Additive Effect of Unoprostone and Latanoprost in Patients with Elevated Intraocular Pressure

Home , Latanoprost, Unoprostone

CLINICAL SCIENCE Br J Ophthalmol: first published as 10.1136/bjo.86.1.75 on 1 January 2002. Downloaded from Additive effect of unoprostone and latanoprost in patients with elevated intraocular pressure Tin Aung, Paul T K Chew, Francis T S Oen, Yiong-Huak Chan, Lennard H Thean, Leonard Yip, Boon-Ang Lim, Steve K L Seah ......

Br J Ophthalmol 2002;86:75–79

Aims: To assess the additive effect of unoprostone and latanoprost in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT) Methods: 32 patients with POAG or OHT were randomised to receive either latanoprost once daily or unoprostone twice daily for 4 weeks. After 4 weeks, all patients received both latanoprost and unoprostone for another 4 weeks. The IOP was measured at 9 am and 5 pm on the baseline, day 28, and day 56 visits, and at 9 am on day 14 and day 42 visits. The medications were given to the patients in an open label fashion. The observer was masked to the treatment given. The mean of the measurements was calculated. Safety parameters were also recorded. The additive effect of the medications was assessed by the reduction in intraocular pressure (IOP) when both medications were used, compared with when one medication was used. Results: 28 patients completed both treatment periods and had IOP data available for evaluation. See end of article for After 1 month of treatment, latanoprost significantly reduced IOP (mean by 6.1 (SEM 0.8) mm Hg authors’ affiliations (p<0.001) and unoprostone by 4.9 (1.0) mm Hg (p<0.001) from the baseline of 24.4 (0.6) mm Hg ...... and 24.4 (1.1) mm Hg respectively (p = 0.18). When latanoprost once daily was given to patients Correspondence to: treated with unoprostone, there was additional IOP lowering of 1.9 (0.6) mm Hg (p = 0.012). How- ProfessorPTKChew, ever, adding unoprostone to those being treated with latanoprost produced an IOP change of +0.4 Department of (0.5) mm Hg (p = 0.42). Ocular symptoms and findings were mild and equally distributed between Ophthalmology, National treatment groups, and after combined therapy. Hyperaemia and ocular irritation were the most University Hospital, 5 Lower Kent Ridge Road, frequently reported events. Over a third of patients experienced ocular irritation with the combination Singapore 119074; of medications. [email protected] Conclusions: Latanoprost once daily causes additional IOP lowering in eyes which were being treated Accepted for publication with unoprostone twice a day. However, there was no additional IOP lowering when unoprostone was 23 July 2001 added to eyes which were being treated with latanoprost. Both drugs were well tolerated together with

...... few ocular adverse events. http://bjo.bmj.com/

herapeutic regimens for glaucoma have changed dramati- study was thus designed to assess the additive ocular cally in the past few years. Newer glaucoma therapies hypotensive effect and side effects of using unoprostone and Tsuch as the prostaglandin analogues, latanoprost and latanoprost together in patients with elevated IOP. unoprostone, have few side effects and convenient dose schedules. Latanoprost, a prostaglandin F2α analogue, has MATERIALS AND METHODS on September 24, 2021 by guest. Protected copyright. proved to be an effective ocular hypotensive drug.1–7 Its main This two centre study was prospectively carried out at the Sin- mechanism for reducing intraocular pressure (IOP) is an gapore National Eye Centre and the National University Hos- increase in the uveoscleral outflow.89 In long term studies, pital, Singapore. After obtaining approval from the ethics latanoprost 0.005% applied once daily reduced IOP as committees of each centre and by the Ministry of Health of effectively as the β adrenergic receptor antagonist timolol in Singapore, a signed informed consent was obtained from all patients with primary open angle glaucoma (POAG) or ocular patients before study enrolment. The study was performed hypertension (OHT).67Unoprostone isopropylate is a docosa- according to the Declaration of Helsinki and the Singapore noid derived from a metabolite of a primary prostaglandin, guidelines on good clinical practice. 13,14-dihydro-15-ketoprostaglandin. It was found to have a Patients 21 years of age or older with primary open angle significant ocular hypotensive effect, and was as effective as glaucoma or ocular hypertension were eligible. All patients timolol in reducing IOP in POAG.10 11 It is thought to act by recruited had IOP >21 mm Hg at the prestudy visit and were increasing uveoscleral outflow, similar to latanoprost.12 13 previously untreated. POAG was defined as glaucomatous However, a study by Taniguchi et al14 suggested that optic neuropathy with a compatible visual field defect and unoprostone may increase conventional trabecular outflow. open angles on gonioscopy, while OHT patients had normal There is no published literature on the additive effect of optic discs and visual fields and open angles. Glaucomatous latanoprost with unoprostone for treatment of primary open optic neuropathy was defined as a cup:disc ratio of >0.6, or the angle glaucoma and ocular hypertension. In view of the possi- presence of notching. A threshold examination of the central bility that they may have differing mechanisms of action, it 24° of visual field (24-2 program) showing a glaucoma hemi- would be interesting to know if the two drugs exert greater field test (GHT) “outside normal limits,” and a cluster of three IOP lowering effect when used together. This is especially so in contiguous points on the pattern deviation plot depressed at patients who are intolerant or have contraindications to β p<5% level (compared with age matched normal subjects) not blocker therapy and a prostaglandin analogue may need to be crossing the horizontal meridian, was considered compatible used. It would also be useful to determine the side effects in with glaucoma. Test reliability was determined by the instru- patients based on the combined response to these drugs. This ment’s algorithm.

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Patients requiring bilateral treatment had to fulfil all eligi- Statistical evaluation Br J Ophthalmol: first published as 10.1136/bjo.86.1.75 on 1 January 2002. Downloaded from bility criteria for both eyes to be included. However, if only one For each patient, the IOP value was calculated at baseline and eye fulfilled the inclusion criteria, that eye was included as the day 28 of each period as the mean of all measurements made study eye and the fellow eye could be treated with the on the study eye(s) on that day (mean diurnal IOP). If the allocated study therapy provided that no exclusion criteria patient had only one study eye, the average was based on the were met. measurements made in that eye only. For patients with bilat- Exclusion criteria were gonioscopic appearance of angle eral disease, data from one eye chosen at random in each indi- closure, secondary glaucoma such as uveitis, neovascular vidual were selected for analysis. In the event that the patient glaucoma or post-trauma, previous intraocular surgery, previ- was missing one or more measurements, the average was ous trauma to the eye with damage of the anterior chamber based on the non-missing measurements. angle, the fellow eye on treatment with another IOP reducing The primary objective of the study was to test if latanoprost drug, previous treatment with glaucoma therapy, previous was additive to unoprostone, and vice versa. The null hypoth- corneal infection or corneal abnormalities, uveitis or dry eyes, esis was defined as IOP reduction on day 28 (monotherapy) current use of contact lenses, oral drugs known to affect the being equal to the IOP reduction on day 56 (combined IOP,and known allergy to benzalkonium chloride. Also, a his- therapy), in both cases compared with the IOP on day 0. The tory of cerebrovascular, hepatic, or metabolic disease (except alternative hypothesis was that the combination therapy fur- diabetes mellitus) was considered a reason for exclusion. Cur- ther reduced IOP by 3 mm Hg compared with treatment with rently, pregnant or nursing women, or women considering only one drug. The further reduction was presumed to repre- pregnancy were also excluded, as well as patients with a his- sent the additive effect of the second drug since the effect of tory of non-compliance or patients who participated in the first drug is assumed to be stable after 28 days of another therapeutic drug study within 1 month. treatment. There were two treatment periods of 4 weeks each. At the It is anticipated that the between treatment groups SD is 3 prestudy visit, medical and ocular history was taken. Visual mm Hg. The trial size of 32 will be sufficient to detect a differ- acuity and refraction, slit lamp examination, ophthalmoscopy, ence in IOP between day 42 and day 28 of 3.0 mm Hg, with a and measurement of the IOP were performed. Gonioscopy and 15 two sided test size of 5% and power 90%. perimetry were also carried out. Patients were included after All statistical tests were conducted at the 5% level using SPSS these eligibility assessments. software version 8.0 (Statistical Package for Social Sciences, On the baseline day, the patients were randomised (by block Chicago, IL, USA). randomisation) to two parallel study groups: one group was assigned to treatment with latanoprost 0.005% in the evening and the other group received unoprostone 0.12% twice daily, RESULTS for a duration of 4 weeks. After 4 weeks, all patients were given Of the 32 patients randomised to the study, 15 were 0.12% unoprostone twice daily (in the morning and evening) randomised to start with latanoprost and 17 started with and latanoprost 0.005% in the evening, for another 4 weeks. unoprostone. Two patients starting on unoprostone withdrew All types of medication were dispensed open label as the after day 14 because of side effects. commercially available preparation, latanoprost (Xalatan, At day 28, the remaining 30 patients had the other Pharmacia Corporation, Uppsala, Sweden) and unoprostone medication added and were on both medications. Two (Rescula, Ciba Vision Ophthalmics, Bulach, Switzerland). additional patients withdrew before the day 42 visit. Both Patients were instructed to instil unoprostone at approxi-

subjects (one on unoprostone and the other on latanoprost) http://bjo.bmj.com/ mately 8 am and 8 pm each day and latanoprost at 8 pm. When on both medications, the evening unoprostone and latano- could not tolerate the side effects. prost doses were administered 10 minutes apart. On visit days Unless otherwise stated, the following analyses will take to the clinic (days 14, 28, 42, and 56), those on unoprostone into account 15 subjects on day 28 and 14 subjects on day 56 administered the eye drops in the mornings at 7 am before the in each of the groups. clinic visit. Patients were informed to adhere strictly to the Table 1 refers to the baseline demographic characteristics. timing of the drops and the time of administration of drops There were no significant differences between the two groups with respect to sex, race, and age. As for other factors such as was recorded. on September 24, 2021 by guest. Protected copyright. During each study period there were three scheduled visits; laterality of eyes involved, type of glaucoma, medical history, at day 0, day 14, and day 28. The IOP was measured at 9 am use of concomitant treatment, ocular symptoms and findings, and 5 pm on the baseline, day 28, and day 56 visits, and at 9 am and vital signs at the prestudy visit, the two treatment groups on day 14 and day 42 visits. The IOP was measured with a were comparable. Goldmann applanation tonometer. Three measurements were performed in each eye, and the mean of the three Change in intraocular pressure during the study measurements was used in the statistical analyses. The periods observer was masked to the treatment given. Best corrected Table 2 summarises the change in IOP in the two groups in Snellen visual acuity and refractive error, systemic blood pres- each study period. sure, and pulse rate were determined at each visit, and a slit At the end of period 1 (day 28), the mean decrease in IOP lamp examination was performed. The presence of cells and was 6.1 (0.8) mm Hg (p<0.0001) for latanoprost treated flare in the anterior chamber was investigated during slit lamp patients, and 4.9 (1.0) mm Hg (p<0.0001) for unoprostone examination. Flare was graded as none, moderate, or severe, treated patients. The mean difference in IOP drop between the and cells present in a slit of 2 mm width were graded as none two groups was 1.2 (1.3) mm Hg in favour of latanoprost (p = (1–2 cells), mild (3–5 cells), moderate (6–20 cells), or severe 0.35). Every patient had IOP lowering with the medications in (>20 cells). this study period (100% response). Adverse events were monitored carefully throughout the At the end of period 2 (day 56), mean decrease in IOP in the study. An adverse event was defined as any undesirable event latanoprost-unoprostone group was +0.4 (0.5) mm Hg occurring in a subject regardless of whether it was considered (p=0.42). However, for the unoprostone-latanoprost group, related to the drug being investigated. A serious adverse event the mean change in IOP during period 2 was 1.9 (0.6) mm Hg was defined as an event that was potentially fatal, life threat- (p=0.012). This difference in IOP change of 2.3 (0.8) mm Hg ening, permanently disabling, requiring hospitalisation, or between the two groups in period 2 was significant (p=0.009). requiring intervention to prevent permanent impairment or Adjusting for day 28 IOP,this difference increases to 2.5 (0.9) damage. (p = 0.009, 95% CI 0.7 to 4.3).

www.bjophthalmol.com Additive effect of unoprostone and latanoprost in patients with elevated intraocular pressure 77 Br J Ophthalmol: first published as 10.1136/bjo.86.1.75 on 1 January 2002. Downloaded from Table 1 Demographic characteristics of study Table 3 Adverse events experienced by patients groups No of eyes with side effect Latanoprost- Unoprostone- Characteristics unoprostone latanoprost Period 1 Latanoprost Unoprostone

No of patients 15 17 Eye irritation 4 3 Age: Blurred vision 1 0 Mean 58.0 60.8 Eyelid swelling 1 0 SD 14.0 14.1 Dry eye 0 1 Sex: Eye redness/conjunctiva 50 Male 4 8 hyperaemia Female 11 9 Cornea PEEs 0 2 Race: Uveitis 0 1 Chinese 9 14 Palpitations 0 1 Malay 1 1 Latanoprost + Unoprostone + Indian 3 2 Period 2 unoprostone latanoprost Others 2 0 Type of glaucoma: Eye irritation 6 4 POAG 10 12 Tearing 1 0 OHT 5 5 Eye itch 1 1 Laterality: Conjunctiva 21 Unilateral 1 4 redness/hyperaemia Bilateral 14 13 Body itch 0 1 Fatigue 0 1 Giddiness 0 1

Only 43% of patients on latanoprost had IOP lowering when unoprostone was added. In contrast, 86% of patients on uno- ocular irritation and redness. Over a third of patients prostone experienced lowering of IOP when latanoprost was experienced ocular irritation with the combination of medica- added to unoprostone treatment. tions. There was only one subject who had mild anterior chamber inflammation, while on unoprostone only. Interest- Adverse events ingly, there was no case of ocular inflammation found in the The adverse events experienced by the subjects by period are second study period when subjects were on two medications. summarised in Table 3. There were a few patients with systemic adverse events DISCUSSION during the study. In the first period, one patient experienced Many glaucoma patients are treated with more than one ocu- palpitations while on unoprostone, stopped the medication on lar hypotensive medication. This is especially so after the day 14, and withdrew from the study. During the second study introduction of newer medications with fewer side effects and period, there was one patient who had body itch after having convenient dose schedules, such as the prostaglandin ana- latanoprost added to her treatment. Another subject experi- logues. Determination of additive effects on IOP of such glau- enced fatigue and giddiness, but neither complaint was of coma medications will help define optimum treatment http://bjo.bmj.com/ sufficient severity to stop treatment. In all cases, the systemic regimens for patients. It has been previously reported that symptoms resolved after cessation of treatment. latanoprost has an additive IOP lowering effect when used There were three subjects who withdrew from the study with timolol,16 17 pilocarpine,18 19 dipivefrin,20 dorzolamide,21 because of ocular side effects. One subject stopped the trial acetazolamide,22 and the combination of timolol and medication (in this case unoprostone) on day 14, as she devel- dorzolamide.23 The question of whether two of the new oped eye redness and pain after applying the drops. This prostaglandin analogues, latanoprost and unoprostone, are

resolved on stopping the medication. The other two subjects additive when used together is interesting. Theoretically, this on September 24, 2021 by guest. Protected copyright. withdrew on day 42 as they experienced intolerable eye irrita- is possible if the two medications have differing mechanisms tion after having the second medication added. of action on aqueous outﬂow. Ocular adverse effects were generally mild in nature and Our study found that when latanoprost once daily was similar in the two groups. The commonest adverse events were added to patients being treated with unoprostone twice daily,

Table 2 IOP profile in the two groups

Latanoprost-unoprostone Unoprostone-latanoprost

Day 0 Mean (SE) 24.4 (0.6) 24.4 (1.1) Day 14 Mean (SE) 17.4 (0.7) 19.4 (1.2) Day 28 Mean (SE) 17.8 (0.4) 19.6 (0.9) Day 42 Mean (SE) 18.5 (0.6) 18.8 (1.1) Day 56 Mean (SE) 18.2 (0.6) 18.0 (1.2)

Change in IOP (mean (SE))

Days 28 and 0 −6.1 (0.8 (p <0.001) −4.9 (1.0 (p <0.001) Days 56 and 28 +0.4 (0.5 (p = 0.42) −1.9 (0.6 (p = 0.012)

www.bjophthalmol.com 78 Aung, Chew, Oen, et al

there was an additional IOP lowering of 1.9 (0.6) mm Hg the morning dose in the latanoprost group. Accordingly, the Br J Ophthalmol: first published as 10.1136/bjo.86.1.75 on 1 January 2002. Downloaded from (p=0.012) indicating that there was additive effect. However, side effects found when the second medication was added adding unoprostone to those being treated with latanoprost must be interpreted with caution because of the open label produced a negligible effect on IOP (change of +0.4 (0.5) mm dosing and lack of placebo in the trial. Hg, p=0.42). The findings are in agreement with those of In conclusion, this study has shown that latanoprost once Stewart and colleagues who also found no significant daily causes additional IOP lowering in eyes which were being reduction in the mean diurnal curve of the IOP compared with treated with unoprostone twice a day. However, there was no placebo when adding unoprostone to latanoprost, although additional IOP lowering when unoprostone was added to eyes there was some variance in response that appeared to be based which were being treated with latanoprost. Both drugs were 24 on the baseline IOP of latanoprost treated eyes. well tolerated together with few systemic or ocular adverse Several reasons may account for the difference in effect events. It would be interesting to discover the pathway and found in our study. A plausible explanation is that unopros- molecular basis through which these medications interact and tone is less effective in reducing IOP at lower IOP levels. This function. Long term studies would be useful to determine if was the case at the beginning of study period 2 when the these additive effects are sustainable and if the two drugs can mean baseline IOP of latanoprost-unoprostone treated pa- be used continuously without clinically unacceptable side tients was 17.8 (0.4) mm Hg, which was in the physiological effects. range. A previous report found that unoprostone reduces IOP by about 10% in normal tension glaucoma.25 Latanoprost, on the other hand, has been previously shown to be effective at so ACKNOWLEDGMENTS called “low” IOPs in patients with this form of glaucoma, and Proprietary interest: Nil produces an IOP reduction of approximately 20%.26 27 In this Support: Grant from Singapore Eye Research Institute (SERI). Dr study, the mean baseline IOP of unoprostone-latanoprost Aung is also supported by the National Medical Research Council, patients at the start of study period 2 was 19.6 (0.9) mm Hg. Singapore. Although this was also within the physiological range, it was within the efficacy range of latanoprost...... Another possible reason to explain the lack of additive effect Authors’ affiliations when unoprostone was added to latanoprost is that there were T Aung, P T K Chew, FTSOen,LHThean, L Yip, B-A Lim, J Soh, S many patients who did not show IOP lowering with unopros- K L Seah, Singapore National Eye Centre P T K Chew, National University of Singapore tone in the second study period. Only 43% of patients on Y-H Chan, Jade Soh, Clinical Trials and Epidemiology Research Unit, latanoprost had IOP lowering when unoprostone was added. Singapore In contrast, 86% of patients on unoprostone experienced lowering of IOP when latanoprost was added to unoprostone REFERENCES treatment. In the first study period, all patients (100%) in both 1 Alm A, Widengard I, Kjellgren D, et al. Latanoprost administered once groups had IOP lowering with the study medications. It is daily caused a maintained reduction of intraocular pressure in glaucoma possible that both latanoprost and unoprostone are competing patients treated concomitantly with timolol. Br J Ophthalmol for the same prostaglandin receptor sites, and latanoprost is 1995;79:12–6. more highly competitive or more potent than unoprostone. 2 Alm A, Stjernschantz J, the Scandinavian Latanoprost Study Group. Effects on intraocular pressure and side effects of 0.005% latanoprost Thus, when latanoprost is added to unoprostone therapy, there once daily, evening and morning. A comparison with timolol. is additional effect, but not vice versa. Ophthalmology 1995;102:1743–52. Camras CB Finally, the additional IOP lowering attributed to the addi- 3 , the United States Latanoprost Study Group. Comparison of http://bjo.bmj.com/ tion of latanoprost may actually be due to the delayed latanoprost and timolol in patients with ocular hypertension and glaucoma. A six-month, masked, multicenter trial in the United States. response of unoprostone. This is possible if unoprostone had Ophthalmology 1996;103:138–47. not achieved maximum IOP lowering at the end of 4 weeks of 4 Watson P, Stjernschantz J, the Latanoprost Study Group. A six month treatment (the first study period), and it only reached its randomized double-masked study comparing latanoprost to timolol in open angle glaucoma and ocular hypertension. Ophthalmology maximum response later. The time required for maximum IOP 1996;103:126–37. lowering effect for unoprostone is not known. However, a pre- 5 Mishima HK, Masuda K, Kitazawa Y, et al. A comparison of latanoprost vious study has shown that after 2 weeks of treatment, and timolol in primary open-angle glaucoma and ocular hypertension. A latanoprost had almost reached maximum response, com- 12-week study. Arch Ophthalmol 1996;114:929–39. on September 24, 2021 by guest. Protected copyright. 28 6 Camras CB, Alm A, Watson P, et al. 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16 Alm A, Widengard I, Kjellgren D, et al. Latanoprost administered once 24 Stewart WC, Sharpe ED, Stewart JA, et al. Additive efficacy of Br J Ophthalmol: first published as 10.1136/bjo.86.1.75 on 1 January 2002. Downloaded from daily caused a maintained reduction of intraocular pressure in glaucoma unoprostone isopropyl 0.12% (Rescula) to latanoprost 0.005%. Am J patients treated concomitantly with timolol. Br J Ophthalmol Ophthalmol 2001;131:339–4. 1995;79:12–16 25 Fujimori C, Yamabayashi S, Hosoda M, et al. A clinical evaluation of 17 Rulo AH, Greve EL, Hoyng PF. Additive effect of latanoprost, a UF-021, a new prostaglandin-related compound, in low-tension prostaglandin F analogue, and timolol in patients with elevated 2á glaucoma patients. J Jpn Ophthalmol Soc 1993, 97:1231–5. intraocular pressure. Br J Ophthalmol 1994;78:899–902. Rulo AH 18 Fristrom B, Nilsson SEG. Interaction of PhXA41, a new prostaglandin 26 , Greve EL, Geijssen HC, et al. Reduction of intraocular pressure analogue with pilocarpine. Arch Ophthalmol 1993;111:662–5. with treatment of latanoprost once daily in patients with normal-pressure 19 Diestelhorst M. The additive intraocular pressure-lowering effect of glaucoma. Ophthalmology 1996;103:1276–82. latanoprost 0.005% once daily and pilocarpine 2% tid in patients with 27 McKibbin M, Menage MJ. The effect of once-daily latanoprost on open-angle glaucoma or ocular hypertension, a six-month randomized intraocular pressure and pulsatile ocular blood flow in normal tension multicenter study. German latanoprost study group. Graefes Arch Clin glaucoma. Eye 1999;13:31–4. Exp Ophthalmol 2000;238:433–9. 28 Bucci G, and the Latanoprost Study Group. Intraocular pressure lowering 20 Hoyng PF, Rulo AH, Greve EL, et al. The additive intraocular effects of latanoprost monotherapy versus latanoprost or pilocarpine in pressure-lowering effect of latanoprost in combined therapy with other combination with timolol:a randomised, observer masked multicenter ocular hypotensive agents. Surv Ophthalmol 1997;41(Suppl 2):S93–8. study in patients with open angle glaucoma. J Glaucoma 1999;8:24–30. 21 Arici K, Topalkara A, Guler C. Additive effect of latanoprost and 29 Guiffre G. The effects of prostaglandin F2 in the human eye. Graefes dorzolamide in patients with elevated intraocular pressure. Int 222 Ophthalmol 1998;22:37–42. Arch Clin Exp Ophthalmol 1985; :139–41. 22 Rulo AH, Greve EL, Hoyng PF. The additive ocular hypotensive effect of 30 Warwar RE, Bullock JD, Ballal D. Cystoid macular edema and anterior latanoprost and acetazolamide. A short-term study in patients with uveitis associated with latanoprost use. Ophthalmology elevated intraocular pressure. Ophthalmology 1997;104:1503–7. 1998;105:263–8. 23 Susanna R, Nicolela MT, Oga E. Additive effect of latanoprost to the 31 Fechtner RD, Khouri AS, Zimmerman TJ, et al. Anterior uveitis combination of timolol and dorzolamide. J Glaucoma 2000;9:183–6. associated with latanoprost. Am J Ophthalmol 1998;126:37–41.

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published retrospective study of 682 consecu- inflammatory agents,3 topical steroids, and a LETTERS tive patients who underwent conventional topical cycloplegic. SIDS should be considered extracapsular cataract surgery (ECCE) under in the differential diagnosis of a painful red the same consultant firm at a time where eye postoperatively. Prompt diagnosis and ECCE was the preferred technique.1 appropriate therapy lead to early resolution of If you have a burning desire to respond to Final visual acuities reached 6/12 or greater SIDS and improved visual outcome. a paper published in the BJO, why not in 80% of phacoemulsification patients and make use of our “rapid response” option? 67% of ECCE patients. The commonest com- J Sen Log on to our website plications occurring in both groups and in the St Paul’s Eye Unit, Royal Liverpool University (www.bjophthalmol.com), find the paper National Cataract Surgery Survey (NCSS) Hospital, Prescot Street, Liverpool L7 8XP, UK that interests you, and send your response 1997–8 are listed in Table 1. G G Kamath, L G Clearkin via email by clicking on the “eLetters” Comment Department of Ophthalmology, Arrowe Park option in the box at the top right hand Ten (1.5%) of the patients who underwent Hospital, Wirral CH49 5PE, UK corner. phacoemulsification cataract extraction (in- Providing it isn’t libellous or obscene, it Correspondence to: Dr Sen cluding one whose procedure was combined will be posted within seven days. You can with trabeculectomy) were diagnosed with Accepted for publication 21 November 2001 retrieve it by clicking on “read eLetters” SIDS. This was approximately half the pro- on our homepage. portion, (21 = 3.1%) of the ECCE group, but References The editors will decide as before was the second commonest complication in 1 Scott JA, Clearkin LG. Surgically induced whether to also publish it in a future both groups of patients. However, it does not scleritis following cataract extraction. Eye paper issue. feature in the list of postoperative complica- 1994;8:292–7. tions reported in the National Cataract Sur- 2 Desai P, Minassian DC, Reidy A. National gery Survey 1997–8.2 SIDS has previously cataract surgery survey 1997–8; a report of the results of the clinical outcomes. Br J been described as an underdiagnosed clinical 83 1 Ophthalmol 1999; :1336–40. Surgically induced diffuse entity and it may be failure to recognise it 3 Sainz-de-la Maza M, Jabbur NS, Foster CS. scleritis: comparison of incidence which explains its absence from the national An analysis of therapeutic decision for statistics. scleritis. Ophthalmology 1993;100:1372– in phacoemulsification and Patients who had undergone previous ipsi- 6.Br J Ophthalmol conventional extracapsular lateral iris surgery (trabeculectomy, Scheie’s cataract extraction procedure, or YAG iridotomy) appeared to be Total exudative detachment as a at increased risk, although this only attained Surgically induced diffuse scleritis (SIDS) is a statistical significance in the phacoemulsifca- first presentation of von Hippel recognised but less well reported cause of pain tion group (p=0.01). General anaesthesia was Lindau disease and reduced vision following cataract associated with higher statistical risk for Von Hippel Lindau disease is a rare condition surgery.1 1 ECCE patients only (p=0.009). It is unclear characterised by retinal and central nervous We have previously reported on complica- why this should have been the case. Intraop- system haemangioblastomas. It is also associ- tions of conventional extracapsular cataract erative complications did not increase the risk ated with renal cell carcinoma, phaeochromo- extraction in which SIDS was the second most of developing SIDS, and there was no associ- cytoma, and renal, pancreatic, and epididymal common.1 Recently, we conducted an audit of ation with concurrent ocular or systemic cysts. patients who underwent phacoemulsification disease. The mean age of the SIDS patients in The disease usually presents with neuro- cataract extraction to compare the incidence the ECCE group was approximately 11 years logical symptoms and/or visual disturbance; of SIDS in these patients relative to that found younger than that in the phako group (62.5 v angiomas if seen in the retina can often be in the ECCE group. 73.6). treated in an attempt to prevent progression It is our practice to take a thorough history to retinal detachment. Methods and results from the postoperative patient. Severe pain, We report a young girl with von Hippel From a computerised departmental database, especially that waking the patient from sleep, Lindau disease whose initial presentation was 666 consecutive patients who had undergone is a common feature. Examination of the phacoemulsification cataract surgery with patient both on the slit lamp and in daylight is with a total exudative retinal detachment. intraocular lens (IOL) implantation under a conducted, the latter to recognise the charac- Case report single consultant firm were identified. The teristic violaceous injection of the scleral vas- A 14 year old girl presented to the eye casualty case notes were examined and all postopera- culature. B-scan ultrasonography is per- department with no perception of light in her tive complications arising within the first 3 formed to measure scleral thickness. Relative left eye. She gave a 2 month history of months were documented. The patients’ thickening compared to the contralateral eye gradual, painless loss of vision, but had preoperative ophthalmic and general medical or absolute thickness greater than 1.8 mm delayed previously mentioning her symptoms. histories were also recorded to identify addi- supports the diagnosis. Affected patients usu- Past ocular history was unremarkable; an tional risk factors. The results of the study ally show a favourable response to a combina- optometrist visit a year previously was nor- were compared with those from a previously tion therapy with oral non-steroidal anti- mal. She was otherwise well. Slit lamp examination on the left revealed a quiet anterior segment, with retinal folds vis- Table 1 Postoperative complications requiring intervention ible abutting the posterior lens capsule (Fig 1A). The right eye was entirely normal. An Complication Phako (%) ECCE (%) NCSS (%) ultrasound B-scan showed a left total funnel retinal detachment (Fig 1B). Computed tomo- Astigmatism* – 9.5 graph scan demonstrated normal orbits. Cystoid macular oedema 1.95 – 0.05 The patient’s identical twin was also SIDS 1.5 3.1 – present and was examined: both her eyes Uveitis 1.35 2.3 5.6 were normal. Posterior capsule opacification 0.75 1.9 0.4 At this stage the family history proved Endophthalmitis 0.6 <1 0.03 Corneal decompensation 0.3 – – helpful. The patient’s father had recently been Subluxed IOL 0.15 <1 0.1 diagnosed with renal cell carcinoma and Iris prolapse/wound dehiscence 0.15 <1 1.2 pituitary vascular tumours. Hyphaema 0.15 – 1.1 The paternal line had a cluster of various carcinomas, including three relatives with *Astigmatism requiring suture removal. cerebellar tumours. Further investigation revealed at least one of these to be histologically

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Anomalous venous drainage of a plexiform (pial) arteriovenous malformation mimicking an indirect caroticocavernous sinus fistula We report a case of a 35 year old man who presented with proptosis of the left globe and congested episcleral and retinal veins. We present angiographic evidence to show that the venous engorgement of the left orbit was related to anomalous venous drainage of a previously posteriorly draining parietal arte- Figure 1 (A) Retinal folds visible behind lens. (B) Ultrasound B-scan showing funnel retinal riovenous malformation (AVM). detachment. Case report A 35 year old man presented complaining of a Symbol definitions: 3 month history of a red eye and a 1 month history of progressive swelling and protrusion Male Female of the left eye. His only significant past medi- Unaffected cal history was that of a subarachnoid haem- vHL mutation orrhage from an intracranial AVM 7 years ? ? ? carrier previously for which he had undergone stereo- ??Possibly vHL tactic radiosurgery. Ocular examination re- affected vealed a visual acuity of 6/5 in either eye. There wasa5mmaxial displacement of the vHL affected left globe with normal ocular motility. The Case report proptosis was non-pulsatile, non-reducible, patient and Valsalva manoeuvre was negative. There was no audible bruit. Anterior segment Figure 2 Family pedigree. examination was unremarkable aside from congested episcleral vessels. Examination of the fundus revealed dilated and tortuous reti- confirmed haemangioblastoma. The possi- with a 2 month delay between onset of symp- nal veins but a normal arterial system. There bility of von Hippel Lindau disease was raised toms and first presentation. was no disc swelling. and the patient’s father was screened: the Treatment comprises laser photocoagula- A computed tomography (CT) scan of the diagnosis was confirmed with polymerase tion of angiomas less than one disc diameter.2 brain and orbits revealed an AVM in the left chain reaction analysis; showing a frame shift Cryotherapy, or vitreoretinal surgery with primary sensory cortex, proptosis of the left mutation (single base pair deletion [G]) in trans-scleral drainage and endolaser may be globe and a dilated superior ophthalmic vein codon 195 (exon 3) of the von Hippel Lindau indicated in larger lesions,3 especially if vitre- (Fig 1). A magnetic resonance image (MRI) gene. Subsequent extended family screening ous traction is present.2 Early treatment with angiography confirmed the presence of has revealed the same mutation in the patient necessarily offers a better prognosis. an AVM in the left perirolandic region which and nine other living relatives (Fig 2), includ- This case underscores the value of taking a was fed by the left middle cerebral artery and ing the patient’s identical twin. Five of these good family history in order to detect heredi- the pericallosal branch of the left anterior cerebral artery (Fig 2). The dominant venous relatives have clinical manifestations of the tary diseases, which can then be confirmed drainage was via a large superficial vein disease, and in one case an asymptomatic with genetic molecular analysis. The import- upwards to the superior sagittal sinus. Al- stage 1 renal cell carcinoma was diagnosed ance of identification and subsequent screen- and successfully resected. though the AVM did not appear to have ing of von Hippel Lindau gene mutation carri- Miss AB’s left eye has subsequently devel- changed significantly in overall size when ers (both affected and unaffected) is oped pupil block glaucoma which is currently compared with previous angiograms (Fig 3), exemplified in our patient’s family—with the well controlled medically. It remains blind it was clear that there had been significant with a rigid total retinal detachment. The potential benefit of early diagnosis and treat- changes in the venous structures distant to cause of this detachment is most likely to be ment of asymptomatic retinal and cerebellar the AVM. A relative constriction at the an optic nerve or retinal haemangioblastoma; haemangioblastomas, as well as potentially junction of the ipsilateral transverse and however, no causal lesion was identified on fatal tumours. The screening should be main- sigmoid sinuses had developed (Fig 4) and as ultrasound or computed tomography (CT). tained regularly, as the protean manifesta- The few retinal vessels that can be seen (Fig tions of von Hippel Lindau disease may occur 3 1A) do not show any abnormality. Her other de novo at any age. eye remains normal and screening for signs of the disease elsewhere has proved negative. A Ferguson, J Singh Princess Alexandra Eye Pavilion, Chalmers Street, Comment Edinburgh EH3 9HA, UK This case highlights the importance of considering von Hippel Lindau disease as a diagnosis Correspondence to: Andrew Ferguson; when confronted with a patient with an [email protected] unexplained exudative retinal detachment. Accepted for publication 9 January 2002 Von Hippel Lindau disease has an auto- somal dominant inheritance pattern with an incidence of one in 36 000; with a 70% preva- References lence of ocular haemangioblastomas. Von 1 Webster AR, Maher ER, Moore AT. Clinical Hippel Lindau gene mutation carriers have a characteristics of ocular angiomatosis in von 35% probability of visual loss by age 50.1 Hippel-Lindau disease and correlation with Ocular angiomas occur commonly in the germline mutation. Arch Ophthalmol superotemporal mid-peripheral retina, less 1999;117:371–8. Ridley M commonly on the optic disc (8%), and at the 2 , Green J, Johnson G. Retinal angiomatosis: the ocular manifestations of von 1 Figure 1 posterior pole (1%). Hippel-Lindau disease. Can J Ophthalmol CT scan of the orbits showing If left untreated, lesions can cause vitreous 1986;21:276–83. dilated superior ophthalmic vein. The haemorrhage, macular oedema, epiretinal 3 Garcia-Arumi J, Sararols LH, Cavero L, et al. majority of the venous outflow from the membrane formation, and exudative or trac- Therapeutic options for capillary papillary cavernous sinus is via the superior tional retinal detachment. This last complica- hemangiomas. Ophthalmology ophthalmic vein which is markedly dilated as tion is well demonstrated in our patient’s case, 2000;107:48–54. seen in this scan.

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Comment Arteriovenous malformations (AVM) are lesions which consist of racemose networks of arterial and venous channels which communi- cate directly rather than through a normal capillary bed. These communications are of two types: fistulous and plexiform. In the fistulous type an arterial channel empties directly into a venous channel, while in the plexiform type one or more arterial channels feed a vascular conglomerate that comprises multiple arteriovenous communications from which one or more venous channels emerge as draining veins.1 The fistulous types are usually supplied by meningeal branches of the exter- nal carotid artery and therefore they are also known as dural AVMs. The plexiform type, in contrast, are supplied by branches of the cerebral or cerebellar arteries and hence are also known as pial AVMs. The AVM most commonly encountered by the ophthalmologist is the acquired caroticocavernous sinus fistula, a dural AVM whose characteristic neuro- ophthalmic presentation results from the arterialisation of the orbital venous system. Proptosis and orbital venous engorgement secondary to direct arterialisation of the venous system has also been reported in dural AVMs involving the torcular herophili2 and the Galenic system.3 The more common plexiform (pial) AVMs typically present with complications that arise from the massive venous run off that is generated by the associated arteriovenous shunts—namely, intracranial haemorrhage, seizures, and recurrent headache.4 Symptomatic orbital drainage of plexiform (pial) AVMs is rare and when it does occur the AVM is usually in an anterior location.5–8 We describe a patient with a posteriorly located plexiform (pial) AVM who presented with proptosis and vascular engorgement of the left globe as a result of the venous outflow of the Figure 2 Anterior segment photographs showing the dilated episcleral vessels in the left eye. AVM being shunted anteriorly through newly opened collateral channels. Unilateral proptosis associated with anterior shunting has previ- a consequence there was a relative hold up to which was markedly dilated as a conse- ously been described in a child with bilateral 9 the filling of the sigmoid sinus. The AVM quence. The patient’s symptoms of unilateral sigmoid sinus hypoplasia, but has never been therefore now drained anteriorly via a collat- proptosis and venous engorgement were described in a patient with a posteriorly located eral circulation into the cavernous sinus. The therefore a manifestation of increased blood plexiform AVM. Our case is also extremely later phases of the angiogram revealed that flow through collateral shunts that had devel- unusual in that we have angiographic evidence there was relatively little downward venous oped as a consequence of a stricture in the which shows that these collateral channels outflow from the cavernous sinus and the principal drainage channel of the existing developed as a result of an acquired stenosis at majority of this venous outflow was therefore AVM, which itself had not changed signifi- the junction of the transverse and sigmoid shunted via the superior ophthalmic vein cantly in size. sinus, previously its dominant route of venous drainage. The aetiology of this focal stenosis is unknown. It is unlikely to be a consequence of the stereotactic radiosurgery as the site of the stenosis is remote to the previously treated area. It is more likely that the stenosis represents a response to the chronic endothe- lial damage that is known to accompany the hyperdynamic circulation of AVMs.1 This case serves to illustrate that not all adults who present with proptosis and venous engorgement of the globe have a caroticocavernous sinus fistula and other anomalies of venous drainage must occasionally be considered. D Squirrell, P Puri, P A Rundle Department of Ophthalmology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK C Romanowski Department of Radiology I G Rennie University Department of Ophthalmology and Orthoptics, Floor O, Royal Hallamshire Hospital, Sheffield S10 2RX, UK Figure 3 Cerebral angiogram dated 1994. A moderately sized arteriovenous malformation is shown fed by branches of the left middle cerebral and anterior cerebral arteries. It is Correspondence to: Mr P Puri drained by a large superficial vein which continues into the superior sagittal sinus. Accepted for publication 4 February 2002

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Figure 4 Cerebral angiogram dated 2000. There has been no significant change in the size of the arteriovenous malformation since the angiogram was performed in 1994. There is constriction at the junction of the transverse and sigmoid sinuses with hold up in the transverse sinus. Multiple cortical collateral vessels are seen draining into the cavernous sinus.

References Case report tion, ataxia, or areflexia. On ocular 1 Valavanis A. The role of angiography in the We examined a 10 month old male child who examination, the patient had moderate ptosis evaluation of cerebral vascular malformations. presented to us with complaints of ptosis and of the right upper lid with absence of any vol- Neuroimaging Clin N Am 1996;6: ophthalmoplegia of the right eye for a month untary movement of the right eyeball. Ocular 679–704. before presentation. The child was born movements of the left eye appear to be Buchnanan TA 2 , Harper DG, Hoyt WF. normally at full term to a healthy young normal. The child was attentive to both visual Bilateral proptosis, dilation of conjunctival mother with an uneventful perinatal and and auditory stimuli and frequently changed veins and papilloedema: a his head posture to look in the direction of neuro-ophthalmological syndrome caused by postnatal period. The milestones of the child arteriovenous malformation of the torcular were recorded as normal. The child had an origin of the visual or auditory stimuli. The herophili. Br J Ophthalmol 1982;66: older sister aged 3 years who gave no history pupillary reactions were normal in both eyes. 186–9. of similar complaints. There was no history of In the primary gaze position, the visual axes 3 Eckman PB, Fountain EM. Unilateral fever, vomiting, pain, trauma, seizures, diffi- of both eyes were parallel (Fig 1). The child proptosis. Association with arteriovenous culty in swallowing or chewing, or any history was examined twice after a period of sleep malformations involving the galenic system. of excessive lassitude or listlessness given by and similar findings were recorded again. Arch Neurol 1974;31:350–1. Examination of the anterior and posterior Mackenzie I the parents with regard to the child. 4 . The clinical presentation of the segment of both eyes under general anaesthe- cerebral angioma; a review of 50 cases. General physical examination revealed a Brain 1953;76:184–214. child with normal physical and mental devel- sia was unremarkable. The forced duction test 5 Sibony PA, Lessell S, Wray S. Chiasmal opment. Systemic examination revealed no was negative. Based on the above findings, a syndrome caused by arteriovenous presence of heart block or any other cardio- tentative diagnosis of an intracranial space malformations. Arch Ophthalmol vascular abnormality. Neurological examina- occupying lesion was made. However, a 1982;100:438–42. tion revealed no motor weakness, incoordina- contrast enhanced computed tomograph (CT) 6 Volpe NJ, Sharma MC, Galetta SL, et al. scan of the head and orbit revealed no abnor- Orbital drainage from cerebral arteriovenous malities. Cerebrospinal fluid examination was malformations. Neurosurgery also normal. 2000;46:820–4. 7 Malzone WF, Gonyea EF. Exophthalmos with The child was subsequently subjected to an intracerebral arteriovenous malformations. edrophonium test (0.15 mg /kg body weight Neurology 1973;23:534–8. intravenously), which was unequivocally 8 Forman AR, Luessenhop AJ, Limaye SR. positive with complete resolution of the ptosis Ocular findings in patients with arteriovenous and ophthalmoplegia (Fig 2). A repetitive malformations of the head and neck. Am J stimulation of the left median nerve demon- Ophthalmol 1975;79:626–33. strated a significant decremental response Tech KE 9 , Becker CJ, Lazo A, et al. Anomalous (22%). Subsequently, a serum analysis of anti- Intracranial venous drainage mimicking orbital or cavernous arteriovenous fistula. Am J acetylcholine receptor binding, blocking, and Neuroradiol 1995;16:171–4. modulating antibodies was performed. Ab- normal titres of anti-acetylcholine receptor binding antibodies (5.8 nmol/l; normal is less Childhood myasthenia gravis in than 0.8 nmol/l) were present which con- an infant firmed the diagnosis of childhood myasthenia gravis. A contrast enhanced CT scan of the Myasthenia gravis is defined as an acquired thorax was normal. The child was started on autoimmune disorder where there is abnor- tablet neostigmine 3 mg once daily along with mal fatiguability of muscles due to deficiency oral prednisolone (0.5 mg/kg body weight) of acetylcholine receptors caused by circulat- and followed up regularly. Marked improve- ing antibodies directed against them.1 Ocular ment of the ptosis and ophthalmoplegia was myasthenia is a form of myasthenia gravis observed which persisted at 1 year of follow clinically involving only the levator palpebrae up. Systemic steroids were gradually tapered superioris, the orbicularis oculi, and the off after 6 months. extraocular muscles. Ptosis and ophthalmoplegia, both unilateral and bilateral, constitute Figure 1 Clinical photograph of the patient Comment the only signs in about 20% cases while in showing ptosis of the right upper lid with Our patient was diagnosed to have juvenile about 70% cases, ocular symptoms mark the ophthalmoplegia. There is no strabismus myasthenia gravis, which comprises approxi- onset of generalised myasthenia gravis.1 present in the primary gaze position. mately 1% of all cases of myasthenia gravis.2 It

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Phototoxic maculopathy following uneventful cataract surgery in a predisposed patient Operating microscope light induced foveal damage is a well recognised occurrence following ocular surgery including compli- cated cataract extraction, complex anterior segment procedures, and vitrectomy surgery.1 An increased risk of phototoxicity is associated with an operating time greater than 100 minutes, increased body and therefore retinal temperature, unfiltered blue light, and hyperoxaemia.23 We report a patient who developed a photo- Figure 2 Fluorescein angiogram of left eye. toxic lesion during routine cataract surgery possibly related to underlying systemic lupus temperature and low inspired oxygen concen- erythematosus (SLE) and hydroxychloro- tration during surgery. quine treatment. We examine the measures An uncomplicated right phacoemulsifica- taken to prevent recurrence with second eye tion and lens implant was subsequently surgery and the implications for routine cata- performed. Two weeks after surgery, the right ract surgery are discussed. visual acuity was 6/5, anisometropia was abolished, and funduscopy was normal. Case report Comment A 39 year old woman presented with blurred Phototoxic lesions are defined as the retinal left vision and glare. One year previously she Figure 2 Clinical photograph of the same lesions produced after a relatively short had been diagnosed with SLE for which she patient showing marked improvement of the exposure to an intense light source such as had been taking hydroxychloroquine 200 mg 1 ptosis and ophthalmoplegia after the operating microscope. Historically, these administration of intravenous edrophonium. and prednisolone 5 mg daily for 18 months. lesions were typically located inferior to the She had bilateral subcapsular cataracts and fovea as a result of the slight downgaze of underwent routine left phacoemulsification the eye during extracapsular cataract surgery is considered to be a variant of adult myasthe- and lens implant surgery under general nia with similar clinical and autoimmune and a coaxial microscope beam directed infe- anaesthesia. 134 mechanism of production.3 In contrast with rior to the fovea. The incidence of retinal Directly after surgery, the patient noted two phototoxicity from the operating microscope congenital myasthenia gravis which occurs confluent blind spots immediately below fixa- more commonly in children less than 2 years has been reported at between 0% and 28%, tion in the left eye. When first seen by us the of age, has a familial mode of occurrence, and with large series reporting angiographic left visual acuity was 6/5, intraocular pressure is not responsive to steroid therapy,34juvenile evidence of retinal phototoxicity in 3–7% of was 16 mm Hg, and the eye was quiet with a 4 myasthenia gravis presents usually after 5 cases. well centred posterior chamber lens implant. years of age, shows no familial occurrence, Retinal phototoxic lesions first appear as Fundal examination of the left eye showed and is characterised by a definite autoimmune well circumscribed outer retinal whitening two well circumscribed areas of coarse mot- mechanism.34 Though cases of juvenile (oedema) with mild disturbances of the RPE tled retinal pigment epithelial (RPE) distur- often with a light border visible after a few myasthenia gravis with age of onset at 2 years 4 35 bance, approximately one and a half disc or less have been reported, to the best of days. Ophthalmoscopically, a subtle discrete diameters in size, superotemporal to the fovea our knowledge our patient is the youngest margin can be seen. After the first week, patient with the above diagnosis reported so (Fig 1). There was no subretinal fluid or lesions are characterised by coarse alterations far. We would like to reiterate that investiga- haemorrhage associated with these lesions. A of the RPE layer with fluorescein angiography tions to rule out myasthenia gravis should fluorescein angiogram supported these find- demonstrating characteristic early discrete ings (Fig 2) and the lesions were felt to be mottled hyperfluorescence with late staining be performed in all patients with acquired 4 ptosis and ophthalmoplegia, irrespective of consistent with photic injury. but no leakage. age. The patient was keen to proceed with right Certain photosensitising drugs, such as phacoemulsification and lens implantation in hydroxychloroquine, have been reported to Z Chaudhuri, P K Pandey, S Bhomaj, view of anisometropia. She had stopped her predispose to the development of retinal D Chauhan, L U Rani hydroxychloroquine immediately after the phototoxic lesions. However, there are no Department of Ophthalmology, Guru Nanak Eye first operation and the following precautions published reports of a similar association Centre, New Delhi – 110002, India were agreed with the patient before surgery in with systemic photosensitive conditions such the second eye: the use of the microscope fil- as SLE. It has been suggested that patients Correspondence to: Dr Zia Chaudhuri, E-310, ter throughout surgery, switching off the who have SLE have increased numbers of Purvasha, Anand Lok Society, Mayur Vihar phase microscope light when instruments were not chromosome breaks and rearrangements 1, Delhi-110091, India; [email protected] in the eye, tilting of the eye into downgaze (so correlated with a low molecular weight chromosome damaging agent (clastogenic factor) Accepted for publication 20 January 2002 that any phototoxic lesion would be superior to fixation and not result in a homonymous present in lymphocytes that sensitises them 5 No grants or sponsorships have been requisitioned scotoma), and the maintenance of low body to near ultraviolet light (360–400 nm) light. for this study. The authors do not have any The presence of this photoactivated agent proprietary or financial interest in any product or explains why SLE patients show an aggrava- procedure mentioned in the manuscript. tion of their characteristic skin condition References after exposure to sunlight. Certain pharma- cological agents, such as hydroxychloro- 1 Weinberg DA, Lesser RL, Vollmer TL. Ocular quine, which is used in the treatment of SLE, myasthenia: a protean disorder. Surv can also predispose to the development of Ophthalmol 1994;39:169–209. 2 Kini PG. Juvenile myasthenia gravis with phototoxicity. The mechanisms behind the predominant facial weakness in a 7-year-old predisposition to phototoxicity in humans of boy. Int J Pediatr Otorhinolaryngol chloroquine and its derivatives are less clear. 1995;32:167–9. However, it is known that these drugs 3 Jaison SG, Abraham AP. Childhood accumulate in the RPE layer of the retina and myasthenia gravis in a toddler. Ind J can cause drug induced lysosomal abnor- Ophthalmol 1995;43:136–7. malities including diminished vesicle fusion, 4 Millichap JG, Dodge PR. Diagnosis and diminished exocytosis, and reversible treatment of myasthenia gravis in infancy, 6 childhood and adolescence. Neurology “lysosomal storage disease.” These two 1960;11:1007–14. different predisposing mechanisms to photo- 5 Verma AK, Behari M, Ahuja GK. Myasthenia Figure 1 Left eye showing two well toxicity presumably coexisted in this patient gravis in the young. Indian J Pediatr circumscribed areas of coarse mottled retinal and may have significantly increased her 1986;23:363–9 pigment epithelial disturbance. risk.

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Several procedures were undertaken to who is HLA-B27 negative with isolated bilat- It is impossible to definitively prove that prevent the occurrence of a phototoxic lesion eral uveitis after intravesical BCG therapy. intravesicular BCG caused our patient’s bilat- in the second eye. These included the use of eral anterior uveitis. The possibility of an Case report ultraviolet filters on the microscope, although infective aetiology by active mycobacterium air can also be used in the anterior chamber A 70 year old man presented to the eye casu- must also be considered. If this were the case to defocus the light from the retina as can alty department witha4dayhistory of bilat- definitive diagnosis could have been estab- light barriers on the cornea or in the eral red, painful, and photophobic eyes. He lished by sending a specimen of aqueous for microscope. The time and power of coaxial had no systemic complaints. He had no acid fast staining, culture, and polymerase illumination from the microscope was mini- ophthalmic history of note. He had a medical chain reaction (PCR).6 mised by turning the microscope off when history of hypertension, gout, and recurrent It is plausible that intravesicular BCG can instruments were not in the eye, and the papillary transitional cell carcinoma of the cause acute inflammatory and hypersensitiv- patient’s eye was kept in downgaze so that bladder. Eight weeks previously he had been ity reactions in the eye secondary to a the operating microscope’s axis was aligned seen by a urologist for haematuria and systemic inflammatory response.1–5 Contrary off the patient’s visual axis so that any photo- increased frequency. A diagnosis of recurrent to previous thought, HLA-B27 need not be a toxic lesion would be extrafoveal and not papillary cell carcinoma was made by cysto- determining factor for uveitis associated with cause a homonymous scotoma. Since animal scopy and biopsy. A 6 week course of weekly intravesicular BCG.3 This is the first reported studies have demonstrated a benefit of alter- intravesical BCG therapy was commenced. His case of isolated bilateral anterior uveitis ing core ocular temperature,13 the patient’s medications on presentation were Adalat presumed secondary to intravesicular BCG in (nifedipine) and amlodipine. He was allergic body temperature was kept low to reduce the a patient who is HLA-B27 negative. to penicillin and aspirin. temperature within the eye. Alternatively, On ocular examination his visual acuities M Wertheim, N Astbury irrigation solutions may be cooled relative to were 6/12 right eye and 6/6 left eye. A diagno- Eye Department, Norfolk and Norwich University room temperature to help reduce intraocular sis was made of bilateral acute anterior Hospital, Colney Lane, Norwich NR4 7UZ, UK temperature. It has been shown that an uveitis. He had 2+ cells and posterior syn- increase in inspired oxygen markedly en- Accepted for publication 13 February 2002 echiae bilaterally. No keratic precipitates were hances retinal phototoxicity and so a low seen. He had a right sided epiretinal mem- References inspired oxygen concentration was used for brane. 1 Price GE. Arthritis and iritis after BCG therapy the patient during the procedure.13 The Laboratory studies showed an erythrocyte for bladder cancer. J Rheumatol patient discontinued hydroxychloroquine sedimentation rate of 66 with the rest of hae- 1994;21:564–5. treatment following the surgery to her left matological studies normal. Biochemistry 2 Clavel G, Grados F, Cayrolle G, et al. eye but ophthalmologists should be aware of Polyarthritis following intravesical BCG showed a raised sodium, urea, and creatinine, immunotherapy. Rev Rheum Engl Ed the risk of phototoxic retinal lesions in which were longstanding. Tests for anti- patients taking photosensitising pharmaco- 1999;66:115–18. nuclear antibodies and rheumatoid factor Chevrel G logical agents particularly for underlying 3 , Zech C, Miossec P. Severe uveitis were negative. Angiotensin converting en- followed by reactive arthritis after bacillus potential photosensitising systemic condi- zyme was normal and Treponema pallidum Calmette-Guerin therapy. J Rheumatol tions. Consideration should be given to antibodies were not detected. HLA-B27 was 1999;26:1011. stopping treatment before surgery and taking negative. Chest and pelvis radiographs were 4 Missioux D, Hermabessiere J, Sauvezie B. appropriate surgical precautions. normal. His uveitis resolved completely on Arthritis and iritis after bacillus Calmette-Guerin therapy. J Rheumatol B Manzouri, C A Egan, P G Hykin topical steroid therapy and mydriatics. There 1995;22:2010. Medical Retina Service, Moorfields Eye Hospital, was no recurrence of his uveitis over the sub- 5 Lamm DL, Stodgdill VD, Stodgill B, et al. City Road, London EC1V 2PD, UK sequent follow up period of 3 months. Complications of bacillus Calmette-Guerin Comment immunotherapy in 1,278 patients with Correspondence to: Mr P G Hykin; bladder cancer. J Urol 1986;135:272–4. [email protected] There have been no reported cases of intra- 6 Han DP, Simons KB, Tarkanian CN, et al. vesical BCG causing isolated uveitis in a Endophthalmitis from Mycobacterium Accepted for publication 11 February 2002 patient that is HLA-B27 negative. There have bovis-bacille Calmette-Guerin after been 26 reported cases of reactive arthritis intravesicular bacilli Calmette-Guerin References secondary to intravesical BCG.2 About 8% of injections for bladder cancer. Am J 128 1 Michels M, Sternberg P. Operating these cases were associated with uveitis.2 All Ophthalmol 1999; :648–50. microscope-induced retinal phototoxicity: 7 O’Donnell MA, DeWolf WC. BCG the reported cases of combined arthritis and immunotherapy for superficial bladder cancer. pathophysiology, clinical manifestations and uveitis were HLA-B27 positive.134In the BCG prevention. Surv Ophthalmol New prospects for an old warhorse. Surg 1990;34:237–52. related arthritides the mean time of presenta- Oncol Clin North Am 1995;4:189–202. 2 Stamler JF, Blodi CF, Verdier D, et al. tion was 10.5 days after the last BCG 8 Sokal JE, Aungst CW, Han T. Effect of BCG 2 Microscope light-induced maculopathy in therapy. Our patient started having ocular on delayed hypersensitivity responses of combined penetrating keratoplasty, symptoms 10 days after his last BCG therapy. patients with neoplastic disease. Int J Cancer extracapsular cataract extraction, and In a review of 1278 patients treated with 1973;12:242–9. intraocular lens implantation. Ophthalmology intravesical BCG for bladder cancer, 95% had 9 Puett DW, Fuchs HA. Arthritis after bacillus 1988;95:1142–6. no complications.5 There were no reported Calmette-Guerin therapy. Ann Intern Med 1992;117:537. 3 Davidson PC, Sternberg P. Potential retinal cases of uveitis. Arthritis and arthralgia phototoxicity. Am J Ophthalmol accounted for 0.5% of the complications.5 1993;116:497–501. There has been one reported case of 4 Michels M. Intraoperative retinal NOTICES phototoxicity. Int Ophthalmol Clin endophthalmitis from Mycobacterium bovis- 6 1995;35:157–72. BCG used to treat bladder cancer. This was 5 Emerit I, Michelson AM. Mechanism of proved microbiologically and histologically. Childhood blindness photosensitivity in systemic lupus This presentation was delayed with the The latest issue of Community Eye Health (No 40) erythematosus patients. Proc Natl Acad Sci patient presenting 14 months after his last discusses new issues in childhood blindness, USA 1981;78:2537–40. intravesical BCG therapy. 6 Motten AG, Martinez LF, Holt N, et al. with an editorial by Clare Gilbert, senior lecturer Intravesical BCG contains live attenuated at the International Centre for Eye Health. For Photophysical studies on antimalarial drugs. mycobacteria. The intravesical BCG promotes Photochem Photobiol 1999;69:282–7. further information please contact: Journal of a local acute inflammatory and subacute Community Eye Health, International Centre granulomatous reaction with macrophage for Eye Health, Institute of Ophthalmology, Bilateral uveitis after intravesical and lymphocyte infiltrates in the superficial 7 11–43 Bath Street, London EC1V 9EL, UK (tel: BCG immunotherapy for bladder bladder. The exact mechanism of action is +44 (0)20 7608 6910; fax: +44 (0)20 7250 unknown but the antineoplastic effect seems carcinoma 7 3207; email: [email protected]; website: to be T lymphocyte dependent. This en- www.jceh.co.uk). Annual subscription (4 is- Intravesical bacille Calmette-Guerin (BCG) is hanced cell mediated immunity results in rec- 8 sues) UK£25/US$40. Free to workers in devel- indicated for the treatment and prophylaxis of ognition and suppression of neoplastic cells. oping countries. carcinoma in situ of the urinary bladder and It has been hypothesised that the systemic prophylaxis of primary or recurrent papillary inflammatory response is seen as part of an International Centre for Eye tumours.1 All previous reports of uveitis after immune response initiated by BCG and then intravesical BCG therapy have been associated continued by cross reactivity with particular Health with arthritis.1–4 HLA-B27 has been positive in host proteins presented by the class I MHC The International Centre for Eye Health has all cases with uveitis.1–4 We describe a patient receptor.9 published a new edition of the Standard List of

www.bjophthalmol.com PostScript 707

Medicines, Equipment, Instruments and Optical medical research into an eventual cure for this 2002 in Singapore. Further details: Ms Amy Supplies (2001) for eye care services in develop- hereditary disease, and through the BRPS Lim, Organising Secretariat, Singapore Na- ing countries. It is compiled by the TaskForce of welfare service, help members and their fami- tional Eye Centre, 11 Third Hospital Avenue, the International Agengy for the Prevention of lies copy with the everyday concerns caused Singapore 168751 (tel: (65) 322 8374;fax: (65) Blindness. Further details: Sue Stevens, Inter- by retinitis pigmentosa. Part of the welfare 227 7290; email: [email protected]). national Centre for Eye Health, 11–43 Bath service is the telephone helpline (+44 Street, London EC1V 9EL, UK (tel: +44 (0)20 (0)1280 860 363), which is a useful resource BEAVRS Meeting 7608 6910; email: [email protected]). for any queries or worries relating to the The next BEAVRS meeting will be held in the problems retinitis pigmentosa can bring. This Dalmahoy Hotel near Edinburgh on 31 October Second Sight service is especially valuable for those recently to 1 November 2002. Further details: Susan Campbell, Medical Secretary, Gartnavel Gen- Second Sight, a UK based charity whose aims diagnosed with retinitis pigmentosa, and all eral Hospital (email: susan.j.campbell.wg@ are to eliminate the backlog of cataract blind calls are taken in the strictest confidence. northglasgow.scot.nhs.uk). in India by the year 2020 and to establish Many people with retinitis pigmentosa have strong links between Indian and British found the Society helpful, providing encour- ophthalmologists, is regularly sending volun- agement, and support through the Helpline, teer surgeons to India. Details can be found at the welfare network and the BRPS branches CORRECTIONS the charity website (www.secondsight.org.uk) throughout the UK. (tel: +44 (0)1280 821 or by contacting Dr Lucy Mathen 334; email: [email protected]; web site: www.brps.demon.co.uk) We regret that an error occurred in a paper ([email protected]). that appeared in the May 2001 issue of the 3rd Interdisciplinary Symposium BJO by Lauande-Pimentel et al (Discrimina- SPecific Eye ConditionS (SPECS) tion between normal and glaucomatous eyes SPecific Eye ConditionS (SPECS) is a not for on the Treatment of with visual field and scanning laser polarim- profit organisation which acts as an umbrella Autoimmune Disorders etry measurements. 2001;85:586–91). After revision of the paper the authors organisation for support groups of any condi- The 3rd Interdisciplinary Symposium on the found that the published cut-off point of the tions or syndrome with an integral eye disor- Treatment of Autoimmune Disorders will be structural linear discriminant formula (LDF) der. SPECS represents over fifty different held in Leipzig, Germany on the 6–8 June was incorrect. organisations related to eye disorders ranging 2002. Topics to be covered include: basic from conditions that are relatively common to The original formula described by Lauande- aspects of autoimmune diseases, experimen- Pimentel et al is: very rare syndromes. We also include groups tal therapeutic concepts, and clinical studies − × who offer support of a more general nature to LDF = 3.131 + (0.994 ellipse modula- providing novel concepts or novel focus on tion) − (0.017 × the number) − (0.086 × aver- visually impaired and blind people. Support established therapies. There will also be the × groups meet regularly in the Boardroom at age thickness) + (0.111 ellipse average) presentation of the Nils-Ilja-Richter Award The correct suggested cut-off point, defined Moorfields Eye Hospital to offer support to (application deadline is April 2002, further as abnormal, is <0.43 instead of <−0.547. The each other, share experiences and explore new details on the web site). Further details: Prof. use of such formula, with the suggested ways of working together. The web site Dr. med. Michael Sticherline, Department of cut-off point, resulted in an enhancement in www.eyeconditions.org.uk acts as a portal Dermatology, University of Leipzig (email: the sensitivity (sensitivity = 90.4%, specificity giving direct access to support groups own [email protected]; website: ww- = 82.4%) of the scanning laser polarimeter to sites. The SPECS web page is a valuable w.autoimmun.org); Fördergesellschaft zur detect glaucomatous changes. resource for professionals and may also be Therapie von Autoimmunerkrankugen e.V. of interest to people with a visual impairment (email: [email protected]) or who are blind. For further details An error occured in the article: Additive effect about SPECS contact: Kay Parkinson, SPECS International Society for Behçet’s of unoprostone and latanoprost in patients Development Officer (tel: +44 (0)1803 with elevated intraocular pressure Br J Oph- 524238; email: [email protected]; Disease thalmol 2002;86:75–9. The authors should www.eyeconditions.org.uk). The 10th International Congress on Behçet’s have been listed as Tin Aung, Paul T K Chew, Disease will be held in Berlin 27–29 June Francis T S Oen, Yiong-Huak Chan, Lennard H 2002. Further details: Professor Ch Zouboulis Thean, Leonard Yip, Boon-Ang Lim, Jade Soh, The British Retinitis Pigmentosa and Steve K L Seah. Society (email: [email protected]). The British Retinitis Pigmentosa Society Singapore National Eye Centre An error occurred in the article: Fluoxetine (BRPS) was formed in 1975 to bring together oral administration increases intraocular people with retinitis pigmentosa and their 5th International Meeting pressure. Br J Ophthalmol 1996;80:678. The families. The principle aims of BRPS are to The Singapore National Eye Centre 5th Inter- authors should have been listed as C Costag- raise funds to support the programme of national Meeting will be held on 3–5 August liola, L Mastropasqua, L Steardo, N Testa.