CLINICAL FEATURES AND INCIDENCE RATE OF OCULAR COMPLICATIONS IN PUNCTATE INNER CHOROIDOPATHY THERESA G. LEUNG, MD,* AHMADREZA MORADI, MD,* DIANNA LIU, MD,* QUAN D. NGUYEN, MD,†‡ JAMES P. DUNN, MD,* BRYN BURKHOLDER, MD,* NICHOLAS J. BUTLER, MD,* TRUCIAN OSTHEIMER, MD,* JENNIFER E. THORNE, MD, PHD*§ Purpose: To study the clinical features and incidence rate of ocular complications in patients with punctate inner choroidopathy. Methods: This is a retrospective cohort study conducted in a single-center academic practice setting. Patients diagnosed with punctate inner choroidopathy at the Wilmer Eye Institute, Johns Hopkins University from 1984 to 2012 were identified. Demographics and clinical features including the presence of choroidal neovascularization (CNV) and structural complications were collected. Main outcome measures, including visual impairment and incidence rate of ocular complications, were analyzed. Results: Thirty-one patients (59 eyes) were included in the study. Follow-up data were available for 24 patients (47 eyes) with a mean follow-up time of 3.4 years (range, 2 months to 8.7 years). In the affected eyes with follow-up, the incidence rate of visual impairment to 20/50 or worse was 0.06 per eye-year (EY) (95% confidence interval, 0.022/EY–0.114/EY). The incidence rate of visual loss to 20/200 or worse was 0.006/EY (95% confidence interval, 0.0001/EY–0.034/EY). Thirty-six eyes (77%) had an ultimate visual acuity of 20/40 or better. All of the 13 patients with more than $3 years of follow-up had a visual acuity of $20/40 in at least 1 eye at 3 years after presentation. Two thirds of the follow-up patients (67%) on immunomodulatory drug therapy did not have new or recurrent CNV. However, this was not a statistically significant difference. Three eyes with follow-up had recurrence of CNV for an incidence rate of 0.04/EY (95% confidence interval, 0.008/EY–0.12/EY). Two eyes developed new CNV during follow-up for an incidence rate of 0.02/EY (95% confidence interval, 0.002/EY–0.066/EY). Conclusion: The visual prognosis in most cases of punctate inner choroidopathy is very good. The incidence rate of new CNV and recurrent CNV was 0.02/EY and 0.04/EY, respectively. RETINA 34:1666–1674, 2014
P
unctate inner choroidopathy (PIC) is a rare ocular inflammatory syndrome characterized by punctate yellow-white lesions (100–300 mm) in the posterior pole at the level of the inner choroid and retinal pigment epithelium.1–4 Classically thought to affect healthy young myopic women, PIC is predominantly a bilateral disease. Watzke et al1 first described this entity in 1984 with a series of 10 female patients who presented with blurred vision, photopsia, and paracentral scotomas with multiple small, discrete, yellow-white lesions associated with serous retinal detachments and choroidal neovascularization (CNV). Punctate inner choroidopathy is classified as one of the “white dot syndromes,” a spectrum of clinically
diagnosed uveitides that include multifocal choroiditis with panuveitis and birdshot chorioretinitis among others. However, there is debate among experts whether PIC and multifocal choroiditis with panuveitis represent two distinct disorders or whether they represent the same morphologic disease along a clinical spectrum.5 Punctate inner choroidopathy lesions are mostly limited to the posterior pole and are typically smaller than those lesions observed with multifocal choroiditis with panuveitis. The absence of intraocular inflammation also may distinguish PIC from multifocal choroiditis.1,2,4 The main ocular complication resulting in visual loss in patients with PIC is the development of CNV and subretinal fibrosis.1–4,6–8 1666
INCIDENCE RATE OF COMPLICATIONS IN PIC LEUNG ET AL
This retrospective cohort study describes the demographics, clinical features, and incidence rates of ocular complications in a series of patients with PIC evaluated at our institution.
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is limited. Interferon-gamma release assays or the QuantiFERON-TB Gold test was performed based on the history of exposure or the risk factors for exposure. Data Collection
Methods Study Population A retrospective review of medical records was performed on all patients diagnosed with PIC seen in the Divisions of Ocular Immunology and Retina at the Wilmer Eye Institute in Baltimore, MD, from 1984 to 2012. This study was conducted with the approval of the Johns Hopkins University School of Medicine Institutional Review Board and in accordance with the principles of the Declaration of Helsinki. Clinical records and photographs were reviewed, and the diagnosis of PIC was made based on the clinical presentation of multiple yellow-white punctate lesions ,300 mm in size in the posterior pole with minimal to no vitritis. Exclusion criteria included patients with larger lesions (.300 mm), multiple lesions outside of the posterior pole, and/ or anterior, intermediate panuveitis, which we classified as multifocal choroiditis or multifocal choroiditis with panuveitis.9 No patients who met the inclusion criteria had to be excluded later during the follow-up. To exclude other causes of posterior uveitis secondary to sarcoidosis, syphilis, or Lyme disease, all patients had a laboratory workup and imaging studies, which included a chest x-ray, fluorescent treponemal antibody absorption test, rapid plasma regain, and Borrelia burgdorferi antibody test. Additional diagnostic testing was performed as clinically indicated. In our experience, chest x-ray is a more effective screening tool for sarcoidosis. We did not routinely estimate serum angiotensin I–converting enzyme (ACE) or lysozyme level in PIC patients because the diagnostic value for sarcoidosis From the *Division of Ocular Immunology, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland; †Department of Ophthalmology and Visual Sciences, Division of Retina, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland; ‡Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, Nebraska; and §Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland. Q. D. Nguyen is consultant for Bausch & Lomb and Santen and received grants from Genentech, Acucela, and Regeneron. J. E. Thorne is consultant for Navigant and Gilead, and received grants from Abbott, XOMA, Allergan, the Research to Prevent Blindness, and the National Health Institute). The other authors have no financial/conflicting interests to disclose. Reprint requests: Jennifer E. Thorne, MD, PhD, Division of Ocular Immunology, Department of Ophthalmology and Epidemiology, The Wilmer Eye Institute, Johns Hopkins School of Medicine, 600 North Wolfe Street, Woods Building, Rm 476, Baltimore, MD 21287; e-mail: [email protected]
Information on all patients evaluated and treated for PIC was collected retrospectively from clinical records. Demographic information collected included age, gender, and race. Medical history of autoimmune disease, family history of autoimmune disease, and history of tobacco use were documented. Clinical information collected at every visit included visual acuity, intraocular pressure, slit-lamp examination, the grade of inflammation in the anterior chamber and in the vitreous, fundus examination, and the presence of complications in the fundus, such as CNV or cystoid macular edema.10 Results of ancillary testing, such as Humphrey visual fields, fluorescein angiography, and optical coherence tomography, were recorded when performed. Treatment data collected included the use of ophthalmic drops, the use of corticosteroids including the dose and route of administration, and the use of immunomodulatory drugs. Ocular surgeries, laser or photodynamic therapy, and intravitreal injections before presentation and during the course of followup were also documented in the database. The decision for treatment for each patient was made according to the best medical judgment, in conjunction with published guidelines.9 Data were entered into a standardized longitudinal database for subsequent statistical analysis. Because the data have been gathered over a broad time frame and the treatment modalities have changed in recent years, we compared the demographics, clinical characteristics, and ocular complications of patients in 2 groups (before and after 2005) based on the time of presentation to our clinics. Main Outcome Measures The incidence rates of loss of visual acuity and of structural ocular complications were assessed. Visual acuity outcomes included loss of visual acuity to the 20/50 or worse and the 20/200 or worse thresholds. Visual acuity was measured at each clinical visit using a Snellen or Early Treatment Diabetic Retinopathy Study chart. Refractions to determine best-corrected visual acuity were performed as clinically indicated. The incidence of structural ocular complications was also assessed. Choroidal neovascularization was diagnosed by the presence of typical findings on dilated fundoscopic examination and confirmed by fluorescein angiogram.8 Active disease was defined as the presence of new or active chorioretinal lesions and/or the development of CNV. Active disease was assessed based on
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clinical examination, CNV or leakage of lesions on fluorescein angiography, or intraretinal fluid or subretinal fluid on optical coherence tomography. The development of cystoid macular edema was defined as the presence of macular thickening as seen by clinical examination or by the presence of macular leakage on fluorescein angiogram or on optical coherence tomography. The development of new-onset cataract was defined as the presence of 1+ nuclear sclerosis, 1+ cortical change, or trace posterior subcapsular change seen on clinical examination in an eye in which no cataract had been reported on previous visits. Ocular hypertension
2014 VOLUME 34 NUMBER 8
was defined as an intraocular pressure of 22 mmHg or greater in an eye that had not had an intraocular pressure of $22 mmHg previously. Statistical Analysis All statistical analyses were performed using Stata software Version 10.0 (Stata Corp 2007 Stata Statistical Software: Release 10; StataCorp LP, College Station, TX). Demographics and clinical characteristics at presentation were tabulated for study patients and affected eyes in Tables 1 and 2, respectively. Incidence rates of
Table 1. Demographics and Clinical Characteristics of Patients With PIC at Presenting Visit
Demographics Age, years Mean ± SD Median Range Female gender, % (n) Race, % (n) White African American Asian Cigarette smoking, % (n) No Current Past History of autoimmune diseases, % (n) Family history of autoimmune diseases, % (n) Number of F/U visits Mean ± SD Range Duration of F/U, months Mean ± SD Range Clinical characteristics, % (n) Bilateral involvement Eye drop use Topical steroid use Glaucoma drops use CNV* History of CNV Active CNV at presentation Bilateral involvement More than one occurrence Cataract (unilateral or bilateral) Current oral corticosteroids use Current immunosuppressive therapy History of PDT or laser therapy History of injections Intravitreal Anti-VEGF alone (Bevacizumab) Intravitreal triamcinolone alone Bevacizumab and triamcinolone† Periocular triamcinolone alone
Total (n = 31)
No F/U (n = 7)
With F/U (n = 24)
33.19 ± 9.07 29 20–57 94 (29)
33.42 ± 8.23 36 20–44 100 (7)
33.12 ± 9.28 29 22–57 91.7 (22)
91 (28) 6 (2) 3 (1)
100 (7) 0 (0) 0 (0)
87.5 (21) 8.3 (2) 4.2 (1)
78 (24) 16 (5) 6 (2) 23 (7) 16 (5)
42.8 42.8 14.3 28.6 14.3
87.5 (21) 8.3 (2) 4.2 (1) 20.8 (5) 16.7 (4)
(3) (3) (1) (2) (1)
N/A N/A
N/A N/A
11.08 ± 6.92 1–26
N/A N/A
N/A N/A
40.95 ± 28.82 2–104
90 (28) 12.9 (4) 3.2 (1) 0 (0)
71.4 (5) 28.6 (2) 0 (0) 0 (0)
95.8 (23) 8.3 (2) 4.2 (1) 0 (0)
45.2 (14) 19.3 (6) 16 (5) 16 (5) 9.7 (3) 16 (5) 6.5 (2) 30 (9) 30 (9) 9.7 (3) 3.2 (1) 9.7 (3) 6.5 (2)
28.6 (2) 0 (0) 0 (0) 28.6 (2) 0 (0) 14.3 (1) 0 (0) 42.8 (3) 28.6 (2) 0 (0) 14.3 (1) 14.3 (1) 0 (0)
50 (12) 25 (6) 20.8 (5) 12.5 (3) 12.5 (3) 16.7 (4) 8.3 (2) 25 (6) 29.2 (7) 12.5 (3) 0 (0) 8.3 (2) 8.3 (2)
*Two patients had active CNV in one eye and a history of previous CNV in the other eye. One patient had bilateral active CNV, and two patients had a history of previous CNV in both eyes. †Triamcinolone was administered intravitreally or periocularly. AC, anterior chamber; F/U, follow-up; N/A, not applicable; PDT, photodynamic therapy; SD, standard deviation.
INCIDENCE RATE OF COMPLICATIONS IN PIC LEUNG ET AL
ocular complications were calculated as the number of events divided by the sum of the eye-years (EY) of the at-risk eyes. Kaplan–Meier analyses and 95% confidence intervals (CIs) were used to define the median time to ocular complications during the follow-up period. Regression analyses on possible confounding factors, such as immunosuppression, use of anti–vascular endothelial growth factor (VEGF) agents, and time were not performed because of the small sample size. Results Clinical Characteristics at Presentation Thirty-one patients (59 eyes) were included in the study (Table 1). Most patients had bilateral disease (90%, n = 28); only 3 cases were unilateral (10%). The majority of patients were female (94%) compared with males (6%). The mean age at presentation was 33 years (range, 20–57 years). Refractive data were available for 15 patients. The mean and median spherical equivalent were −3.71 and −4.00 sphere, respectively, with a range of plano to −8.00 sphere. Caucasians comprised 91% of patients (n = 28), followed by African Americans (6%) and Asians (3%). Approximately 23% of patients (n = 7) reported a preexisting autoimmune disease, such as hyperthyroidism, hypothyroidism, systemic lupus erythematosus, or other autoimmune condition not specified. Family history of autoimmune disease was present in 16% of patients (n = 5). One patient was receiving topical corticosteroid eye drops at the time of presentation. At the initial visit to our clinic, 16% of patients were taking oral corticosteroids (n = 5) and 6% were receiving treatment with immunosuppressive drug therapy (n = 2). Nearly half of the patients (45%, n = 14) had a history of CNV in at least 1 eye, and 19% presented with active CNV in at least 1 eye, requiring therapy at the initial visit (n = 6). Approximately one third of the patients (30%) had a history of treatment with photodynamic therapy or laser photocoagulation at initial presentation, and approximately one third of patients (30%) had previous intravitreal (corticosteroid or anti-VEGF) injections or periocular corticosteroid injections. At the time of presentation, the prevalence of visual acuity of 20/50 or worse and the prevalence of visual acuity of 20/200 or worse were 29% and 15%, respectively (Table 2). The mean duration of disease at the time of presentation was 4.3 years (range, 0–21.3 years). No eyes presented with anterior chamber reaction or posterior synechiae. Of 59 affected eyes, 1 had mild vitritis noted only at the initial examination. Macular edema was not noted in any of the eyes at presentation. Seven eyes (12%) demonstrated active CNV at presentation.
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A total of 10 eyes (17%) had received some form of intravitreal or periocular injection at the time of presentation. Three eyes received an anti-VEGF intravitreal injection alone (1.25 mg of bevacizumab); 2 eyes received intravitreal triamcinolone acetonide (4 mg) alone; 3 eyes received both intravitreal bevacizumab and triamcinolone acetonide (intravitreal or periocular); 2 eyes received periocular triamcinolone acetonide (40 mg) alone. Follow-up Data Follow-up data were available for 24 patients (47 eyes) with a mean follow-up time of 3.4 years (range, 2 months to 8.7 years). Thirty-six eyes (77%) had an ultimate visual acuity of 20/40 or better. Thirteen patients (25 eyes) had $3 years (36 months) of follow-up, and all 13 patients had at least 1 eye with a visual acuity of $20/40 (21 of 25 eyes) at 3 years after presentation. Of the 24 patients with follow-up data, 10 (42%) were started on oral corticosteroids during the clinical course for evidence of active disease (Table 3). In 13 of these 24 patients (54%), immunomodulatory drug therapy was initiated during the clinical course. Ten of 15 patients (67%) on immunomodulatory drug therapy did not have new or recurrent CNV. During follow-up, 8 eyes (17%) were treated with at least 1 anti-VEGF intravitreal injection for active disease. Three eyes received a total of one anti-VEGF intravitreal injection (bevacizumab). Three eyes received a total of two anti-VEGF intravitreal injections (bevacizumab or ranibizumab). One eye received a total of three anti-VEGF intravitreal injections (bevacizumab), and one eye received a total of five anti-VEGF intravitreal injections (bevacizumab). Intravitreal sirolimus was used in 1 eye as part of a clinical trial (a total of 3 injections given every 2 months) and intravitreal triamcinolone acetonide was used in 1 eye 3 times over the course of follow-up for a total of 3 injections. One eye received the Retisert implant (fluocinolone acetonide intravitreal implant 0.59 mg). Prevalence and Incidence of Visual Impairment and Ocular Complications The prevalence of ocular complications during followup at different time intervals is summarized in Table 4. At presentation (month = 0), 14 eyes (30%) had a visual acuity of 20/50 or worse, and 7 eyes (15%) had active CNV. At 36 months, 3 eyes (13%) had a visual acuity of 20/50 or worse, and no eyes had active CNV. Incidence rates for visual impairment and ocular complications are summarized in Table 5. In affected eyes with follow-up, the incidence rate of visual
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Table 2. Clinical Characteristics of Eyes With PIC at Presenting Visit Characteristics BCVA, logMAR equivalent Mean ± SD Range BCVA # 20/50, % (n) BCVA # 20/200, % (n) Refraction data Refraction data available for Mean spherical equivalent Median spherical equivalent Range IOP, mmHg Mean ± SD Range Duration of disease at presentation, months Mean ± SD Range Confirmed PIC diagnosis before presentation Number, % (n) Mean time of involvement, months Lag time to diagnosis at our clinic, months Mean ± SD Range AC cells AC flare Posterior synechiae Vitreous cells, % (n) Vitreous haze, % (n) Cup-to-disc ratio Mean ± SD Range Macular edema at presentation Epiretinal membrane Cataract, % (n) CNV, % (n) Active CNV History of CNV More than one occurrence Optic neuropathy History of injections, % (n) Intravitreal anti-VEGF alone (bevacizumab) Intravitreal triamcinolone alone Bevacizumab and triamcinolone* Periocular triamcinolone alone
Total (n = 59)
No F/U (n = 12)
With F/U (n = 47)
0.29 ± 0.44 −0.2 to +2.0 28.81 (17) 15.25 (9)
0.31 ± 0.33 0 to +1.0 25 (3) 8.3 (1)
0.29 ± 0.47 −0.2 to +2.0 29.78 (14) 17.02 (8)
15 patients −3.71 −4.00 Plano to −8.00
1 patient −6.25 −6.25 −6.00 to −6.50
14 patients −3.53 −3.87 Plano to −8.00
14 ± 3.07 8–23
14.33 ± 4.09 8–22
13.91 ± 2.79 8–23
51.39 ± 68.22 0–255.23
81.44 ± 94.59 0.43–255.23
44.77 ± 60.79 0–223.93
44.06 (26) 50.66
58.3 (7) 132.21
40.43 (19) −20.62
7.69 ± 27.5 0–113.87 0 0 0 1.69 (1) 1.69 (1)
0 N/A 0 0 0 0 0
9.06 ± 29.7 0–113.87 0 0 0 2.13 (1) 2.13 (1)
0.25 ± 0.13 0.1–0.75 0 0 6.87 (4)
0.22 ± 0.09 0.1–0.4 0 0 0 (0)
0.26 ± 0.14 0.1–0.75 0 0 8.5 (4)
11.86 (7) 27.12 (16) 10.16 (6) 0 16.95 (10) 5.08 (3) 3.39 (2) 5.08 (3) 3.39 (2)
0 (0) 16.7 (2) 16.7 (2) 0 25 (3) 0 (0) 16.7 (2) 8.3 (1) 0 (0)
14.89 (7) 29.79 (14) 8.5 (4) 0 14.89 (7) 6.38 (3) 0 (0) 4.25 (2) 4.25 (2)
*Triamcinolone was administered intravitreally or periocularly. AC, anterior chamber; BCVA, best-corrected visual acuity; F/U, follow-up; IOP, intraocular pressure; logMAR, logarithm of the minimum angle of resolution; PDT, photodynamic therapy; SD, standard deviation.
impairment to 20/50 or worse was 0.06 per EY (95% CI, 0.022/EY–0.114/EY). However, 71% (5 of 7) of the eyes with visual impairment to the level of 20/50 were able to improve to better than 20/50 during the followup period. In affected eyes with follow-up, the incidence rate of visual loss to 20/200 or worse was 0.006/EY (95% CI, 0.0001/EY–0.034/EY). The 1 eye with vision loss to the level of 20/200 or worse was able to improve to better than 20/200 during the follow-up period but not better than 20/50. Thirty-six eyes had an ultimate visual acuity of 20/40 or better (77%).
Three eyes had recurrence of CNV with an incidence rate of 0.04/EY (95% CI, 0.008/EY–0.119/EY). Two eyes developed new-onset CNV during the follow-up with an incidence rate of 0.02/EY (95% CI, 0.002– 0.066/EY). The incidence rate of epiretinal membrane was 0.02/EY (95% CI, 0.003/EY–0.046/EY), diagnosed in 3 eyes during the follow-up period. One of the three eyes had associated CNV. Cataracts developed in 7 eyes (incidence rate, 0.043/EY; 95% CI, 0.017/ EY–0.09/EY) with 1 eye requiring cataract surgery. The incidence of new-onset ocular hypertension was
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INCIDENCE RATE OF COMPLICATIONS IN PIC LEUNG ET AL
Table 3. Summary of Treatment Regimens Used in Patients/Eyes With PIC at Presentation and During the Follow-up Treatment
At Presentation
Start/Change During the F/U Course
Total*
16.7 (4) 8.3 (2) 4.2 (1) 0 (0) 4.2 (1)
41.6 (10) 54.2 (13) 54.2 (13)† 4.2 (1) 0 (0)
58.3 (14) 62.5 (15) 58.3 (14) 4.2 (1) 0 (0)
6.38 (3) 0 (0) 4.25 (2)
17 (8)‡ 2.1 (1)§ 0 (0)
19.2 (9) 2.1 (1) 4.25 (2)
4.25 (2) 0 (0) 0 (0)
— 2.1 (1) 2.1 (1)¶
4.25 (2) 2.1 (1) 2.1 (1)
Patients (n = 24) Oral corticosteroids, % (n) Immunomodulatory treatment, % (n) Mycophenolate mofetil, % (n) Azathioprine, % (n) Methotrexate, % (n) Eyes (n = 47) Intravitreal Anti-VEGF alone, % (n) Intravitreal triamcinolone alone, % (n) Intravitreal Anti-VEGF + intravitreal/periocular triamcinolone, % (n) Periocular triamcinolone acetonide alone, % (n) Retisert implant, % (n) Intraocular sirolimus, % (n)
*Patients/eyes on that particular treatment at presentation and continued the treatment at least for one visit during the F/U. †The patient who was receiving methotrexate at presentation was treated with mycophenolate mofetil for the rest of F/U period. ‡Three eyes received a total of one intravitreal injection of bevacizumab. Three eyes received a total of two anti-VEGF (one eye received bevacizumab and ranibizumab, others received only bevacizumab). One eye received a total of three intravitreal injections of bevacizumab, and one eye received a total of five intravitreal injections of bevacizumab. §Intravitreal triamcinolone acetonide was used in one eye three times over the course of F/U for a total of three injections. ¶Intraocular sirolimus was used in 1 eye as part of a clinical trial (every 2 months for a total of 3 injections). This eye received 5 bevacizumab injections before receiving sirolimus. F/U, follow-up.
after 2005, 2 eyes (7%) had visual impairment of 20/50 or worse, and no eyes had vision loss of 20/200 or worse. New CNV occurred in 1 eye before 2005 and 1 eye after 2005. Recurrence of CNV occurred in 3 eyes that presented after 2005.
0.03/EY (95% CI, 0.012/EY–0.075/EY), occurring in 6 eyes with 1 eye requiring glaucoma surgery. None of these 6 eyes had received an intraocular or periocular corticosteroid injection during the follow-up period. Of the 47 eyes with follow-up, 1 developed macular edema during the follow-up period and no eyes developed posterior synechiae or optic neuropathy. A comparison of ocular complications in patients who presented before and after 2005 is summarized in Table 6. Of the 19 eyes with follow-up that presented before 2005, 5 eyes (26%) had visual impairment of 20/ 50 or worse, and 1 eye (5%) had vision loss of 20/200 or worse. Of the 28 eyes with follow-up that presented
Discussion Punctate inner choroidopathy is a predominantly bilateral, multifocal chorioretinopathy characterized by small, discrete, punctate lesions in the posterior pole. The development of CNV is the most worrisome
Table 4. Prevalence of Ocular Complications in Eyes With PIC During Follow-up at Different Time Intervals
Sample size at each time point, eyes BCVA of 20/50 or worse, % (n) BCVA 20/200 or worse, % (n) Macular edema, % (n) Epiretinal membrane, % (n) Cataract, % (n) Cataracts surgery, % (n) Active CNV, % (n) Inactive CNV/scar, % (n) Ocular HTN ($22 mmHg), % (n) Glaucoma surgery, % (n) Optic neuropathy, % (n) Posterior synechiae, % (n)
M0
M6
M12
M24
M36
M60
47 29.8 (14) 17 (8) 0 (0) 0 (0) 8.5 (4) 0 (0) 14.6 (7) 29.8 (14) 2.1 (1) 0 (0) 0 (0) 0 (0)
39 25.7 (10) 10.3 (4) 0 (0) 2.6 (1) 5.1 (2) 0 (0) 5.1 (2) 38.5 (15) 5.1 (2) 0 (0) 0 (0) 0 (0)
35 20 (7) 8.6 (3) 0 (0) 0 (0) 14.3 (5) 0 (0) 5.7 (2) 40 (14) 0 (0) 0 (0) 0 (0) 0 (0)
33 21.2 (7) 9 (3) 3 (1) 3 (1) 21.2 (7) 0 (0) 3 (1) 39.4 (13) 6 (2) 3 (1) 0 (0) 0 (0)
23 13 (3) 4.3 (1) 4.3 (1) 0 (0) 21.7 (5) 0 (0) 0 (0) 43.5 (10) 0 (0) 0 (0) 0 (0) 0 (0)
9 22.2 (2) 0 (0) 0 (0) 11.1 (1) 22.2 (2) 11.1 (1) 0 (0) 22.2 (2) 11.1 (1) 0 (0) 0 (0) 0 (0)
M, month; BCVA, best-corrected visual acuity; HTN, hypertension.
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Table 5. Incidence of Outcomes in Eyes With PIC During the Follow-up Period (n = 47) Kaplan–Meier Outcome BCVA of 20/50 or worse BCVA drop to 20/200 or worse New CNV Recurrence of CNV New ocular HTN ($22 mmHg) Glaucoma surgery Cataracts develop Cataracts surgery Macular edema development ERM Posterior synechiae Optic neuropathy development
Number at Risk
Number of Event
Incidence Rate*
Poisson Exact, CI 95%
Median, months
CI 95%
33 39
7 1
0.055 0.006
0.022–0.114 0.0001–0.034
28.7 40
22.19–40.9 40–40
26 21 46
2 3 6
0.018 0.040 0.034
0.002–0.066 0.008–0.119 0.012–0.075
11.21 32.28 29.9
4.40–18.01 17.69–73.74 12.90–28.49
46 43 43 47
1 7 1 1
0.005 0.043 0.005 0.005
0.0001–0.030 0.017–0.090 0.0001–0.032 0.0001–0.030
80.66 43.2 57.6 20.06
80.66–80.66 39.12–52.35 57.6–57.6 20.06–20.06
47 47 47
3 0 0
0.016 0 0
0.003–0.046 N/A N/A
23.53 N/A N/A
16.82–30.39 N/A N/A
*Per Eye-Year. BCVA, best-corrected visual acuity; ERM, epiretinal membrane; F/U, follow-up; HTN, hypertension; N/A, not applicable.
visually debilitating complication. Our study reviewed 31 patients who were diagnosed at our clinic over a 28-year period. Follow-up data were available for 24 of 31 patients (77%). The frequency of bilateral disease in our study (90%) was similar to previously published reports of PIC.1–4,6–8 Overall, 94% of patients in our study were female, and PIC has been traditionally described as a disease affecting primarily healthy young myopic women.1–4,6,7 However, part of the historical bias in demographic data on this disease may be that female subjects are more likely than male subjects to seek medical care in general,11 and PIC can be a disease of mild or infrequent symptoms that may otherwise be ignored. Moreover, myopic patients are more likely to have eye examinations and undergo dilated ophthalmoscopy, which allows for the detection of mild or otherwise asymptomatic cases. Our data support previous reports demonstrating that the visual prognosis of most cases of PIC is very good.1–4,6,7 Of 25 eyes with at least 3 years of followup, 21 eyes (84%) had an ultimate visual acuity of 20/ 40 or better. However, ocular complications from CNV may lead to poor visual outcomes, and the frequency of CNV has been reported from 27% to 77%.1–4,6–8 In our study, 19% of patients presented with active CNV, and 45% presented with a history of CNV. We speculate that the reported rates of CNV may be collectively biased because it may be the more severely affected patients with decreased vision secondary to CNV who are seeking treatment. Accordingly, in our study, we calculated the incidence rate for ocular complications including the development of new CNV and recurrent
CNV. To the best of our knowledge, there are no other studies in which the incidence rate of ocular complications in PIC has been reported. The incidence rate of the development of new CNV was approximately 0.02/ EY, and the incidence rate of recurrent CNV in eyes with previously inactive CNV was 0.04/EY. Because of the small sample size, regression analyses on possible confounding factors, such as immunomodulatory drug therapy, use of anti-VEGF agents, and time, were not performed. These incidence rates were lower than we had expected, and it is possible that more aggressive treatment with immunomodulatory drug therapy may have contributed to the lower rates. We also divided the eyes with follow-up data to those presenting before and after 2005 because treatment modalities have evolved in recent years, and our data covers approximately 3 decades. With better imaging technology, it is possible that we are better able to detect CNV. This may account for why more cases of recurrent CNV were noted after 2005 (n = 3). Similarly, the advent of anti-VEGF and increased use of immunomodulatory drug therapy may explain why after 2005 there were less eyes with visual impairment of 20/50 or worse (n = 2) and no eyes with vision loss of 20/200 or worse. However, because of the small sample sizes, these were observed trends and not statistically significant differences. Our sample size of 31 patients and 59 eyes is still relatively large compared with several previous retrospective studies1,2,7 investigating the clinical outcomes of patients with PIC. Larger studies, such as Zhang et al,12 included 75 Chinese patients with PIC. Of 43 eyes with follow-up, 5 (12%) developed new CNV.
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INCIDENCE RATE OF COMPLICATIONS IN PIC LEUNG ET AL
Table 6. Comparison of Demographics and Clinical Characteristics of Eyes With PIC Presented to Our Clinics Before and After 2005 Characteristics Age, years Mean ± SD Range Female gender, % (n) Race, % (n) White African American Asian Cigarette smoking, % (n) No Current Past History of IMT before presentation, % (n)
Before 2005 n = 27
After 2005 n = 32
30.40 ± 8.00 20–45 93 (25)
35.93 ± 9.33 22–57 94 (30)
78 (21) 15 (4) 7 (2)
100 (32) 0 (0) 0 (0)
74 (20) 26 (7) 0 (0) 7 (2)
81 (26) 6 (2) 13 (4) 6 (2)
Eyes With F/U
Duration of F/U, months Mean ± SD Range Number of F/U visits Mean ± SD Range Ocular complications VA drop to 20/50 or worse, n VA drop to 20/200 or worse, n New CNV Recurrence of CNV New ocular HTN ($22 mmHg) New cataracts development Cataracts surgery Macular edema development New ERM development
n = 19
n = 28
52.52 ± 34.04 2–104
31.1 ± 19.15 3–69
12.26 ± 8.46 3–26
10.28 ± 5.84 1–23
5 1 1 0 3 2 1 0 3
2 0 1 3 3 5 0 1 0
ERM, epiretinal membrane; F/U, follow-up; HTN, hypertension; IMT, immunomodulatory therapy; SD, standard deviation; VA, visual acuity.
Essex et al8 reported 136 patients in their study, but the series included 53 patients (47%) with atypical PIC, as defined by larger lesions within and outside of the arcades, typically in a peripapillary pattern as seen in presumed ocular histoplasmosis syndrome. Treatment of CNV in PIC in our patients and in the literature has included the use of oral, intraocular, and periocular corticosteroids, immunomodulatory drug therapy, and anti-VEGF intravitreal injections. Local treatment of CNV in PIC also has included laser photocoagulation and photodynamic therapy,6,13–15 although in our hands, the availability of anti-VEGF therapy eliminated the need for laser photocoagulation or photodynamic therapy. Indeed, several studies have demonstrated the efficacy of intravitreal bevacizumab or ranibizumab in treating CNV in PIC.16–19 At presentation, nearly one third of the patients in our study had been administered at least one injection of intravitreal bevacizumab.
Turkcuoglu et al20 examined the frequency of active disease in eight patients before and after immunomodulatory drug therapy with mycophenolate mofetil. There was a statistically significant decrease in the rates of attack with treatment with mycophenolate mofetil. A larger retrospective cohort study of CNV in uveitides found that there was no significant difference in the incidence of CNV in patients who were treated with immunomodulatory drug therapy and those who were not; however, this study included patients with CNV associated with any type of uveitis and not only PIC.21 In our study, immunomodulatory drug therapy was initiated in more than half of the follow-up patients (n = 13), and two thirds of patients on immunomodulatory therapy did not have new or recurrent CNV. However, our sample size is not large enough to conclude on the efficacy of immunomodulatory therapy on CNV. All three cases of recurrent CNV in our study occurred in patients who had received multiple anti-VEGF intravitreal injections, oral
1674 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
corticosteroids, and immunomodulatory drug therapy, perhaps indicating aggressive forms of disease in these particular cases. Although it is not the aim of this study to evaluate the efficacy of different treatment outcomes, further longitudinal and prospective studies would be useful in this area. Other limiting factors of our study include the retrospective nature of the study, variable follow-up, classification bias, and referral bias as our institution is a tertiary referral center. The patients included in the study may represent more severe forms of disease referred to our clinic for management. However, we believe the data and conclusions gathered in this study still have application for understanding the prognosis and ocular complications associated with this disease, particularly in the referral-based setting. In summary, our data confirm that the visual prognosis in most patients with PIC is very good. The incidence rate of visual impairment of 20/50 or worse or 20/200 or worse was low. In addition, the incidence rate of new CNV and recurrent CNV in our study was much lower than expected, which may be the result of more aggressive therapy. Key words: punctate inner choroidopathy, choroidal neovascularization, intravitreal anti-VEGF. References 1. Watzke RC, Packer AJ, Folk JC, et al. Punctate inner choroidopathy. Am J Ophthalmol 1984;98:572–584. 2. Kedhar SR, Thorne JE, Wittenberg S, et al. Multifocal choroiditis with panuveitis and punctate inner choroidopathy: comparison of clinical characteristics at presentation. Retina 2007; 27:1174–1179. 3. Gerstenblith AT, Thorne JE, Sobrin L, et al. Punctate inner choroidopathy: a survey analysis of 77 persons. Ophthalmology 2007;114:1201–1204. 4. Amer R, Lois N. Punctate inner choroidopathy. Surv Ophthalmol 2011;56:36–53. 5. Essex RW, Wong J, Jampol LM, et al. Idiopathic multifocal choroiditis: a comment on present and past nomenclature. Retina 2013;33:1–4. 6. Brown J Jr, Folk JC, Reddy CV, Kimura AE. Visual prognosis of multifocal choroiditis, punctate inner choroidopathy, and the diffuse subretinal fibrosis syndrome. Ophthalmology 1996;103:1100–1105. 7. Patel KH, Birnbaum AD, Tessler HH, Goldstein DA. Presentation and outcome of patients with punctate inner choroidopathy at a tertiary referral center. Retina 2011;31:1387–1391.
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8. Essex RW, Wong J, Fraser-Bell S, et al. Punctate inner choroidopathy: clinical features and outcomes. Arch Ophthalmol 2010;128:982–987. 9. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol 2000;130:492–513. 10. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005;140: 509–516. 11. Tudiver F, Talbot Y. Why don’t men seek help? Family physicians’ perspectives on help-seeking behavior in men. J Fam Pract 1999;48:47–52. 12. Zhang X, Wen F, Zuo C, et al. Clinical features of punctate inner choroidopathy in Chinese patients. Retina 2011;31: 1680–1691. 13. Coco RM, de Souza CF, Sanabria MR. Photodynamic therapy for subfoveal and juxtafoveal choroidal neovascularization associated with punctate inner choroidopathy. Ocul Immunol Inflamm 2007;15:27–29. 14. Brouzas D, Charakidas A, Rotsos T, et al. Choroidal neovascularization due to punctate inner choroidopathy: long-term follow-up and review of literature. Clin Ophthalmol 2010;4: 871–876. 15. Chan WM, Lai TY, Lau TT, et al. Combined photodynamic therapy and intravitreal triamcinolone for choroidal neovascularization secondary to punctate inner choroidopathy or of idiopathic origin: one-year results of a prospective series. Retina 2008;28:71–80. 16. Vossmerbaeumer U, Spandau UH, V Baltz S, et al. Intravitreal bevacizumab for choroidal neovascularisation secondary to punctate inner choroidopathy. Clin Experiment Ophthalmol 2008;36:292–294. 17. Chan WM, Lai TY, Liu DT, Lam DS. Intravitreal bevacizumab (avastin) for choroidal neovascularization secondary to central serous chorioretinopathy, secondary to punctate inner choroidopathy, or of idiopathic origin. Am J Ophthalmol 2007;143: 977–983. 18. Zhang H, Liu ZL, Sun P, Gu F. Intravitreal bevacizumab as primary treatment of choroidal neovascularization secondary to punctate inner choroidopathy: results of a 1-year prospective trial. Retina 2012;32:1106–1113. 19. Rouvas A, Petrou P, Douvali M, et al. Intravitreal ranibizumab for the treatment of inflammatory choroidal neovascularization. Retina 2011;31:871–879. 20. Turkcuoglu P, Chang PY, Rentiya ZS, et al. Mycophenolate mofetil and fundus autofluorescence in the management of recurrent punctate inner choroidopathy. Ocul Immunol Inflamm 2011;19:286–292. 21. Baxter SL, Pistilli M, Pujari SS, et al. Risk of choroidal neovascularization among the uveitides. Am J Ophthalmol 2013; 156:468–477.
P
unctate inner choroidopathy (PIC) is a rare ocular inflammatory syndrome characterized by punctate yellow-white lesions (100–300 mm) in the posterior pole at the level of the inner choroid and retinal pigment epithelium.1–4 Classically thought to affect healthy young myopic women, PIC is predominantly a bilateral disease. Watzke et al1 first described this entity in 1984 with a series of 10 female patients who presented with blurred vision, photopsia, and paracentral scotomas with multiple small, discrete, yellow-white lesions associated with serous retinal detachments and choroidal neovascularization (CNV). Punctate inner choroidopathy is classified as one of the “white dot syndromes,” a spectrum of clinically
diagnosed uveitides that include multifocal choroiditis with panuveitis and birdshot chorioretinitis among others. However, there is debate among experts whether PIC and multifocal choroiditis with panuveitis represent two distinct disorders or whether they represent the same morphologic disease along a clinical spectrum.5 Punctate inner choroidopathy lesions are mostly limited to the posterior pole and are typically smaller than those lesions observed with multifocal choroiditis with panuveitis. The absence of intraocular inflammation also may distinguish PIC from multifocal choroiditis.1,2,4 The main ocular complication resulting in visual loss in patients with PIC is the development of CNV and subretinal fibrosis.1–4,6–8 1666
INCIDENCE RATE OF COMPLICATIONS IN PIC LEUNG ET AL
This retrospective cohort study describes the demographics, clinical features, and incidence rates of ocular complications in a series of patients with PIC evaluated at our institution.
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is limited. Interferon-gamma release assays or the QuantiFERON-TB Gold test was performed based on the history of exposure or the risk factors for exposure. Data Collection
Methods Study Population A retrospective review of medical records was performed on all patients diagnosed with PIC seen in the Divisions of Ocular Immunology and Retina at the Wilmer Eye Institute in Baltimore, MD, from 1984 to 2012. This study was conducted with the approval of the Johns Hopkins University School of Medicine Institutional Review Board and in accordance with the principles of the Declaration of Helsinki. Clinical records and photographs were reviewed, and the diagnosis of PIC was made based on the clinical presentation of multiple yellow-white punctate lesions ,300 mm in size in the posterior pole with minimal to no vitritis. Exclusion criteria included patients with larger lesions (.300 mm), multiple lesions outside of the posterior pole, and/ or anterior, intermediate panuveitis, which we classified as multifocal choroiditis or multifocal choroiditis with panuveitis.9 No patients who met the inclusion criteria had to be excluded later during the follow-up. To exclude other causes of posterior uveitis secondary to sarcoidosis, syphilis, or Lyme disease, all patients had a laboratory workup and imaging studies, which included a chest x-ray, fluorescent treponemal antibody absorption test, rapid plasma regain, and Borrelia burgdorferi antibody test. Additional diagnostic testing was performed as clinically indicated. In our experience, chest x-ray is a more effective screening tool for sarcoidosis. We did not routinely estimate serum angiotensin I–converting enzyme (ACE) or lysozyme level in PIC patients because the diagnostic value for sarcoidosis From the *Division of Ocular Immunology, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland; †Department of Ophthalmology and Visual Sciences, Division of Retina, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland; ‡Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, Nebraska; and §Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland. Q. D. Nguyen is consultant for Bausch & Lomb and Santen and received grants from Genentech, Acucela, and Regeneron. J. E. Thorne is consultant for Navigant and Gilead, and received grants from Abbott, XOMA, Allergan, the Research to Prevent Blindness, and the National Health Institute). The other authors have no financial/conflicting interests to disclose. Reprint requests: Jennifer E. Thorne, MD, PhD, Division of Ocular Immunology, Department of Ophthalmology and Epidemiology, The Wilmer Eye Institute, Johns Hopkins School of Medicine, 600 North Wolfe Street, Woods Building, Rm 476, Baltimore, MD 21287; e-mail: [email protected]
Information on all patients evaluated and treated for PIC was collected retrospectively from clinical records. Demographic information collected included age, gender, and race. Medical history of autoimmune disease, family history of autoimmune disease, and history of tobacco use were documented. Clinical information collected at every visit included visual acuity, intraocular pressure, slit-lamp examination, the grade of inflammation in the anterior chamber and in the vitreous, fundus examination, and the presence of complications in the fundus, such as CNV or cystoid macular edema.10 Results of ancillary testing, such as Humphrey visual fields, fluorescein angiography, and optical coherence tomography, were recorded when performed. Treatment data collected included the use of ophthalmic drops, the use of corticosteroids including the dose and route of administration, and the use of immunomodulatory drugs. Ocular surgeries, laser or photodynamic therapy, and intravitreal injections before presentation and during the course of followup were also documented in the database. The decision for treatment for each patient was made according to the best medical judgment, in conjunction with published guidelines.9 Data were entered into a standardized longitudinal database for subsequent statistical analysis. Because the data have been gathered over a broad time frame and the treatment modalities have changed in recent years, we compared the demographics, clinical characteristics, and ocular complications of patients in 2 groups (before and after 2005) based on the time of presentation to our clinics. Main Outcome Measures The incidence rates of loss of visual acuity and of structural ocular complications were assessed. Visual acuity outcomes included loss of visual acuity to the 20/50 or worse and the 20/200 or worse thresholds. Visual acuity was measured at each clinical visit using a Snellen or Early Treatment Diabetic Retinopathy Study chart. Refractions to determine best-corrected visual acuity were performed as clinically indicated. The incidence of structural ocular complications was also assessed. Choroidal neovascularization was diagnosed by the presence of typical findings on dilated fundoscopic examination and confirmed by fluorescein angiogram.8 Active disease was defined as the presence of new or active chorioretinal lesions and/or the development of CNV. Active disease was assessed based on
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clinical examination, CNV or leakage of lesions on fluorescein angiography, or intraretinal fluid or subretinal fluid on optical coherence tomography. The development of cystoid macular edema was defined as the presence of macular thickening as seen by clinical examination or by the presence of macular leakage on fluorescein angiogram or on optical coherence tomography. The development of new-onset cataract was defined as the presence of 1+ nuclear sclerosis, 1+ cortical change, or trace posterior subcapsular change seen on clinical examination in an eye in which no cataract had been reported on previous visits. Ocular hypertension
2014 VOLUME 34 NUMBER 8
was defined as an intraocular pressure of 22 mmHg or greater in an eye that had not had an intraocular pressure of $22 mmHg previously. Statistical Analysis All statistical analyses were performed using Stata software Version 10.0 (Stata Corp 2007 Stata Statistical Software: Release 10; StataCorp LP, College Station, TX). Demographics and clinical characteristics at presentation were tabulated for study patients and affected eyes in Tables 1 and 2, respectively. Incidence rates of
Table 1. Demographics and Clinical Characteristics of Patients With PIC at Presenting Visit
Demographics Age, years Mean ± SD Median Range Female gender, % (n) Race, % (n) White African American Asian Cigarette smoking, % (n) No Current Past History of autoimmune diseases, % (n) Family history of autoimmune diseases, % (n) Number of F/U visits Mean ± SD Range Duration of F/U, months Mean ± SD Range Clinical characteristics, % (n) Bilateral involvement Eye drop use Topical steroid use Glaucoma drops use CNV* History of CNV Active CNV at presentation Bilateral involvement More than one occurrence Cataract (unilateral or bilateral) Current oral corticosteroids use Current immunosuppressive therapy History of PDT or laser therapy History of injections Intravitreal Anti-VEGF alone (Bevacizumab) Intravitreal triamcinolone alone Bevacizumab and triamcinolone† Periocular triamcinolone alone
Total (n = 31)
No F/U (n = 7)
With F/U (n = 24)
33.19 ± 9.07 29 20–57 94 (29)
33.42 ± 8.23 36 20–44 100 (7)
33.12 ± 9.28 29 22–57 91.7 (22)
91 (28) 6 (2) 3 (1)
100 (7) 0 (0) 0 (0)
87.5 (21) 8.3 (2) 4.2 (1)
78 (24) 16 (5) 6 (2) 23 (7) 16 (5)
42.8 42.8 14.3 28.6 14.3
87.5 (21) 8.3 (2) 4.2 (1) 20.8 (5) 16.7 (4)
(3) (3) (1) (2) (1)
N/A N/A
N/A N/A
11.08 ± 6.92 1–26
N/A N/A
N/A N/A
40.95 ± 28.82 2–104
90 (28) 12.9 (4) 3.2 (1) 0 (0)
71.4 (5) 28.6 (2) 0 (0) 0 (0)
95.8 (23) 8.3 (2) 4.2 (1) 0 (0)
45.2 (14) 19.3 (6) 16 (5) 16 (5) 9.7 (3) 16 (5) 6.5 (2) 30 (9) 30 (9) 9.7 (3) 3.2 (1) 9.7 (3) 6.5 (2)
28.6 (2) 0 (0) 0 (0) 28.6 (2) 0 (0) 14.3 (1) 0 (0) 42.8 (3) 28.6 (2) 0 (0) 14.3 (1) 14.3 (1) 0 (0)
50 (12) 25 (6) 20.8 (5) 12.5 (3) 12.5 (3) 16.7 (4) 8.3 (2) 25 (6) 29.2 (7) 12.5 (3) 0 (0) 8.3 (2) 8.3 (2)
*Two patients had active CNV in one eye and a history of previous CNV in the other eye. One patient had bilateral active CNV, and two patients had a history of previous CNV in both eyes. †Triamcinolone was administered intravitreally or periocularly. AC, anterior chamber; F/U, follow-up; N/A, not applicable; PDT, photodynamic therapy; SD, standard deviation.
INCIDENCE RATE OF COMPLICATIONS IN PIC LEUNG ET AL
ocular complications were calculated as the number of events divided by the sum of the eye-years (EY) of the at-risk eyes. Kaplan–Meier analyses and 95% confidence intervals (CIs) were used to define the median time to ocular complications during the follow-up period. Regression analyses on possible confounding factors, such as immunosuppression, use of anti–vascular endothelial growth factor (VEGF) agents, and time were not performed because of the small sample size. Results Clinical Characteristics at Presentation Thirty-one patients (59 eyes) were included in the study (Table 1). Most patients had bilateral disease (90%, n = 28); only 3 cases were unilateral (10%). The majority of patients were female (94%) compared with males (6%). The mean age at presentation was 33 years (range, 20–57 years). Refractive data were available for 15 patients. The mean and median spherical equivalent were −3.71 and −4.00 sphere, respectively, with a range of plano to −8.00 sphere. Caucasians comprised 91% of patients (n = 28), followed by African Americans (6%) and Asians (3%). Approximately 23% of patients (n = 7) reported a preexisting autoimmune disease, such as hyperthyroidism, hypothyroidism, systemic lupus erythematosus, or other autoimmune condition not specified. Family history of autoimmune disease was present in 16% of patients (n = 5). One patient was receiving topical corticosteroid eye drops at the time of presentation. At the initial visit to our clinic, 16% of patients were taking oral corticosteroids (n = 5) and 6% were receiving treatment with immunosuppressive drug therapy (n = 2). Nearly half of the patients (45%, n = 14) had a history of CNV in at least 1 eye, and 19% presented with active CNV in at least 1 eye, requiring therapy at the initial visit (n = 6). Approximately one third of the patients (30%) had a history of treatment with photodynamic therapy or laser photocoagulation at initial presentation, and approximately one third of patients (30%) had previous intravitreal (corticosteroid or anti-VEGF) injections or periocular corticosteroid injections. At the time of presentation, the prevalence of visual acuity of 20/50 or worse and the prevalence of visual acuity of 20/200 or worse were 29% and 15%, respectively (Table 2). The mean duration of disease at the time of presentation was 4.3 years (range, 0–21.3 years). No eyes presented with anterior chamber reaction or posterior synechiae. Of 59 affected eyes, 1 had mild vitritis noted only at the initial examination. Macular edema was not noted in any of the eyes at presentation. Seven eyes (12%) demonstrated active CNV at presentation.
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A total of 10 eyes (17%) had received some form of intravitreal or periocular injection at the time of presentation. Three eyes received an anti-VEGF intravitreal injection alone (1.25 mg of bevacizumab); 2 eyes received intravitreal triamcinolone acetonide (4 mg) alone; 3 eyes received both intravitreal bevacizumab and triamcinolone acetonide (intravitreal or periocular); 2 eyes received periocular triamcinolone acetonide (40 mg) alone. Follow-up Data Follow-up data were available for 24 patients (47 eyes) with a mean follow-up time of 3.4 years (range, 2 months to 8.7 years). Thirty-six eyes (77%) had an ultimate visual acuity of 20/40 or better. Thirteen patients (25 eyes) had $3 years (36 months) of follow-up, and all 13 patients had at least 1 eye with a visual acuity of $20/40 (21 of 25 eyes) at 3 years after presentation. Of the 24 patients with follow-up data, 10 (42%) were started on oral corticosteroids during the clinical course for evidence of active disease (Table 3). In 13 of these 24 patients (54%), immunomodulatory drug therapy was initiated during the clinical course. Ten of 15 patients (67%) on immunomodulatory drug therapy did not have new or recurrent CNV. During follow-up, 8 eyes (17%) were treated with at least 1 anti-VEGF intravitreal injection for active disease. Three eyes received a total of one anti-VEGF intravitreal injection (bevacizumab). Three eyes received a total of two anti-VEGF intravitreal injections (bevacizumab or ranibizumab). One eye received a total of three anti-VEGF intravitreal injections (bevacizumab), and one eye received a total of five anti-VEGF intravitreal injections (bevacizumab). Intravitreal sirolimus was used in 1 eye as part of a clinical trial (a total of 3 injections given every 2 months) and intravitreal triamcinolone acetonide was used in 1 eye 3 times over the course of follow-up for a total of 3 injections. One eye received the Retisert implant (fluocinolone acetonide intravitreal implant 0.59 mg). Prevalence and Incidence of Visual Impairment and Ocular Complications The prevalence of ocular complications during followup at different time intervals is summarized in Table 4. At presentation (month = 0), 14 eyes (30%) had a visual acuity of 20/50 or worse, and 7 eyes (15%) had active CNV. At 36 months, 3 eyes (13%) had a visual acuity of 20/50 or worse, and no eyes had active CNV. Incidence rates for visual impairment and ocular complications are summarized in Table 5. In affected eyes with follow-up, the incidence rate of visual
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Table 2. Clinical Characteristics of Eyes With PIC at Presenting Visit Characteristics BCVA, logMAR equivalent Mean ± SD Range BCVA # 20/50, % (n) BCVA # 20/200, % (n) Refraction data Refraction data available for Mean spherical equivalent Median spherical equivalent Range IOP, mmHg Mean ± SD Range Duration of disease at presentation, months Mean ± SD Range Confirmed PIC diagnosis before presentation Number, % (n) Mean time of involvement, months Lag time to diagnosis at our clinic, months Mean ± SD Range AC cells AC flare Posterior synechiae Vitreous cells, % (n) Vitreous haze, % (n) Cup-to-disc ratio Mean ± SD Range Macular edema at presentation Epiretinal membrane Cataract, % (n) CNV, % (n) Active CNV History of CNV More than one occurrence Optic neuropathy History of injections, % (n) Intravitreal anti-VEGF alone (bevacizumab) Intravitreal triamcinolone alone Bevacizumab and triamcinolone* Periocular triamcinolone alone
Total (n = 59)
No F/U (n = 12)
With F/U (n = 47)
0.29 ± 0.44 −0.2 to +2.0 28.81 (17) 15.25 (9)
0.31 ± 0.33 0 to +1.0 25 (3) 8.3 (1)
0.29 ± 0.47 −0.2 to +2.0 29.78 (14) 17.02 (8)
15 patients −3.71 −4.00 Plano to −8.00
1 patient −6.25 −6.25 −6.00 to −6.50
14 patients −3.53 −3.87 Plano to −8.00
14 ± 3.07 8–23
14.33 ± 4.09 8–22
13.91 ± 2.79 8–23
51.39 ± 68.22 0–255.23
81.44 ± 94.59 0.43–255.23
44.77 ± 60.79 0–223.93
44.06 (26) 50.66
58.3 (7) 132.21
40.43 (19) −20.62
7.69 ± 27.5 0–113.87 0 0 0 1.69 (1) 1.69 (1)
0 N/A 0 0 0 0 0
9.06 ± 29.7 0–113.87 0 0 0 2.13 (1) 2.13 (1)
0.25 ± 0.13 0.1–0.75 0 0 6.87 (4)
0.22 ± 0.09 0.1–0.4 0 0 0 (0)
0.26 ± 0.14 0.1–0.75 0 0 8.5 (4)
11.86 (7) 27.12 (16) 10.16 (6) 0 16.95 (10) 5.08 (3) 3.39 (2) 5.08 (3) 3.39 (2)
0 (0) 16.7 (2) 16.7 (2) 0 25 (3) 0 (0) 16.7 (2) 8.3 (1) 0 (0)
14.89 (7) 29.79 (14) 8.5 (4) 0 14.89 (7) 6.38 (3) 0 (0) 4.25 (2) 4.25 (2)
*Triamcinolone was administered intravitreally or periocularly. AC, anterior chamber; BCVA, best-corrected visual acuity; F/U, follow-up; IOP, intraocular pressure; logMAR, logarithm of the minimum angle of resolution; PDT, photodynamic therapy; SD, standard deviation.
impairment to 20/50 or worse was 0.06 per EY (95% CI, 0.022/EY–0.114/EY). However, 71% (5 of 7) of the eyes with visual impairment to the level of 20/50 were able to improve to better than 20/50 during the followup period. In affected eyes with follow-up, the incidence rate of visual loss to 20/200 or worse was 0.006/EY (95% CI, 0.0001/EY–0.034/EY). The 1 eye with vision loss to the level of 20/200 or worse was able to improve to better than 20/200 during the follow-up period but not better than 20/50. Thirty-six eyes had an ultimate visual acuity of 20/40 or better (77%).
Three eyes had recurrence of CNV with an incidence rate of 0.04/EY (95% CI, 0.008/EY–0.119/EY). Two eyes developed new-onset CNV during the follow-up with an incidence rate of 0.02/EY (95% CI, 0.002– 0.066/EY). The incidence rate of epiretinal membrane was 0.02/EY (95% CI, 0.003/EY–0.046/EY), diagnosed in 3 eyes during the follow-up period. One of the three eyes had associated CNV. Cataracts developed in 7 eyes (incidence rate, 0.043/EY; 95% CI, 0.017/ EY–0.09/EY) with 1 eye requiring cataract surgery. The incidence of new-onset ocular hypertension was
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INCIDENCE RATE OF COMPLICATIONS IN PIC LEUNG ET AL
Table 3. Summary of Treatment Regimens Used in Patients/Eyes With PIC at Presentation and During the Follow-up Treatment
At Presentation
Start/Change During the F/U Course
Total*
16.7 (4) 8.3 (2) 4.2 (1) 0 (0) 4.2 (1)
41.6 (10) 54.2 (13) 54.2 (13)† 4.2 (1) 0 (0)
58.3 (14) 62.5 (15) 58.3 (14) 4.2 (1) 0 (0)
6.38 (3) 0 (0) 4.25 (2)
17 (8)‡ 2.1 (1)§ 0 (0)
19.2 (9) 2.1 (1) 4.25 (2)
4.25 (2) 0 (0) 0 (0)
— 2.1 (1) 2.1 (1)¶
4.25 (2) 2.1 (1) 2.1 (1)
Patients (n = 24) Oral corticosteroids, % (n) Immunomodulatory treatment, % (n) Mycophenolate mofetil, % (n) Azathioprine, % (n) Methotrexate, % (n) Eyes (n = 47) Intravitreal Anti-VEGF alone, % (n) Intravitreal triamcinolone alone, % (n) Intravitreal Anti-VEGF + intravitreal/periocular triamcinolone, % (n) Periocular triamcinolone acetonide alone, % (n) Retisert implant, % (n) Intraocular sirolimus, % (n)
*Patients/eyes on that particular treatment at presentation and continued the treatment at least for one visit during the F/U. †The patient who was receiving methotrexate at presentation was treated with mycophenolate mofetil for the rest of F/U period. ‡Three eyes received a total of one intravitreal injection of bevacizumab. Three eyes received a total of two anti-VEGF (one eye received bevacizumab and ranibizumab, others received only bevacizumab). One eye received a total of three intravitreal injections of bevacizumab, and one eye received a total of five intravitreal injections of bevacizumab. §Intravitreal triamcinolone acetonide was used in one eye three times over the course of F/U for a total of three injections. ¶Intraocular sirolimus was used in 1 eye as part of a clinical trial (every 2 months for a total of 3 injections). This eye received 5 bevacizumab injections before receiving sirolimus. F/U, follow-up.
after 2005, 2 eyes (7%) had visual impairment of 20/50 or worse, and no eyes had vision loss of 20/200 or worse. New CNV occurred in 1 eye before 2005 and 1 eye after 2005. Recurrence of CNV occurred in 3 eyes that presented after 2005.
0.03/EY (95% CI, 0.012/EY–0.075/EY), occurring in 6 eyes with 1 eye requiring glaucoma surgery. None of these 6 eyes had received an intraocular or periocular corticosteroid injection during the follow-up period. Of the 47 eyes with follow-up, 1 developed macular edema during the follow-up period and no eyes developed posterior synechiae or optic neuropathy. A comparison of ocular complications in patients who presented before and after 2005 is summarized in Table 6. Of the 19 eyes with follow-up that presented before 2005, 5 eyes (26%) had visual impairment of 20/ 50 or worse, and 1 eye (5%) had vision loss of 20/200 or worse. Of the 28 eyes with follow-up that presented
Discussion Punctate inner choroidopathy is a predominantly bilateral, multifocal chorioretinopathy characterized by small, discrete, punctate lesions in the posterior pole. The development of CNV is the most worrisome
Table 4. Prevalence of Ocular Complications in Eyes With PIC During Follow-up at Different Time Intervals
Sample size at each time point, eyes BCVA of 20/50 or worse, % (n) BCVA 20/200 or worse, % (n) Macular edema, % (n) Epiretinal membrane, % (n) Cataract, % (n) Cataracts surgery, % (n) Active CNV, % (n) Inactive CNV/scar, % (n) Ocular HTN ($22 mmHg), % (n) Glaucoma surgery, % (n) Optic neuropathy, % (n) Posterior synechiae, % (n)
M0
M6
M12
M24
M36
M60
47 29.8 (14) 17 (8) 0 (0) 0 (0) 8.5 (4) 0 (0) 14.6 (7) 29.8 (14) 2.1 (1) 0 (0) 0 (0) 0 (0)
39 25.7 (10) 10.3 (4) 0 (0) 2.6 (1) 5.1 (2) 0 (0) 5.1 (2) 38.5 (15) 5.1 (2) 0 (0) 0 (0) 0 (0)
35 20 (7) 8.6 (3) 0 (0) 0 (0) 14.3 (5) 0 (0) 5.7 (2) 40 (14) 0 (0) 0 (0) 0 (0) 0 (0)
33 21.2 (7) 9 (3) 3 (1) 3 (1) 21.2 (7) 0 (0) 3 (1) 39.4 (13) 6 (2) 3 (1) 0 (0) 0 (0)
23 13 (3) 4.3 (1) 4.3 (1) 0 (0) 21.7 (5) 0 (0) 0 (0) 43.5 (10) 0 (0) 0 (0) 0 (0) 0 (0)
9 22.2 (2) 0 (0) 0 (0) 11.1 (1) 22.2 (2) 11.1 (1) 0 (0) 22.2 (2) 11.1 (1) 0 (0) 0 (0) 0 (0)
M, month; BCVA, best-corrected visual acuity; HTN, hypertension.
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2014 VOLUME 34 NUMBER 8
Table 5. Incidence of Outcomes in Eyes With PIC During the Follow-up Period (n = 47) Kaplan–Meier Outcome BCVA of 20/50 or worse BCVA drop to 20/200 or worse New CNV Recurrence of CNV New ocular HTN ($22 mmHg) Glaucoma surgery Cataracts develop Cataracts surgery Macular edema development ERM Posterior synechiae Optic neuropathy development
Number at Risk
Number of Event
Incidence Rate*
Poisson Exact, CI 95%
Median, months
CI 95%
33 39
7 1
0.055 0.006
0.022–0.114 0.0001–0.034
28.7 40
22.19–40.9 40–40
26 21 46
2 3 6
0.018 0.040 0.034
0.002–0.066 0.008–0.119 0.012–0.075
11.21 32.28 29.9
4.40–18.01 17.69–73.74 12.90–28.49
46 43 43 47
1 7 1 1
0.005 0.043 0.005 0.005
0.0001–0.030 0.017–0.090 0.0001–0.032 0.0001–0.030
80.66 43.2 57.6 20.06
80.66–80.66 39.12–52.35 57.6–57.6 20.06–20.06
47 47 47
3 0 0
0.016 0 0
0.003–0.046 N/A N/A
23.53 N/A N/A
16.82–30.39 N/A N/A
*Per Eye-Year. BCVA, best-corrected visual acuity; ERM, epiretinal membrane; F/U, follow-up; HTN, hypertension; N/A, not applicable.
visually debilitating complication. Our study reviewed 31 patients who were diagnosed at our clinic over a 28-year period. Follow-up data were available for 24 of 31 patients (77%). The frequency of bilateral disease in our study (90%) was similar to previously published reports of PIC.1–4,6–8 Overall, 94% of patients in our study were female, and PIC has been traditionally described as a disease affecting primarily healthy young myopic women.1–4,6,7 However, part of the historical bias in demographic data on this disease may be that female subjects are more likely than male subjects to seek medical care in general,11 and PIC can be a disease of mild or infrequent symptoms that may otherwise be ignored. Moreover, myopic patients are more likely to have eye examinations and undergo dilated ophthalmoscopy, which allows for the detection of mild or otherwise asymptomatic cases. Our data support previous reports demonstrating that the visual prognosis of most cases of PIC is very good.1–4,6,7 Of 25 eyes with at least 3 years of followup, 21 eyes (84%) had an ultimate visual acuity of 20/ 40 or better. However, ocular complications from CNV may lead to poor visual outcomes, and the frequency of CNV has been reported from 27% to 77%.1–4,6–8 In our study, 19% of patients presented with active CNV, and 45% presented with a history of CNV. We speculate that the reported rates of CNV may be collectively biased because it may be the more severely affected patients with decreased vision secondary to CNV who are seeking treatment. Accordingly, in our study, we calculated the incidence rate for ocular complications including the development of new CNV and recurrent
CNV. To the best of our knowledge, there are no other studies in which the incidence rate of ocular complications in PIC has been reported. The incidence rate of the development of new CNV was approximately 0.02/ EY, and the incidence rate of recurrent CNV in eyes with previously inactive CNV was 0.04/EY. Because of the small sample size, regression analyses on possible confounding factors, such as immunomodulatory drug therapy, use of anti-VEGF agents, and time, were not performed. These incidence rates were lower than we had expected, and it is possible that more aggressive treatment with immunomodulatory drug therapy may have contributed to the lower rates. We also divided the eyes with follow-up data to those presenting before and after 2005 because treatment modalities have evolved in recent years, and our data covers approximately 3 decades. With better imaging technology, it is possible that we are better able to detect CNV. This may account for why more cases of recurrent CNV were noted after 2005 (n = 3). Similarly, the advent of anti-VEGF and increased use of immunomodulatory drug therapy may explain why after 2005 there were less eyes with visual impairment of 20/50 or worse (n = 2) and no eyes with vision loss of 20/200 or worse. However, because of the small sample sizes, these were observed trends and not statistically significant differences. Our sample size of 31 patients and 59 eyes is still relatively large compared with several previous retrospective studies1,2,7 investigating the clinical outcomes of patients with PIC. Larger studies, such as Zhang et al,12 included 75 Chinese patients with PIC. Of 43 eyes with follow-up, 5 (12%) developed new CNV.
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INCIDENCE RATE OF COMPLICATIONS IN PIC LEUNG ET AL
Table 6. Comparison of Demographics and Clinical Characteristics of Eyes With PIC Presented to Our Clinics Before and After 2005 Characteristics Age, years Mean ± SD Range Female gender, % (n) Race, % (n) White African American Asian Cigarette smoking, % (n) No Current Past History of IMT before presentation, % (n)
Before 2005 n = 27
After 2005 n = 32
30.40 ± 8.00 20–45 93 (25)
35.93 ± 9.33 22–57 94 (30)
78 (21) 15 (4) 7 (2)
100 (32) 0 (0) 0 (0)
74 (20) 26 (7) 0 (0) 7 (2)
81 (26) 6 (2) 13 (4) 6 (2)
Eyes With F/U
Duration of F/U, months Mean ± SD Range Number of F/U visits Mean ± SD Range Ocular complications VA drop to 20/50 or worse, n VA drop to 20/200 or worse, n New CNV Recurrence of CNV New ocular HTN ($22 mmHg) New cataracts development Cataracts surgery Macular edema development New ERM development
n = 19
n = 28
52.52 ± 34.04 2–104
31.1 ± 19.15 3–69
12.26 ± 8.46 3–26
10.28 ± 5.84 1–23
5 1 1 0 3 2 1 0 3
2 0 1 3 3 5 0 1 0
ERM, epiretinal membrane; F/U, follow-up; HTN, hypertension; IMT, immunomodulatory therapy; SD, standard deviation; VA, visual acuity.
Essex et al8 reported 136 patients in their study, but the series included 53 patients (47%) with atypical PIC, as defined by larger lesions within and outside of the arcades, typically in a peripapillary pattern as seen in presumed ocular histoplasmosis syndrome. Treatment of CNV in PIC in our patients and in the literature has included the use of oral, intraocular, and periocular corticosteroids, immunomodulatory drug therapy, and anti-VEGF intravitreal injections. Local treatment of CNV in PIC also has included laser photocoagulation and photodynamic therapy,6,13–15 although in our hands, the availability of anti-VEGF therapy eliminated the need for laser photocoagulation or photodynamic therapy. Indeed, several studies have demonstrated the efficacy of intravitreal bevacizumab or ranibizumab in treating CNV in PIC.16–19 At presentation, nearly one third of the patients in our study had been administered at least one injection of intravitreal bevacizumab.
Turkcuoglu et al20 examined the frequency of active disease in eight patients before and after immunomodulatory drug therapy with mycophenolate mofetil. There was a statistically significant decrease in the rates of attack with treatment with mycophenolate mofetil. A larger retrospective cohort study of CNV in uveitides found that there was no significant difference in the incidence of CNV in patients who were treated with immunomodulatory drug therapy and those who were not; however, this study included patients with CNV associated with any type of uveitis and not only PIC.21 In our study, immunomodulatory drug therapy was initiated in more than half of the follow-up patients (n = 13), and two thirds of patients on immunomodulatory therapy did not have new or recurrent CNV. However, our sample size is not large enough to conclude on the efficacy of immunomodulatory therapy on CNV. All three cases of recurrent CNV in our study occurred in patients who had received multiple anti-VEGF intravitreal injections, oral
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corticosteroids, and immunomodulatory drug therapy, perhaps indicating aggressive forms of disease in these particular cases. Although it is not the aim of this study to evaluate the efficacy of different treatment outcomes, further longitudinal and prospective studies would be useful in this area. Other limiting factors of our study include the retrospective nature of the study, variable follow-up, classification bias, and referral bias as our institution is a tertiary referral center. The patients included in the study may represent more severe forms of disease referred to our clinic for management. However, we believe the data and conclusions gathered in this study still have application for understanding the prognosis and ocular complications associated with this disease, particularly in the referral-based setting. In summary, our data confirm that the visual prognosis in most patients with PIC is very good. The incidence rate of visual impairment of 20/50 or worse or 20/200 or worse was low. In addition, the incidence rate of new CNV and recurrent CNV in our study was much lower than expected, which may be the result of more aggressive therapy. Key words: punctate inner choroidopathy, choroidal neovascularization, intravitreal anti-VEGF. References 1. Watzke RC, Packer AJ, Folk JC, et al. Punctate inner choroidopathy. Am J Ophthalmol 1984;98:572–584. 2. Kedhar SR, Thorne JE, Wittenberg S, et al. Multifocal choroiditis with panuveitis and punctate inner choroidopathy: comparison of clinical characteristics at presentation. Retina 2007; 27:1174–1179. 3. Gerstenblith AT, Thorne JE, Sobrin L, et al. Punctate inner choroidopathy: a survey analysis of 77 persons. Ophthalmology 2007;114:1201–1204. 4. Amer R, Lois N. Punctate inner choroidopathy. Surv Ophthalmol 2011;56:36–53. 5. Essex RW, Wong J, Jampol LM, et al. Idiopathic multifocal choroiditis: a comment on present and past nomenclature. Retina 2013;33:1–4. 6. Brown J Jr, Folk JC, Reddy CV, Kimura AE. Visual prognosis of multifocal choroiditis, punctate inner choroidopathy, and the diffuse subretinal fibrosis syndrome. Ophthalmology 1996;103:1100–1105. 7. Patel KH, Birnbaum AD, Tessler HH, Goldstein DA. Presentation and outcome of patients with punctate inner choroidopathy at a tertiary referral center. Retina 2011;31:1387–1391.
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8. Essex RW, Wong J, Fraser-Bell S, et al. Punctate inner choroidopathy: clinical features and outcomes. Arch Ophthalmol 2010;128:982–987. 9. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol 2000;130:492–513. 10. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005;140: 509–516. 11. Tudiver F, Talbot Y. Why don’t men seek help? Family physicians’ perspectives on help-seeking behavior in men. J Fam Pract 1999;48:47–52. 12. Zhang X, Wen F, Zuo C, et al. Clinical features of punctate inner choroidopathy in Chinese patients. Retina 2011;31: 1680–1691. 13. Coco RM, de Souza CF, Sanabria MR. Photodynamic therapy for subfoveal and juxtafoveal choroidal neovascularization associated with punctate inner choroidopathy. Ocul Immunol Inflamm 2007;15:27–29. 14. Brouzas D, Charakidas A, Rotsos T, et al. Choroidal neovascularization due to punctate inner choroidopathy: long-term follow-up and review of literature. Clin Ophthalmol 2010;4: 871–876. 15. Chan WM, Lai TY, Lau TT, et al. Combined photodynamic therapy and intravitreal triamcinolone for choroidal neovascularization secondary to punctate inner choroidopathy or of idiopathic origin: one-year results of a prospective series. Retina 2008;28:71–80. 16. Vossmerbaeumer U, Spandau UH, V Baltz S, et al. Intravitreal bevacizumab for choroidal neovascularisation secondary to punctate inner choroidopathy. Clin Experiment Ophthalmol 2008;36:292–294. 17. Chan WM, Lai TY, Liu DT, Lam DS. Intravitreal bevacizumab (avastin) for choroidal neovascularization secondary to central serous chorioretinopathy, secondary to punctate inner choroidopathy, or of idiopathic origin. Am J Ophthalmol 2007;143: 977–983. 18. Zhang H, Liu ZL, Sun P, Gu F. Intravitreal bevacizumab as primary treatment of choroidal neovascularization secondary to punctate inner choroidopathy: results of a 1-year prospective trial. Retina 2012;32:1106–1113. 19. Rouvas A, Petrou P, Douvali M, et al. Intravitreal ranibizumab for the treatment of inflammatory choroidal neovascularization. Retina 2011;31:871–879. 20. Turkcuoglu P, Chang PY, Rentiya ZS, et al. Mycophenolate mofetil and fundus autofluorescence in the management of recurrent punctate inner choroidopathy. Ocul Immunol Inflamm 2011;19:286–292. 21. Baxter SL, Pistilli M, Pujari SS, et al. Risk of choroidal neovascularization among the uveitides. Am J Ophthalmol 2013; 156:468–477.
