Original Paper
Ophthalmologica
Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
Received: March 23, 2014 Accepted after revision: August 29, 2014 Published online: November 26, 2014
Comparison of Topical Dorzolamide and Ketorolac Treatment for Cystoid Macular Edema in Retinitis Pigmentosa and Usher’s Syndrome Ricardo Filipe Lemos Reis a Nuno Moreira-Gonçalves a Sérgio E. Estrela Silva a Elisete M. Brandão a Fernando M. Falcão-Reis a, b a
Department of Ophthalmology, Hospital de São João, and b Department of Sense Organs, Faculty of Medicine, University of Porto, Porto, Portugal
Abstract Purpose: To investigate the topical effect of dorzolamide versus ketorolac on retinitis pigmentosa (RP) and Usher’s syndrome (US) macular edema. Methods: Prospective, randomized and interventional study. A total of 28 eyes of 18 patients were included. Five eyes had US, 23 had RP. Fifteen eyes were allocated to ketorolac tromethamine 0.5% (4 drops daily regimen) and 13 eyes to dorzolamide hydrochloride 2% (3 drops daily regimen) treatment groups. Snellen’s best-corrected visual acuity (BCVA), foveal thickness (FT) and foveal zone thickness (FZT) measured by Stratus® optical coherence tomography (OCT) were evaluated at baseline, 1, 3, 6 and 12 months after treatment. Results: Patients assigned to ketorolac had a baseline BCVA of 0.37 ± 0.17 logMAR which improved at the end of 1 year to 0.28 ± 0.16 (p = 0.02). Three eyes (20%) of 2 patients improved by 7 letters or more. Mean FT and FZT did not change significantly during the study follow-up. After 1 year of treatment, 4 eyes (27%) of 3 patients showed an improvement of at least 16% of FT and 11% of FZT. Patients assigned to dorzolamide had a baseline BCVA of 0.48 ± 0.34 logMAR which improved in the first 6 months (0.40 ± 0.30; p = 0.01), with a decrease at 1 year (0.42 ± 0.27; p = 0.20). Seven eyes (54%) of 5 patients had an
© 2014 S. Karger AG, Basel 0030–3755/14/2331–0043$39.50/0 E-Mail [email protected] www.karger.com/oph
improvement of 7 letters or more. Mean FT and FZT did not change significantly either. After 1 year of treatment, 3 eyes (23%) of 2 patients showed an improvement of at least 16% on FT and 11% on FZT. Conclusions: Results suggest that dorzolamide and ketorolac might improve visual acuity and therefore be of interest in selected cases. No relationship between retinal thickness fluctuation and visual acuity was found. Sample size was a limitation to the study. © 2014 S. Karger AG, Basel
Retinitis pigmentosa (RP) is a broad concept that embraces a spectrum of different hereditary retinal diseases. A group of gene abnormalities is at the basis of a degenerative and progressive loss of photoreceptors, causing nyctalopia, peripheral visual field impairment and a typical fundus appearance [1–4]. Presenting itself as an autosomal recessive disorder, Usher’s syndrome (US) combines both RP and sensorineural hearing loss manifestations [5–7]. Its most prevalent form, US type II, is characterized by congenital deafness and early onset of visual symptoms (second decade) [8, 9]. Visual acuity, usually preserved until a late stage [10], can be affected by cystoid macular edema (CME) in 10– 40% of cases diagnosed with RP [11–13] and 8–25% of cases diagnosed with US [9, 14, 15]. Several factors have been connected to visual deterioration, namely cell loss Ricardo Filipe da Silva Lemos Reis, MD Hospital de São João Rua Dr. Manuel Laranjeira No. 138, 5° Frente PT–4200-384 Paranhos, Porto (Portugal) E-Mail r.lemosreis @ gmail.com
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Key Words Dorzolamide · Ketorolac · Cystoid macular edema · Retinitis pigmentosa · Usher’s syndrome
Methods The study protocol was reviewed and approved by the ethics board at Centro Hospitalar de São João in Oporto, Portugal, and followed the tenets of the Declaration of Helsinki on biomedical research involving human beings. Informed consent was obtained from all participating subjects. This prospective, comparative and randomized study was developed by the Department of Ophthalmology, at the Centro Hospitalar de São João. Clinical records on ocular genetics were reviewed from a computer database between January 1, 2009, and December 31, 2011. A population of 85 patients with at least 18 years of age and diagnosed with RP or US was obtained. The diagnosis of RP was based on a symptomatic nyctalopia, typical fundus changes (i.e. waxy optic disk pallor, midperipheral bone-spicule-like pigment clumping and retinal arteriolar attenuation), constricted visual field (documented by Goldmann perimetry – Carl Zeiss, Humphrey® Field Analyzer) and markedly reduced to nonrecordable a- and b-wave amplitudes on electroretinogram testing. If, in addition, a moderate
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Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
sensorineural hearing loss in the absence of vestibular disturbances was present and confirmed by audiometric and otorhinolaryngologic examinations, patients were diagnosed with US type II. Between January 1, 2012, and March 31, 2012, the 85 previously selected subjects were contacted, either by telephone or post, observed and tested afterwards. To be included in the study, patients had to fulfill the following criteria: CME in at least 1 eye, as documented by OCT (detection of intraretinal cysts within the 1,000 μm centered in the foveola in the absence of vitreous traction), stable fixation and a best-corrected visual acuity (BCVA) of at least 20/200 in the affected eye(s). Patients were excluded if any other cause of CME was plausible, such as diabetes mellitus, pseudophakia or aphakia after cataract extraction (performed within 1 year from this study) and posterior uveitis. Other possible causes for decreased visual acuity, such as amblyopia, ocular trauma, central media opacities or a maculopathy from any other source beyond RP, were also used as exclusion criteria. Finally, the use of steroids, thiazide diuretics or nonsteroidal anti-inflammatory drugs either systemic or topically 1 year before or during the study follow-up period, also motivated exclusion. Twenty-eight eyes from 18 patients fulfilled all criteria and were therefore enrolled in the study. A Snellen’s BCVA was obtained for every patient at baseline. For comparative purposes, and based on a previous study on the subject [43], an increase of 7 or more letters (0.235 natural log units) from baseline was considered significant in the follow-up visits. A slitlamp biomicroscopy examination of the anterior segment and an intraocular pressure measurement with Goldmann’s applanation tonometer were performed. The pupils were dilated with one drop each of phenylephrine 2.5% and tropicamide 0.1% ophthalmic solutions, and a subsequent fundus examination under mydriasis was performed with a +78-dpt lens. Baseline time domain OCT (Carl Zeiss Stratus® OCT 3000) was performed utilizing 6-mm single radial scans spaced by a 30-degree interval between them and centered on fixation. The central foveal thickness (FT) was calculated and recorded as an average of the 6 measurements obtained at the intersection of the 6 radial scans. The foveal zone thickness (FZT) was also calculated and recorded as an average of 100 automatic measurements performed in the 1,000-μm ring centered on the foveola by the OCT scanner, using a retinal mapping software available with the device. As suggested by Grover et al. [44], both an FT change >16% (mean ± 2 SD) and an FZT change >11% from baseline were considered as statistically significant in the follow-up visits. After the baseline examination and OCT measurement, all patients underwent a simple randomization process into two study groups. Nine patients, 7 men and 2 women (15 eyes), were randomized to the first group, named ketorolac group (KG), and treated with topical ketorolac tromethamine 0.5% in a 4 drops daily regimen. A total of 9 patients, 6 men and 3 women (13 eyes), were assigned to the second group, named dorzolamide group (DG), and instructed to use topical dorzolamide hydrochloride 2% in a 3 drops daily regimen. Once the treatment had been initiated, all patients returned for reassessment at 1, 3, 6 and 12 months from baseline. In every follow-up visit, the patients performed BCVA testing, anterior segment biomicroscopy, intraocular pressure measurements, funduscopic examination and OCT scans as described previously for the baseline assessment. Patients were advised to report any possible side effect or visual phenomena occurring during the study period. In the KG, patient 2 (table 1) data from the yearly visit was with-
Lemos Reis/Moreira-Gonçalves/ Estrela Silva/Brandão/Falcão-Reis
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and subsequent atrophic thinning of the retina and retinal thickening [16] induced by swelling either of the fovea or the parafovea [17]. Optical coherence tomography (OCT) is currently a widely used device to monitor RP patients, being at least as sensitive as fluorescein angiography when detecting CME [18–20]. Finding an effective treatment for CME has motivated several studies on this subject. The therapeutic approaches previously described are numerous and include the use of periocular or intravitreal steroid injection [21–25], intravitreal bevacizumab [26], grid laser photocoagulation [27, 28], pars plana vitrectomy [29] and the administration of topical or oral carbonic anhydrase inhibitors [10, 30–33]. Nonsteroidal anti-inflammatory drugs act through inhibition of both cyclooxygenase isozymes 1 and 2 and therefore block prostaglandin synthesis [34–36]. Its use in ophthalmology is vast and includes postcataract surgery CME prophylaxis and treatment [37, 38]. Topical ketorolac tromethamine 0.5% was the first nonsteroidal anti-inflammatory drug to show effectiveness for the treatment of chronic CME [39, 40]. More recently, topical nepafenac and bromfenac were used as they penetrate into the vitreous cavity [41], potentiating the therapeutic effect of intravitreal corticosteroids and antivascular endothelial growth factor for chronic pseudophakic CME [42]. The present study compares, during a 12-month period, the efficacy of topical dorzolamide hydrochloride 2% versus ketorolac tromethamine 0.5% for the management of CME in patients with RP and US as well as their impact on visual acuity.
Patient Disease No. Ketorolac 1 RP
Gender
Age, years
Visit
BCVA OD
BCVA OS
FT OD, μm
FZT OD, μm
FT OS, μm
FZT OS, μm
F
20
Pre 1M 3M 6M 12M
20/100 20/60 20/50–2 20/25–1 20/50
20/50 20/30 20/30–1 20/30+1 20/25–1
562 402 (–28) 465 (–17) 458 (–19) 390 (–31)
536 404 (–25) 446 (–17) 440 (–18) 402 (–25)
393 283 (–18) 312 (–21) 393 (0) 280 (–29)
398 321 (–19) 339 (–15) 398 (0) 316 (–21)
2
RP
F
59
Pre 1M 3M 6M 12M
20/60 20/80 20/80 20/60–2
276 274 (–1) 271 (–2) 268 (–3)
294 299 (+2) 295 (0) 286 (–3)
3
RP
M
38
Pre 1M 3M 6M 12M
20/60 20/100 20/120 20/60–2 20/60
608 683 (+12) 573 (–6) 733 (+21) 499 (–18)
641 657 (+2) 615 (–4) 697 (+9) 526 (–18)
4
RP
M
56
Pre 1M 3M 6M 12M
20/25+1
20/40–2
213
251
220
258
20/25 20/25 20/25
20/40+2 20/25 20/40–2
203 (–5) 190 (–11) 198 (–7)
248 (–1) 240 (–4) 247 (–2)
208 (–5) 218 (–1) 250 (+14)
266 (+3) 261 (+1) 275 (+7)
Pre 1M 3M 6M 12M
20/40 20/40–2 20/30–1 20/40+1 20/30–1
20/60 20/120 20/80 20/60–1 20/60–1
217
247
541
524
206 (–5) 209 (–4) 210 (–3)
253 (+2) 245 (–1) 245 (–1)
659 (+22) 492 (–9) 611 (+13)
619 (+18) 487 (–7) 573 (+9)
176 179 (+2) 182 (+3) 200 (+14) 172 (–2)
237 230 (–3) 245 (+3) 237 (0) 234 (–1)
5
RP
M
48
6
RP
M
28
Pre 1M 3M 6M 12M
20/25–2 20/30+2 20/25–1 20/25 20/25
7
RP
M
44
Pre 1M 3M 6M 12M
20/60
20/30
20/50 20/50
20/20 20/25
310 320 (+3) 241 (–22) 313 (+1) 260 (–16)
310 317 (+2) 289 (–7) 321 (+3) 283 (–9)
230 228 (–1) 234 (+2) 270 (+17) 391 (+70)
271 249 (–8) 272 (0) 305 (+13) 342 (+26)
8
RP
M
31
Pre 1M 3M 6M 12M
20/50 20/50 20/50+1 20/50 20/50–1
20/50 20/60+1 20/40 20/50 20/50+1
210 223 (+6) 298 (+42) 245 (+14) 206 (–2)
252 253 (0) 326 (+29) 264 (+5) 240 (–5)
395 394 (0) 427 (+8) 412 (+5) 310 (–27)
399 396 (–1) 419 (+5) 407 (+2) 333 (–17)
9
RP
M
52
Pre 1M 3M 6M 12M
20/30 20/25+1 20/20–2 20/25 20/25
20/40 20/40 20/30–2 20/30–1 20/30+2
229 223 (–3) 218 (–5) 226 (–1) 229 (0)
268 267 (0) 266 (–1) 261 (–3) 269 (0)
221 222 (0) 210 (–5) 203 (–8) 220 (0)
267 265 (0) 256 (–4) 249 (–7) 262 (–2)
Topical Dorzolamide and Ketorolac Treatment for CME
Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
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Table 1. Patient characteristics and BCVA and FT before and after treatment
Table 1. (continued)
Patient Disease No. Dorzolamide 10 RP
Gender
Age, years
Visit
M
25
Pre 1M 3M 6M 12M
BCVA OD
BCVA OS
FT OD, μm
FZT OD, μm
FT OS, μm
FZT OS, μm
20/60 20/60 20/60 20/60 20/100
422
419
565 (+34) 501 (+19) 530 (+26)
550 (+31) 495 (+18) 527 (+26)
11
US
M
25
Pre 1M 3M 6M 12M
20/50 20/50 20/50 20/40 20/30–1
291 270 (–7) 244 (–16) 220 (–24) 220 (–24)
292 273 (–7) 260 (–11) 240 (–18) 240 (–22)
12
RP
M
70
Pre 1M 3M 6M 12M
20/40–2 20/30 20/30 20/30 20/30+1
303 310 (+2) 309 (+2) 311 (+3) 305
306 307 (0) 312 (+2) 312 (+2) 312
13
US
F
55
Pre 1M 3M 6M 12M
20/160 20/100 20/100 20/100 20/80–1
20/200 20/100 20/100 20/125 20/125–1
362 300 (–17) 275 (–24) 281 (–22) 272 (–25)
336 298 (–11) 271 (–19) 270 (–20) 270 (–20)
225 175 (–22) 154 (–31) 135 (–40) 166 (–26)
233 184 (–21) 179 (–23) 164 (–30) 177 (–24)
14
RP
F
71
Pre 1M 3M 6M 12M
20/50 20/40 20/30 20/30 20/30–1
20/30 20/30 20/40 20/25–1 20/30
191 182 (–5) 176 (–8) 176 (–8) 213 (+12)
226 213 (+6) 211 (+7) 212 (+6) 225 (0)
174 168 (–3) 169 (–3) 169 (–3) 174 (0)
215 203 (–6) 202 (–6) 208 (–3) 203 (–6)
15
US
F
21
Pre 1M 3M 6M 12M
20/200 20/160 20/160 20/160 20/160
20/125 20/80 20/80 20/125 20/100
771 821 (+6) 779 (+1) 897 (+16) 679 (–12)
763 800 (+5) 771 (+1) 883 (+16) 675 (–12)
674 701 (+4) 592 (–12) 609 (–10) 604 (–10)
661 683 (+3) 576 (–13) 595 (–10) 575 (–13)
16
RP
M
51
Pre 1M 3M 6M 12M
239 247 (+3) 250 (+5) 250 (+5) 251 (+5)
267 266 (0) 269 (+1) 269 (+1) 271 (+1)
17
RP
M
41
Pre 1M 3M 6M 12M
20/40 20/40 20/40 20/40 20/40
18
RP
M
30
Pre 1M 3M 6M 12M
20/25 20/25 20/20–1 20/25–2 20/25
372 280 (–25) 311 (–16) 352 (–5) 347 (–7)
352 280 (–20) 303 (–14) 332 (–6) 324 (–8)
20/25 20/25 20/25 20/25 20/30
20/30 20/30+2 20/20–2 20/30–1 20/40
169 168 (–1) 172 (+2) 156 (–8) 143 (–15)
216 205 (–5) 193 (–11) 184 (–15) 224 (+4)
406 302 (–26) 368 (–9) 387 (–5) 380 (–6)
383 299 (–22) 334 (–13) 347 (–9) 345 (–10)
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Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
Lemos Reis/Moreira-Gonçalves/ Estrela Silva/Brandão/Falcão-Reis
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F = Female; M = male; pre = before treatment; 1M, 3M, 6M, 12M = visits after 1, 3, 6 and 12 months. Figures in parentheses indicate percent altered.
370
0.6
KG DG
0.5
FT KG FT DG FZT KG FZT DG
360
Thickness (μM)
BCVA (logMAR)
350 0.4 0.3 0.2
340 330 320
0.1 310 Baseline
1 month
3 months
6 months
1 year
300
Baseline
1 month
3 months
6 months
1 year
Fig. 1. BCVA variation.
Fig. 2. FT and FZT variation.
drawn and not considered for statistical analysis due to cataract surgery performed on her left (included) eye. Statistical analysis was performed with SPSS 17.0. Wilcoxon’s signed-ranks test was used to compare variations of mean BCVA, FT and FZT within each group, as this data was not normally distributed. The Mann-Whitney U test was used to compare continuous variables between groups, and Fisher’s exact test was used to compare categorical outcomes.
The mean age at the initial visit of DG was 43.54 ± 19.59 years, and that of KG was 41.80 ± 13.05 years. There was no significant difference between the groups (paired t test, p = 0.79). Patients assigned to KG had a baseline BCVA of 0.37 ± 0.17 logMAR. After 1 month of treatment, the mean BCVA was 0.41 ± 0.23 (p = 0.72), and after 3 months 0.33 ± 0.23 (p = 0.38). At 6 months it improved to 0.27 ± 0.18 (p = 0.03), and at the end of 1 year it remained similar (0.28 ± 0.16; p = 0.02; fig. 1). Three eyes (20%) of 2 patients improved 7 letters or more. The BCVA of the remaining 12 eyes was similar to baseline at the end of the follow-up (table 1). In KG, baseline FT was 320.07 ± 145.02 μm. At subsequent visits (1, 3, 6 months and 1 year, respectively) it was 311.91 ± 142.65 (p = 0.82), 313.80 ± 148.37 (p = 0.28), 322.00 ± 151.27 (p = 1.00) and 306.21 ± 125.02 (p = 0.31). FZT at baseline was 343.53 ± 128.03, and at subsequent visits it was 332.55 ± 121.90 (p = 0.29), 343.60 ± 126.28
(p = 0.91), 339.87 ± 127.50 (0.86) and 324.79 ± 106.56 (p = 0.12; fig. 2). After 1 year of treatment, 4 eyes (27%) of 3 patients showed an improvement of at least 16% of FT and 11% of FZT. One eye (patient 7) showed a large increase in both FT and FZT. The other 10 eyes (67%) remained stable (table 1). Patients assigned to the DG had a baseline BCVA of 0.48 ± 0.34 logarithm of the minimal angle of resolution (logMAR). After 1 month of treatment, it improved to 0.40 ± 0.26 (p = 0.02), remaining stable after 3 (0.38 ± 0.28; p = 0.01) and 6 months of treatment (0.40 ± 0.30; p = 0.01). After 1 year of treatment, the mean BCVA was 0.42 ± 0.27 (p = 0.20; fig. 1). Seven eyes (54%) of 5 patients had an improvement of 7 letters or more. One eye (patient 10) showed a significant decrease in visual acuity, and the remaining 5 eyes (38%) remained stable (table 1). In this group, baseline FT was 353.77 ± 185.66 μm. At subsequent visits (1, 3, 6 months and 1 year, respectively) it was 327.00 ± 211.51 (p = 0.20), 335.69 ± 193.58 (p = 0.17), 341.85 ± 217.88 (p = 0.22) and 329.38 ± 173.64 (p = 0.10). FZT at baseline was 359.15 ± 170.71, and at subsequent visits it was 334.25 ± 196.43 (p = 0.08), 340.85 ± 179.62 (p = 0.06), 347.00 ± 202.74 (p = 0.22) and 336.15 ± 156.79 (p = 0.10; fig. 2). After 1 year of treatment, 3 eyes (23%) of 2 patients showed an improvement of at least 16% on FT and 11% on FZT. Both eyes of patient 18 had a significant thickness reduction at 1 and 3 months, returning to baseline values at subsequent follow-up visits. Patient 17 had a significant improvement in FZT at 3 and 6 months, returning to baseline values at the 1-year visit.
Topical Dorzolamide and Ketorolac Treatment for CME
Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
Results
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0
Discussion
Despite being a well-known complication in RP, CME does not have an established cause or proven mechanism. Several theories have been stated; Cox et al. [45] suggested that CME genesis could occur due to changes in retinal pigment epithelium polarity which would affect its pumping ability and therefore cause the edema. Other authors have related this complication either with circulating antiretinal antibodies [30] or with a blood-retina barrier breakdown [46]. 48
Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
The present study investigated and compared the efficacy of topical dorzolamide versus ketorolac for the treatment of RP and US patients complicated with CME. This comparison was based on the assumption that the former would optimize retinal pigment epithelium function and the latter would block inflammatory mediators, and consequently affect the development of an autoimmune response, reducing the CME. Although no significant differences were shown at baseline between groups concerning BCVA, different progression patterns where observed during the followup period. In the DG, an immediate and statistically significant improvement in visual acuity was noticed and kept stable for a total period of 6 months. After reaching a peak at the third month, BCVA started decreasing, with loss of significance at the end of follow-up. In the final visit, however, 55.6% of patients had still an improvement -7 letters in at least one of the treated eyes compared to baseline. Previous studies have already suggested a potential visual benefit of topical dorzolamide for this subset of patients, with reported success rates between 20 and 37.5% of cases [31–33]. The present study has put into evidence that even better visual outcomes can be attained, mainly in the first 6 months of treatment. Looking at the KG, after a first month of disappointing results, a progressive increase in BCVA occurred, reaching a plateau after 6 months of treatment. Interestingly and despite a statistically significant improvement seen in the 2 final visits, only 2 patients (22.2%) have gained 7 or more letters at the end of the study. When a patient-bypatient analysis is performed, statistics becomes clearer. The achievement of significance can be explained by a shifting effect in the overall BCVA caused by an individual highly responsive behavior to ketorolac, rather than a group response to the drug. The small number of enrolled patients is the other cofactor explaining this statistical phenomenon. Generally, both drugs failed to show a consistent decrease in CME in the majority of patients, and no statistical difference was shown when both drugs were compared. Our results concerning the dorzolamide effect on retinal thickness are clearly worse when compared with other studies [10, 31, 32]. Photoreceptor layer integrity [47] and a long-standing CME with atrophic changes of the neurosensory retina might explain this difference. An OCT qualitative analysis could therefore bring value, enlightening and possibly explaining our results. Its absence constitutes an obvious limitation to this topic. Lemos Reis/Moreira-Gonçalves/ Estrela Silva/Brandão/Falcão-Reis
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One eye (patient 10) showed a large increase in both FT and FZT. The remaining 7 eyes (54%) remained stable during the period of follow-up (table 1). There was no statistically significant difference between both groups regarding the mean improvement of BCVA (–0.05 DG vs. –0.08 KG; p = 0.86). Although the number of eyes showing an improvement of 7 letters or more was higher in the DG (7/13) compared to the KG (3/15), this difference was not statistically significant (p = 0.11). In the current study, 5 DG patients showed some decrease in retinal thickness in at least 1 eye during the follow-up period. In this group, however, only 2 patients (22.2%) reached a statistically significant and sustained response (table 1). All patients except 1 (patient 15 – both eyes) developed a response within the first month of follow-up. The right and left eyes of patient 15 responded to treatment at 12 and 3 months, respectively. Regarding the KG, 3 (33.3%) out of 9 patients had a statistically significant decrease in retinal thickness in at least 1 eye (table 1). Both eyes of patient 1 showed a response to treatment within the first 4 weeks while the left eyes of patients 3 and 8 only developed a statistically significant decrease in retinal thickness at the end of follow-up. There was no statistically significant difference between both groups regarding the percentage of reduction of FT (6.5% DG vs. 0.3% KG; p = 0.72) or the percentage of reduction of FZT (5.9% DG vs. 4.0% KG; p = 0.73). There was no difference comparing the number of eyes showing significant structural improvement (DG 3/13 vs. KG 4/15; p = 1.0). The only reported side effect was an allergic blepharitis after 1 month of treatment in one of the patients (patient 15). That patient was changed to a preservative-free dorzolamide intake plus regular eyelid hygiene bilaterally and the condition settled within 1 week.
Concerning the previously described rebound effect on retinal thickness that can be obtained with longterm dorzolamide treatment [31–33], again different results were shown by this study. Despite some fluctuation on retinal thickness measurements during treatment, none of the patients had a consistent rebound of macular edema. This finding was also observed with ketorolac. The small number of subjects who developed a response to dorzolamide drops can represent a bias for this analysis. When comparing visual acuity with retinal thickness results, a poor correlation was obtained, showing that there is not a pure cause-effect relationship and that more variables are possibly implicated in the visual outcome. Other authors described similar observations [31–33]. Again, retinal atrophic changes, photoreceptor layer integrity [47] and possibly macular cyst characteristics (morphology, size and distribution in the macula) might explain this correlation. Population size presents itself as the major limitation for the present study, portraying the small prevalence of
RP and US. Other possible limitations are the time domain technology used in the OCT, the Snellen visual acuity charts and the absence of a control group to address a possible placebo effect. In conclusion, this study shows a possible benefit of topical dorzolamide treatment on visual acuity for RP and US patients for at least 6 months. Ketorolac’s role in this subset of patients was not completely clear; however, it might be of interest in selected cases, either singly or complementing dorzolamide. There are no other studies in the literature regarding ketorolac treatment in these diseases, which limits any further interpretation. Given the poor correlation between visual acuity and retinal thickness, macular thickness measured by Stratus OCT did not show to be an accurate examination to predict visual acuity improvement. Development of larger studies on both drugs, looking at their individual action, duration and to a possible synergistic effect between them might bring further knowledge on the pathogenesis and treatment of CME in RP and US patients.
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Topical Dorzolamide and Ketorolac Treatment for CME
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17 Sandberg MA, Brockhurst RJ, Gaudio AR, et al: Visual acuity is related to parafoveal retinal thickness in patients with retinitis pigmentosa and macular cysts. Invest Ophthalmol Vis Sci 2008;49:4568–7452. 18 Apushkin MA, Fishman GA, Janowicz MJ: Monitoring cystoid macular edema by optical coherence tomography in patients with retinitis pigmentosa. Ophthalmology 2004; 111: 1899–1904. 19 Stanga PE, Downes SM, Ahuja RM, et al: Comparison of optical coherence tomography and fluorescein angiography in assessing macular edema in retinal dystrophies: preliminary results. Int Ophthalmol 2001;23:321–325. 20 Hirakawa H, Iijima H, Gohdo T, et al: Optical coherence tomography of cystoid macular edema associated with retinitis pigmentosa. Am J Ophthalmol 1999;128:185–191. 21 Saraiva VS, Sallum JM, Farah ME: Treatment of cystoid macular edema related to retinitis pigmentosa with intravitreal triamcinolone acetonide. Ophthalmic Surg Lasers Imaging 2003;34:398–400. 22 Ozdemir H, Karacorlu M, Karacorlu S: Intravitreal triamcinolone acetonide for treatment of cystoid macular oedema in patients with retinitis pigmentosa. Acta Ophthalmol Scand 2005;83:248–251. 23 Kim JE: Intravitreal triamcinolone for treatment of cystoid macular edema associated with retinitis pigmentosa. Retina 2006; 26: 1094–1096.
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32 Fishman GA, Apushkin MA: Continued use of dorzolamide for the treatment of cystoid macular oedema in patients with retinitis pigmentosa. Br J Ophthalmol 2007;91:743–745. 33 Genead MA, Fishman GA: Efficacy of sustained topical dorzolamide therapy for cystic macular lesions in patients with retinitis pigmentosa and Usher syndrome. Arch Ophthalmol 2010;128:1146–1150. 34 Mitchell JA, Warner TD: COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs. Nat Rev Drug Discov 2006;5:75–86. 35 Nichols J, Snyder R: Topical nonsteroidal anti-inflammatory agents in ophthalmology. Curr Opin Ophthalmol 1998;9:40–44. 36 Pallapies D, Salinger A, Meyer zum Gottesberge A, et al: Effects of lysine onixinate and ketorolac tromethamine on prostanoid release from various rat organs incubated ex vivo. Life Sci 1995;57:83–89. 37 Sivaprasad S, Bunce C, Patel N: Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery. Cochrane Database Syst Rev 2005; 1: CD004239. 38 Flach AJ: The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery. Trans Am Ophthalmol Soc 1998;96:557–634. 39 Flach AJ, Dolan BJ, Irvine AR: Effectiveness of ketorolac tromethamine 0.5% ophthalmic solution for chronic aphakic and pseudophakic cystoid macular edema. Am J Ophthalmol 1987;103:479–486. 40 Flach AJ, Jampol LM, Weinberg D, et al: Improvement in visual acuity in chronic aphakic and pseudophakic cystoid macular edema after treatment with topical 0.5% ketorolac tromethamine. Am J Ophthalmol 1991;112:514– 519.
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41 Heier JS, Awh CC, Busbee BG, et al: Vitreous nonsteroidal antiinflammatory drug concentrations and prostaglandin E2 levels in vitrectomy patients treated with ketorolac 0.4%, bromfenac 0.09%, and nepafenac 0.1%. Retina 2009;29:1310–1313. 42 Warren KA, Bahrani H, Fox JE: NSAIDs in combination therapy for the treatment of chronic pseudophakic cystoid macular edema. Retina 2010;30:260–266. 43 Grover S, Fishman GA, Gilbert LD, et al: Reproducibility of visual acuity measurements in patients with retinitis pigmentosa. Retina 1985;17:33–37. 44 Grover S, Apushkin MA, Fishman GA: Topical dorzolamide in the management of chronic cystoid macular edema in patients with retinitis pigmentosa. Am J Ophthalmol 2006; 141:850–858. 45 Cox SN, Hay E, Bird AC: Treatment of chronic macular edema with acetazolamide. Arch Ophthalmol 1988;106:1190–1195. 46 Moldow B, Sander B, Larsen M, et al: The effect of acetazolamide on passive and active transport of fluorescein across the blood-retina barrier in retinitis pigmentosa complicated by macular edema. Graefes Arch Clin Exp Ophthalmol 1988;236:881–889. 47 Oishi A, Otani A, Sasahara M, et al: Photoreceptor integrity and visual acuity in cystoid macular oedema associated with retinitis pigmentosa. Eye 2009;23:1411–1416.
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24 Wang C, Hu J, Bernstein PS, Teske MP, et al: Intravitreal injection of triamcinolone acetonide for macular edema due to retinitis pigmentosa and other retinal diseases. Adv Exp Med Biol 2006;572:309–314. 25 Scorolli L, Morara M, Meduri A, et al: Treatment of cystoid macular edema in retinitis pigmentosa with intravitreal triamcinolone. Arch Opththalmol 2007;125:759–764. 26 Melo GB, Farah ME, Aggio FB: Intravitreal injection of bevacizumab for cystoid macular edema in retinitis pigmentosa. Acta Ophthalmol Scand 2007;85:461–463. 27 Newsome DA, Blacharski PA: Grid photocoagulation for macular edema in patients with retinitis pigmentosa. Am J Ophthalmol 1987; 103:161–166. 28 Heckenlively JR: Grid photocoagulation for macular edema in patients with retinitis pigmentosa. Am J Ophthalmol 1987;104:94–95. 29 Garcia-Arumi J, Martinez V, Sararols L, et al: Vitreoretinal surgery of cystoid macular edema associated with retinitis pigmentosa. Ophthalmology 2003;110:1164–1169. 30 Wolfensberger TJ: The role of carbonic anhydrase inhibitors in the management of macular edema. Doc Ophthalmol 1999; 97: 387– 397. 31 Grover S, Apushkin MA, Fishman GA: Topical dorzolamide for the treatment of cystoid macular edema in patients with retinitis pigmentosa. Am J Opththalmol 2006; 141: 850– 858.
Ophthalmologica
Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
Received: March 23, 2014 Accepted after revision: August 29, 2014 Published online: November 26, 2014
Comparison of Topical Dorzolamide and Ketorolac Treatment for Cystoid Macular Edema in Retinitis Pigmentosa and Usher’s Syndrome Ricardo Filipe Lemos Reis a Nuno Moreira-Gonçalves a Sérgio E. Estrela Silva a Elisete M. Brandão a Fernando M. Falcão-Reis a, b a
Department of Ophthalmology, Hospital de São João, and b Department of Sense Organs, Faculty of Medicine, University of Porto, Porto, Portugal
Abstract Purpose: To investigate the topical effect of dorzolamide versus ketorolac on retinitis pigmentosa (RP) and Usher’s syndrome (US) macular edema. Methods: Prospective, randomized and interventional study. A total of 28 eyes of 18 patients were included. Five eyes had US, 23 had RP. Fifteen eyes were allocated to ketorolac tromethamine 0.5% (4 drops daily regimen) and 13 eyes to dorzolamide hydrochloride 2% (3 drops daily regimen) treatment groups. Snellen’s best-corrected visual acuity (BCVA), foveal thickness (FT) and foveal zone thickness (FZT) measured by Stratus® optical coherence tomography (OCT) were evaluated at baseline, 1, 3, 6 and 12 months after treatment. Results: Patients assigned to ketorolac had a baseline BCVA of 0.37 ± 0.17 logMAR which improved at the end of 1 year to 0.28 ± 0.16 (p = 0.02). Three eyes (20%) of 2 patients improved by 7 letters or more. Mean FT and FZT did not change significantly during the study follow-up. After 1 year of treatment, 4 eyes (27%) of 3 patients showed an improvement of at least 16% of FT and 11% of FZT. Patients assigned to dorzolamide had a baseline BCVA of 0.48 ± 0.34 logMAR which improved in the first 6 months (0.40 ± 0.30; p = 0.01), with a decrease at 1 year (0.42 ± 0.27; p = 0.20). Seven eyes (54%) of 5 patients had an
© 2014 S. Karger AG, Basel 0030–3755/14/2331–0043$39.50/0 E-Mail [email protected] www.karger.com/oph
improvement of 7 letters or more. Mean FT and FZT did not change significantly either. After 1 year of treatment, 3 eyes (23%) of 2 patients showed an improvement of at least 16% on FT and 11% on FZT. Conclusions: Results suggest that dorzolamide and ketorolac might improve visual acuity and therefore be of interest in selected cases. No relationship between retinal thickness fluctuation and visual acuity was found. Sample size was a limitation to the study. © 2014 S. Karger AG, Basel
Retinitis pigmentosa (RP) is a broad concept that embraces a spectrum of different hereditary retinal diseases. A group of gene abnormalities is at the basis of a degenerative and progressive loss of photoreceptors, causing nyctalopia, peripheral visual field impairment and a typical fundus appearance [1–4]. Presenting itself as an autosomal recessive disorder, Usher’s syndrome (US) combines both RP and sensorineural hearing loss manifestations [5–7]. Its most prevalent form, US type II, is characterized by congenital deafness and early onset of visual symptoms (second decade) [8, 9]. Visual acuity, usually preserved until a late stage [10], can be affected by cystoid macular edema (CME) in 10– 40% of cases diagnosed with RP [11–13] and 8–25% of cases diagnosed with US [9, 14, 15]. Several factors have been connected to visual deterioration, namely cell loss Ricardo Filipe da Silva Lemos Reis, MD Hospital de São João Rua Dr. Manuel Laranjeira No. 138, 5° Frente PT–4200-384 Paranhos, Porto (Portugal) E-Mail r.lemosreis @ gmail.com
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Key Words Dorzolamide · Ketorolac · Cystoid macular edema · Retinitis pigmentosa · Usher’s syndrome
Methods The study protocol was reviewed and approved by the ethics board at Centro Hospitalar de São João in Oporto, Portugal, and followed the tenets of the Declaration of Helsinki on biomedical research involving human beings. Informed consent was obtained from all participating subjects. This prospective, comparative and randomized study was developed by the Department of Ophthalmology, at the Centro Hospitalar de São João. Clinical records on ocular genetics were reviewed from a computer database between January 1, 2009, and December 31, 2011. A population of 85 patients with at least 18 years of age and diagnosed with RP or US was obtained. The diagnosis of RP was based on a symptomatic nyctalopia, typical fundus changes (i.e. waxy optic disk pallor, midperipheral bone-spicule-like pigment clumping and retinal arteriolar attenuation), constricted visual field (documented by Goldmann perimetry – Carl Zeiss, Humphrey® Field Analyzer) and markedly reduced to nonrecordable a- and b-wave amplitudes on electroretinogram testing. If, in addition, a moderate
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Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
sensorineural hearing loss in the absence of vestibular disturbances was present and confirmed by audiometric and otorhinolaryngologic examinations, patients were diagnosed with US type II. Between January 1, 2012, and March 31, 2012, the 85 previously selected subjects were contacted, either by telephone or post, observed and tested afterwards. To be included in the study, patients had to fulfill the following criteria: CME in at least 1 eye, as documented by OCT (detection of intraretinal cysts within the 1,000 μm centered in the foveola in the absence of vitreous traction), stable fixation and a best-corrected visual acuity (BCVA) of at least 20/200 in the affected eye(s). Patients were excluded if any other cause of CME was plausible, such as diabetes mellitus, pseudophakia or aphakia after cataract extraction (performed within 1 year from this study) and posterior uveitis. Other possible causes for decreased visual acuity, such as amblyopia, ocular trauma, central media opacities or a maculopathy from any other source beyond RP, were also used as exclusion criteria. Finally, the use of steroids, thiazide diuretics or nonsteroidal anti-inflammatory drugs either systemic or topically 1 year before or during the study follow-up period, also motivated exclusion. Twenty-eight eyes from 18 patients fulfilled all criteria and were therefore enrolled in the study. A Snellen’s BCVA was obtained for every patient at baseline. For comparative purposes, and based on a previous study on the subject [43], an increase of 7 or more letters (0.235 natural log units) from baseline was considered significant in the follow-up visits. A slitlamp biomicroscopy examination of the anterior segment and an intraocular pressure measurement with Goldmann’s applanation tonometer were performed. The pupils were dilated with one drop each of phenylephrine 2.5% and tropicamide 0.1% ophthalmic solutions, and a subsequent fundus examination under mydriasis was performed with a +78-dpt lens. Baseline time domain OCT (Carl Zeiss Stratus® OCT 3000) was performed utilizing 6-mm single radial scans spaced by a 30-degree interval between them and centered on fixation. The central foveal thickness (FT) was calculated and recorded as an average of the 6 measurements obtained at the intersection of the 6 radial scans. The foveal zone thickness (FZT) was also calculated and recorded as an average of 100 automatic measurements performed in the 1,000-μm ring centered on the foveola by the OCT scanner, using a retinal mapping software available with the device. As suggested by Grover et al. [44], both an FT change >16% (mean ± 2 SD) and an FZT change >11% from baseline were considered as statistically significant in the follow-up visits. After the baseline examination and OCT measurement, all patients underwent a simple randomization process into two study groups. Nine patients, 7 men and 2 women (15 eyes), were randomized to the first group, named ketorolac group (KG), and treated with topical ketorolac tromethamine 0.5% in a 4 drops daily regimen. A total of 9 patients, 6 men and 3 women (13 eyes), were assigned to the second group, named dorzolamide group (DG), and instructed to use topical dorzolamide hydrochloride 2% in a 3 drops daily regimen. Once the treatment had been initiated, all patients returned for reassessment at 1, 3, 6 and 12 months from baseline. In every follow-up visit, the patients performed BCVA testing, anterior segment biomicroscopy, intraocular pressure measurements, funduscopic examination and OCT scans as described previously for the baseline assessment. Patients were advised to report any possible side effect or visual phenomena occurring during the study period. In the KG, patient 2 (table 1) data from the yearly visit was with-
Lemos Reis/Moreira-Gonçalves/ Estrela Silva/Brandão/Falcão-Reis
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and subsequent atrophic thinning of the retina and retinal thickening [16] induced by swelling either of the fovea or the parafovea [17]. Optical coherence tomography (OCT) is currently a widely used device to monitor RP patients, being at least as sensitive as fluorescein angiography when detecting CME [18–20]. Finding an effective treatment for CME has motivated several studies on this subject. The therapeutic approaches previously described are numerous and include the use of periocular or intravitreal steroid injection [21–25], intravitreal bevacizumab [26], grid laser photocoagulation [27, 28], pars plana vitrectomy [29] and the administration of topical or oral carbonic anhydrase inhibitors [10, 30–33]. Nonsteroidal anti-inflammatory drugs act through inhibition of both cyclooxygenase isozymes 1 and 2 and therefore block prostaglandin synthesis [34–36]. Its use in ophthalmology is vast and includes postcataract surgery CME prophylaxis and treatment [37, 38]. Topical ketorolac tromethamine 0.5% was the first nonsteroidal anti-inflammatory drug to show effectiveness for the treatment of chronic CME [39, 40]. More recently, topical nepafenac and bromfenac were used as they penetrate into the vitreous cavity [41], potentiating the therapeutic effect of intravitreal corticosteroids and antivascular endothelial growth factor for chronic pseudophakic CME [42]. The present study compares, during a 12-month period, the efficacy of topical dorzolamide hydrochloride 2% versus ketorolac tromethamine 0.5% for the management of CME in patients with RP and US as well as their impact on visual acuity.
Patient Disease No. Ketorolac 1 RP
Gender
Age, years
Visit
BCVA OD
BCVA OS
FT OD, μm
FZT OD, μm
FT OS, μm
FZT OS, μm
F
20
Pre 1M 3M 6M 12M
20/100 20/60 20/50–2 20/25–1 20/50
20/50 20/30 20/30–1 20/30+1 20/25–1
562 402 (–28) 465 (–17) 458 (–19) 390 (–31)
536 404 (–25) 446 (–17) 440 (–18) 402 (–25)
393 283 (–18) 312 (–21) 393 (0) 280 (–29)
398 321 (–19) 339 (–15) 398 (0) 316 (–21)
2
RP
F
59
Pre 1M 3M 6M 12M
20/60 20/80 20/80 20/60–2
276 274 (–1) 271 (–2) 268 (–3)
294 299 (+2) 295 (0) 286 (–3)
3
RP
M
38
Pre 1M 3M 6M 12M
20/60 20/100 20/120 20/60–2 20/60
608 683 (+12) 573 (–6) 733 (+21) 499 (–18)
641 657 (+2) 615 (–4) 697 (+9) 526 (–18)
4
RP
M
56
Pre 1M 3M 6M 12M
20/25+1
20/40–2
213
251
220
258
20/25 20/25 20/25
20/40+2 20/25 20/40–2
203 (–5) 190 (–11) 198 (–7)
248 (–1) 240 (–4) 247 (–2)
208 (–5) 218 (–1) 250 (+14)
266 (+3) 261 (+1) 275 (+7)
Pre 1M 3M 6M 12M
20/40 20/40–2 20/30–1 20/40+1 20/30–1
20/60 20/120 20/80 20/60–1 20/60–1
217
247
541
524
206 (–5) 209 (–4) 210 (–3)
253 (+2) 245 (–1) 245 (–1)
659 (+22) 492 (–9) 611 (+13)
619 (+18) 487 (–7) 573 (+9)
176 179 (+2) 182 (+3) 200 (+14) 172 (–2)
237 230 (–3) 245 (+3) 237 (0) 234 (–1)
5
RP
M
48
6
RP
M
28
Pre 1M 3M 6M 12M
20/25–2 20/30+2 20/25–1 20/25 20/25
7
RP
M
44
Pre 1M 3M 6M 12M
20/60
20/30
20/50 20/50
20/20 20/25
310 320 (+3) 241 (–22) 313 (+1) 260 (–16)
310 317 (+2) 289 (–7) 321 (+3) 283 (–9)
230 228 (–1) 234 (+2) 270 (+17) 391 (+70)
271 249 (–8) 272 (0) 305 (+13) 342 (+26)
8
RP
M
31
Pre 1M 3M 6M 12M
20/50 20/50 20/50+1 20/50 20/50–1
20/50 20/60+1 20/40 20/50 20/50+1
210 223 (+6) 298 (+42) 245 (+14) 206 (–2)
252 253 (0) 326 (+29) 264 (+5) 240 (–5)
395 394 (0) 427 (+8) 412 (+5) 310 (–27)
399 396 (–1) 419 (+5) 407 (+2) 333 (–17)
9
RP
M
52
Pre 1M 3M 6M 12M
20/30 20/25+1 20/20–2 20/25 20/25
20/40 20/40 20/30–2 20/30–1 20/30+2
229 223 (–3) 218 (–5) 226 (–1) 229 (0)
268 267 (0) 266 (–1) 261 (–3) 269 (0)
221 222 (0) 210 (–5) 203 (–8) 220 (0)
267 265 (0) 256 (–4) 249 (–7) 262 (–2)
Topical Dorzolamide and Ketorolac Treatment for CME
Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
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Table 1. Patient characteristics and BCVA and FT before and after treatment
Table 1. (continued)
Patient Disease No. Dorzolamide 10 RP
Gender
Age, years
Visit
M
25
Pre 1M 3M 6M 12M
BCVA OD
BCVA OS
FT OD, μm
FZT OD, μm
FT OS, μm
FZT OS, μm
20/60 20/60 20/60 20/60 20/100
422
419
565 (+34) 501 (+19) 530 (+26)
550 (+31) 495 (+18) 527 (+26)
11
US
M
25
Pre 1M 3M 6M 12M
20/50 20/50 20/50 20/40 20/30–1
291 270 (–7) 244 (–16) 220 (–24) 220 (–24)
292 273 (–7) 260 (–11) 240 (–18) 240 (–22)
12
RP
M
70
Pre 1M 3M 6M 12M
20/40–2 20/30 20/30 20/30 20/30+1
303 310 (+2) 309 (+2) 311 (+3) 305
306 307 (0) 312 (+2) 312 (+2) 312
13
US
F
55
Pre 1M 3M 6M 12M
20/160 20/100 20/100 20/100 20/80–1
20/200 20/100 20/100 20/125 20/125–1
362 300 (–17) 275 (–24) 281 (–22) 272 (–25)
336 298 (–11) 271 (–19) 270 (–20) 270 (–20)
225 175 (–22) 154 (–31) 135 (–40) 166 (–26)
233 184 (–21) 179 (–23) 164 (–30) 177 (–24)
14
RP
F
71
Pre 1M 3M 6M 12M
20/50 20/40 20/30 20/30 20/30–1
20/30 20/30 20/40 20/25–1 20/30
191 182 (–5) 176 (–8) 176 (–8) 213 (+12)
226 213 (+6) 211 (+7) 212 (+6) 225 (0)
174 168 (–3) 169 (–3) 169 (–3) 174 (0)
215 203 (–6) 202 (–6) 208 (–3) 203 (–6)
15
US
F
21
Pre 1M 3M 6M 12M
20/200 20/160 20/160 20/160 20/160
20/125 20/80 20/80 20/125 20/100
771 821 (+6) 779 (+1) 897 (+16) 679 (–12)
763 800 (+5) 771 (+1) 883 (+16) 675 (–12)
674 701 (+4) 592 (–12) 609 (–10) 604 (–10)
661 683 (+3) 576 (–13) 595 (–10) 575 (–13)
16
RP
M
51
Pre 1M 3M 6M 12M
239 247 (+3) 250 (+5) 250 (+5) 251 (+5)
267 266 (0) 269 (+1) 269 (+1) 271 (+1)
17
RP
M
41
Pre 1M 3M 6M 12M
20/40 20/40 20/40 20/40 20/40
18
RP
M
30
Pre 1M 3M 6M 12M
20/25 20/25 20/20–1 20/25–2 20/25
372 280 (–25) 311 (–16) 352 (–5) 347 (–7)
352 280 (–20) 303 (–14) 332 (–6) 324 (–8)
20/25 20/25 20/25 20/25 20/30
20/30 20/30+2 20/20–2 20/30–1 20/40
169 168 (–1) 172 (+2) 156 (–8) 143 (–15)
216 205 (–5) 193 (–11) 184 (–15) 224 (+4)
406 302 (–26) 368 (–9) 387 (–5) 380 (–6)
383 299 (–22) 334 (–13) 347 (–9) 345 (–10)
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Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
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F = Female; M = male; pre = before treatment; 1M, 3M, 6M, 12M = visits after 1, 3, 6 and 12 months. Figures in parentheses indicate percent altered.
370
0.6
KG DG
0.5
FT KG FT DG FZT KG FZT DG
360
Thickness (μM)
BCVA (logMAR)
350 0.4 0.3 0.2
340 330 320
0.1 310 Baseline
1 month
3 months
6 months
1 year
300
Baseline
1 month
3 months
6 months
1 year
Fig. 1. BCVA variation.
Fig. 2. FT and FZT variation.
drawn and not considered for statistical analysis due to cataract surgery performed on her left (included) eye. Statistical analysis was performed with SPSS 17.0. Wilcoxon’s signed-ranks test was used to compare variations of mean BCVA, FT and FZT within each group, as this data was not normally distributed. The Mann-Whitney U test was used to compare continuous variables between groups, and Fisher’s exact test was used to compare categorical outcomes.
The mean age at the initial visit of DG was 43.54 ± 19.59 years, and that of KG was 41.80 ± 13.05 years. There was no significant difference between the groups (paired t test, p = 0.79). Patients assigned to KG had a baseline BCVA of 0.37 ± 0.17 logMAR. After 1 month of treatment, the mean BCVA was 0.41 ± 0.23 (p = 0.72), and after 3 months 0.33 ± 0.23 (p = 0.38). At 6 months it improved to 0.27 ± 0.18 (p = 0.03), and at the end of 1 year it remained similar (0.28 ± 0.16; p = 0.02; fig. 1). Three eyes (20%) of 2 patients improved 7 letters or more. The BCVA of the remaining 12 eyes was similar to baseline at the end of the follow-up (table 1). In KG, baseline FT was 320.07 ± 145.02 μm. At subsequent visits (1, 3, 6 months and 1 year, respectively) it was 311.91 ± 142.65 (p = 0.82), 313.80 ± 148.37 (p = 0.28), 322.00 ± 151.27 (p = 1.00) and 306.21 ± 125.02 (p = 0.31). FZT at baseline was 343.53 ± 128.03, and at subsequent visits it was 332.55 ± 121.90 (p = 0.29), 343.60 ± 126.28
(p = 0.91), 339.87 ± 127.50 (0.86) and 324.79 ± 106.56 (p = 0.12; fig. 2). After 1 year of treatment, 4 eyes (27%) of 3 patients showed an improvement of at least 16% of FT and 11% of FZT. One eye (patient 7) showed a large increase in both FT and FZT. The other 10 eyes (67%) remained stable (table 1). Patients assigned to the DG had a baseline BCVA of 0.48 ± 0.34 logarithm of the minimal angle of resolution (logMAR). After 1 month of treatment, it improved to 0.40 ± 0.26 (p = 0.02), remaining stable after 3 (0.38 ± 0.28; p = 0.01) and 6 months of treatment (0.40 ± 0.30; p = 0.01). After 1 year of treatment, the mean BCVA was 0.42 ± 0.27 (p = 0.20; fig. 1). Seven eyes (54%) of 5 patients had an improvement of 7 letters or more. One eye (patient 10) showed a significant decrease in visual acuity, and the remaining 5 eyes (38%) remained stable (table 1). In this group, baseline FT was 353.77 ± 185.66 μm. At subsequent visits (1, 3, 6 months and 1 year, respectively) it was 327.00 ± 211.51 (p = 0.20), 335.69 ± 193.58 (p = 0.17), 341.85 ± 217.88 (p = 0.22) and 329.38 ± 173.64 (p = 0.10). FZT at baseline was 359.15 ± 170.71, and at subsequent visits it was 334.25 ± 196.43 (p = 0.08), 340.85 ± 179.62 (p = 0.06), 347.00 ± 202.74 (p = 0.22) and 336.15 ± 156.79 (p = 0.10; fig. 2). After 1 year of treatment, 3 eyes (23%) of 2 patients showed an improvement of at least 16% on FT and 11% on FZT. Both eyes of patient 18 had a significant thickness reduction at 1 and 3 months, returning to baseline values at subsequent follow-up visits. Patient 17 had a significant improvement in FZT at 3 and 6 months, returning to baseline values at the 1-year visit.
Topical Dorzolamide and Ketorolac Treatment for CME
Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
Results
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0
Discussion
Despite being a well-known complication in RP, CME does not have an established cause or proven mechanism. Several theories have been stated; Cox et al. [45] suggested that CME genesis could occur due to changes in retinal pigment epithelium polarity which would affect its pumping ability and therefore cause the edema. Other authors have related this complication either with circulating antiretinal antibodies [30] or with a blood-retina barrier breakdown [46]. 48
Ophthalmologica 2015;233:43–50 DOI: 10.1159/000368052
The present study investigated and compared the efficacy of topical dorzolamide versus ketorolac for the treatment of RP and US patients complicated with CME. This comparison was based on the assumption that the former would optimize retinal pigment epithelium function and the latter would block inflammatory mediators, and consequently affect the development of an autoimmune response, reducing the CME. Although no significant differences were shown at baseline between groups concerning BCVA, different progression patterns where observed during the followup period. In the DG, an immediate and statistically significant improvement in visual acuity was noticed and kept stable for a total period of 6 months. After reaching a peak at the third month, BCVA started decreasing, with loss of significance at the end of follow-up. In the final visit, however, 55.6% of patients had still an improvement -7 letters in at least one of the treated eyes compared to baseline. Previous studies have already suggested a potential visual benefit of topical dorzolamide for this subset of patients, with reported success rates between 20 and 37.5% of cases [31–33]. The present study has put into evidence that even better visual outcomes can be attained, mainly in the first 6 months of treatment. Looking at the KG, after a first month of disappointing results, a progressive increase in BCVA occurred, reaching a plateau after 6 months of treatment. Interestingly and despite a statistically significant improvement seen in the 2 final visits, only 2 patients (22.2%) have gained 7 or more letters at the end of the study. When a patient-bypatient analysis is performed, statistics becomes clearer. The achievement of significance can be explained by a shifting effect in the overall BCVA caused by an individual highly responsive behavior to ketorolac, rather than a group response to the drug. The small number of enrolled patients is the other cofactor explaining this statistical phenomenon. Generally, both drugs failed to show a consistent decrease in CME in the majority of patients, and no statistical difference was shown when both drugs were compared. Our results concerning the dorzolamide effect on retinal thickness are clearly worse when compared with other studies [10, 31, 32]. Photoreceptor layer integrity [47] and a long-standing CME with atrophic changes of the neurosensory retina might explain this difference. An OCT qualitative analysis could therefore bring value, enlightening and possibly explaining our results. Its absence constitutes an obvious limitation to this topic. Lemos Reis/Moreira-Gonçalves/ Estrela Silva/Brandão/Falcão-Reis
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One eye (patient 10) showed a large increase in both FT and FZT. The remaining 7 eyes (54%) remained stable during the period of follow-up (table 1). There was no statistically significant difference between both groups regarding the mean improvement of BCVA (–0.05 DG vs. –0.08 KG; p = 0.86). Although the number of eyes showing an improvement of 7 letters or more was higher in the DG (7/13) compared to the KG (3/15), this difference was not statistically significant (p = 0.11). In the current study, 5 DG patients showed some decrease in retinal thickness in at least 1 eye during the follow-up period. In this group, however, only 2 patients (22.2%) reached a statistically significant and sustained response (table 1). All patients except 1 (patient 15 – both eyes) developed a response within the first month of follow-up. The right and left eyes of patient 15 responded to treatment at 12 and 3 months, respectively. Regarding the KG, 3 (33.3%) out of 9 patients had a statistically significant decrease in retinal thickness in at least 1 eye (table 1). Both eyes of patient 1 showed a response to treatment within the first 4 weeks while the left eyes of patients 3 and 8 only developed a statistically significant decrease in retinal thickness at the end of follow-up. There was no statistically significant difference between both groups regarding the percentage of reduction of FT (6.5% DG vs. 0.3% KG; p = 0.72) or the percentage of reduction of FZT (5.9% DG vs. 4.0% KG; p = 0.73). There was no difference comparing the number of eyes showing significant structural improvement (DG 3/13 vs. KG 4/15; p = 1.0). The only reported side effect was an allergic blepharitis after 1 month of treatment in one of the patients (patient 15). That patient was changed to a preservative-free dorzolamide intake plus regular eyelid hygiene bilaterally and the condition settled within 1 week.
Concerning the previously described rebound effect on retinal thickness that can be obtained with longterm dorzolamide treatment [31–33], again different results were shown by this study. Despite some fluctuation on retinal thickness measurements during treatment, none of the patients had a consistent rebound of macular edema. This finding was also observed with ketorolac. The small number of subjects who developed a response to dorzolamide drops can represent a bias for this analysis. When comparing visual acuity with retinal thickness results, a poor correlation was obtained, showing that there is not a pure cause-effect relationship and that more variables are possibly implicated in the visual outcome. Other authors described similar observations [31–33]. Again, retinal atrophic changes, photoreceptor layer integrity [47] and possibly macular cyst characteristics (morphology, size and distribution in the macula) might explain this correlation. Population size presents itself as the major limitation for the present study, portraying the small prevalence of
RP and US. Other possible limitations are the time domain technology used in the OCT, the Snellen visual acuity charts and the absence of a control group to address a possible placebo effect. In conclusion, this study shows a possible benefit of topical dorzolamide treatment on visual acuity for RP and US patients for at least 6 months. Ketorolac’s role in this subset of patients was not completely clear; however, it might be of interest in selected cases, either singly or complementing dorzolamide. There are no other studies in the literature regarding ketorolac treatment in these diseases, which limits any further interpretation. Given the poor correlation between visual acuity and retinal thickness, macular thickness measured by Stratus OCT did not show to be an accurate examination to predict visual acuity improvement. Development of larger studies on both drugs, looking at their individual action, duration and to a possible synergistic effect between them might bring further knowledge on the pathogenesis and treatment of CME in RP and US patients.
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