Latanoprost Accelerates Disruption of the Blood-Aqueous Barrier and the Incidence of Angiographic Cystoid Macular Edema in Early Postoperative Pseudophakias

CLINICAL SCIENCES Latanoprost Accelerates Disruption of the Blood-Aqueous Barrier and the Incidence of Angiographic Cystoid Macular Edema in Early Postoperative Pseudophakias

Kensaku Miyake, MD; Ichiro Ota, MD; Kumiko Maekubo, MD; Satomi Ichihashi, MD; Sampei Miyake, MD

Objective: To study the effect of latanoprost, a prosta- day before surgery on the day of surgery and 3 times a glandin analog, on the blood-aqueous barrier and angio- day until the fifth postoperative week. graphic cystoid macular edema (CME) formation in early postoperative pseudophakias. Results: In group B compared with group D, the amount of flare 3 days and 1 and 2 weeks after surgery Patients and Methods: Included in the study were and the incidence of angiographic CME in the fifth eyes with ocular hypertension, normal-tension glau- postoperative week were significantly higher. These 2 coma, or primary open-angle glaucoma undergoing sur- factors were significantly higher in group B than in gery for cataract. The study consisted of a randomized group A (PϽ.05) and in group D than in group C double-masked trial for latanoprost and an open-label con- (PϽ.01). There was no significant difference in these trolled trial for determining the effects of diclofenac so- factors between groups A and C. The intraocular pres- dium or fluorometholone eyedrop use on latanoprost or sure decline was significant in groups A and B com- its placebo. We compared 4 groups of eyes with concur- pared with groups C and D (PϽ.05), but there was no rent application of latanoprost and diclofenac (group A), significant difference between groups A and B and latanoprost and fluorometholone (group B), latano- between groups C and D. prost placebo and diclofenac (group C), and latanoprost placebo and fluorometholone (group D). A laser Conclusions: Latanoprost therapy enhances disrup- flare cell meter was used to determine the severity of tion of the blood-aqueous barrier and increases the in- blood-aqueous barrier disruption, and fluorescein angi- cidence of angiographic CME formation in early post- ography was performed to determine angiographic CME operative pseudophakias. Because administration of formation. Mean diurnal intraocular pressure differ- nonsteroidal eyedrops such as diclofenac seems to pre- ences were compared on the preoperative baseline day vent the adverse effects of latanoprost therapy while main- and in the fifth postoperative week. Latanoprost (0.005%) taining its effect to lower intraocular pressure, we sug- or its placebo was given once a day starting 2 days be- gest their concurrent application. fore surgery until the fifth postoperative week. Diclof- enac or fluorometholone eyedrops were given 4 times a Arch Ophthalmol. 1999;117:34-40

SE OF prostaglandin F2␣ Although the major mechanism of la- and its prodrug forms ef- tanoprost in lowering IOP is thought to fectively lowers intraocu- be an increase in uveoscleral outflow,9-12 lar pressure (IOP).1,2 Re- the drug’s physiologic mechanisms and ad- sults of further studies3,4 verse effects are not fully understood. With Uusing human volunteers, however, reveal experimental animals, although there was that topical application of these drugs leads a slight difference among various types of to severe conjunctival hyperemia, foreign animals, the effects of latanoprost therapy body sensation, and headache. Stjern- on aqueous humor dynamics, blood- schantz and Resul5 found that a group of aqueous barrier function, and blood- phenyl-substituted compounds had the least retinal barrier function were mini- number of adverse effects. Based on these mal.13-16 In human eyes, in addition to From the Shohzankai Medical findings, a clinical trial was conducted to de- Foundation, Miyake Eye Hospital, Nagoya, Japan. The termine the effects of latanoprost (PhXA41), authors do not have any an analog of the group mentioned above, as an antiglaucoma agent, and positive re- This article is also available on our commercial interest in the Web site: ama-assn.org/ophth. products mentioned in the sults with minimal findings on its clinical article. adverse effects were reported.6-8

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 PATIENTS AND METHODS tories Inc, Fort Worth, Tex) was implanted inside the lens capsule. All surgical procedures were performed by 1 of 2 surgeons (K.M. or I.O.). To study the effect of latanoprost on disruption of the blood- In patients who had been taking medication for glau- aqueous barrier and on the incidence of angiographic CME coma, the antiglaucoma treatment was discontinued 2 weeks formation after cataract and IOL surgery, eyes with ocular before initiation of the study to wash out the drug. Treat- hypertension, normal-tension glaucoma, or primary open- ment with either latanoprost or placebo was started 2 days angle glaucoma were entered in the double-masked con- before surgery and was given once a day at 8 AM until the trolled trial using latanoprost (0.005% Xalatan, Pharma- fifth postoperative week. In addition, either fluorometho- cia & Upjon, Kalamazoo, Mich) and its placebo, which was lone or diclofenac was given 4 times on the day of surgery sterile phosphate-buffered saline solution prepared in the (3, 2, and 1 hour and 30 minutes before surgery) and then hospital pharmacy. At the same time, a study on the effect 3 times a day until the fifth postoperative week. Other drugs of concurrent application of either diclofenac sodium (a non- taken concurrently included oral and topical antimicro- steroidal drug; 0.1% Diclod, Wakamoto Pharmaceutical Co bial medications. Ltd, Tokyo, Japan) or fluorometholone (a steroidal drug; Examination and observation criteria included pa- 0.1% Flumetholon, Santen Pharmaceutical Co Ltd, Osaka, tient background, surgical detail, visual acuity, IOP, amount Japan) was conducted. Fluorometholone, which has simi- of aqueous flare as measured by a laser flare cell meter, and lar anti-inflammatory effects as betamethasone sodium phos- presence of angiographic CME as determined by fluores- phate or dexamethasone sodium phosphate32-35 but is less cein angiography. likely to cause steroidal glaucoma,33-35 was chosen for an Visual acuity was measured 1 to 3 days before sur- ethical reason. However, because fluorometholone is a gery and 1 and 3 days and 1, 2, and 5 weeks after surgery. milky-white substance, making it difficult to conduct this The fluctuation in IOP was evaluated using the average di- part of the study as a double-masked trial, we performed urnal IOP measured 4 times a day—at 8 AM,12PM,4PM, it as an open-label study. and 8 PM—3 days before surgery as the baseline, compar- Latanoprost and its placebo were randomly assigned; ing it with the average found in the fifth postoperative week. and fluorometholone and diclofenac were also randomly A laser flare cell meter (FC1000, Kowa Co Ltd, Tokyo) was assigned to latanoprost or its placebo. used to determine the severity of blood-aqueous barrier dis- Groups of 40 eyes (160 eyes total) receiving latano- ruption 4 to 6 days before surgery and 1 and 3 days and 1, prost and diclofenac (group A), latanoprost and fluoro- 2, and 5 weeks after surgery. metholone (group B), latanoprost placebo and diclofenac Fluorescein angiography was performed to determine (group C), and latanoprost placebo and fluorometholone angiographic CME formation in the fifth postoperative week (group D) initially entered the study. Inclusion criteria for after IOP measurement. The late phase (15 minutes after in- these 160 consecutive patients required the patient to be travenous injection of 10% sodium fluorescein) of fluores- older than 40 years and to have cataract and ocular hyper- cein angiograms was graded by 1 of us (S.M.) using the tension, normal-tension glaucoma, or primary open-angle method previously mentioned22 in a double-masked man- glaucoma; only 1 eye from each patient was considered ner. Briefly, 0° means there is no sign of fluorescein leak- for the trial during follow-up (5 weeks). Exclusion criteria age; I°, there is a slight fluorescein leakage into the cystic were as follows: eyes unable to obtain a pupil diameter space but not sufficient enough to enclose the entire fovea larger than 4 mm when mydriasis was induced for opera- centralis; II°, there is a complete circular accumulation of tion; eyes reacting to administration of diclofenac, fluoro- the fluorescein in the cystic space but its diameter is less than metholone, latanoprost, or fluorescein sodium; eyes with 2.0 mm; and III°, the circular accumulation of the fluores- a previous history of ocular surgery; and patients with cein is larger than 2.0 mm in diameter. The Figure shows a other ocular or systemic disorders except glaucoma and representative example of each grade. cataract. Patient age, surgical data, visual acuity, aqueous flare This study was conducted in accordance with the Dec- amount, and IOP among the 4 groups were analyzed us- laration of Helsinki after receiving approval from the In- ing 1-way analysis of variance. Furthermore, if there were stitutional Review Board of the Miyake Eye Hospital, Nagoya, differences in each comparison, we used the Tukey test for Japan. Written informed consent was obtained from each multiple comparisons to specify the site of difference. The patient before inclusion in the study and after sufficient ex- reduction of IOP in each group was analyzed using the paired planation about the nature of the study and the method in t test. The distribution of sex, types of glaucoma, antiglau- which fluorescein angiography is performed. coma medications, and family history of glaucoma were ana- In all patients, surgery consisted of creating a 3-mm lyzed using the ␹2 method. The incidence of angiographic clear corneal incision and placing 1 suture if necessary. Af- CME was analyzed using the Fisher exact test. At all times, ter continuous curvilinear capsulorhexis and phacoemul- PϽ.05 was considered significant; the data are presented sification, an acrylic foldable IOL (Acrysof, Alcon Labora- as mean ± SD unless stated otherwise.

finding no sign of latanoprost therapy causing disrup- play a role as inflammatory mediators,19-21 we evalu- tion of the blood-aqueous barrier,17,18 administration of ated the effects of latanoprost administration on the the drug also had no effect on cystoid macular edema blood-ocular barrier in diseased eyes with abnormal (CME) formation in long-standing pseudophakic eyes.16 activity and transport of endogenous prostaglandins. The studies discussed above, however, were con- Results of studies22-27 indicate that endogenous pros- ducted in animal eyes or in human eyes without any taglandins, synthesized at the anterior uvea, are in- eye disorders except for glaucoma and long-standing volved in disrupting the blood-aqueous barrier and in in- pseudophakias. Because prostaglandins are believed to ducing CME after cataract extraction. Results of recent

ARCH OPHTHALMOL / VOL 117, JAN 1999 35

A C

I° III°

B D

A representative example of each of grades at the late phase (15 minutes after intravenous injection of 10% sodium fluorescein) of fluorescein angiograms. 0° indicates no sign of fluorescein leakage; I°, slight fluorescein leakage into the cystic space but not sufficient enough to enclose the entire fovea centalis; II°, complete circular accumulation of the fluorescein in the cystic space but its diameter is less than 2.0 mm; and III°, the circular accumulation of fluorescein is greater than 2.0 in diameter.

studies28,29 suggest that the synthesis of prostaglandins glaucoma, this study was relevant from both clinical and and cytokine may also be related to the wound healing basic points of view. process, proliferation, and metaplasia of lens epithelial cells after surgery. In addition, the active transport of pros- taglandins30 is reduced during the time the inflamma- RESULTS tory reaction remains active after lens extraction.31 How external prostaglandins such as latanoprost may affect Because continuous curvilinear capsulorhexis failed in these pseudophakic eyes under these circumstances also 1 eye from group A, the posterior capsule ruptured in 1 remains unclear. eye from group C, and several patients from each group In this study, we applied latanoprost eyedrops or its did not meet the follow-up requirements (such as fluo- placebo to glaucomatous eyes to evaluate the early post- rescein angiography) because of health or social rea- operative effects of latanoprost on the blood-aqueous bar- sons, 35 eyes from group A, 37 eyes from group B, 36 rier function and on the incidence of angiographic CME eyes from group C, and 37 eyes from group D (145 eyes after cataract extraction and intraocular lens (IOL) im- total) remained in the study. Included in the follow-up plantation. The effects of concurrently applied steroidal group were several patients unable to meet all laser flare or nonsteroidal eyedrops were also investigated. Be- cell metric evaluations and visual acuity measurements cause many eyes undergoing cataract surgery often have because of social or physical reasons.

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Group A: Group B: Group C: Group D: Latanoprost and Latanoprost and Placebo and Placebo and Characteristic Diclofenac Sodium Fluorometholone Diclofenac Fluorometholone No. of eyes 35 37 36 37 Age, mean ± SD, y 68.2 ± 7.2 69.9 ± 8.2 70.1 ± 8.4 69.8 ± 7.8 Sex, M/F 13:22 18:19 15:21 17:20 Ocular diagnosis Ocular hypertension 13 15 15 16 Normal-tension glaucoma 9 12 10 10 Primary open-angle glaucoma 13 10 11 11 Antiglaucoma medications† 23 22 22 24 0.5% Timolol maleate 18 15 16 16 Isopropyl unoprostone 16 15 12 13 1% Pilocarpine hydrochloride 1 1 1 2 0.1% Dipivefrin hydrochloride 1 1 1 0 Family history of glaucoma 11 8 9 9

*Data are given as number of eyes, except for age and sex. †Some eyes may be receiving 2 or more medications.

Table 2. Surgical Data*

Group A Group B Group C Group D (n = 35) (n = 37) (n = 36) (n = 37) Operation time, min 14.08 ± 2.42 15.01 ± 3.21 14.56 ± 2.62 14.77 ± 3.01 Nucleus hardness, degree 2.45 ± 0.36 2.36 ± 0.42 2.51 ± 0.31 2.60 ± 0.35 Ultrasound time, s 74.26 ± 42.62 69.26 ± 33.42 71.33 ± 22.62 70.56 ± 46.21 Intraocular irrigation solution,† mL 101.64 ± 36.27 98.46 ± 46.21 102.22 ± 40.21 99.58 ± 34.26

*Data are given as mean ± SD. See Table 1 for description of drug treatment groups. †Balanced salt solution.

Table 4 summarizes the changes in IOP. Before sur- Table 3. Corrected Visual Acuity* gery, there was no significant difference in IOP among the 4 groups of eyes. All 4 groups revealed significant de- Mean ± SD Corrected Visual Acuity cline in IOP in the fifth postoperative week compared with Group A Group B Group C Group D preoperative diurnal IOP, which is used as the baseline (n = 35) (n = 37) (n = 36) (n = 37) (PϽ.01). Furthermore, compared with the 2 groups of Before operation 0.35 ± 0.25 0.33 ± 0.26 0.41 ± 0.25 0.34 ± 0.27 eyes receiving placebo (groups C and D), the amount of Postoperative decline was significantly larger in the 2 groups receiv- 1 d 0.81 ± 0.26 0.79 ± 0.31 0.84 ± 0.29 0.79 ± 0.29 ing latanoprost (groups A and B) (PϽ.05), although there 3 d 0.94 ± 0.22 0.89 ± 0.22 0.91 ± 0.31 0.92 ± 0.29 was no significant difference between the former 2 groups 1 wk 0.95 ± 0.28 0.92 ± 0.22 0.96 ± 0.26 0.95 ± 0.31 and between the latter 2 groups. 2 wk 0.97 ± 0.30 0.98 ± 0.22 0.99 ± 0.35 0.98 ± 0.28 5 wk 0.98 ± 0.40 0.99 ± 0.36 0.98 ± 0.25 0.99 ± 0.31 Table 5 lists the incidence of angiographic CME formation in the fifth postoperative week. The inci- *See Table 1 for description of drug treatment groups. dence was significantly higher in eyes receiving fluorometholone (groups B and D) than in those receiving di- Table 1 shows demographic and clinical charac- clofenac (groups A and C) (PϽ.01) and was significantly teristics of the patients. There was no significant differ- higher in eyes receiving latanoprost and fluorometho- ence in age, sex, type of glaucoma, history of drug use, lone (group B) compared with those receiving placebo and family history among patients in the 4 groups of and fluorometholone (group D) (PϽ.01). However, there eyes. was no significant difference in the incidence between Table 2 summarizes surgical data. Again, there was eyes receiving latanoprost and diclofenac (group A) and no significant difference in operation time, hardness of those receiving placebo and diclofenac (group C). the lens (classified using the method previously men- Table 6 lists the amount of aqueous flare. None of tioned36), ultrasound time, and amount of irrigating so- the 4 groups showed any differences in the amount of flare lution used among the 4 groups. determined before surgery and 1 day after surgery. In 2 Table 3 summarizes the results of corrected vi- groups of eyes receiving fluorometholone (groups B and sual acuity measurements. There was no significant dif- D), the amount of flare 3 days and 1, 2, and 5 weeks after ference among the 4 groups in fluctuation of visual acu- surgery was significantly higher compared with the other ity after surgery. 2 groups receiving diclofenac (groups A and C) (PϽ.05),

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Mean ± SD IOP Reduction, mm Hg

Group A Group B Group C Group D (n = 35) (n = 37) (n = 36) (n = 37) Mean diurnal IOP At baseline 21.9 ± 4.1 21.3 ± 5.6 20.3 ± 4.9 21.9 ± 4.9 PϽ.001 PϽ.001 PϽ.01 PϽ.01 At 5 wk after operation 15.5 ± 3.2 15.8 ± 3.3 18.6 ± 2.9 18.2 ± 3.5

PϽ.05 PϽ.05

*See Table 1 for description of drug treatment groups.

the amount of aqueous flare 1 to 2 weeks after surgery Table 5. Incidence of Cystoid Macular Edema (CME)* rather than immediately afterward.28,37 We found that aqueous flare amount was the same 1 day after surgery Incidence of CME, No. of Eyes in eyes receiving latanoprost and in those receiving pla- Group A Group B Group C Group D cebo but was increased 3 days and 1 and 2 weeks after Grading (n = 35) (n = 37) (n = 36) (n = 37) surgery in eyes receiving latanoprost and fluorometho- 0° 32 7 34 24 lone. The fact that such an elevation of aqueous flare is I°21516enhanced by use of latanoprost eyedrops is of interest. II° 1 10 1 5 The receptors of prostaglandin F2␣, including la- III° 0502tanoprost, exist within the entire eye and in the lens epithelial cells.39 Therefore, it is highly likely that acceler- *See Table 1 for description of drug treatment groups. PϽ.01 group A vs ated production of inflammatory mediators, which results group B, group C vs group D, and group B vs group D. from latanoprost encouraging proliferation and metaplasia of lens epithelial cells, enhances disruption of the except when comparing groups C and D 2 weeks after sur- blood-aqueous barrier 1 to 2 weeks after surgery. In other gery. There was no significant difference in the flare amount words, latanoprost, an external prostaglandin F2␣,isnot throughout the study between eyes receiving latanoprost the actual mediator to disrupt the blood-aqueous bar- and diclofenac (group A) and those receiving placebo and rier. If latanoprost is directly related to blood-aqueous diclofenac (group C); however, the amount of flare was sig- barrier disruption, the disruption 1 day after surgery nificantly higher in eyes receiving latanoprost and fluoro- should be more severe in eyes receiving the drug. Fur- metholone (group B) compared with those receiving pla- thermore, we discovered that blood-aqueous barrier dis- cebo and fluorometholone (group D) 3 days and 1 and 2 ruption was prevented to the same level in eyes receiv- weeks after surgery (PϽ.05). ing nonsteroidal and latanoprost eyedrops compared with those receiving nonsteroidal eyedrops and placebo. This COMMENT denies any direct relationship of latanoprost therapy in inducing barrier disruption and supports recent find- In this study, we confirmed that use of latanoprost eye- ings from studies reporting that latanoprost therapy has drops leads to disruption of the blood-aqueous barrier only a minimum effect, if any, on blood-aqueous barrier and significantly increases the incidence of angio- function.13,14,17,18 graphic CME soon after cataract extraction and IOL im- The present results should not neglect nonspecific plantation in eyes with glaucoma and its related condi- actions, such as inducing inflammation and hyperper- tions. These adverse effects, however, can be prevented meability of the vessels, of prostaglandin F2␣ and relat- when latanoprost is given concurrently with nonsteroi- ing compounds.20,21 Further studies are necessary to prove dal eyedrops. Use of latanoprost eyedrops was never re- the above-mentioned hypothesis that latanoprost acts in- ported to induce disruption of the blood-aqueous and directly in enhancing postsurgical inflammation and also blood-retinal barriers in experimental animal eyes and that latanoprost modifies biosynthesis of chemical me- in human eyes or to lead to CME in long-standing pseu- diators during lens epithelial cell proliferation and pseudophakias.13-18 Thus, it is worthwhile to discuss the mecha- dometaplasia. Direct detection of inflammatory chemi- nism by which latanoprost disrupts the blood-ocular bar- cal mediators in a culture medium using lens epithelial rier in pseudophakias shortly after surgery. cells and with latanoprost may be meaningful. Results of recent in vivo28 and in vitro29 studies show There is an active transport function of prostaglan- that in eyes traumatized by surgery, the lens epithelial dins at the anterior uvea.30 Immediately after cataract sur- cells during their process of proliferation and metamor- gery, and especially when there is a vitreous prolapse, phosis synthesize various chemical mediators. Such a this function (also known as Bito pump) is lost.31 The process is believed to possibly modify postoperative in- loss of this transport function may also be related to and flammation, leading to pupillary fibrin membrane for- explain the enhanced disruption of the blood-aqueous mation.37,38 The synthesis of chemical mediators by lens barrier after latanoprost instillation. If so, however, the epithelial cells also explains the significant elevation in disruption should be most severe immediately after sur-

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Mean ± SD Aqueous Flare, PC/ms (No. of Eyes)

Group A Group B Group C Group D Before operation 8.2 ± 3.0 (35) 8.4 ± 4.2 (37) 8.6 ± 5.7 (36) 8.9 ± 5.7 (37) Postoperative 1 d 19.8 ± 9.4 (35) 22.0 ± 9.8 (37) 19.1 ± 7.9 (36) 20.9 ± 7.8 (37)

3 d 14.6 ± 4.6 (35) 50.7 ± 28.1 (37) 13.7 ± 6.1 (36) 30.7 ± 19.1 (37)

1 wk 12.9 ± 4.1 (34) 66.4 ± 55.3 (35) 11.7 ± 4.6 (36) 27.9 ± 36.2 (36)

2 wk 11.7 ± 5.3 (34) 55.6 ± 68.3 (35) 12.0 ± 6.5 (35) 18.5 ± 7.8 (35)

5 wk 9.6 ± 2.1 (35) 15.4 ± 7.6 (37) 9.0 ± 1.8 (36) 12.8 ± 5.7 (37)

*See Table 1 for description of drug treatment groups. PC indicates photon count; braced data, PϽ.05 for comparison between these groups.

gery and thus cannot explain why the elevation in the wound healing process of lens epithelial cells, which is flare level was most significant 3 days and 1 to 2 weeks relatively a long-term phenomenon, the period of appli- after surgery, as stated above. We therefore conclude that cation should generally be long. Even a longer duration in pseudophakias receiving latanoprost, diminished ac- of application may be indicated in eyes in which the blood- tive transport of prostaglandins plays a small role, if any, ocular barrier is predisposed by aging, diabetes melli- in inducing blood-aqueous barrier disruption. tus, and other factors, making the eye more vulnerable In our study, we encountered an increased inci- to latanoprost therapy. Fragile blood-ocular barrier is of- dence of angiographic CME in eyes receiving latano- ten associated with eyes with broken posterior lens cap- prost shortly after cataract and IOL surgery, but this phe- sules. In these eyes, use of latanoprost should again be nomenon was significantly prevented by concurrent done with care. Recently, Rowe and associates40 re- application of nonsteroidal eyedrops. The magnitude of ported a pseudophakic eye that disclosed angiographic blood-aqueous barrier disruption is directly propor- CME at an early postoperative stage and recurrent an- tional to the incidence of angiographic CME.23 Thus, the giographic CME a year after topical latanoprost applica- increased incidence of angiographic CME because of la- tion. This finding suggests that the blood-ocular barrier tanoprost therapy is understandable because the drug was remains fragile to latanoprost application even a year af- confirmed to indirectly disrupt the blood-aqueous bar- ter surgery. rier. Again, latanoprost itself is probably not the major factor related to angiographic CME formation, but its in- Accepted for publication September 15, 1998. stillation affects the wound healing process of lens epi- Reprints: Kensaku Miyake, MD, Shohzankai Medical thelial cells, resulting in biosynthesis of prostaglandins Foundation, Miyake Eye Hospital, 1070-Kami 5, Higash- and other mediators that eventually lead to angio- iozone-cho, Kita-ku, Nagoya 462-0823, Japan (e-mail: graphic CME; we speculate that these same mediators are [email protected]). involved in blood-aqueous barrier disruption as well. Although latanoprost is effective in decreasing IOP and may become the first choice of drug in treating va- REFERENCES rieties of glaucoma,1 it is a prostaglandin analog, neces- sitating careful selection of patients for indication and 1. Higginbotham EJ. Will latanoprost be the “wonder” drug of the ’90s for the treat- close monitoring of the intraocular conditions of each ment of glaucoma? Arch Ophthalmol. 1996;114:998-999. 2. Bito LZ. Prostaglandins: a new approach to glaucoma management with a new, eye during drug use. Results of our study confirm that intriguing side effect. Surv Ophthalmol. 1997;41(suppl 2):S1-S14.

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From the Archives of the ARCHIVES

A look at the past...

alf an hour after a toxic dose of quinine is given to a dog, the retinal vessels become greatly constricted and vision is completely lost. After two or three days, a fair degree of vision returns, as a rule, and remains unless another Hdose is given. In this investigation a number of dogs were killed at periods ranging from two hours to seven weeks after the first injection of quinine, and the eyes, optic nerves, brains and cords were examined by the Nissl methylen-blue method for cell changes and the Marchi osmic-acid method for nerve-fibre changes. Two hours after injection no changes were found. Reti- nas examined on the third day after several toxic doses had been given, revealed degenerative changes in a few ganglion cells (vacuolation, paleness and absence of chromophilic granules, breaking down of the cell body), and changes in the nerve fibres (a deposition in the nerve-fibre layer of large globules of a myelin-like character). On the 9th and 17th days more ganglion cells were found affected and more myelin globules were present. On the 17th day the first changes in the optic nerve were noticed, consisting in a breaking down of the medullary sheaths of a number of fibres. On the 42d and 47th days, the ganglion-cell layer and the nerve-fibre layer had almost entirely disappeared, leaving large cavities, and the myelin globules were no longer present. Many of the fibres of the optic nerve were broken down, and the degeneration of the nerve could be traced up to the termination of its fibres in the external geniculate body and pulvinar.

Reference: Holden WA. The pathology of experimental quinine amblyopia. Arch Ophthalmol. 1898;27:457.

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