DECREASED MACULAR THICKNESS IN NONPROLIFERATIVE MACULAR TELANGIECTASIA TYPE 2 WITH ORAL CARBONIC ANHYDRASE INHIBITORS JOHN J. CHEN, MD, PHD, ELLIOTT H. SOHN, MD, JAMES C. FOLK, MD, VINIT B. MAHAJAN, MD, PHD, CHRISTINE N. KAY, MD, H. CULVER BOLDT, MD, STEPHEN R. RUSSELL, MD Purpose: To evaluate whether carbonic anhydrase inhibitors reduce the macular thickness and/or cystic spaces in patients with macular telangiectasia (MacTel) Type 2. Methods: Retrospective review of patients with nonproliferative cystoid changes associated with MacTel seen at the University of Iowa between 2009 and 2012. Carbonic anhydrase inhibitors were used in 8 patients with MacTel Type 2. Five patients with MacTel Type 2 were observed during this period. Initial and final visual acuities were documented. The presence of cystic spaces and the retinal thickness were measured with spectraldomain optical coherence tomography. Results: Patients treated with oral carbonic anhydrase inhibitors showed significant reduction in both the cystoid cavities and central macular thickness when compared with the patients who were observed (−12.2 mm; P = 0.020). The reduction in retinal thickness was more pronounced in patients receiving acetazolamide (−20.13 mm; P = 0.007) compared with methazolamide (−6.25 mm; P = 0.177). There was no significant change in visual acuity in patients receiving carbonic anhydrase inhibitors. Five patients with MacTel Type 2 did not receive treatment and demonstrated no change in visual acuity, cystoid cavities, or central macular thickness. Conclusion: Oral carbonic anhydrase inhibitors, particularly acetazolamide, may decrease macular cystic cavities and reduce central macular thickness but does not appear to improve visual acuity. These findings have yet to be confirmed with a prospective treatment trial. RETINA 34:1400–1406, 2014
I
sition; and Type 2, referred to as MacTel Type 2, which is the most common form of idiopathic juxtafoveal telangiectasia and typically presents with bilateral juxtafoveal telangiectasias and minimal exudate. Early changes seen with MacTel Type 2 can include macular cystic cavities, temporal leakage on fluorescein angiography, and right-angle vessels. Visual acuity decreases slowly, and eyes can later develop hyperplasia of the retinal pigment epithelium. In some patients, deep retinal neovascularization with retinal feeders may occur as an acute complication and is then called the proliferative form. The natural progression of the disease is slow but often results in large increments of visual loss in the majority of patients with MacTel Type 2.2 The pathogenesis of MacTel Type 2 is unclear, but one hypothesis involves Muller cell dysfunction or loss.3,4 Since its first description more than 30 years ago, there remains no treatment for the visual loss seen in
diopathic juxtafoveal telangiectasia, also known as macular telangiectasia (MacTel), is a disorder characterized by telangiectatic vessels in the juxtafoveolar region of one or both eyes. According to Gass and Blodi,1 idiopathic juxtafoveal telangiectasia can be divided into 2 predominant groups based on the phenotype: Type 1 idiopathic juxtafoveal telangiectasia, also termed MacTel Type 1, which is typically a unilateral disease characterized by parafoveal dilation of capillaries, microaneurysms, leakage, and lipid depoFrom the Department of Ophthalmology and Visual Science, University of Iowa, Iowa City, Iowa. None of the authors have any financial/conflicting interests to disclose. Dr. Folk is the Judith (Gardner) and Donald H. Beisner Professor of Vitreoretinal Diseases and Surgery. Dr. Boldt is the Marion and Frederick Fuerste Professor of Ophthalmology. Reprint requests: Elliott H. Sohn, MD, Department of Ophthalmology and Visual Science, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242-1091; e-mail: [email protected]
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CARBONIC ANHYDRASE INHIBITORS IN MACTEL II CHEN ET AL
the nonproliferative form (i.e., no choroidal neovascularization) of MacTel Type 2. Bevacizumab was shown to be effective in the treatment of the intraretinal neovascularization associated with MacTel Type 2 but does not appear to consistently affect the course or cystic changes in nonproliferative MacTel.5–9 Similarly, ranibizumab failed to show a functional benefit in a prospective interventional trial of patients with nonproliferative MacTel Type 2.10 Multiple other interventions have been tried, including focal grid laser,11 photodynamic therapy,12 and intravitreal triamcinolone,13 with no clear improvement in visual acuity or reduction in the cystoid cavities in patients with MacTel Type 2. Several studies show that carbonic anhydrase inhibitors (CAIs) can resolve cystoid macular changes in patients with chronic macular edema, including those with retinitis pigmentosa and X-linked retinoschisis.14–17 Patients with MacTel Type 2 often have cystoid cavities within the macula, which are thought to be the result of perifoveal Muller cell dysfunction or loss.3,4 Although MacTel has a different pathogenesis than other forms of chronic macular edema, we hypothesized that CAIs could potentially decrease the cystoid changes observed in this condition by acting on the remaining Muller cells. Therefore, we reviewed the effect of off-label use of CAIs in a series of patients with MacTel Type 2.
1401
patients with MacTel Type 2 who did not receive treatment and had at least 1 month of follow-up with Heidelberg Spectralis OCT imaging were included for comparison. In this retrospective review, the data collected included age, gender, best-corrected visual acuity (BCVA), treatments, and OCT results (including central macular thickness [CMT] and the presence of cystoid changes in the macula). Best-corrected visual acuity was recorded using a Snellen chart. The CMT was defined as the central 1-mm subfield as specified by the Early Treatment Diabetic Retinopathy Study, and changes were based on the CMT at the time of initiation of CAI treatment.18 Optical coherence tomography was performed with the Heidelberg Spectralis, and subsequent images were registered to the initial OCT image (i.e., progression scans). Fluorescein angiography was performed on all patients at the time of diagnosis of MacTel. Statistical analyses of CMT were based on an average of the two eyes for each patient at any given visit because all treated eyes had symmetric stage of disease and were subject to the same systemic treatment.19,20 A one-sample t-test was used to determine if the observation group had a significant change in CMT away from zero. Significant differences between the treatment groups and the observation group were determined using one-way analysis of variance with the Holm–Sidak method for multiple pairwise comparisons. Statistics were performed using SigmaPlot 12.0. A P , 0.05 was considered statistically significant.
Methods The study protocol was approved by the Institutional Review Board for Human Subjects Research at the University of Iowa, and it adhered to the tenets set forth in the Declaration of Helsinki. Patients with potential MacTel were identified by the current procedural terminology code and photographic coding. A retrospective review of patients given the diagnosis of MacTel Type 2 seen in the Department of Ophthalmology and Visual Sciences at the University of Iowa resulted in the identification of 8 patients who had received oral CAIs for MacTel that had follow-up of at least 1 month after the initiation of treatment and progression through spectral-domain optical coherence tomography (OCT) imaging with the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany). Patients who had a history of neovascularization associated with MacTel were excluded. Six patients were started on systemic methazolamide (50 mg 2 times a day), 2 of whom were switched to acetazolamide because of insurance coverage. Two other patients were started on acetazolamide (500 mg 2 times a day) as their initial therapy. Data from 5
Results Natural History of Macular Telangiectasia Type 2 Five patients were observed without CAI therapy during the course of the study. Two were men and 3 were women with a mean age at the initial presentation being 58 years, ranging from 42 years to 76 years (Table 1). The average follow-up was 14 months, with a range from 2 months to 22 months. During follow-up, there was no change in the cystoid spaces or in the CMT (+4.8 mm; standard deviation, ±6.6; P = 0.18; Figure 1; Table 2). There was an average −2.4 letter decrease in BCVA, which was not significant (Table 2). Treatment With Carbonic Anhydrase Inhibitors Systemic CAIs were given to a total of eight patients. Six patients were women and 2 were men with a mean age at the initial presentation being 60 years, ranging from 43 years to 76 years (Table 1). The average follow-up was 5.8 months, with a range from 1 month to 9 months.
20/25−1 OD, 20/25 OS 20/30+1 OD, 20/160 OS 20/40+2 OD, 20/30−1 OS 20/25−3 OD, 20/30−2 OS
57/F 73/F 54/M 76/F 42/F 55/M 59/F 7 8 9 10 11‡ 12§ 13
20/20 OD 20/40 OD, 20/20−2 OS
20/60−1 OD, 20/60 OS 43/M 6
*Patients changed from methazolamide to acetazolamide. Change in CMT and BCVA was compared with the initial CMT and BCVA before the initiation of any CAI. †Half dose of acetazolamide. ‡Patient has functional overlay causing visual acuity to be unreliable. §Left eye had a history of choroidal neovascularization so was excluded from the study. CMT, central macular thickness averaged between both eyes; OD, right eye; OS, left eye.
20/25−2 OD, 20/25 OS 20/30−2 OD, 20/50−2 OS 20/50−2 OD, 20/30−1 OS 20/60 OD, 20/70+1 OS 20/40−3 OD, 20/30−2 OS 20/30 OD, 20/20−3 OS 20/50+2 OD, 20/60+1 OS 20/60+1 OD, 20/60+3 OS 20/40+2 OD, 20/20−1 OS 20/30 OD, 20/150 OS 20/30−2 OD, 20/30+2 OS 20/40−1 OD, 20/50−2 OS — 20/20−2 20/50−1 OD, 20/25 OS 9 1 6 4 4.5 4.5 (9) 4 5 (9) 7 1.5 2 22 10 19 18 −7 −4.5 +0.5 −6 +2 −18.5* −22.5 −28* −6.5 −27.5 6 −5 +12 +2 +9 20/30−2 OD, 20/30+2 OS 20/40−1 OD, 20/50−2 OS 20/60 OD, 20/50 OS 20/60−1 OU 20/30+2 OD, 20/25+1 OS 54/M 76/F 46/F 64/F 65/M 1 2 3 4 5
Methazolamide Methazolamide Methazolamide Methazolamide Methazolamide Acetazolamide Methazolamide Acetazolamide Acetazolamide† Acetazolamide Observation Observation Observation Observation Observation
Duration of Treatment (months) CMT D (mm) Treatment Baseline BCVA Age (years) at Diagnosis/Gender Patient
Table 1. Summary of Patients With MacTel Type 2 Treated With CAIs
Final BCVA
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2014 VOLUME 34 NUMBER 7
Systemic methazolamide was prescribed for 6 patients with the nonproliferative form of MacTel Type 2. There was a very modest decrease in the cystoid cavities in some patients treated with methazolamide and a nonsignificant decrease in CMT when compared with the patients who were observed (−6.25 mm; standard deviation, ±8.73; P = 0.177; Table 2). Two of the patients were changed to acetazolamide. Among these two patients, one responded well to methazolamide and had a small additional reduction in CMT in response to acetazolamide. The other patient had no response to methazolamide but had a visible reduction in cystoid cavities and a significant decrease in CMT when changed to acetazolamide (Figure 2). Two patients were treated with oral acetazolamide as an initial therapy, one of whom had a modest decrease in CMT while the other had a significant decrease with an accompanying decrease in the cystoid cavities (Figure 3). Overall, the 4 patients treated with acetazolamide had a significant decrease in CMT when compared with tthose who were observed (−20.13 mm; standard deviation, ±10.08; P = 0.007; Table 2). When the patients treated with oral CAI were combined as a single group, there was a significant decrease in CMT when compared with those who were observed (−12.2 mm; standard deviation, ±10.97; P = 0.020; Table 2), where the decrease in thickness was largely driven by the patients treated with acetazolamide as shown above. The decrease in cystoid changes and CMT was seen within 1 month to 3 months after the initiation of the CAIs. Among the patients who responded to CAIs, we have not seen a loss or reversal of the effect, although we do not have long-term follow-up on these patients yet. Although there was a subjective improvement in vision in the majority of patients treated with oral CAIs, on average, the patients had a 1 to 2 letter improvement in BCVA, which was not significant (Table 2). The CAIs were well tolerated in our patients. One patient developed a kidney stone on methazolamide, which was attributed to dehydration and has not recurred with better hydration since. One patient’s dosage of acetazolamide was reduced to 125 mg 2 times a day because of fatigue induced by the higher dosage.
Discussion Oral CAIs seem to reduce the cystoid cavities and macular thickness on OCT associated with MacTel Type 2. Patients receiving acetazolamide had an average reduction of 20.13 mm, which was seen within 1 month to 3 months of the initiation of therapy. This is significantly more than expected for normal
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Fig. 1. Heidelberg Spectralis OCT from a patient with MacTel Type 2 who was observed without treatment (Table 1, Patient 10). The baseline Heidelberg Spectralis OCT demonstrates subfoveal cystlike spaces. The retinal thickness map is shown in the right (CMT = 218 mm). After 22 months of observation, there is little change in the cystic spaces or CMT (CMT = 219 mm). Images were obtained in the same meridian and registered to the original visit.
variation in sequential Spectralis OCT images, where normal eyes have a coefficient of repeatability of 2.2 mm,21 and patients with diabetic macular edema have a coefficient of repeatability of 6.84 mm.22 Acetazolamide appeared to have a more prominent effect than methazolamide, which was evidenced by a larger average decrease in CMT. In addition, of the two patients changed from methazolamide to acetazolamide for insurance reasons, one patient had a significant decrease in the CMT with near resolution of the cystoid cavities. The other patient only had a modest reduction in retinal thickness, but he previously had a reduction of −22.5 mm in CMT in response to methazolamide and therefore may not have had much room for improvement with the change to acetazolamide; in addition, he only tolerated one fourth of the typically prescribed acetazolamide dosage (500 mg 2 times a day) because of fatigue. Overall, the percentage of MacTel Type 2 patients demonstrating reduction in cystoid cavities in response to CAIs was similar to those found in the treatment of cystoid macular edema with CAIs in patients with
retinitis pigmentosa and X-linked juvenile retinoschisis.16–18,20,21 We find this an interesting observation because MacTel Type 2 patients have subtle cystoid cavities that are much less pronounced than the cystoid macular edema and thickening seen in retinitis pigmentosa and X-linked juvenile retinoschisis and therefore likely represents a different underlying pathogenesis that may also be amenable to CAIs. The mechanism by which CAIs reduce retinal thickness and cystoid spaces is uncertain. Carbonic anhydrase inhibitors are thought to increase fluid transport from the retina to the choroid by acting on the retinal pigment epithelium and/or acidification of the subretinal space.23 Additionally, CAIs may modulate membrane-bound carbonic anhydrase and reestablish their apical polarization in the retinal pigment epithelium, which may be lost from the structural or biochemical effects of macular edema. These mechanisms are thought to underlie the therapeutic effects of CAIs in retinitis pigmentosa and other disease processes.14,16,23 Although these mechanisms may be used by CAIs in their effect on cystoid change seen
Table 2. Summary of Treatment Response to CAIs CMT D ± SD Methazolamide Acetazolamide* Combined CAIs* Observation
−6.25 −20.13 −12.19 4.8
± ± ± ±
8.73 10.08† 10.97† 6.61
D in Snellen Letters ± SD 0.75 1.0 1.88 −2.4
± ± ± ±
5.47 2.12 2.6 4.1
Mean Duration, months
Number of Patients
4.75 6.63 5.81 14.2
6 4 8 5
*Includes two patients who were previously treated with methazolamide. Change in CMT and BCVA was compared with the initial CMT and BCVA before the initiation of any CAI. †P , 0.05. CMT, central macular thickness averaged between both eyes; SD, standard deviation.
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2014 VOLUME 34 NUMBER 7
Fig. 2. Heidelberg Spectralis OCT from a patient with MacTel Type 2 treated with methazolamide and acetazolamide (Table 1, Patient 5). Baseline OCT demonstrates subfoveal cystlike spaces. The retinal thickness map is shown in the right (CMT = 283 mm). After 4 months of treatment with methazolamide, there is no change in the cystic spaces or macular thickness (CMT = 285 mm). Additionally, after 4 months of treatment with acetazolamide, there is a decrease in the cystic spaces and macular thickness (CMT = 264 mm). Images were obtained in the same meridian and registered to the original visit.
in MacTel Type 2, it has been speculated that the spaces seen on OCT in MacTel Type 2 may represent tissue loss from retinal degeneration, specifically because of the dysfunction or loss of Muller cells3,4
Fig. 3. Heidelberg Spectralis OCT from a patient with MacTel Type 2 treated with acetazolamide (Table 1, Patient 8). The baseline Heidelberg Spectralis OCT demonstrates subfoveal cystlike spaces. The retinal thickness map is shown in the right (CMT = 311 mm). After 3 months of treatment with acetazolamide, there is a decrease in the cystic spaces and macular thickness (CMT = 279 mm). Images were obtained in the same meridian and registered to the original visit.
rather than fluid-filled cysts. Therefore, CAIs in MacTel Type 2 may have a different mechanism of action in improving the form and structure seen in these patients. Because Muller cells have been shown to have
CARBONIC ANHYDRASE INHIBITORS IN MACTEL II CHEN ET AL
high concentrations of carbonic anhydrase,24 CAIs may have their effect in patients with MacTel Type 2 by acting on the few remaining functional Muller cells rather than on retinal pigment epithelium. Oral CAIs are not the only treatment shown to reduce the retinal thickness in patients with MacTel Type 2. A prospective study using ranibizumab to treat nonproliferative MacTel Type 2 also demonstrated a significant decrease in macular thickness.10 However, the retinal thickness returned to baseline within 3 months to 5 months after the cessation of ranibizumab; the authors concluded that ranibizumab was not an effective treatment for nonproliferative MacTel Type 2 because there was no significant improvement in BCVA at 12 months. Similarly, although there was a mild subjective improvement in many of our patients, there was no significant improvement in BCVA in response to CAIs. However, it is possible that there could be long-term benefit in decreasing the cystoid spaces and macular thickness in these patients. The risk of monthly ranibizumab does not allow this to be tested, but relatively well-tolerated CAIs may allow us to address the possibility that decrease in the cystoid spaces and reduction in macular thickness could be protective in the long term. This is important because the natural course of MacTel Type 2 results in significant vision loss over time.2 In this retrospective study, the treatment results compare favorably against the 5 untreated patients with MacTel Type 2. No improvement in visual acuity or macular cystoid spaces was found in the patients who were observed. Stability in macular thickness and visual acuity in eyes without treatment was also observed in a study by Charbel Issa et al,10 where the fellow control eye of 10 patients receiving monthly injections of ranibizumab in the contralateral eye had an average decrease of −2 mm in CMT and a +3.5 letter improvement in BCVA over 1 year, which were both not significant. In summary, our study demonstrates that the offlabel use of CAIs may be effective in decreasing the cystic spaces and reducing macular thickness associated with MacTel Type 2. Side effects were minimal with adequate hydration of patients and reduction in dose for those with fatigue. Limitations of our study include its retrospective nature and small sample size, and thus, our results must be considered preliminary. Although we cannot presently advocate the routine use of oral CAIs for nonproliferative MacTel Type 2, there are no treatments for this disease, and thus, we believe that prospective studies with larger numbers of patients is warranted to fully elucidate the efficacy of CAIs in the treatment of this vision-threatening condition.
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Key words: acetazolamide, carbonic anhydrase inhibitors, cystic spaces, idiopathic juxtafoveal telangiectasia, MacTel Type 2, methazolamide. References 1. Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal telangiectasis. Update of classification and follow-up study. Ophthalmology 1993;100:1536–1546. 2. Watzke RC, Klein ML, Folk JC, et al. Long-term juxtafoveal retinal telangiectasia. Retina 2005;25:727–735. 3. Eliassi-Rad B, Green WR. Histopathologic study of presumed parafoveal telangiectasis. Retina 1999;19:332–335. 4. Powner MB, Gillies MC, Tretiach M, et al. Perifoveal muller cell depletion in a case of macular telangiectasia type 2. Ophthalmology 2010;117:2407–2416. 5. Roller AB, Folk JC, Patel NM, et al. Intravitreal bevacizumab for treatment of proliferative and nonproliferative type 2 idiopathic macular telangiectasia. Retina 2011;31:1848–1855. 6. Mandal S, Venkatesh P, Abbas Z, et al. Intravitreal bevacizumab (Avastin) for subretinal neovascularization secondary to type 2A idiopathic juxtafoveal telangiectasia. Graefes Arch Clin Exp Ophthalmol 2007;245:1825–1829. 7. Konstantinidis L, Mantel I, Zografos L, Ambresin A. Intravitreal ranibizumab as primary treatment for neovascular membrane associated with idiopathic juxtafoveal retinal telangiectasia. Graefes Arch Clin Exp Ophthalmol 2009;247:1567–1569. 8. Matsumoto Y, Yuzawa M. Intravitreal bevacizumab therapy for idiopathic macular telangiectasia. Jpn J Ophthalmol 2010; 54:320–324. 9. Kovach JL, Rosenfeld PJ. Bevacizumab (avastin) therapy for idiopathic macular telangiectasia type II. Retina 2009;29:27–32. 10. Charbel Issa P, Finger RP, Kruse K, et al. Monthly ranibizumab for nonproliferative macular telangiectasia type 2: a 12-month prospective study. Am J Ophthalmol 2011;151:876–886.e1. 11. Park DW, Schatz H, McDonald HR, Johnson RN. Grid laser photocoagulation for macular edema in bilateral juxtafoveal telangiectasis. Ophthalmology 1997;104:1838–1846. 12. De Lahitte GD, Cohen SY, Gaudric A. Lack of apparent shortterm benefit of photodynamic therapy in bilateral, acquired, parafoveal telangiectasis without subretinal neovascularization. Am J Ophthalmol 2004;138:892–894. 13. Wu L, Evans T, Arevalo JF, et al. Long-term effect of intravitreal triamcinolone in the nonproliferative stage of type II idiopathic parafoveal telangiectasia. Retina 2008;28:314–319. 14. Cox SN, Hay E, Bird AC. Treatment of chronic macular edema with acetazolamide. Arch Ophthalmol 1988;106:1190–1195. 15. 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. 16. 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. 17. Genead MA, Fishman GA, Walia S. Efficacy of sustained topical dorzolamide therapy for cystic macular lesions in patients with Xlinked retinoschisis. Arch Ophthalmol 2010;128:190–197. 18. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796–1806. 19. Altman DG, Bland JM. Statistics notes. Units of analysis. BMJ 1997;314:1874.
1406 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 20. Murdoch IE, Morris SS, Cousens SN. People and eyes: statistical approaches in ophthalmology. Br J Ophthalmol 1998;82:971–973. 21. Wolf-Schnurrbusch UE, Ceklic L, Brinkmann CK, et al. Macular thickness measurements in healthy eyes using six different optical coherence tomography instruments. Invest Ophthalmol Vis Sci 2009;50:3432–3437. 22. Sohn EH, Chen JJ, Lee K, et al. Reproducibility of diabetic macular edema estimates from SD-OCT is affected by the
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choice of image analysis algorithm. Invest Ophthalmol Vis Sci 2013;54:4184–4188. 23. Wolfensberger TJ. The role of carbonic anhydrase inhibitors in the management of macular edema. Doc Ophthalmol 1999;97: 387–397. 24. Bhattacherjee P. Distribution of carbonic anhydrase in the rabbit eye as demonstrated histochemically. Exp Eye Res 1971; 12:356–359.
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sition; and Type 2, referred to as MacTel Type 2, which is the most common form of idiopathic juxtafoveal telangiectasia and typically presents with bilateral juxtafoveal telangiectasias and minimal exudate. Early changes seen with MacTel Type 2 can include macular cystic cavities, temporal leakage on fluorescein angiography, and right-angle vessels. Visual acuity decreases slowly, and eyes can later develop hyperplasia of the retinal pigment epithelium. In some patients, deep retinal neovascularization with retinal feeders may occur as an acute complication and is then called the proliferative form. The natural progression of the disease is slow but often results in large increments of visual loss in the majority of patients with MacTel Type 2.2 The pathogenesis of MacTel Type 2 is unclear, but one hypothesis involves Muller cell dysfunction or loss.3,4 Since its first description more than 30 years ago, there remains no treatment for the visual loss seen in
diopathic juxtafoveal telangiectasia, also known as macular telangiectasia (MacTel), is a disorder characterized by telangiectatic vessels in the juxtafoveolar region of one or both eyes. According to Gass and Blodi,1 idiopathic juxtafoveal telangiectasia can be divided into 2 predominant groups based on the phenotype: Type 1 idiopathic juxtafoveal telangiectasia, also termed MacTel Type 1, which is typically a unilateral disease characterized by parafoveal dilation of capillaries, microaneurysms, leakage, and lipid depoFrom the Department of Ophthalmology and Visual Science, University of Iowa, Iowa City, Iowa. None of the authors have any financial/conflicting interests to disclose. Dr. Folk is the Judith (Gardner) and Donald H. Beisner Professor of Vitreoretinal Diseases and Surgery. Dr. Boldt is the Marion and Frederick Fuerste Professor of Ophthalmology. Reprint requests: Elliott H. Sohn, MD, Department of Ophthalmology and Visual Science, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242-1091; e-mail: [email protected]
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CARBONIC ANHYDRASE INHIBITORS IN MACTEL II CHEN ET AL
the nonproliferative form (i.e., no choroidal neovascularization) of MacTel Type 2. Bevacizumab was shown to be effective in the treatment of the intraretinal neovascularization associated with MacTel Type 2 but does not appear to consistently affect the course or cystic changes in nonproliferative MacTel.5–9 Similarly, ranibizumab failed to show a functional benefit in a prospective interventional trial of patients with nonproliferative MacTel Type 2.10 Multiple other interventions have been tried, including focal grid laser,11 photodynamic therapy,12 and intravitreal triamcinolone,13 with no clear improvement in visual acuity or reduction in the cystoid cavities in patients with MacTel Type 2. Several studies show that carbonic anhydrase inhibitors (CAIs) can resolve cystoid macular changes in patients with chronic macular edema, including those with retinitis pigmentosa and X-linked retinoschisis.14–17 Patients with MacTel Type 2 often have cystoid cavities within the macula, which are thought to be the result of perifoveal Muller cell dysfunction or loss.3,4 Although MacTel has a different pathogenesis than other forms of chronic macular edema, we hypothesized that CAIs could potentially decrease the cystoid changes observed in this condition by acting on the remaining Muller cells. Therefore, we reviewed the effect of off-label use of CAIs in a series of patients with MacTel Type 2.
1401
patients with MacTel Type 2 who did not receive treatment and had at least 1 month of follow-up with Heidelberg Spectralis OCT imaging were included for comparison. In this retrospective review, the data collected included age, gender, best-corrected visual acuity (BCVA), treatments, and OCT results (including central macular thickness [CMT] and the presence of cystoid changes in the macula). Best-corrected visual acuity was recorded using a Snellen chart. The CMT was defined as the central 1-mm subfield as specified by the Early Treatment Diabetic Retinopathy Study, and changes were based on the CMT at the time of initiation of CAI treatment.18 Optical coherence tomography was performed with the Heidelberg Spectralis, and subsequent images were registered to the initial OCT image (i.e., progression scans). Fluorescein angiography was performed on all patients at the time of diagnosis of MacTel. Statistical analyses of CMT were based on an average of the two eyes for each patient at any given visit because all treated eyes had symmetric stage of disease and were subject to the same systemic treatment.19,20 A one-sample t-test was used to determine if the observation group had a significant change in CMT away from zero. Significant differences between the treatment groups and the observation group were determined using one-way analysis of variance with the Holm–Sidak method for multiple pairwise comparisons. Statistics were performed using SigmaPlot 12.0. A P , 0.05 was considered statistically significant.
Methods The study protocol was approved by the Institutional Review Board for Human Subjects Research at the University of Iowa, and it adhered to the tenets set forth in the Declaration of Helsinki. Patients with potential MacTel were identified by the current procedural terminology code and photographic coding. A retrospective review of patients given the diagnosis of MacTel Type 2 seen in the Department of Ophthalmology and Visual Sciences at the University of Iowa resulted in the identification of 8 patients who had received oral CAIs for MacTel that had follow-up of at least 1 month after the initiation of treatment and progression through spectral-domain optical coherence tomography (OCT) imaging with the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany). Patients who had a history of neovascularization associated with MacTel were excluded. Six patients were started on systemic methazolamide (50 mg 2 times a day), 2 of whom were switched to acetazolamide because of insurance coverage. Two other patients were started on acetazolamide (500 mg 2 times a day) as their initial therapy. Data from 5
Results Natural History of Macular Telangiectasia Type 2 Five patients were observed without CAI therapy during the course of the study. Two were men and 3 were women with a mean age at the initial presentation being 58 years, ranging from 42 years to 76 years (Table 1). The average follow-up was 14 months, with a range from 2 months to 22 months. During follow-up, there was no change in the cystoid spaces or in the CMT (+4.8 mm; standard deviation, ±6.6; P = 0.18; Figure 1; Table 2). There was an average −2.4 letter decrease in BCVA, which was not significant (Table 2). Treatment With Carbonic Anhydrase Inhibitors Systemic CAIs were given to a total of eight patients. Six patients were women and 2 were men with a mean age at the initial presentation being 60 years, ranging from 43 years to 76 years (Table 1). The average follow-up was 5.8 months, with a range from 1 month to 9 months.
20/25−1 OD, 20/25 OS 20/30+1 OD, 20/160 OS 20/40+2 OD, 20/30−1 OS 20/25−3 OD, 20/30−2 OS
57/F 73/F 54/M 76/F 42/F 55/M 59/F 7 8 9 10 11‡ 12§ 13
20/20 OD 20/40 OD, 20/20−2 OS
20/60−1 OD, 20/60 OS 43/M 6
*Patients changed from methazolamide to acetazolamide. Change in CMT and BCVA was compared with the initial CMT and BCVA before the initiation of any CAI. †Half dose of acetazolamide. ‡Patient has functional overlay causing visual acuity to be unreliable. §Left eye had a history of choroidal neovascularization so was excluded from the study. CMT, central macular thickness averaged between both eyes; OD, right eye; OS, left eye.
20/25−2 OD, 20/25 OS 20/30−2 OD, 20/50−2 OS 20/50−2 OD, 20/30−1 OS 20/60 OD, 20/70+1 OS 20/40−3 OD, 20/30−2 OS 20/30 OD, 20/20−3 OS 20/50+2 OD, 20/60+1 OS 20/60+1 OD, 20/60+3 OS 20/40+2 OD, 20/20−1 OS 20/30 OD, 20/150 OS 20/30−2 OD, 20/30+2 OS 20/40−1 OD, 20/50−2 OS — 20/20−2 20/50−1 OD, 20/25 OS 9 1 6 4 4.5 4.5 (9) 4 5 (9) 7 1.5 2 22 10 19 18 −7 −4.5 +0.5 −6 +2 −18.5* −22.5 −28* −6.5 −27.5 6 −5 +12 +2 +9 20/30−2 OD, 20/30+2 OS 20/40−1 OD, 20/50−2 OS 20/60 OD, 20/50 OS 20/60−1 OU 20/30+2 OD, 20/25+1 OS 54/M 76/F 46/F 64/F 65/M 1 2 3 4 5
Methazolamide Methazolamide Methazolamide Methazolamide Methazolamide Acetazolamide Methazolamide Acetazolamide Acetazolamide† Acetazolamide Observation Observation Observation Observation Observation
Duration of Treatment (months) CMT D (mm) Treatment Baseline BCVA Age (years) at Diagnosis/Gender Patient
Table 1. Summary of Patients With MacTel Type 2 Treated With CAIs
Final BCVA
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Systemic methazolamide was prescribed for 6 patients with the nonproliferative form of MacTel Type 2. There was a very modest decrease in the cystoid cavities in some patients treated with methazolamide and a nonsignificant decrease in CMT when compared with the patients who were observed (−6.25 mm; standard deviation, ±8.73; P = 0.177; Table 2). Two of the patients were changed to acetazolamide. Among these two patients, one responded well to methazolamide and had a small additional reduction in CMT in response to acetazolamide. The other patient had no response to methazolamide but had a visible reduction in cystoid cavities and a significant decrease in CMT when changed to acetazolamide (Figure 2). Two patients were treated with oral acetazolamide as an initial therapy, one of whom had a modest decrease in CMT while the other had a significant decrease with an accompanying decrease in the cystoid cavities (Figure 3). Overall, the 4 patients treated with acetazolamide had a significant decrease in CMT when compared with tthose who were observed (−20.13 mm; standard deviation, ±10.08; P = 0.007; Table 2). When the patients treated with oral CAI were combined as a single group, there was a significant decrease in CMT when compared with those who were observed (−12.2 mm; standard deviation, ±10.97; P = 0.020; Table 2), where the decrease in thickness was largely driven by the patients treated with acetazolamide as shown above. The decrease in cystoid changes and CMT was seen within 1 month to 3 months after the initiation of the CAIs. Among the patients who responded to CAIs, we have not seen a loss or reversal of the effect, although we do not have long-term follow-up on these patients yet. Although there was a subjective improvement in vision in the majority of patients treated with oral CAIs, on average, the patients had a 1 to 2 letter improvement in BCVA, which was not significant (Table 2). The CAIs were well tolerated in our patients. One patient developed a kidney stone on methazolamide, which was attributed to dehydration and has not recurred with better hydration since. One patient’s dosage of acetazolamide was reduced to 125 mg 2 times a day because of fatigue induced by the higher dosage.
Discussion Oral CAIs seem to reduce the cystoid cavities and macular thickness on OCT associated with MacTel Type 2. Patients receiving acetazolamide had an average reduction of 20.13 mm, which was seen within 1 month to 3 months of the initiation of therapy. This is significantly more than expected for normal
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CARBONIC ANHYDRASE INHIBITORS IN MACTEL II CHEN ET AL
Fig. 1. Heidelberg Spectralis OCT from a patient with MacTel Type 2 who was observed without treatment (Table 1, Patient 10). The baseline Heidelberg Spectralis OCT demonstrates subfoveal cystlike spaces. The retinal thickness map is shown in the right (CMT = 218 mm). After 22 months of observation, there is little change in the cystic spaces or CMT (CMT = 219 mm). Images were obtained in the same meridian and registered to the original visit.
variation in sequential Spectralis OCT images, where normal eyes have a coefficient of repeatability of 2.2 mm,21 and patients with diabetic macular edema have a coefficient of repeatability of 6.84 mm.22 Acetazolamide appeared to have a more prominent effect than methazolamide, which was evidenced by a larger average decrease in CMT. In addition, of the two patients changed from methazolamide to acetazolamide for insurance reasons, one patient had a significant decrease in the CMT with near resolution of the cystoid cavities. The other patient only had a modest reduction in retinal thickness, but he previously had a reduction of −22.5 mm in CMT in response to methazolamide and therefore may not have had much room for improvement with the change to acetazolamide; in addition, he only tolerated one fourth of the typically prescribed acetazolamide dosage (500 mg 2 times a day) because of fatigue. Overall, the percentage of MacTel Type 2 patients demonstrating reduction in cystoid cavities in response to CAIs was similar to those found in the treatment of cystoid macular edema with CAIs in patients with
retinitis pigmentosa and X-linked juvenile retinoschisis.16–18,20,21 We find this an interesting observation because MacTel Type 2 patients have subtle cystoid cavities that are much less pronounced than the cystoid macular edema and thickening seen in retinitis pigmentosa and X-linked juvenile retinoschisis and therefore likely represents a different underlying pathogenesis that may also be amenable to CAIs. The mechanism by which CAIs reduce retinal thickness and cystoid spaces is uncertain. Carbonic anhydrase inhibitors are thought to increase fluid transport from the retina to the choroid by acting on the retinal pigment epithelium and/or acidification of the subretinal space.23 Additionally, CAIs may modulate membrane-bound carbonic anhydrase and reestablish their apical polarization in the retinal pigment epithelium, which may be lost from the structural or biochemical effects of macular edema. These mechanisms are thought to underlie the therapeutic effects of CAIs in retinitis pigmentosa and other disease processes.14,16,23 Although these mechanisms may be used by CAIs in their effect on cystoid change seen
Table 2. Summary of Treatment Response to CAIs CMT D ± SD Methazolamide Acetazolamide* Combined CAIs* Observation
−6.25 −20.13 −12.19 4.8
± ± ± ±
8.73 10.08† 10.97† 6.61
D in Snellen Letters ± SD 0.75 1.0 1.88 −2.4
± ± ± ±
5.47 2.12 2.6 4.1
Mean Duration, months
Number of Patients
4.75 6.63 5.81 14.2
6 4 8 5
*Includes two patients who were previously treated with methazolamide. Change in CMT and BCVA was compared with the initial CMT and BCVA before the initiation of any CAI. †P , 0.05. CMT, central macular thickness averaged between both eyes; SD, standard deviation.
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Fig. 2. Heidelberg Spectralis OCT from a patient with MacTel Type 2 treated with methazolamide and acetazolamide (Table 1, Patient 5). Baseline OCT demonstrates subfoveal cystlike spaces. The retinal thickness map is shown in the right (CMT = 283 mm). After 4 months of treatment with methazolamide, there is no change in the cystic spaces or macular thickness (CMT = 285 mm). Additionally, after 4 months of treatment with acetazolamide, there is a decrease in the cystic spaces and macular thickness (CMT = 264 mm). Images were obtained in the same meridian and registered to the original visit.
in MacTel Type 2, it has been speculated that the spaces seen on OCT in MacTel Type 2 may represent tissue loss from retinal degeneration, specifically because of the dysfunction or loss of Muller cells3,4
Fig. 3. Heidelberg Spectralis OCT from a patient with MacTel Type 2 treated with acetazolamide (Table 1, Patient 8). The baseline Heidelberg Spectralis OCT demonstrates subfoveal cystlike spaces. The retinal thickness map is shown in the right (CMT = 311 mm). After 3 months of treatment with acetazolamide, there is a decrease in the cystic spaces and macular thickness (CMT = 279 mm). Images were obtained in the same meridian and registered to the original visit.
rather than fluid-filled cysts. Therefore, CAIs in MacTel Type 2 may have a different mechanism of action in improving the form and structure seen in these patients. Because Muller cells have been shown to have
CARBONIC ANHYDRASE INHIBITORS IN MACTEL II CHEN ET AL
high concentrations of carbonic anhydrase,24 CAIs may have their effect in patients with MacTel Type 2 by acting on the few remaining functional Muller cells rather than on retinal pigment epithelium. Oral CAIs are not the only treatment shown to reduce the retinal thickness in patients with MacTel Type 2. A prospective study using ranibizumab to treat nonproliferative MacTel Type 2 also demonstrated a significant decrease in macular thickness.10 However, the retinal thickness returned to baseline within 3 months to 5 months after the cessation of ranibizumab; the authors concluded that ranibizumab was not an effective treatment for nonproliferative MacTel Type 2 because there was no significant improvement in BCVA at 12 months. Similarly, although there was a mild subjective improvement in many of our patients, there was no significant improvement in BCVA in response to CAIs. However, it is possible that there could be long-term benefit in decreasing the cystoid spaces and macular thickness in these patients. The risk of monthly ranibizumab does not allow this to be tested, but relatively well-tolerated CAIs may allow us to address the possibility that decrease in the cystoid spaces and reduction in macular thickness could be protective in the long term. This is important because the natural course of MacTel Type 2 results in significant vision loss over time.2 In this retrospective study, the treatment results compare favorably against the 5 untreated patients with MacTel Type 2. No improvement in visual acuity or macular cystoid spaces was found in the patients who were observed. Stability in macular thickness and visual acuity in eyes without treatment was also observed in a study by Charbel Issa et al,10 where the fellow control eye of 10 patients receiving monthly injections of ranibizumab in the contralateral eye had an average decrease of −2 mm in CMT and a +3.5 letter improvement in BCVA over 1 year, which were both not significant. In summary, our study demonstrates that the offlabel use of CAIs may be effective in decreasing the cystic spaces and reducing macular thickness associated with MacTel Type 2. Side effects were minimal with adequate hydration of patients and reduction in dose for those with fatigue. Limitations of our study include its retrospective nature and small sample size, and thus, our results must be considered preliminary. Although we cannot presently advocate the routine use of oral CAIs for nonproliferative MacTel Type 2, there are no treatments for this disease, and thus, we believe that prospective studies with larger numbers of patients is warranted to fully elucidate the efficacy of CAIs in the treatment of this vision-threatening condition.
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1406 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 20. Murdoch IE, Morris SS, Cousens SN. People and eyes: statistical approaches in ophthalmology. Br J Ophthalmol 1998;82:971–973. 21. Wolf-Schnurrbusch UE, Ceklic L, Brinkmann CK, et al. Macular thickness measurements in healthy eyes using six different optical coherence tomography instruments. Invest Ophthalmol Vis Sci 2009;50:3432–3437. 22. Sohn EH, Chen JJ, Lee K, et al. Reproducibility of diabetic macular edema estimates from SD-OCT is affected by the
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