabetic retinopathy were observed. Results of the following laboratory tests were abnormal: erythrocyte sedimentation rate (67 mm in the rst hour), hematocrit (35% consistent with anemia of chronic disease), platelet counts (146,000/mm3 on the rst hospital day and 136,000/mm3 on the second hospital day), fasting blood glucose (257 mg/dL), alanine transferase (ALT) (63 U/L), aspartate transferase (AST) (101 U/L), and lactic dehydrogenase (LDH) (1,043 U/L). C-reactive protein was not assessed. Abdominal ultrasonography showed an enlarged

Fig. 2. Midphase of uorescein angiogram of the right eye shows peripheral vasculitis in the superotemporal quadrant of the retina.

Fig. 4. Fundus photograph of the right eye 2 months after the initial examination.

BRIEF REPORTS
spleen (141 mm). The most commonly used test for rickettsioses is the Weil-Felix agglutination test, which is an old test with low sensitivity and specicity. A denite increase of the Weil-Felix reaction from negative (OX19, OX2, and OXK) to 1/160 (OX19) and 1/320 (OX2) was observed within 10 days. Serology for Brucella, Salmonella, Treponema pallidum, hepatitis B and C, human immunodeciency virus, Epstein-Barr virus, and toxoplasmosis were all negative. The IgG antibodies for hepatitis A, rubella virus, cytomegalovirus, and herpes simplex Type I were positive. The patient was treated with 100 mg of doxycycline twice daily for 10 days. The fever decreased in the third day, and the skin rash decreased by the seventh day after the onset of treatment. Platelet count and AST, ALT, and LDH levels returned to normal after 10 days. An oral hypoglycemic agent was prescribed for his diabetes mellitus and the blood glucose level was regulated. Two months after the initial examination, all ophthalmic and angiographic signs of peripapillary leakage and punctuate hyperuorescent areas resolved with no chorioretinal scar (Figure 4).

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In acute posterior multifocal placoid pigment epitheliopathy, uorescence blockage occurs in the early phases of the angiogram. Conversely, the lesions in acute retinal pigment epitheliitis are hypouorescent surrounded with hyperuorescence. With the lack of the vitreous reaction and the clinical course, we excluded birdshot retinochoroidopathy. Multiple evanescent white dot syndrome cannot be excluded by uorescein angiography ndings, but with history and serology, we excluded it. In this report, we showed small retinal hyperuorescent punctuate lesions by angiography in R conorii infection, which were similar to the presentation of MEWDS. References
1. Lukas JR, Egger S, Parshalk B, et al. Bilateral small retinal inltrates during rickettsial infection. Br J Ophthalmol 1998; 82:12171218. Alio J, Roiz-Beltran R, Herrero-Herrero JI, et al. Retinal manifestations of Mediterranean spotted fever. Ophthalmologica 1987;195:3137. Sulewski ME, Green WR. Ocular histopathologic features of a presumed case of Rocky Mountain spotted fever. Retina 1986; 6:125130. McDade JE. Rickettsial diseases. In: Hausler WJ, Sussman M, eds. Topley & Wilsons Microbiology and Microbial Infections, 9th ed. London: Arnold, 1998;3:9951011. Walker DH, Raoult D. Rickettsia rickettsii and other spotted fever group rickettsiae (Rocky Mountain spotted fever and other spotted fevers). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennetts Principles and Practice of Infectious Disease, 4th ed. New York: Churchill Livingstone, 1995:17211727.

Discussion Based on the patients history, clinical signs, and serology, we concluded that the illness presented was associated with rickettsiae. Members of the genus Rickettsia have been divided into three groups of antigenically related species: typhus, scrub typhus, and spotted fever.4 The patients activity in taking care of the neighbors dog and tick bite history, the incubation time, and the marked titer increase of OX19 and OX2 when assessed with epidemiologic ndings directed us toward an infectious agent of the spotted fever group, most likely R conorii, which occurs in the Mediterranean area, Africa, parts of Europe, and India. As in other Mediterranean countries, in Turkey, Mediterranean spotted fever caused by R conorii is endemic. In ticks, R conorii is maintained transovarially and is transmitted to humans by the dog tick Rhipicephalus sanguineus, and the main reservoir of infection is in domestic dogs, rabbits, and rodents. A careful clinical examination may show a tache noire, which facilitates the clinical diagnosis.5 In rickettsioses, proliferation of organisms in the endothelium of small arteries, veins, and capillaries results in vasculitis and microinfarcts.4,5 The cottonwool exudates, peripapillary leakage from capillaries, peripheral vasculitis, and hyperuorescent dots found in our patient is supposedly based on microvessel destruction and extravasation of blood into the retina. The differential diagnosis of the ocular ndings includes many diseases that were excluded by history, clinical course, and serology. Punctuate hyperuorescent lesions may mimic white dot syndromes. The most important criterion in the differential diagnosis is that the white dots are not apparent by ophthalmoscopy, as they were our patient. In addition, the complete disappearance of the lesions without any scar formation excluded chorioretinitis from other causes.
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INDOCYANINE GREEN VIDEOANGIOGRAPHY OF MULTIFOCAL CRYPTOCOCCUS NEOFORMANS CHOROIDITIS IN A PATIENT WITH ACQUIRED IMMUNODEFICIENCY SYNDROME J. FERNANDO AREVALO, MD,* DARIO FUENMAYORRIVERA, MD, AURA E. GIRAL, MD, ENRIQUE MURCIA* From the *Retina and Vitreous Service, Clinica Oftalmologica Centro Caracas, and the Instituto de Oftalmologia, Caracas, Venezuela. Cryptococcus neoformans is a fungus that causes opportunistic infection in patients with acquired
None of the authors has a proprietary or nancial interest in any of the products or techniques described in this article. Reprint requests: J. Fernando Arevalo, MD, Clinica Oftalmologica Centro Caracas, Centro Caracas PH-1, Av. Panteon, San Bernardino, Caracas 1010, Venezuela; e-mail: areval1@telcel.net.ve

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immunodeciency syndrome (AIDS). Patients commonly have meningitis and are referred to the ophthalmologist with ophthalmoplegia, diplopia, nystagmus, sixth cranial nerve palsy, ptosis, optic atrophy, cryptococcal choroiditis, and papilledema.1 The clinical features of cryptococcal choroiditis are cells in the vitreous with focal choroidal lesions. The presence of the fungus in the choroid implies hematogenous spread and, consequently, is associated with poor prognosis. Fluorescein angiography characteristics have been reported in some cases of cryptococcal choroiditis.12 To our knowledge, this report describes for the rst time the indocyanine green videoangiography (ICG-V) characteristics of a patient with AIDS and cryptococcal choroidal disease. Case Report
A 37-year-old man with AIDS was examined in March 1999 because of a 5-day history of decreased visual acuity in both eyes and headaches and general lethargy. He had been human immunodeciency virus (HIV)-positive since 1984, and his CD4 count was 54 cells/L. Highly active antiretroviral therapy had been started 2 months before this visit. Ophthalmic examination showed a visual acuity of counting ngers in both eyes. The eyes were white, and slit-lamp examination was unremarkable with no anterior chamber or vitreous inammation. Fundus examination showed a pattern of multiple deep, 300- to 400-m, yellowish lesions that looked to be located beneath the retina at the level of the retinal pigment epithelium and choroid (Figure 1). The optic disk and retinal vessels were healthy. A uorescein angiogram conrmed the presence of round lesions that were located under the neural retina. These lesions masked uorescence early during the study, and there was no signicant leakage in the late stages of the angiogram, although some late hyperuorescence may be seen on the nasal aspect of the optic disk in both eyes. The retinal component of the uorescein angiogram was normal (Figure 2). Indocyanine green videoangiography conrmed the presence of lesions that were at the level of the choroid. These lesions masked uorescence throughout the study. Most of these hypouorescent dark spots were already visible in the early phase of the videoangiogram, became more sharply delineated in the intermediate angiographic frames, and remained hypouorescent in the late frames (Figure 3). They were more irregular in shape (some of them conuent) and more numerous than those seen on fundus examination. The differential diagnosis included cryptococcal meningitis, toxoplasma encephalitis, and cerebral lymphoma with posterior segment involvement. Lumbar puncture performed 1 week later showed cryptococcal meningitis. He was treated with intravenous amphotericin B but died of cryptococcal systemic complications 3 weeks later. The family refused an autopsy.

Fig. 1. Fundus photographs of the right (A) and left (B) eyes show multiple deep, 300- to 400-m, yellowish lesions that seem to be located beneath the retina at the level of the retinal pigment epithelium and choroid.

Discussion C neoformans is a yeastlike fungus widely found in nature. An uncommon cause of human disease, it may infect healthy persons but has a special predilection for immunocompromised patients. This case report

describes a patient with visual symptoms and a fundus picture that, on uorescein angiography and ICG-V, was consistent with disease of the retinal pigment epithelium or choroid in a patient with AIDS. A diagnosis of cryptococcal choroiditis was eventually made after lumbar puncture performed 1 week later showed cryptococcal meningitis. The diagnosis of cryptococcal choroiditis was presumed after extensive workup and numerous blood cultures showed that our patient had no other evidence of hematogenous opportunistic infections. In addition, visual symptoms and the fundus lesions started to resolve on systemic treatment, but the patient died of cryptococcal systemic complications 3 weeks later. The multifocal pattern and irregularly shaped hypouorescent spots on ICG-V were also seen on uorescein angiography. This nding may be related to an active disease stage that may have involved the choriocapillaris. More hypouorescent spots on

BRIEF REPORTS

539

Fig. 2. Fluorescein angiography conrmed the presence of round lesions that were located under the neural retina. These lesions masked uorescence early during the study (top). There was no signicant leakage in the late stages of the angiogram, although some late hyperuorescence may be seen on the nasal aspect of the optic disk in both eyes (bottom).

ICG-V were detected than would correspond to the yellowish areas seen in color and red-free photographs. Their distribution was most dense surrounding the optic nerve and fovea. In addition, they had a tendency to be conuent, and this characteristic was better depicted with ICG-V (Figure 3) than with uorescein angiography. Choroidal inltration, which prevented normal choroidal indocyanine green impregnation, probably was the physiopathologic explanation for these persistent hypouorescent dark spots. These ICG-V features described in our patient were nonspecic for the disease. Similar ndings have been described in other inammatory conditions involving the choroid, such as bird-

shot chorioretinopathy, VogtKoyanagiHarada disease, sympathetic ophthalmia, posterior sarcoidosis, posterior tuberculosis, toxoplasmic retinochoroiditis, and acute posterior multifocal placoid pigment epitheliopathy.37 To our knowledge, this is the rst report of ICG-V characteristics in a case of cryptococcal choroiditis. Our patient had a pigmented fundus, and the peculiar multifocal pattern of choroiditis was subtle. In patients with lightly pigmented fundi, choroidal lesions may not appear on fundus photographs and ICG-V may be helpful in detecting and documenting the extent of choroidal involvement. Furthermore, ICG-V may provide information on the pathophysiology of some oc-

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Fig. 3. Indocyanine green videoangiography conrmed the presence of lesions, which were at the level of the choroid. These lesions masked uorescence throughout the study. Most of these hypouorescent dark spots were already visible in the early phase of the videoangiogram, became more sharply delineated in the intermediate frames (top), and remained hypouorescent in the late frames (bottom). The white circle in the bottom images is an artifact.

ular inammatory diseases and may be useful in monitoring the effect of therapeutic interventions. The ophthalmologist plays a valuable role in the treatment of patients with AIDS because an important number of these patients have ocular diseases. Cytomegalovirus retinitis is the most common ocular opportunistic infection, although its incidence has decreased in the last few years because of the introduction of highly active antiretroviral therapy. The incidence of opportunistic infections that metastasize to the choroid is much lower and includes C neoformans, Mycobacterium avium, and Pneumocystis carinii. The prognosis for these patients is poor by this stage, and the diagnosis may elude the physician

until choroidal involvement develops. It is therefore important for ophthalmologists to recognize the pattern of choroidal involvement produced by opportunistic infections in AIDS because prompt treatment will prolong life. References
1. 2. Carney MD, Combs JL, Waschler W. Cryptococcal choroiditis. Retina 1990;10:2732. Saran BR, Pomilla PV. Retinal vascular nonperfusion and retinal neovascularization as a consequence of cytomegalovirus retinitis and cryptococcal choroiditis. Retina 1996;16:510 512. Auer C, Herbort CP. Indocyanine green angiographic features in posterior scleritis. Am J Ophthalmol 1998;126:471 476.

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BRIEF REPORTS
4. Auer C, Bernasconi O, Herbort CP. Toxoplasmic retinochoroiditis: new insights provided by indocyanine green angiography. Am J Ophthalmol 1997;123:131133. Oshima Y, Harino S, Hara Y, et al. Indocyanine green angiographic ndings in VogtKoyanagiHarada disease. Am J Ophthalmol 1996;122:58 66. Bernasconi O, Auer C, Zografos L, et al. Indocyanine green angiographic ndings in sympathetic ophthalmia. Graefes Arch Clin Exp Ophthalmol 1998;236:635 638. Wolfensberger TJ, Piguet B, Herbort CP. Indocyanine green angiographic features in tuberculous chorioretinitis. Am J Ophthalmol 1999;127:350 353.

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SPONTANEOUS RESOLUTION OF CYTOMEGALOVIRUS RETINITIS IN AN INFANT WITH CONGENITAL CYTOMEGALOVIRUS INFECTION AMY S. NOFFKE, MD, MARILYN B. METS, MD From the Division of Ophthalmology, Childrens Memorial Hospital, Chicago; and the Department of Ophthalmology, Northwestern University Medical School, Chicago, Illinois. The treatment of active cytomegalovirus (CMV) retinitis in infants with congenital CMV is not well established. We report a case of bilateral CMV retinitis involving the posterior pole in a neonate with congenital CMV. The retinitis did not progress and resolved spontaneously within 3 weeks without intravenous therapy. Case Report
A female infant was born at 37 weeks gestation with microcephaly, hepatosplenomegaly, and petechiae. She was diagnosed with congenital CMV infection after isolation of virus from the urine. Ophthalmic examination at 1 week of age showed bilateral intraretinal hemorrhages without evidence of retinitis. Dilated fundus examination 5 weeks later showed multiple areas of retinitis in a perivascular distribution bilaterally (Figure 1). The retinitis was considered immediately sight-threatening because it extended into the posterior pole of each eye. Consultation with the Pediatric Infectious Disease service regarding systemic antiviral therapy was obtained. Because of the infants otherwise stable condition and the potential toxicity of ganciclovir, the recommendation was for close follow-up, with institution of ganciclovir therapy if the retinitis progressed. Frequent dilated fundus examinations were performed, and the This work was supported by the Heed Ophthalmic Foundation, Cleveland, Ohio (Dr. Noffke), and by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York. Reprint requests: Marilyn B. Mets, MD, Childrens Memorial Hospital, Division of Ophthalmology, 2300 Childrens Plaza Box 70, Chicago, IL 60614.

Fig. 1. Color fundus photographs show multiple perivascular foci of retinitis in each eye.

fundus appearance was documented using the RetCam 120 retinal imaging system (Massie Instruments, Los Angeles, CA). The retinitis did not progress. At the end of the second week, early pigmented scarring of the lesions was noted. The retinitis had fully resolved within 3 weeks and remained inactive during the next 6 months. Subsequently, the childs family returned to Mexico, and she was lost to follow-up.

Discussion Ocular involvement in congenital CMV infection most commonly presents with inactive chorioretinal scars.1 There are only a few reports in the literature of active retinitis in neonates with congenital CMV infection. Coats et al2 found that only 1 of the 125 infants with congenital CMV they examined had active retinitis, which progressed over several weeks but resolved rapidly with ganciclovir therapy. Baumal et al3 reported a case of bilateral retinitis of the posterior pole in an infant with congenital CMV and encephalitis that resolved with intravenous ganciclovir. The treatment of CMV retinitis in neonates is not well established.4 Retinitis in infants with congenital CMV differs from that in immunocompromised patients in that it is reported to rarely progress postna-

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tally and not to recur without immunocompromise.1 The use of ganciclovir is limited by its bone marrow toxicity, and concerns exist regarding its potential reproductive toxicity. A Phase II multicenter clinical trial5 evaluating ganciclovir for the treatment of infants with symptomatic congenital CMV infection and central nervous system involvement has established that ganciclovir at 12 mg/kg/day in two divided doses can be administered without inordinate toxicity. A Phase III trial is ongoing to evaluate the efcacy of ganciclovir in reducing visual, auditory, and neurologic impairment in children with congenital CMV. The case reported herein illustrates the dilemma that clinicians may face regarding treatment of active retinitis in an infant with congenital CMV. Our patient had no concomitant life-threatening systemic illness, as did the infant with encephalitis described by Baumal et al,3 nor did the retinitis progress, as it had in the child Coats et al2 described; instead, the retinitis resolved spontaneously while the patient was under close observation. Although the authors of the Phase II trial5 caution against the routine use of ganciclovir for symptomatic congenital CMV until efcacy has been shown, other authors1,2 suggest that its use may be cautiously considered in specic life- or sightthreatening situations. References
1. 2. Demmler GJ. Congenital cytomegalovirus infection and disease. Adv Pediatr Infect Dis 1996;11:135162. Coats DK, Demmler GJ, Paysse EA, et al. Ophthalmologic ndings in children with congenital cytomegalovirus infection. J AAPOS 2000;4:110 116. Baumal CR, Levin AV, Read SE. Cytomegalovirus retinitis in immunosuppressed children. Am J Ophthalmol 1999;127: 550 558. Yoser SL, Forster DJ, Rao NA. Systemic viral infections and their retinal and choroidal manifestations. Surv Ophthalmol 1993;37:313352. Whitley RJ, Cloud G, Gruber W, et al. Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. J Infect Dis 1997;175:1080 1086.

Human immunodeciency virus (HIV) retinopathy affects as many as 50% of HIV-infected patients, typically when CD4 T-lymphocyte counts are below 100 cells/L.1 Cotton-wool spots and intraretinal hemorrhages, the hallmarks of HIV retinopathy, are usually asymptomatic, although a few patients experience vision loss from macular ischemia.2,3 There are, however, a number of additional causes of retinal microvasculopathy,4 and they also must be considered in all HIV-positive patients who have cotton-wool spots and intraretinal hemorrhages, particularly when the presentation is atypical. We describe a patient with acquired immunodeciency syndrome (AIDS) and retinal whitening and nonperfusion that was subsequently identied as Purtscher retinopathy occurring in the setting of drug-induced pancreatitis. Case Report
A 32-year-old man with AIDS and a recent CD4 T-lymphocyte count of 82 cells/L was seen by an ophthalmologist because of decreased vision that was worse in his left eye for 1 week. The patients ocular history was notable for toxoplasmic retinochoroiditis in his left eye that was diagnosed 7 months before the onset of his current visual symptoms and that was treated with sulfadiazine for 1 month with resolution. His medical history was notable for esophageal candidiasis, cutaneous herpes zoster infection, and high-grade non-Hodgkin lymphoma affecting his oral and rectal mucosa. Four months before the onset of the patients presenting visual symptoms, his lymphoma recurred and he was administered the experimental antilymphoma drug, diethylhomospermine, with partial improvement. The patients other medications included 1 tablet of 160/800 trimethoprim/sulfamethoxazole 3 times a week, 20 mg of omeprazole daily, 2 tablets of 5/500 hydrocodone/ acetaminophen each night, and 10 mg of bisacodyl daily. He had stopped taking all antiretroviral medications 2 months earlier because of intolerance. Ocular examination on referral revealed a best-corrected visual acuity of 20/25 in the right eye and counting ngers at 3 feet in the left eye. An afferent pupillary defect was present on the left. External and slit-lamp examinations were unremarkable. Posterior segment examination showed areas of peripapillary and macular whitening with scattered intraretinal hemorrhages in each eye (Figure 1, A and B) and two inactive retinochoroidal scars in the temporal periphery of the left eye consistent with previous toxoplasmic retinochoroiditis. Fluorescein angiography showed patchy retinal nonperfusion with late staining at the edge consistent with nerve ber layer infarction (Figure 1, C and D). The cause of the nerve ber layer infarcts was unknown, but because of the decreased vision in the left eye and the history of ocular toxoplasmosis, the patient was given 2 g of sulfadiazine daily, 75 mg of pyrimethamine daily, 5 mg of leucovorin twice daily, and 600 mg of clindamycin four times daily. During the next 2 weeks, the patient experienced progressive

3.

4.

5.

PURTSCHER RETINOPATHY FOLLOWING DRUG-INDUCED PANCREATITIS IN AN HIV-POSITIVE PATIENT STEVEN K. BUI, MD,* JOAN M. OBRIEN, MD, EMMETT T. CUNNINGHAM, JR, MD, PHD, MPH* From the *Francis I. Proctor Foundation and the Department of Ophthalmology, University of California at San Francisco Medical Center.

Supported by a Career Development Award from Research to Prevent Blindness, Inc., New York, New York (Dr. Cunningham). Reprint requests: Emmett T. Cunningham, Jr., MD, PhD, MPH, Pearl & Samuel J. Kimura Ocular Immunology Laboratory, Francis I. Proctor Foundation, UCSF Medical Center, San Francisco, CA 94143-0944; e-mail: emmett@itsa.ucsf.edu

BRIEF REPORTS
abdominal pain, nausea, bloating, and loss of appetite for which he was admitted to the hospital. During this time, his vision decreased to hand motions in both eyes. Posterior segment examination showed massive, conuent peripapillary and macular whitening (Figure 2, A and B). A repeat uorescein angiogram showed enlargement in the areas of nonperfusion, and late staining of the involved vessels. The toxoplasmic retinochoroidal scars in the left eye remained inactive. Laboratory testing at that time showed a serum amylase level of 2,400 U/L (normal range, 19 91 U/L), a serum lipase level of 146 U/dL (normal range, 135 U/dL), and an anion gap acidosis. Retrospective review of the patients chemistry panel at the onset of his visual symptoms showed a similar anion gap acidosis that had gone unrecognized. The patient was diagnosed with acute pancreatitis with secondary Purtscher retinopathy. The toxoplasmosis therapy, the antilymphoma medication (diethylhomospermine), and the Pneumocystis carinii prophylaxis (160/800 trimethoprim/sulfamethoxazole) were discontinued. Four weeks after presentation, the patients visual acuity improved to 20/20 in the right eye and 20/80 in the left eye. He was subsequently lost to follow-up.

543

Discussion Although HIV retinopathy is the most common cause of retinal whitening and nonperfusion in an

HIV-positive patient, the temporal correlation between our patients ocular ndings and the onset of acute pancreatitis strongly suggests that our patient had Purtscher retinopathy. Moreover, the partial resolution of our patients vision loss and fundus ndings after drug discontinuation strongly suggests that the pancreatitis and Purtscher retinopathy were drug-induced. Purtscher retinopathy can occur after severe head trauma, as rst described by Purtscher himself in 1910,5 or in association with other conditions, including thoracic trauma, childbirth, renal failure, pancreatitis, barotrauma, retrobulbar anesthesia, and connective tissue disorders.6 Although the pathogenesis of Purtscher retinopathy is likely to be multifactorial, a possible shared mechanism may involve embolic retinal arteriolar obstruction. Various forms of emboli have been implicated, including air, fat, brin clots, and leukocyte aggregates.6 In acute pancreatitis, current evidence suggests that leukoemboli form when pancreatic damage releases proteolytic enzymes into the systemic circulation, thereby causing activation of

Fig. 1. Color (A, B) and uorescein angiographic (C, D) images of the right and left posterior segments taken at presentation show peripapillary and macular whitening with corresponding areas of nonperfusion.

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Fig. 2. Color (A, B) and uorescein angiographic (C, D) images of the right and left posterior segments taken 2 weeks after presentation show worsening of the peripapillary and macular whitening with corresponding enlargement in the areas of nonperfusion and late staining of the involved vessels.

the complement cascade and the formation of C5ainduced leukocyte, platelet, and brin aggregates.6 Our case of Purtscher retinopathy after drug-induced pancreatitis in an HIV-positive patient is, to our knowledge, the rst to be reported in the literature. The diagnosis of acute pancreatitis can be difcult, as it was in our patient, because pancreatitis is often mild or clinically silent in patients with AIDS. In fact, although autopsy studies indicate that as many as 90% of patients with AIDS have pancreatitis at the time of their death,7 fewer than 10% of HIV-positive patients with pancreatitis seek medical attention.7 AIDS-specic causes of pancreatitis include opportunistic infections, tumors, and most importantly, adverse drug reactions.7,8 HIV-positive patients are often prescribed complex drug regimens that include antiretroviral agents and a number of chemotherapeutic and prophylactic medications that can be individually or additively toxic to the pancreas. The agents that have been

implicated most often in pancreatitis in HIV-positive patients include pentamidine, dideoxyinosine, and dideoxycytidine, although trimethoprimsulfamethoxazole, which was used by our patient, has also been linked to pancreatitis in this population.8 In summary, Purtscher retinopathy should be included in the differential diagnosis of HIV retinopathy, particularly because of the prevalence and lifethreatening potential of unrecognized pancreatitis in this population of patients. Clues to the diagnosis of Purtscher retinopathy in our patient included extensive and progressive retinal ischemia in the setting of severe abdominal pain. Serum amylase and lipase levels can be used to conrm the diagnosis in patients suspected of having this disorder. References
1. Cunningham ET Jr, Margolis TP. Ocular manifestations of HIV infection. N Engl J Med 1998;339:236 244.

BRIEF REPORTS
2. Akduman L, Feiner MA, Olk RJ, et al. Macular ischemia as a cause of decreased vision in a patient with acquired immunodeciency syndrome. Am J Ophthalmol 1997;124:699 702. Roth DB, McCabe CM, Davis JL. HIV-related occlusive vasculitis. Arch Ophthalmol 1999;117:696 698. Brown GC, Brown MM, Hiller T, et al. Cotton-wool spots. Retina 1985;5:206 214. Purtscher O. Noch unbekannte befunde nach schadeltrauma. Ber Dtsch Opththalmol Ges 1910;36:294 301. Behrens-Baumann W, Scheurer G, Schroer H. Pathogenesis of Purtschers retinopathy: an experimental study. Graefes Arch Clin Exp Ophthalmol 1992;1230:286 291. Chehter EZ, Longo MA, Laudanna AA, et al. Involvement of the pancreas in AIDS: a prospective study of 109 postmortems. AIDS 2000;14:1879 1886. Dassopoulos T, Ehrenpreis ED. Acute pancreatitis in human immunodeciency virus-infected patients: a review. Am J Med 1999;107:78 84.

545

Case Report
A 28-year-old woman with a history of left temporal lobe medulloblastoma resection underwent whole brain and craniospinal radiotherapy of approximately 3,600 cGy in 20 fractions with a left temporal boost consisting of 1,980 cGy in 11 fractions. Approximately 10 months after the stereotactic radiosurgery, the patient noticed a change in vision of her left eye. She described the change as a piece of gum stuck to the eyeball that she could see around but not through. The obscuration did not enlarge in size but underwent some variation in shape. She visited our clinic 2 months after the onset of her visual symptoms. Best-corrected visual acuity was 20/20 in the right eye and 20/200 in the left eye. A left relative afferent pupillary defect was present. Slit-lamp examination ndings, intraocular pressures, and ocular motility were normal bilaterally. Goldmann visual eld testing showed a right homonymous superior quadrantanopsia, consistent with a left temporal lobe resection, and a paracentral scotoma approaching xation inferotemporally in the left eye. The dilated fundus examination showed normal-appearing optic nerves bilaterally. There were multiple small dot-and-blot and ameshaped hemorrhages in the posterior pole of the left eye and cotton-wool spots just superior and nasal to the macula region (Figure 1). Fluorescein angiography showed areas of macular nonperfusion and capillary telangiectasias in the macular region (Figure 2). A trial of oral pentoxifylline (400 mg 3 times a day) was begun. Eight months after initiation of pentoxifylline therapy, Snellen visual acuity in the left eye had improved to 20/40. Results of her anterior segment and neuroophthalmologic examination remained unchanged, but her dilated fundus examination showed a considerably decreased number of dot-and-blot hemorrhages and cottonwool spots (Figure 3). A uorescein angiogram showed normal perfusion of the previously nonperfused capillary beds (Figure 4) in comparison with the same region 8 months earlier (Figure 2), suggesting a signicant improvement of the radiation-induced retinopathy in her left eye.

3. 4. 5. 6.

7.

8.

RADIATION RETINOPATHY: The Role of Pentoxifylline PRANAY GUPTA, MD,* BARRY MEISENBERG, MD, PRADIP AMIN, MD, HOWARD D. POMERANZ, MD, PHD* From the *Department of Ophthalmology, the University of Maryland Greenebaum Cancer Center, and the Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore. Radiation retinopathy is a potential vision-threatening consequence of radiation treatment to the orbit or the adjacent structures in the brain. The primary damage occurs in the retinal capillary endothelium. The variable extent of capillary nonperfusion based on radiation exposure of the endothelium leads to varying degrees of severity of retinopathy.1 Clinical reports have examined the useful effect of pentoxifylline on the course of ocular diseases associated with capillary nonperfusion, such as central retinal vein occlusion and diabetic retinopathy.2 Its rheologic properties make it a potentially useful therapeutic agent in the treatment of radiation retinopathy. We describe a patient with radiation-induced retinopathy. Treatment with oral pentoxifylline (400 mg 3 times a day) was initiated. Within 8 months of treatment, a nearly full reversal of the effects of the radiation retinopathy was noted.
This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York. Reprint requests: Howard Pomeranz, MD, Department of Ophthalmology, University of Minneapolis, Box 493, 420 Delaware St. SE, Minneapolis, MN 55455.

Discussion First described in 1935, radiation-induced retinopathy is a delayed effect of radiation to the retina and may progress with time. The exact pathogenesis is uncertain, but selective destruction of the capillary endothelial cells appears to be the principal mechanism. Vascular occlusion and atrophy of the capillaries may occur and result in retinal ischemia.3 Macular telangiectatic vessels are a key feature, if not a hallmark, of radiation damage.4 Many published studies discuss the pathogenesis and prevention of radiation retinopathy, but little information has been published regarding treatment for this condition. There is anecdotal evidence that laser treatment has a therapeutic effect on radiation macular edema, particularly in less severe disease. Neovascularization appears to regress with panretinal photocoagulation.4 To our knowledge, no therapeutic trial has been reported for the treatment of ischemic changes induced by radiation retinopathy. Pentoxifylline is a synthetic xanthine derivative that

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Fig. 1. Red-free photograph of the left fundus at the initial examination shows intraretinal hemorrhages and multiple cotton-wool spots superior and nasal to the macula.

Fig. 3. Red-free photograph of the left fundus at the 8-month examination shows a signicant reduction of the intraretinal hemorrhages and cotton-wool spots.

is used in treatment of peripheral vascular disorders. This drug has the ability to increase blood ow by decreasing blood viscosity and improving the exibility of erythrocytes and leukocytes. In addition, it has a direct vasodilatory action.5 Pentoxifylline has been shown to increase ocular blood ow in healthy patients, in patients with nonproliferative diabetic retinopathy, and in patients with branch or central retinal vein occlusions.2 6

The patient described herein had nearly complete reperfusion of the retinal capillary bed and resolution of retinopathy in her left eye. A possible explanation for this is the unique rheologic properties of pentoxifylline, which caused an increase in blood ow and oxygenation to the damaged retina. Improvement in vision and reperfusion of retinal capillaries in patients with untreated radiation retinopathy is not usual, but

Fig. 2. Early-phase uorescein angiogram of the left eye at the initial examination shows large areas of capillary nonlling and telangiectasia in addition to blockage that corresponds to the areas of intraretinal hemorrhage.

Fig. 4. Early-phase uorescein angiogram at the 8-month examination shows reperfusion of the retinal capillary bed and resolution of the telangiectatic vessels.

BRIEF REPORTS

547

has been shown in some cases to occur. Therefore, the use of pentoxifylline may have been coincidental to the natural history of this condition. Because this patient improved, however, we present this single case to report our observation of the possible benet of pentoxifylline on the course of radiation retinopathy. A controlled, randomized prospective study would be required to show a denitive effect of pentoxifylline in the treatment of radiation retinopathy. References
1. 2. Kinyoun JL, Lawrence BS, Barlow WE. Proliferative radiation retinopathy. Arch Ophthalmol 1996;114:10971100. Jay WM, Aziz MZ, Chapman JM, et al. Effect of oral or intravenous pentoxifylline on ocular and optic nerve blood ow. Ophthalmic Res 1987;19:318 321. Noble KG, Kupersmith MJ. Retinal vascular remodelling in radiation retinopathy. Br J Ophthalmol 1984;68:475 478. Archer DB. Radiation retinopathy and papillopathy. In: Yanoff M, Duker JS, eds. Ophthalmology, 1st ed. Philadelphia: Mosby, 1999:8.24.1 8.24.4. Schmetterer L, Kemmler D, Breiteneder H, et al. A randomized, placebo controlled, double-blind, crossover study of the effect of pentoxifylline on ocular fundus pulsations. Am J Ophthalmol 1996;121:169 176. Kruger A, Matulla B, Wolzt M, et al. Short term oral pentoxifylline use increases choroidal blood ow in patients with age-related macular degeneration. Arch Ophthalmol 1998;116: 2730.

3. 4.

Fig. 1. View through the microscope of the right eye. The selfretaining cannula has been inserted inferotemporally through a selfsealing sclerotomy. The two superiorly located sclerotomies have the entry ports (straight lines) of the tunnels (dashed lines) directed toward the surgeon.

5.

6.

SELFSEALING SCLEROTOMIES IN PARS PLANA VITRECTOMY FREDERIK J. G. M. VAN KUIJK, MD, PHD, SAMI UWAYDAT, MD, BERNARD F. GODLEY, MD, PHD From the Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas. Vitreoretinal surgery is usually performed through sclerotomies that are placed in the anterior pars plana, 3 to 4 mm posterior to the limbus, depending on the
Supported by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York. Dr. Godley is an RPB Sybil B. Harrington scholar. None of the authors has proprietary interest in any of the products mentioned in this article. The material in this paper was presented in part at the annual ARVO meeting, Ft. Lauderdale, Florida, April 30 May 4, 2000 and at Club Vit, Sarasota, Florida, May 18 20, 2000. Reprint requests: Bernard F. Godley, MD, PhD, 336 Clinical Science Building, Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, Galveston, TX 77550-0787; e-mail: bgodley@utmb.edu

phakic status of the eye. They are usually done with a disposable 20-gauge microvitreoretinal (MVR) blade directed perpendicular to the sclera at the superotemporal, inferotemporal, and superonasal quadrants. Vitrectomy instruments are introduced through the two superior sclerotomy sites, and all three sclerotomies must be closed with a 7-0 coated Vicryl interrupted suture at the end of surgery. Complications related to the sclerotomy sites are vitreous incarceration, dragging of the retina, entry site breaks, injury to the ciliary body, brovascular downgrowth, suture protrusion, wound dehiscence, and difculty in maintaining intraocular pressure during closure of the inferotemporal sclerotomy after removal of the infusion cannula.1 To overcome these problems, several investigators have reported the use of self-sealing pars plana sclerotomies.1 4 Initially, Chen et al1 reported the use of scleral tunnels directed radially in the anterior to posterior direction. In a later study, they modied their method by placing the tunnels in a circumferential direction parallel to the limbus, but the tunnels were constructed with the entrance away from the surgeon.3 In addition, the inferotemporal tunnel for the cannula was constructed conventionally with an MVR blade. In this study, we created scleral tunnels parallel to the corneoscleral limbus, with the entrance of the tunnel toward the surgeon, which is different from the previous methods (Figure 1).1 4 In addition, the site for the cannula was created as a self-sealing sclerotomy. Furthermore, we performed the procedure on more patients to establish whether this approach would be contraindicated in some patients.

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Table 1. Patients Who Underwent a Pars Plana Vitrectomy (PPV) With Sutureless Sclerotomies
IOP Patient Age, yr/sex 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 61/F 54/M 40/F 53/F 46/F 36/M 57/M 45/M 30/M 15/M 73/F 70/F 62/M 29/M 29/F 54/F 51/M 58/F 25/M 84/M 49/F 38/M 53/F 60/F 72/M 46/F 64/F 56/F 59/F 70/M 43/M 45/F 54/M 41/M 61/M 49/F 40/M 65/F 38/M 58/M Diagnosis RRD RRD PDR, VH, ERM OS Tractional macular edema OD PDR, cataract, TRD PDR, TRD OS Pseudophake RD OS PDR, NVG OD PDR, VH OD Traumatic VH, cataract OD PDR, VH OS Cataract, PDR, tractional macular detachment OS PDR, TRD, ERM OD PVR, chronic RD OD PDR, TRD, RRD OD PDR, VH OS RRD, macular hole OS Dropped nucleus OD PDR, TRD, ERM OD Pseudophake RRD OS PDR, VH, macular hole OD PDR, TRD OD PDR, TRD OD Endophthalmitis OD PDR, TRD, VH OS PDR, TRD, VH OS Dropped nucleus OS Pseudophake RRD OD VH, RRD OS CRVO OS VH, PDR OD VH, PDR OD PDR, TRD, macular hole OD Cataract, vitreous membrane OS Pseudophake RRD OD PDR, VH OD PDR, TRD, ERM OD Cataract, vitreous-macular traction OD Dropped nucleus OS Pseudophake RRD, PVR OS Procedure PPV, EL, SF6 PPV, SB, C3F8 PPV, EL, EMP PPV, EMP PPV, EL, EMP, C3F8, phaco PPV, EMP, EL, AFX PPV, SB, cryo, C3F8 PPV, EL PPV, EMP, EL PPV, PPL PPV, EMP, EL Phaco, PPV, EL, C3F8 PPV, EL, EMP, AFX PPV, PPL, SB, C3F8 PPV, silicone oil, EL PPV, EL, EMP, AFX PPV, SB, C3F8 PPV, PPL PPV, EMP, EL PPV, SB, C3F8 PPV, EMP, EL, C3F8 PPV, EMP, EL, AFX PPV, EL, EMP PPV, intravitreal vancomycin PPV, EL, EMP, AFX PPV, EMP PPV, PPL PPV, SB, C3F8 PPV, C3F8 PPV, TPA PPV, EL PPV PPV, EMP PPV, PPL PPV, 240 SB, C3F8 PPV PPV, EMP Phaco IOL, PPV PPV, PPL PPV, SB, PFO, EMP, SO Intraoperative complications POD 1 POD 30 14 21 17 7 27 23 21 14 11 40 18 21 14 19 16 13 23 11 12 31 17 16 12 17 16 9 4 17 15 30 22 13 16 34 26 13 7 7 20 22 12 16 31 13 10 22 13 28 12 18 NA NA NA 13 19 9 25 20 9 22 11 21 12 14 17 26 12 18 10 40 13 14 14 50 17 15 7 6 16 18

Leak at 2; sutured

Leak at 4, 11; sutured Leak at 2, 4, 11; sutured Infusion extruded; choroidals Procedure was interrupted Leak at 11; sutured

Leak at 11; sutured Infusion extruded

Infusion extruded; choroidals

Choroidals at 4 Entry site break at 2 Bleeding at 11 into vitrectomy Tunnel at 2 burned by phaco

Leak at 4; sutured

IOP, intraocular pressure; POD, postoperative day; RRD, rhegmatogenous retinal detachment; EL, endolaser; SB, scleral buckle; PDR, proliferative diabetic retinopathy; VH, vitreous hemorrhage; ERM, epiretinal membrane; OS, left eye; EMP, ERM peel; OD, right eye; TRD, tractional retinal detachment; phaco, phacoemulsication; AFX, airuid exchange; cryo, cryocoagulation; NVG, neovascular glaucoma; NA, not applicable; PPL, pars plana lensectomy; CRVO, central retinal vein occulsion; TPA, tissue plasminogen activator; IOL, intraocular lens; PFO, peruoro-octane.

Methods We performed 120 self-sealing sclerotomies on 40 consecutive patients, using a modication of the method initially described by Chen et al1 and modied by Kwok et al.3 Chen et al1 constructed scleral tunnels perpendicular to the limbus, and Kwok et al3 modied the procedure by creating scleral tunnels parallel to the limbus. We constructed scleral tunnels 3.0 mm posterior to the limbus, with the entry of the tunnels positioned superiorly toward the surgeon, instead of away from the surgeon, and the tunnel itself directed inferiorly and parallel to the limbus (Figure 1). To standardize the depth of the initial scleral incision, a guarded beaver blade (depth, 0.3 mm) was used. Subsequently a 1.5-mm scleral tunnel was made with a

crescent knife (width, 2.0 mm) (Alcon, Forth Worth, TX), and the tunnel was completed by using a black MVR blade (Laseredge; Bausch & Lomb Surgical, Claremont, CA). The cannulas we used were a straight 6.0-mm and a Weiss self-retaining 5.0-mm cannula (DORC, Kingston, NH). Indications for vitrectomy included proliferative diabetic retinopathy, retinal detachment, endophthalmitis, dropped nucleus, and central retinal vein occlusion. Additional intraoperative procedures performed included scleral buckle, endolaser, membrane peel, pars plana lensectomy, air gas uid exchange (SF6 or C3F8), and silicone oil injection. The same surgeon (B.F.G.) constructed all the scleral tunnels and was present during the entire procedure in each case. In

BRIEF REPORTS Table 2. Comparison of Changes in the Corneal Curvature With Sutureless and Sutured Sclerotomies Patient Preop avK POD 7 avK 42.9 41.75 46.26 42.8 40.83 45.6 43.73 44.32 43.95 DK7 0.15 0.5 0.56 0.2 1.07 1.74 0.06 0.11 0.24 0.55 0.07 POD 30 avK 42.83 42.05 44.21 42.88 43.28 45.21 43.64 44.67 43.9

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DK30 0.22 0.2 1.49 0.12 1.38 1.35 0.12 0.2 0.11 0.5 0.14

Sutureless sclerotomies 1 43.05 2 42.25 3 45.7 4 43 5 41.9 6 43.86 Mean Sutured sclerotomies 1 43.84 2 44.56 3 43.4 Mean

Preop avK, averaged preoperative K reading taken 17 days before surgery; POD 7 avK, averaged K reading done on the 7th postoperative day; DK7, change in the averaged corneal curvature on the 7th postoperative day; POD 30 avK, averaged K reading done on the 30th postoperative day; DK30, change in the averaged corneal curvature on the 30th postoperative day.

nine cases, corneal topography or keratometry was performed before, 1 week after, and 1 month after surgery. Six patients were included in the series of 40 patients, and three additional patients were treated with conventional sutured sclerotomy sites, as described in the introduction, to evaluate the effect of sutureless sclerotomies on corneal refractive power. Results The indications and results in this series of 40 patients are shown in Table 1. Nine sclerotomies required a suture because of a leak. All occurred in patients 40 years of age or younger. In two cases, the infusion cannula extruded during the procedure. This was related to indirect ophthalmoscopy with indentation to examine the retina for entry site breaks. We then changed from a 6.0-mm straight cannula to a curved Weiss self-retaining 5.0-mm cannula (DORC), which can be secured by partial rotation. Subsequently, one additional cannula extrusion occurred, and further recurrences were prevented by placing a single retaining suture. One patient had an entry site break with a localized retinal detachment. No cases of hypotony or endophthalmitis developed. The patient with the central retinal vein occlusion developed neovascular glaucoma with an intraocular pressure of more than 50 mmHg, but no leaks were noted at the site of the self-sealing sclerotomies. Effects on corneal curvature are shown in Table 2. Arciniegas and Amaya5 reported in rabbit eyes that a sclerotomy parallel to the limbus leads to attening in the meridian where the surgery is performed and slight steepening of the orthogonal meridian. We found no

signicant difference in average keratometry values before and after surgery in sutured and sutureless sclerotomies. Discussion Self-sealing incisions were pioneered by cataract surgeons and subsequently introduced into vitreoretinal surgery.1 4 The goal of this technique is to avoid the use of sutures to close sclerotomy sites at the end of vitreoretinal surgery to maintain intraocular pressure. Intraoperatively, there is no need to use plugs because the sclerotomy will seal each time an instrument is removed. Both these factors will shorten the operating time by as much as 20%, depending on the length of the procedure. We found that even in longer cases in which multiple instruments, including scissors and lighted forceps, were passed through the sclerotomy sites, no leaks were noted. The single most important risk factor for leaks was patient age. All the leaks in this series occurred in patients younger than 40 years of age. We attribute this to the fact that the sclera of younger patients is much less rigid,6 which makes it more difcult to construct self-sealing tunnels at a depth of half the scleral thickness. Interestingly, Lam et al7 reported the successful use of the original radially oriented scleral tunnel by Chen et al1 in eight eyes of children 8 to 48 months of age. One patient in our series developed shortness of breath because of acute exacerbation of pulmonary edema, and we interrupted the surgical procedure by removing our instruments and the cannula. Because of the self-sealing sclerotomies, the anesthesiologist was able to initi-

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ate resuscitation immediately, and the vitreoretinal surgery was successfully completed at a later date. Our technique differs from techniques previously used in that the entries of the tunnels are constructed toward the surgeon. This facilitates the entry of instruments and avoids interference with the nose or cannula. We also found that the guarded beaver blade is useful because it standardizes the depth of the initial incision in the sclera. This modication allows for each tunnel to be constructed at approximately half the scleral thickness, which minimizes anterior ap tears or inadvertent entry into the posterior chamber, both of which will result in the need of suture to seal the sclerotomy. Kwok et al3 used a 20-gauge hypodermic needle to perforate the sclera at the end of the tunnel to avoid accidental scleral ap lacerations made by the sharp MVR blade. We also found that the black MVR blade used in this series (Laseredge; Bausch & Lomb Surgical) could be safely used. A green MVR blade (V-Lance knife; Alcon) used in two patients not part of this series caused scleral ap lacerations in four tunnels, two of which leaked, requiring a suture. Changing the direction of the scleral tunnel entry did not reduce the success rate of this technique, which is 90% in eyes of patients older than 40 years. By comparison, Rahman et al8 reported a success rate of 76.6% with radially oriented tunnels. Previous reports did not include information on the age of the patients, and we found that young age is an important risk factor for failure of this technique. In the 40 eyes reported in this study, none developed postoperative endophthalmitis. It appears that sutureless sclerotomies are safe in pars plana vitrectomy and do not induce signicant corneal astigmatism. In this study, sutureless sclerotomies in patients younger than 40 years of age are associated with a higher rate of leaks (failure of the tunnel to self-seal) requiring sutures. The safety of this procedure and risk of complications will need to be established in more patients.

7.

8.

AA Jr, Morgan MW, eds. Vision and Aging, 2nd ed. Boston: Butterworth-Heinemann, 1992;111159. Lam DSC, Chua JKH, Leung ATS, et al. Sutureless pars plana anterior vitrectomy through self-sealing sclerotomies in children. Arch Ophthalmol 2000;118:850 851. Rahman R, Rosen PH, Riddell, C, et al. Self-sealing sclerotomies for sutureless pars plana vitrectomy. Ophthalmic Surg Lasers 2000;31:462 466.

DIFFUSE UVEAL MELANOMA PRESENTING AS AN AMELANOTIC CYSTIC EPIBULBAR LESION JERRY A. SHIELDS, MD,* RALPH C. EAGLE, JR, MD, CAROL L. SHIELDS, MD,* ARUN D. SINGH, MD,* LOV K. SARIN, MD From the *Oncology Service, the Pathology Department, and the Retina Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania. Uveal malignant melanoma can assume a variety of growth patterns.1,2 Diffuse uveal melanoma is an aggressive variant that grows in a relatively at pattern.3,4 As compared to the nodular uveal melanoma, it usually has a more malignant cell type, greater tendency toward extrascleral extension, and a higher mortality. Extrascleral extension of a diffuse uveal melanoma usually presents as a pigmented epibulbar mass in the ciliary body area.1,2 We report a largely amelanotic diffuse uveal melanoma in which the initial manifestation was a nonpigmented, pseudocystic, salmon-colored epibulbar mass that extended over the superior aspect of the cornea. Case Report
In December 1998, a 76-year-old man noticed gradual onset of painless blurred vision in his left eye. Ocular examination by his local ophthalmologist revealed no abnormal ndings. He returned 3 months later complaining of worsening vision and a mass beneath his left upper eyelid. Examination revealed an epibulbar mass and choroidal thickening. He was referred to the Oncology Service for further evaluation.

References
1. 2. Chen JC. Sutureless pars plana vitrectomy through self-sealing sclerotomies. Arch Ophthalmol 1996;114:12731275. Milibak T, Suveges I. Complications of sutureless pars plana vitrectomy through self-sealing sclerotomies. Arch Ophthalmol 1998;116:119. Kwok AKH, Tham CCY, Lam DSC, et al. Modied sutureless sclerotomies in pars plana vitrectomy. Am J Ophthalmol 1999; 127:731733. Jackson T. Modied sutureless sclerotomies in pars plana vitrectomy. Am J Ophthalmol 2000;129:116 117. Arciniegas A, Amaya LE. Experimental modication of the corneal curvature by means of scleral surgery. Ann Ophthalmol 1984;16:11551166. Michaels DD. Ocular disease in the elderly. In: Rosenbloom

3.

4. 5.

6.

Supported by the Eye Tumor Research Foundation, Philadelphia, PA; the Award of Merit in Retina Research, Houston, Texas (Dr. J.A. Shields); the Macula Foundation, New York, New York (Dr. C.L. Shields); and the Noel and Sarah Simmonds Endowment for Ophthalmic Pathology, Wills Eye Hospital (Dr. Eagle). Presented at the meeting of the Eastern Ophthalmic Pathology Society, Philadelphia, Pennsylvania, September 22, 2000. Reprint requests: Jerry A. Shields, MD, Oncology Service, Wills Eye Hospital, 900 Walnut Street, Philadelphia, PA 19107.

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Fig. 1. The superior portion of the mass has a eshy, salmon-colored appearance, and the inferior portion has a cyst containing mucoid or purulent material.

Fig. 3. The epibulbar mass is composed of loosely cohesive, round, malignant cells without cytoplasmic pigment (hematoxylin and eosin; original magnication 100).

His medical history included systemic hypertension. He had herpes zoster ophthalmicus on the right side in 1992 and bilateral cataract surgery in 1993. Ocular examination revealed pseudophakic visual acuities of 6/6 in his right eye and 6/60 in his left eye. Intraocular pressures were 19 mmHg in the right eye and 10 mmHg in the left. The right eye was otherwise normal. Examination of the left eye showed a eshy, salmon-colored mass deep to the conjunctival epithelium superonasally with an apparent semiopaque cyst that overhung the cornea and appeared to contain mucoid or purulent material (Figure 1). The temporal part of the iris stroma was displaced anteriorly causing focal narrowing of the anterior chamber angle, and there was diffuse iris neovascularization. Poor pupillary dilation and a hazy intraocular lens precluded a clear fundus view, but there was a diffuse amelanotic thickening of the superior half of the choroid and a retinal detachment. Ultrasonography conrmed choroidal thickening with high internal reectivity and a maximum thickness of 4.7 mm (Figure 2). Blood count, liver enzymes, and a chest radiograph were normal. Our differential diagnosis included lymphoma, metastasis, and intraocular extension of conjunctival mucoepidermoid carcinoma. Uveal melanoma was considered unlikely because a cystic lesion overhanging the cornea would be an unlikely manifestation of extraocular extension of a melanoma. An excisional biopsy was performed of the epibulbar mass. Histopathologic studies suggested melanoma and the eye was enucleated.

Pathologic Findings Conjunctival Mass

The specimen measured 11 8 2.5 mm. Histopathologic examination showed a diffuse cellular inltrate involving the conjunctival stroma but sparing the epithelium. It was composed of round, poorly differentiated, loosely cohesive, nonpigmented cells with relatively small nuclei and prominent nucleoli (Figure 3). Numerous mitotic gures were present. The FontanaMasson stain for melanin was negative. Immunohistochemical stains showed intense cytoplasmic immunoreactivity for vimentin, minimal immunoreactivity to melanoma specic antigen HMB-45, and no reactivity to leukocyte common antigen, cytokeratin marker CAM 5.2, lysozyme, myoglobin, muscle specic actin, smooth muscle actin, and desmin. The diagnosis was poorly differentiated nonepithelial malignant neoplasm, most consistent with melanoma. Based on these ndings, the lesion was thought to represent extraocular extension of a uveal melanoma.

Fig. 2. B-scan ultrasonogram shows diffuse thickening of the choroid with high internal reectivity.

Fig. 4. Gross appearance of sectioned globe, showing diffuse amelanotic tumor of the uveal tract.

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Fig. 5. The anterior part of the tumor is composed of round, loosely cohesive, nonpigmented malignant cells (hematoxylin and eosin; original magnication 250).

Fig. 7. Focus of pigmented tumor within the deeper part of the tumor, consistent with malignant melanoma (hematoxylin and eosin; original magnication 100).

Eyeball
On gross examination, the normal sized eye showed no transillumination abnormalities. The angle was partly occluded by peripheral anterior synechiae, and a posterior chamber intraocular lens was present. The superior iris leaf was displaced forward by the anterior part of a diffuse white mass that thickened the ciliary body and choroid. It measured 18 mm in length and 4 mm in thickness and extended posteriorly to the optic nerve (Figure 4). Microscopic examination revealed a brovascular membrane on the anterior surface of the iris. The superior iris leaf was displaced anteriorly by a retroiridic mass that extended posteriorly to involve the superior part of the ciliary body and choroid, reaching the optic nerve. In the anterior part of the choroid, these cells were loosely cohesive and resembled the cells seen in the epibulbar surface (Figure 5). The more posterior part of the tumor was composed of large mitotically active epithelioid cells (Figure 6). Fifty-ve mitotic gures were counted in 40 high-power elds. Repeat immunohistochemistry of the intraocular part of the tumor gave similar, inconclusive results; the tumor cells showed intense immunoreactivity for vimentin, but HMB 45 and S-100 protein were nonreactive. However, the additional deeper sections prepared for immunohistochemical analysis disclosed a small focus

of intensely pigmented cells (Figure 7) within the largely amelanotic tumor, which conrmed that the tumor was a melanoma. The sections disclosed no residual epibulbar tumor. The nal diagnosis was diffuse choroidal melanoma of the epithelioid cell type with extraocular extension. Within 6 months, metastatic melanoma to the liver and bone developed, and the patient died shortly thereafter.

Discussion Uveal melanoma usually presents as an elevated pigmented mass with a characteristic dome or mushroom conguration. The diagnosis is readily made with ophthalmoscopy by an experienced clinician.1,2 Diffuse uveal melanoma is a relatively uncommon variant in which the tumor grows in a at or slightly elevated pattern.35 There is often a delay in diagnosis and misdirected therapy before a diffuse melanoma is nally recognized. Many diffuse uveal melanomas are nonpigmented, making the diagnosis even more challenging. Extraocular extension is found in 8% to 14% of eyes enucleated for ciliary body or choroidal melanoma.5,6 Diffuse uveal melanomas are generally more aggressive and show extrascleral extension more frequently. In the report of diffuse melanomas by Font et al,4 there was a 39% incidence of extraocular extension. In the series by Shields et al,5 there was a 50% incidence of extraocular extension in eyes that were enucleated. In cases of diffuse melanoma, the extrascleral extension is usually in the ciliary body region and is usually pigmented, ndings that should suggest the diagnosis clinically. When there is extraocular extension of an amelanotic melanoma, the extrascleral component usually appears as a solid lesion without cysts. The case reported here was highly unusual in that the diffuse uveal melanoma presented initially as a

Fig. 6. The more posterior part of the tumor is composed of mitotically active epithelioid cells with prominent mitoses (hematoxylin and eosin; original magnication 250).

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salmon-colored, epibulbar mass that was reminiscent of conjunctival lymphoma. However, a portion of the epibulbar mass overhung the cornea and resembled a cyst lled with mucus or purulent material, making the diagnosis of lymphoma unlikely. The cystic appearance was consistent with a mucoepidermoid carcinoma of the conjunctiva, a tumor that has a tendency to extend into the eye and develop a cystic component.710 Metastatic cancer was also a diagnostic consideration in our patient, because it can also present as a uveal thickening and an amelanotic epibulbar mass.11,12 Although melanoma was considered, it was thought to be unlikely based on the aforementioned clinical features. The histopathologic diagnosis in our case was initially challenging. The extraocular component of the tumor was composed predominantly of round, loosely cohesive malignant cells that lacked cytoplasmic pigment. Although intensely immunoreactive for vimentin, the cells showed only minimal immunoreactivity for melanoma specic antigen HMB-45. However, the choroid contained a focus of heavily pigmented tumor cells in deeper histopathologic sections, supporting the diagnosis of melanoma. In addition, the subsequent clinical course with metastatic melanoma to the liver supported the diagnosis. In summary, we report a highly unusual, if not unique, presentation of a uveal melanoma. The rst manifestation of the diffuse, amelanotic uveal tumor was a eshy, salmon-colored epibulbar lesion with a pseudocyst that overhung the cornea. Clinicians should be cognizant of atypical manifestations of uveal melanoma to make a correct diagnosis and to institute appropriate therapy. References
1. Shields JA, Shields CL. Posterior uveal melanoma: clinical and pathologic features. In: Shields JA, Shields CL, eds. Intraocular Tumors. A Text and Atlas. Philadelphia: WB Saunders, 1996:117136. Shields JA, Shields CL. Clinical features of posterior uveal melanoma. In: Shields JA, Shields CL, eds. Atlas of Intraocular Tumors. Philadelphia: Lippincott Williams & Wilkins, 1999:74 93. Reese AB, Howard GM. Flat uveal melanomas. Am J Ophthalmol 1967;64:10211028. Font RL, Spaulding AG, Zimmerman LE. Diffuse malignant melanoma of the uveal tract: a clinicopathologic report of 54 cases. Trans Am Acad Ophthalmol Otolaryngol 1968;72: 877 895. Shields CL, Shields JA, DePotter P, et al. Diffuse choroidal melanoma: clinical features predictive of metastasis. Arch Ophthalmol 1996;114:956 963. Collaborative Ocular Melanoma Study Group. Histopathologic characteristics of uveal melanomas in eyes enucleated

7.

8. 9.

10.

11.

12.

from the Collaborative Ocular Melanoma Study. COMS report no. 6. Am J Ophthalmol 1998;125:745766. Shields JA, Shields CL. Mucoepidermoid carcinoma of the conjunctiva with intraocular invasion. In: Shields JA, Shields CL, eds. Atlas of Eyelid and Conjunctival Tumors. Philadelphia: Lippincott Williams & Wilkins, 1999;241. Rao NA, Font RL. Mucoepidermoid carcinoma of the conjunctiva. Cancer 1976;38:1699 1709. Brownstein S. Mucoepidermoid carcinoma of the conjunctiva with intraocular invasion. Ophthalmology 1981;88:1126 1130. Gunduz K, Shields JA, Shields CL, et al. Intraocular neoplastic cyst from mucoepidermoid carcinoma of the conjunctiva. Arch Ophthalmol 1998;116:15211523. Shields JA, Shields CL, Eagle RC Jr, Gunduz K, Lin B. Diffuse ocular metastases as an initial sign of metastatic lung cancer. Ophthalmic Surg Lasers 1998;29:598 601. Kiratli H, Shields CL, Shields JA, et al. Metastatic tumors to the conjunctiva. Report of ten cases. Br J Ophthalmol 1996;80:5 8.

VISUAL LOSS AFTER RENAL TRANSPLANTATION AMIR YAMANI, MD,* BRENDA A. MYERSPOWELL, MD, PHD, SCOTT M. WHITCUP, MD, STEVEN B. COHEN, MD, ERIC D. KANTER, MD, BRUCE KAPLAN, MD, PHD, MARCO A. ZARBIN, MD, PHD* From the *Department of Ophthalmology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark; The National Eye Institute, National Institutes of Health, Bethesda, Maryland; Saint Barnabas Medical Center, Livingston, New Jersey; and The Division of Nephrology, Michigan University Health System, Ann Arbor. Visual loss is a rare but devastating complication of organ transplantation. Previous reports have described transplant patients who developed retinal microvasculopathy and sudden visual loss while receiving cyclosporine A (CsA) plus conditioning therapy, including cyclophosphamide (CY), busulfan, and/or total body irradiation (TBI).15 We report the case of a 52-year-old white man with
Dr. Whitcup is currently afliated with Allergan, Irvine, California. Supported in part by Research to Prevent Blindness, Inc., New York, New York; The Eye Institute of New Jersey; and the New Jersey Lions Eye Research Foundation, Newark. Reprint requests: Marco A. Zarbin, MD, PhD, Doctors Ofce Center, 6th Floor, 90 Bergen St, Newark, NJ 07103-2499; e-mail: zarbin@umdnj.edu

2.

3. 4.

5.

6.

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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES Table 1. Test Results
Test Result 0.04 ISR 0.29 ISR 1.66 ISR 0.25 ISR Negative 49.0 units/mL Negative 103.4 nmol/mL/min 7 13 7 7 Performed twice15 mm/h, 11 mm/h Absent 0.703 g/L 0.28 ISR 0.196 g/L Questionable narrowed intracranial arteriole, otherwise normal Normal Normal Normal Normal Negative Negative Negative 1.15 mmol/L 10.5 10*9/L 129 g/L 39.70% 141 10*9/L 82% 9% 3% 31 g/L 50 g/L 6.22 mmol/L 17.14 mmol/L 167.96 mmol/L 138 mmol/L 3.9 mmol/L 107 mmol/L 2.68 mmol/L 10.26 mol/L 58 U/L 15 U/L Negative Negative 0.90 ISR 0.90 ISR 0.90 ISR 0.90 ISR Negative 48153 units/mL Negative

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Interpretation Seronegativeabsence of prior exposure Negative Seropositiveindicates prior exposure Negative Negative Normal Negative Elevated Normal Increased Negative Negative Normal Normal Decreased Seronegative Low normal

CMV IgG Ab CMV IgM Ab Toxoplasmosis IgG Ab Toxoplasmosis IgM Ab Antinuclear antibodies Total complement CH100 Anti-DNA Ab Serum angiotensin converting enzyme Anticardiolipin IgG Anticardiolipin IgM c-ANCA p-ANCA ESR Cryoglobulins C3 compliment QN Lyme Ab (ELISA) C4 compliment QN MRI/MRA of brain and thorax Pelvic MRV Lower extremity electromyogram Echocardiogram MUGA scan Vitreous PCR for Toxoplasmosis gondii DNA Vitreous PCR for herpes simplex virus DNA Vitreous PCR for herpes zoster virus DNA Mg WBC Hgb Hct Plt Polys Lymphocytes Atypical lymphocytes Albumin Total protein Glucose Bun Creatinine Na K Cl Ca Total bilirubin Alk phos SGOT

0.6052.0 nmol/mL/min 014 09 7 7 Male 015 mm/h, female 020 mm/h Absent 0.861.84 g/L 0.9 ISR 0.200.59 g/L

Negative Negative Negative Elevated Normal Decreased Decreased Normal Elevated Decreased Elevated Normal Decreased Normal Elevated Elevated Normal Normal Elevated Normal Normal Normal Normal

Negative 0.661.10 mmol/L 4.0 10*910.5 10*9/L 135170 g/L 39.852.0% 140450 10*9/L 5075% 2040% 3055 g/L 6085 g/L 3.896.38 mmol/L 3.579.28 mmol/L 70.72159.12 mmol/L 136145 mmol/L 3.55.0 mmol/L 96106 mmol/L 2.132.63 mmol/L 3.4220.52 mol/L 30136 U/L 758 U/L

CMV, cytomegalovirus; Ig, immunoglobulin; Ab, antibodies; DNA, deoxyribonucleic acid; c-ANCA, antineutrophil cytoplasmic antibody; ESR, erythrocyte sedimentation rate; QN, quantitative; ELISA, enzyme-linked immunosorbent assay; MRI, magnetic resonance imaging; MRA, magnetic resonance angiography; MRV, magnetic resonance venogram; MUGA, multiple gated acquisition scan; PCR, polymerase chain reaction; WBC, white blood cells; Hgb, hemoglobin; Hct, hematocrit; Plt, platelets; Polys, polymorphonuclear leukocytes; Alk phos, alkaline phosphatase; SGOT, aspartate aminotransferase; PTT, partial thromboplastin time; PT, prothrombin time; INR, international normalized ratio; HDL, high-density lipoprotein; VLDL, very low density lipoprotein.

BRIEF REPORTS Table 1. Continued

Test Inorganic phosphorous CO2 CsA Amylase Lipase Urinalysis PTT PT INR Blood cultures Cholesterol Triglyceride HDL cholesterol VLDL calculated Result 0.775 mmol/L 27 mmol/L 250,258,250,384 ng/mL 44 U/L 11 U/L Normal 27 seconds 13.3 seconds 1.2 Negative 5.65 mmol/L 7.67 mmol/L 0.57 mmol/L 136 mg/dL Normal 0.80815.504 mmol/L 2430 mmol/L 25143 U/L 758 U/L 21.534.5 seconds 10.713.7 seconds Negative 3.115.18 mmol/L 0.1132.15 mmol/L 0.831.86 mmol/L 1040 mg/dL Interpretation Decreased Normal Normal Normal Normal Normal Negative Elevated Elevated Decreased Elevated

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a history of polycystic kidney disease and hypertension who developed progressive retinal vasculopathy 5 months after successful renal transplantation while receiving CsA without conditioning therapy. Although a denite etiology has not been determined, CsA-induced drug toxicity may be the cause. Case Report
A 52-year-old white man with a history of polycystic renal disease was referred for evaluation of acute progressive retinopathy of unknown etiology 5 months after receiving a renal transplant (in May 1998) from an unrelated living donor. The patient reported sudden, bilateral, painless blurring of vision while watching television. The visual loss rendered him unable to carry out activities of daily living without assistance. This episode was preceded by approximately 1 week of troubles with his vision. His medications at the time of the visual symptoms included prednisone 10 mg orally daily, acyclovir 800 mg orally twice daily, cyclosporine 150 mg orally twice daily (4.25 mg/kg/d), mycophenolate mofetil 1,000 mg orally twice daily, trimethoprim 160 mg/sulfamethoxazole 800 mg orally daily, clotrimazole 10 mg orally four times daily, Cernevit (multivitamin) 5 cc injection intravenously daily, omeprazole 20 mg orally daily, tamsulosin hydrochloride 0.4 mg orally daily, furosemide 40 mg orally daily, amlodipine besylate 5 mg orally daily, aspirin 81 mg orally daily, temazepam 15 mg orally every night, niacin 200 mg orally twice daily, alendronate sodium 10 mg orally daily, and digoxin 0.125 mg orally daily. Of note, the patient had received two doses of basiliximab, a monoclonal chimeric antibody directed against the interleukin-2 receptor, during the perirenal transplant period and an intravenous injection of glucagon 12 hours before the onset of symptoms. In addition to polycystic renal disease and renal transplantation, the patients medical history was signicant for hypertension (10year duration), hepatitis C without active hepatitis, a frozen left vocal cord (1996) with spontaneous resolution after 6 months, and steroid-induced acne. Three weeks before the onset of ocular symptoms, the patient had rapidly progressive, bilateral lower extremity edema associated with a 5-pound per week weight gain and bilateral lower extremity proximal muscle pain attributed to pravastatin, which was therefore stopped. Eventually the lower extremity edema improved signicantly, and the pain resolved. A deep venous thrombosis was ruled out with a magnetic resonance angiogram. The patient denied a history of trauma, cold extremi-

ties, fevers, paresthesias, hearing loss, extensive bruising, bleeding problems, or rash. His ophthalmic history was unremarkable except as noted above. The diagnostic work-up was unrevealing (Table 1). The patient was examined immediately by a retinal specialist, who diagnosed cytomegalovirus (CMV) retinitis and started the patient on intravenous ganciclovir; the oral acyclovir was discontinued. However, the patients visual acuity progressively deteriorated. On our initial examination, 167 days after renal transplantation, the patients vital signs were normal (blood pressure 110/70). His weight was 72 kg. His visual acuity without correction was 20/200 in the right eye and 20/400 in the left. With pinhole correction, acuity was 20/400 in the right eye and 20/50 in the left. External examination, visual eld (confrontation) testing, and extraocular motility were normal bilaterally. Slit-lamp examination was notable for trace nuclear sclerosis bilaterally and trace posterior subcapsular changes in the left. The anterior chambers were quiet, and the vitreous was syneretic without cell or denite posterior vitreous detachment. Fundus examination of the right eye showed clear media, a at retina, and a myopic peripapillary temporal crescent. Retinal whitening was present in the macula but spared the foveola, giving a cherry red spot appearance, and the perivascular retina (Figure 1A). A few intraretinal hemorrhages and a moderate number of cottonwool spots were present. The left eye showed a similar fundus pattern as well as a Weiss ring in the vitreous cavity (Figure 1B). The clinical appearance was consistent with occlusive disease involving second and third order retinal vessels. The initial differential diagnosis included Purtscher-like retinopathy, noninfectious vasculitis with secondary vascular occlusion, or viral retinitis such as progressive outer retinal necrosis. Intravenous acyclovir (400 mg intravenously twice daily) was added to the medical regimen, which also included ganciclovir. Cyclosporine was discontinued 5 days after the onset of visual loss. Cyclophosphamide 50 mg orally daily and tacrolimus 1 mg orally daily were prescribed, and the prednisone dose was increased to 30 mg orally twice daily. The patients visual acuity progressively deteriorated to hand motion at 1 foot in the right eye and count ngers at 1 foot in the left over the next 3 weeks. Additional funduscopic ndings included sclerosis of the arterioles, perivasculitis, development of intraretinal hemorrhages extending to the equator (Figure 2), venous beading, impaired central artery perfusion with minimal arterial ow observed at the optic nerve head (as determined by digital compression of the globe), and pale and edematous optic disks. The vitreous was quiet at all times, and no neovascularization of the disk or peripheral retina was noted. By the eleventh day

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Fig. 1. A, Color fundus photograph (October 2, 1998) of the right eye. Macular whitening is present with foveal sparing. A few retinal hemorrhages are present in the area centralis. There is attenuation of vascular caliber at the optic nerve head, and cotton wool spots are present. B, Color fundus photograph (October 2, 1998) of the left eye. A similar picture is present.

Fig. 2. Signicant intraretinal hemorrhage developed during the interval between October 2, 1998 and October 13, 1998. A, Right eye, October 13, 1998. B, Left eye, October 13, 1998.

after presentation, the ganciclovir was discontinued because we believed that the patient did not have a CMV infection. Acyclovir was also temporarily discontinued in preparation for a diagnostic vitreous tap on the eleventh day of follow-up (Table 1). However, it was resumed by the renal transplant team after the vitreous tap per routine post renal transplant prophylaxis. Seven weeks after the onset of ocular symptoms, the Uveitis Service of the National Eye Institute (NEI) evaluated the patient and suggested that the history and examination seemed most consistent with 1) bilateral vascular occlusion at the central retinal artery distal to the branching of the long posterior ciliary arteries and 2) bilateral central retinal vein occlusion or stasis. Fluorescein angiography was done on day 1 of presentation and 2 weeks after presentation (Figure 3). The ndings were consistent with bilateral central retinal artery occlusion and bilateral partial impairment of choroidal vascular lling. At the NEI, a focal electroretinogram was performed, which showed diminished but detectable waveforms bilaterally (not shown). The patients condition appeared to stabilize 6 weeks after presentation, and the cyclophosphamide was discontinued. Pred-

nisone was tapered to 10 mg to preserve renal graft function. Aspirin was increased to 325 mg orally daily, and pentoxifylline was started. Gradually, the intraretinal hemorrhages cleared. Thirty-three weeks after presentation, the patient developed rubeosis iridis and elevated intraocular pressure in the right eye and underwent panretinal photocoagulation in the right eye. The rubeosis regressed and the intraocular pressure normalized. Sixty-two weeks after presentation, the patient developed vitreous hemorrhage in the right eye associated with posterior vitreous detachment. At last follow-up (May 15, 2000), the visual acuity was stable at 1/200 in the right eye and 20/200 in the left. The intraocular pressure was 12 mmHg in the right eye and 14 mmHg in the left. Fundus examination was notable for persistent parafoveal retinal whitening, mild macular intraretinal lipid deposition, marked pallor of the optic nerve head, and attenuation of retinal vessel caliber at the optic nerve head.

Discussion Potential causes of this patients retinal vascular occlusive disease include Purtscher-like retinopathy due to leukoembolization, hypercoagulability, nonin-

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Fig. 3. A, Intravenous uorescein angiogram (October 1, 1998) of the right eye shows focal areas of retinal capillary dropout with a pathologically enlarged foveal avascular zone. B, Left eye (October 1, 1998). C, Intravenous uorescein angiogram (October 13, 1998) of the right eye. Dye was rst noted in the central artery at 23.9 seconds (not shown). Choroidal lling was evident at this time. Filling of the retinal vessels is incomplete. The optic disks stain with minimal leakage in late frames. D, Left eye (October 13, 1998). Findings in the left eye are similar.

fectious vasculitis with secondary retinal vessel occlusion, hypertension during or due to the transplant surgery, and infectious retinitis, such as a viral retinitis. Prednisone was used not only to preserve renal function but also to reduce the possibility of further leukoembolization or inammation. Acyclovir was added to the ganciclovir to cover the possibility of progressive outer retinal necrosis. However, these medications also have toxicities including leukopenia and renal toxicity. The medication regimen was reviewed with the renal transplant team to preserve graft function. This patient used a number of medications with reported ocular side effects (Table 2). The pattern of retinal whitening in this patient is most suggestive of retinal arteriolar occlusion, and we believe this sug-

gests that CsA may have played a role in the development of his condition. We offer this suggestion cautiously in view of the widespread use of cyclosporine for many years in solid organ recipients receiving no irradiation with few proposed cases of clinically evident retinal microvascular changes. It is possible that the observed retinal vascular changes are due to an unrecognized side effect of one or more of the many other medications used by the patient (e.g., Simulect [East Hanover, NJ], which is relatively new). For example, cyclosporine has been implicated in the development of optic nerve head edema, in some cases associated with pseudotumor cerebri.6 8 It is not clear whether the retinal vascular changes seen in our patient, if due to cyclosporine or cyclosporine plus an unidentied adjuvant, share pathogenetic features

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Table 2. Pertinent Medication Adverse Reactions* Medication Cyclosporine Relevant Adverse Reactions Glomerular capillary thrombosis with pathologic changes resembling hemolytic uremic syndrome, thrombosis of the renal microvasculature with plateletbrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, hypertension, viral infections, hepatotoxicity, leukopenia, lymphoma, septicemia, systemic and/or local fungal infections, abscesses, peripheral ischemia, herpes zoster, herpes simplex, bacterial infections, moniliasis, hyperuricemia, diabetes mellitus, cataract, conjunctivitis, eye pain May enhance secondary ocular infections due to fungi or viruses, hypertension, ecchymosis, impaired wound healing, pseudotumor cerebri, cataract, increased intraocular pressure, diabetes mellitus Vasodilation, conjunctivitis, diplopia, eye pain, abnormal visual accommodation, xerophthalmia CNS vascular lesions characterized by perivascular hemorrhages and edema in animal studies, a chemically similar drug in this class produced optic nerve degeneration, retinal ganglion cell chromatolysis in animal studies, progression of cataracts, ophthalmoplegia Photosensitivity, conjunctival and scleral injection, pancreatitis Leukocytosis, increase in certain types of infection, ecchymosis, peripheral vascular disease, thrombosis, vasodilation, hypercholesterolemia, hemorrhage, conjunctivitis, cataract Horizontal nystagmus Systemic vasculitis, necrotizing angiitis (both of which are systemic hypersensitivity reactions) Visual disturbances with blurred or yellow vision Toxic amblyopia, cystoid macular edema Orthostatic hypotension Rarely uveitis Bleeding Hypercholesterolemia, viral infection, sepsis, aggravated hypertension, hypotension, arrhythmia, atrial brillation, diabetes mellitus, hemorrhage, thrombocytopenia, thrombosis, polycythemia, herpes simplex, herpes zoster, vascular disorder, cataract, conjunctivitis, infection

Prednisone

Amlodipine besylate Pravastatin

Trimethoprim/sulfamethoxazole Mycophenolate mofetil

Temazepam Furosemide Digoxin Niacin Tamsulosin hydrochloride Alendronate sodium Aspirin Simulect (basiliximab)

Adapted from Physicians Desk Reference, 53rd edition. Montvale, NJ: Medical Economics Company, 1999.

with the development of optic nerve head edema. Previous reports have documented ischemic retinal microvasculopathy and visual loss in patients treated with CsA conditioned with TBI, busulfan, and/or CY following bone marrow transplantation.2 4 Typical ndings include multiple cotton wool spots, retinal hemorrhages, lipid deposits, focal arteriolar narrowing, and optic disk edema.2 4 Our patients vascular occlusive disease may be related to his CsA use, as has been reported previously.5 Cyclosporine can cause endothelial toxicity. Cyclosporine Ainduced vascular damage may be related to direct endothelial cell injury.5 In previous studies, withdrawal or dose reduction of CsA led to complete resolution of the retinopathy and restoration of vision.2 4 Lopez-Jimenez et al1 described cortical blindness (diagnosed by electroretino-

gram, visual evoked response, and electromyography) in a patient with normal fundi who received the same regimen of medications as in the previous studies described above, which was reversed with discontinuation of the CsA. The range of CsA dosing in the previous studies ranged from 4 to 12 mg/kg/d, and our patient was using 4.0 8.0 mg/kg/d.1 4 Thus far only patients receiving CsA conditioned with TBI, busulfan, and/or CY have been reported to have ischemic fundus lesions, and the lesions were reversible with reduction or discontinuation of CsA.1 4 Previous investigators concluded that CsA and conditioning were additive in causing capillary/ arteriolar damage and were both necessary for the microvasculopathy previously described.2 4 We suggest that CsA alone may be responsible; however,

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CsA, if not solely responsible, may, in the setting of another unknown underlying acquired or inherent condition, have stimulated these changes. In previous studies, estimates of the incidence of retinal microvasculopathy were biased by ascertainment of only symptomatic cases.2 The true incidence may be higher. In a prospective study, Bernauer et al4 discovered that 46% of transplant patients with ischemic fundi were asymptomatic. Therefore it may be benecial to include ophthalmologists in the management of patients taking CsA, particularly those patients taking CsA to prevent transplant rejection. Because in previous studies1 4,6,8 as well as in our case study the onset of symptoms after starting CsA therapy ranged from 31 to 332 days, routine ophthalmologic evaluations of patients using CsA should be considered, especially during the rst year of therapy. References
Lopez-Jimenez J, Sanchez A, Fernandez CS, et al. Cyclosporine-induced retinal toxic blindness. Bone Marrow Transplant 1997;20:243245. 2. ORiordan JM, FitzSimon S, OConnor M, McCann SR. Retinal microvascular changes following bone marrow transplantation: the role of cyclosporine. Bone Marrow Transplant 1994;13:101104. 3. Gloor B, Gratwohl A, Hahn H, et al. Multiple cotton-wool spots following bone marrow transplantation for treatment of acute lymphatic leukaemia. Br J Ophthalmol 1985;69:320 325. 4. Bernauer W, Gratwohl A, Keller A, Daicker B. Microvasculopathy in the ocular fundus after bone marrow transplantation. Ann Intern Med 1991;115:925930. 5. Zoja C, Furci L, Ghilardi F, et al. Cyclosporine-induced endothelial cell injury. Lab Invest 1986;55:455 462. 6. Avery R, Jabs DA, Wingard JR, et al. Optic disc edema after bone marrow transplantation. Possible role of cyclosporine toxicity. Ophthalmology 1991;98:1294 1301. 7. Katz B. Disk edema subsequent to renal transplantation. Surv Ophthalmol 1997;41:315320. 8. Cruz OA, Fogg SG, Roper-Hall G. Pseudotumor cerebri associated with cyclosporine use. Am J Ophthalmol 1996;122: 436 437. 1.

From the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Hospital, New York, New York. In recent years, converging lines of experimental and clinical evidence have clearly identied steroids as a risk factor for acute manifestations of central serous chorioretinopathy (CSC).17 The systemic use of steroids by virtually any route of administration2,3,6,7 or systemic disorders associated with a state of hypercorticalism, such as Cushing syndrome,4 have been implicated in the development of exudative macular detachments in patients with CSC. Drugs that stimulate an adrenergic effect or a catecholamine response are also thought to be potential risk factors for CSC, but this association has not been clearly established.3,5 This report describes a patient who had primary, and subsequently recurrent, acute exudative manifestations of CSC after using the illicit drug methylenedioxymethamphetamine (MDMA), commonly referred to as ecstasy, a popular party or club drug with psychomimetic and adrenergic effects.8 Case Report
A 38-year-old man who was in perfect health and had no remarkable medical or ocular history experienced a visual disturbance in his right eye 3 days after the use of MDMA. The exact formulation and dose of the drug were unknown. His examination at that time showed a visual acuity of 20/40 in his right eye and 20/20 in his left eye. He also had metamorphopsia and a relative central scotoma on Amsler grid testing. A large neurosensory macular detachment was noted on slit-lamp examination with the Goldmann contact lens. No lipid or blood was seen. The macula in the left eye was unremarkable, except for two minor, punctate, atrophic pigment epithelial changes. After several weeks, visual acuity returned to 20/20 in the right eye, and there was a corresponding complete resolution of the neurosensory retinal detachment. Approximately 10 months later, he used the same drug again, and he experienced a decrease in vision of his right eye similar to what had been noted earlier. A recurrent neurosensory macular detachment was seen in the same eye, but this time, the detachment was smaller. The visual acuity was reduced to 20/25. The detachment again spontaneously resolved. This patient had not used MDMA at any other time except before the two episodes of acute macular detachment.

CENTRAL SEROUS CHORIORETINOPATHY IN A PATIENT USING METHYLENEDIOXYMETHAMPHETAMINE (MDMA) OR ECSTASY LAMA HASSAN, MD, CYNTHIA CARVALHO, MD, LAWRENCE A. YANNUZZI, MD, TOMOHIRO IIDA, MD, SILVANO NEGRO, MD

Discussion Central serous chorioretinopathy is a well-known, complex clinical disorder whose pathogenesis is still poorly understood.2,3,5,6 An array of risk factors, including refractive state, systemic blood pressure, genSupported by The Macula Foundation, Inc. Reprint requests: Lawrence A. Yannuzzi, MD, Manhattan Eye, Ear, and Throat Hospital, 210 East 64th Street, New York, NY 10021.

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der, age, and corticosteroids (exogenous or endogenous), have been identied in the past.2,3,5 The relationship between the use of exogenous corticosteroids and the pathogenesis of CSC have been reviewed by Gass and Little.6 Although the precise mechanism for the relationship is unknown, a steroidinduced effect on the choroidal circulation is presumed to be responsible for the exudative changes. In a recent article by Carvalho and Yannuzzi,7 steroids were implicated in the development of acute manifestations of CSC in more than 50% of patients in a prospective, consecutive series. The steroid use was by several routes of systemic administration, including oral, intramuscular, intraarticular, and inhalation. In this report, the authors suggested that other drugs that indirectly stimulate the adrenal cortex, inducing a catecholamine response, could also predispose patients to acute manifestations of CSC. Accordingly, stimulation of the adrenergic system may also be implicated in acute manifestations of CSC, but evidence supporting this possible association, although attractive, is not conclusive. The possible mechanisms by which increased corticosteroid and catecholamine levels may contribute to the pathogenesis of CSC have been reviewed recently by Haimovici et al.3 The basis of this concept involves the release of catecholamines and an increase in the sensitivity of adrenergic receptors by corticosteroids. The supporting evidence includes an experimental model of CSC that was induced by intravenous injections with epinephrine and norepinephrine in primates.9 There is also a primate model for CSC using intravenous epinephrine and intramuscular corticosteroids.10 Also, urinary epinephrine and norepinephrine levels are increased in patients with active CSC compared with control patients.11 Clinical evidence supporting a link between hypercorticalism and adrenergic stimulation can be found in the known abnormal behavioral pattern, specically a Type A personality, seen in patients with CSC.5 These patients have an increased secretion of cortisol and adrenergic agents, such as epinephrine and norepinephrine.5 Also, combined corticosteroids and -adrenergic nasal inhalants have been reported to be a risk factor for CSC.3 Furthermore, systemic hypertension is a known risk factor for CSC.2 Increased catecholamine levels are common to systemic hypertension and to CSC.2,11,12 There is also an increased vasoconstrictive sensitivity to corticosteroids in systemic hypertension.13 Corticosteroids increase catecholamine-mediated vasoconstriction in the peripheral vasculature and in the choroid.13,14 Although still unproven, vasoconstriction and associated perfusion abnormalities in the choroid have been hypothesized to be causative factors in the

pathogenesis of CSC.2,5 Corticosteroids are also known to induce transcription of -adrenergic15 and -adrenergic16 receptor genes, and they may potentiate the effects of adrenergic stimulation on certain target tissues, such as the retinal pigment epithelium.17,18 Accordingly, a potential synergistic state exists between corticosteroids and catecholamine metabolism as a potential causative factor for the development of acute manifestations of CSC. Essentially, corticosteroids may increase catecholamine release and make critical tissues, such as the inner choroid and the retinal pigment epithelium, more susceptible to adrenergic effects. Although an absolute causal relationship between the use of MDMA and the development of CSC in our patient is uncertain, there is a pharmacologic basis for the development of acute manifestations of CSC from the use of this agent. In MDMA, the pharmacologic component theoretically predisposing to CSC is likely to be methamphetamine, which is a combined - and -adrenergic agent.8 It is known to stimulate peripheral and central - and -adrenergic receptors. A causal relationship is particularly possible because the patient experienced symptoms only on the two occasions when he used the drug. Discontinuation of the drug was also associated with spontaneous resolution of the macular manifestations, further implicating the use of the drug with the disorder. The origin of this drug dates back to the early 1960s when MDMA was rst synthesized by the pharmaceutical company, Merck, with no particular purpose in mind. The drug remained dormant until the 1970s, when it was studied by psychotherapists who claimed that it enhanced communication in therapy, essentially as a psychomimetic or psychedelic agent. By the 1980s, however, MDMA emerged as an illicit, socalled party or club drug used in discotheques by young adults. In recent years, this drug has become increasingly popular, and its users have extended into the teenage population. As a drug that is not approved for any medical purpose, its formulation is not regulated or controlled, and its use and distribution continue to be illegal. Research at the animal level to date has established that MDMA shares the properties of the psychedelic drug lysergic acid diethylamide and the adrenergic stimulant amphetamine. Structurally, it is similar to the hallucinogen mescaline and the adrenergic agent methamphetamine. Typically, it is used orally in a capsular, tablet form, and its effects last for 3 to 6 hours, depending on the dose. Persistent cognitive abnormalities, such as confusion, depression, insomnia, anxiety, and paranoia, are known to be side effects of the drug, even several weeks after its use. What is most disturbing about MDMA is that it is

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extremely dangerous with regard to cardiovascular and neurologic effects, with potentially long-lasting adverse complications affecting the brain to alter memory function and motor skills. The adrenergic changes relate to the cardiovascular side effects. Because it is a stimulant, MDMA increases the heart rate, blood pressure, and body temperature, and it may have serious side effects, including dehydration, persistent hypertension, and heart or kidney failure. It is known to increase the release of epinephrine,19 accounting for these systemic cardiovascular changes. Plasma levels of steroids have also been found to be higher in patients using MDMA.20 Thus, there is an adrenergic and a corticosteroid stimulation with MDMA that may be a factor in the development of CSC in our patient. Neurologically, MDMA acts primarily as a serotonergic (5-HT) drug, a major neurotransmitter in the brain, synthesized from tryptophan through the intermediate 5-hydroxetryptophan.8 MDMA actually affects 5-HT in the way that amphetamines affect dopamine, by inhibiting the uptake and causing the release of the molecule. This mechanism of action is similar to the way that selective serotonin reuptake inhibitors work. Serotonin effects are also thought to be responsible for the psychologic and physiologic effects of the drug, including mood, sleep, depression, and obsessive compulsions.8 Its neurotoxicity can have permanent damage to neurons that release serotonin, impairing an individuals memory and cognitive performance. This case report suggests that MDMA may also have ocular effects that are most likely mediated through its adrenergic and corticosteroid stimulation, which in turn may predispose patients to acute manifestations of CSC. In patients with steroids as a contributing causative effect of their acute CSC manifestations, discontinuation of the drug is usually associated with resolution of the neurosensory detachment.7 The same outcome seemed to be evident in this case. Although additional research is obviously needed to conrm this singular observation, the relationship between the use of MDMA and the acute manifestations of CSC is rational, if not compelling. Accordingly, clinicians should be aware of this potential association so that they can counsel their patients, particularly those who have other risk factors for CSC or who are actually known to have had the condition itself. Therefore, patients who have acute manifestations of CSC should be carefully asked about drug use so that they can be advised to discontinue any drug that might have a systemic, adrenergic stimulating effect before any other form of treatment is considered.

References
1. Wakakura M, Ishikawa S. Central serous chorioretinopathy complicating systemic corticosteroid treatment. Br J Ophthalmol 1984;68:329 331. Tittl MK, Spaide RF, Wong D, et al. Systemic ndings associated with central serous chorioretinopathy. Am J Ophthalmol 1999;128:63 68. Haimovici R, Gragoudas ES, Duker JS, et al. Central serous chorioretinopathy associated with inhaled or intranasal corticosteroids. Ophthalmology 1997;104:16531660. Garg SP, Dada T, Talwar D, et al. Endogenous cortisol prole in patients with central serous chorioretinopathy. Br J Ophthalmol 1997;81:962964. Yannuzzi LA. Type A behavior, central serous chorioretinopathy. Retina 1987;7:111131. Gass JD, Little H. Bilateral bullous exudative retinal detachment and complicating idiopathic central serous chorioretinopathy during systemic corticosteroid therapy. Ophthalmology 1995;102:737747. Carvalho C, Yannuzzi L, Coleman H, et al. Central serous chorioretinopathy and corticosteroids. Ophthalmology 2001 (submitted for publication). Rattray M. Ecstasy. Towards an understanding of the biochemical basis of actions of MDMA. Essays Biochem 1991; 26:77 87. Nagayoski K. Experimental study of chorioretinopathy by intravenous injection of adrenaline. Acta Soc Ophthalmol Jpn 1971;75:1720 1727. Yoshioka H, Katsume Y, Akune H. Experimental central serous chorioretinopathy in monkey eyes: uorescein angiography ndings. Ophthalmologica 1982;185:168 178. Wakakura M, Suzuki H. Central serous chorioretinopathy. Jpn J Clin Ophthalmol 1979;33:12371240. Goldstein DS. Plasma catecholamine and essential hypertension: an analytic review. Hypertension 1983;5:86 89. Walker BR, Best R, Schackleton CH, et al. Increased vasoconstrictor sensitivity to glucocorticosteroids in essential hypertension. Hypertension 1996;27:190 196. Koss MG, Gherezgheker T. Adrenoreceptor subtypes involved in neurally evoked sympathetic vasoconstriction in the anterior choroid of cats. Exp Eye Res 1993;57:441 447. Sakuve M, Hoffman B. Glucocorticosteroids induce transcription and expression of alpha adrenergic receptor gene in DDTI MR-2 smooth muscle cells. J Clin Invest 1991;88:385 389. Hadcock JR, Malbon CC. Regulation of beta-adrenergic receptors by permissive hormones: glucocorticoids increase steady-state levels of receptors mRNA. Proc Natl Acad Sci USA 1988;85:8415 8419. Koh SWM, Chader GJ. Retinal pigment epithelium in culture demonstrates a distinct beta adrenergic receptor. Exp Eye Res 1984;38:713. Frambach DA, Fain GL, Farber DB, Bok D. Beta adrenergic receptors on cultured human retinal pigment epithelium. Invest Ophthalmol Vis Sci 1990;31:17671772. Mas M, Favee M, de la Torre R, et al. Cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4 methylenedioxymethamphetamine in humans. J Pharmacol Exp Ther 1999;290:135145. Rothman RB, Baumann MH, Duesch CM, et al. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 2001;39:32 41.

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Correspondence
Reversed SelfSealing Pars Plana Sclerotomies Dear Editor: We read with interest the article by Assi et al1 describing a technique of reversed self-sealing sclerotomies. It is a modication to the methods described by Chen2 and Kwok et al.3 Chen constructed a radial scleral tunnel with opening 2 mm posterior to the intended pars plana entry; Kwok et al modied it by rotating the tunnel through 90 degrees, so that the tunnel was circumferential. The technique of Assi et al was similar to that of Chen,2 except the opening of the tunnel was anterior to the intended pars plana entry. The common advantages of various self-sealing sclerotomy techniques were echoed in his study, including sutureless closure of the sclerotomy sites, reduced intraocular pressure uctuation, and reduced likelihood of vitreous incarceration and leakage of uid or gas. Whereas the approach proposed by Assi et al may have some advantages, the infusion tubing is likely to enter the surgical eld and cause obstruction of view during surgery when the opening of the scleral pocket is anterior and radial. The risk of the tip of the radial infusion cannula touching the peripheral retina may also be higher, especially when a longer infusion cannula is used. Additionally, as the anterior opening of the scleral pocket is only 2 mm posterior to the limbus, the conventional sutured ring system may make insertion of instruments difcult. For example, the width of the sutured ring in the Landers system is already 1.5 mm. Moreover, the instruments are to be inserted in a mediallateral direction before entering the eyeball and this may hit the contact lens in the sutured ring. This problem is even more prevailing with the use of panoramic viewing system, be it contact or noncontact type, as the wide-eld lenses are much larger and hence easily interfere with the insertion of instruments. The above potential problems are not present in our reported modied circumferential sutureless technique.3 It appears to be immature at this

stage to recommend the authors reversed method as the standard for sutureless pars plana sclerotomies. Alvin K. H. Kwok, FRCS El Neoh, FRCS Dennis S. C. Lam, FRCS, FRCOPHTH Department of Ophthalmology & Visual Sciences The Chinese University of Hong Kong Hong Kong Eye Hospital Hong Kong Reply Dear Editor: We thank Drs. Kwok, Neoh, and Lam for their interest in our article describing reversed self-sealing pars plana sclerotomies. We clearly stated that we used a traditional stab incision sclerotomy port for the temporal infusion line and that we studied reversed self-sealing sclerotomies for the instruments in the superotemporal and superonasal quadrants. Kwok et als assumptions about potential problems with the infusion line tubing and tip in the self-sealing sclerotomy are therefore inappropriate and invalid. Regarding the insertion of instruments, we did not encounter any problems with the hand-held Machemer contact lenses nor with the noncontact wide angle system (Biom) that we currently use. As previously stated, the reversed self-sealing sclerotomies offer smoother and better access to the posterior segment and easier exchange and manipulation of instruments owing to the more logical anteroposterior direction of the tunnel. We therefore reiterate the recommendation of our technique as a standard for self-sealing sclerotomies. Alexandre C. Assi, FRCOPHTH Robert A. H. Scott, FRCOPHTH David G. Charteris, MD, FRCS, FRCOPHTH Moorelds Eye Hospital London, United Kingdom References
1. 2. Assi AC, Scott RAH, Charteris DG. Reversed self-sealing pars plana sclerotomies. Retina 2000;20:689 692. Chen JC. Sutureless pars plana vitrectomy through self-sealing sclerotomies. Arch Ophthalmol 1996;114:12731275. Kwok AKH, Tham CCY, Lam DSC, Li M, Chen JC. Modied sutureless sclerotomies in pars plana vitrectomy. Am J Ophthalmol 1999;127:731733.

RETINA, The Journal of Retinal and Vitreous Diseases, encourages readers to submit Correspondence related to recent articles or other material published in the journal. Correspondence should be typed double-spaced on 812 11 bond paper with 112 margins on all four sides.

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ICGAGuided Laser Photocoagulation of Feeder Vessels of Choroidal Neovascular Membranes in AgeRelated Macular Degeneration Dear Editor: I would like to congratulate Desatnik and coworkers1 for attempting to further rene laser photocoagulation of feeder vessels (FV) of choroidal neovascularization (CNV). A number of other recent reports have shown encouraging results after laser treatment of FV.2,3 Although no denitive answers on the indications and efcacy of this procedure can be drawn, some evidence derived from this and previous studies may contribute in identifying the subjects who may benet from the treatment. It is clearly evident that the possibility to identify and treat FV in choroidal neovascular nets depends not only on the different systems appliedi.e., indocyanine green angiography (ICGA) vs uorescein angiography (FA), scanning laser ophthalmoscopes vs digital fundus cameras, confocal aperture but also on the experience, skill, and knowledge of the single physician. In different case series FV have been detected in 22%,2 75%,4 and 86%3 of cases. Anatomic success, dened as occlusion of FV and CNV, has been obtained in 40 80% of treated eyes.13 The application of new systems that permit visualization of choroidal blood ow by high-speed ICGA and simultaneous delivery of laser photocoagulation to the FV might improve the ability to identify and treat the target.5 Not all the FV respond positively to laser photocoagulation. Staurenghi and coworkers3 found that FV that insert into the CNV after a variable course (racquet-like pattern) might have a better outcome than FV that seem to originate from the choroidal vascular bed beneath the CNV (umbrella-like pattern). This is the case of Patient 3 reported by Desatnik and coworkers.1 At the latest follow-up visit FA and ICGA showed progressive retinal pigment epithelium (RPE) atrophy adjacent to the laser scar, possibly due to excessive laser irradiation in the attempt to close the umbrella-like neovascular net. The length of the FV might positively inuence the outcome of laser treatment. There is evidence that the longer the course of the treatable vessels, the better the occlusive effect.3 Similar results are reported by Desatnik and coworkers1 in Cases 1, 2, and 4. The caliber of the FV might be another factor involved in the success rate. In Case 5 the width of the FV was large and repeated laser treatments caused an RPE rip and recurrence of the CNV. Staurenghi et al.3 reported that the success rate of FV laser photocoagulation increased from 40 75% when FV were selected for treatment on the basis

of a width of less than 85 m. The role of other factors prognostic of good outcome after treatment, such as the presence of a small CNV and the closest distance of laser burns to the center of the foveal avascular zone, have been underlined by Shiraga et al.2 and need further studies. The precise mechanisms by which laser photocoagulation is able to close choroidal new vessels have been debated for years and little is known regarding the action by which laser stimulates FV closure. Preliminary experiences with ICGA-guided FV laser photocoagulation have used different wavelengths and techniques. Shiraga et al.2 placed conuent intense burns covering the FV and an area of 300-m beyond it on either side and around its origin with a dye laser (576 nm yellow and 630 nm red). An argon green laser was used by Staurenghi et al.3 The treatment was administered in two consecutive steps: the rst with a 100-m spot size of moderate intensity on both sides of the FV; the second with a 100- or 200-m beam over the FV. Delivery of 810-nm wavelength diode laser pulsed photocoagulation has been effectively applied by Glaser et al.4 Hundreds of nonophthalmoscopically visible or barely visible burns were placed over the FV. Desatnik and coworkers1 used intense conuent burns along the FV with a 200-m spot size and an argon green laser. Although the authors state that an argon green is preferable for treatment of FV, no denitive conclusions on the optimal wavelength and technique for FV laser photocoagulation can be drawn. Only adequate randomized clinical trials will help to dene the efcacy and role of FV photocoagulation and the recommended technique and wavelength. Paolo Lanzetta, MD Department of Ophthalmology University of Udine Udine, Italy

Reply Dear Editor: We would like to thank Dr. Lanzetta for his interest in our article on laser treatment to feeder vessels of CNV in age-related macular degeneration. In our experience this technique can be useful to preserve or even improve vision in select cases of subfoveal CNV when a FV can be detected. There are many unanswered questions regarding this mode of treatment, including the difculty in identifying the FV, the best wavelength and its effectiveness, and

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visual outcome compared to other current treatments for subfoveal CNV: photodynamic therapy, submacular surgery and subfoveal removal, limited macular translocation, and others. Only randomized multicenter clinical trials will help us to place the effectiveness of this treatment modality in its proper perspective. In the meantime, in the absence of such data, we need to use our clinical judgment and experience to decide on an individual patient basis when FV treatment will give better results than other treatment options. Howard Desatnik, MD Joseph Moisseiev, MD Retina Service Goldschleger Eye Institute Sheba Medical Center Tel-Hashomer, Israel

References
1. Desatnik H, Treister G, Alhalel A, Krupsky S, Moisseiev J. ICGA-guided laser photocoagulation of feeder vessels of choroidal neovascular membranes in age-related macular degeneration. Retina 2000;20:143150. Shiraga F, Ojima Y, Matsuo T, Takasu I, Matsuo N. Feeder vessel photocoagulation of subfoveal choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology 1998;105:662 669. Staurenghi G, Orzalesi N, La Capria A, Aschero M. Laser treatment of feeder vessels in subfoveal choroidal neovascular membranes. A revisitation using dynamic indocyanine green angiography. Ophthalmology 1998;105:22972305. Glaser BM, Murphy RP, Lakhanpal RR, Lin SB, Baudo TA. Identication and treatment of modulating choroidal vessels associated with occult choroidal neovascularization [abstract 1687]. Invest Ophthalmol Vis Sci 2000;41:S320. Flower RW. Experimental studies of indocyanine green dyeenhanced photocoagulation of choroidal neovascularization feeder vessels. Am J Ophthalmol 2000;129:501512.

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