Photodiagnosis and Photodynamic Therapy (2014) 11, 565—569
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/pdpdt
Evaluation of the progression rate of atrophy lesions in punctate inner choroidopathy (PIC) based on autofluorescence analysis Rui Hua, Limin Liu, Lei Chen ∗ Department of Ophthalmology, First Hospital of China Medical University, Shenyang, China Available online 18 July 2014
KEYWORDS Punctate inner choroidopathy; Retinal pigment epithelium atrophy; Progression rate; Autofluorescence; Enhanced depth imaging optical coherence tomography
Summary Purpose: To investigate the autofluorescence (AF) characteristics of punctate inner choroidopathy (PIC) and to evaluate the progression rate of retinal pigment epithelium (RPE) atrophy lesions in PIC using confocal scanning laser ophthalmoscopy. Methods: Twenty-two eyes of 14 PIC cases and 21 eyes of 21 non-proliferative diabetic retinopathy (NPDR) cases which received retinal coagulation as a control group were enrolled in this study. Enhanced depth imaging optical coherence tomography (EDI-OCT) and AF were recorded from all patients at 18 months follow-up. The RPE atrophy areas of PIC and laser scars in NPDR were analyzed using the Region Finder software of the Heidelberg Eye Explorer. This software allows direct export of AF images from the database and semi-automated detection of atrophic areas by shadow correction, vessel detection, and selection of seed points. Results: At baseline, both hyperfluorescence and hypofluorescence were observed in the lesions of PIC eyes with a focal elevation of RPE and corresponding disruption of the ellipsoid region of the inner segment ellipsoid zone (EZ). In contrast, hypo-AF was detected when there was a lack of RPE. The mean progression rate of RPE atrophy in PIC and NPDR were 3.735 mm2 /year (0.056—0.545) and 0.127 mm2 /year (0.015—0.466), respectively. Compared with the atrophy area in the last visit, the progression rate in PIC was significantly greater than that in NPDR (Z = 5.615, P < 0.0001). Conclusions: The results of AF reflect the status of PIC and the progression rate of RPE atrophy in PIC, which can be used to predict the progress of PIC noninvasively. © 2014 Elsevier B.V. All rights reserved.
∗ Corresponding author at: Department of Ophthalmology, First Hospital of China Medical University, No. 155, Nanjingbei Street, Heping District, Shenyang, Liaoning Province, China. Tel.: +86 13840583355; fax: +86 24 83282630. E-mail address: [email protected] (L. Chen).
http://dx.doi.org/10.1016/j.pdpdt.2014.07.002 1572-1000/© 2014 Elsevier B.V. All rights reserved.
566
Introduction Punctate inner choroidopathy (PIC) is an idiopathic inflammatory disorder of the inner choroid under the retinal pigment epithelium (RPE). This disease was initially described and named by Watzke et al. in 1984 [1]. Specially, PIC was defined as the presence of multifocal, pale, and atrophic lesions at the level of the RPE and inner choroid without any sign of inflammation elsewhere in the eye [2]. Ongkosuwito et al. [3] also reported that PIC eyes, with a clinical appearance identical to that of presumed ocular histoplasmosis syndrome (POHS), are often observed in non—Histoplasma-endemic areas. It has been hypothesized that the pathogenesis of PIC was related to ‘‘common nondisease specific genes’’ predisposed to autoimmune disease in general, and the major histocompatibility complex (MHC) may also be involved [4—6]. No clear association was found between PIC and herbal supplements, intake of coffee, tea, soda, or alcohol, cigarette smoking, sexual orientation, or immediate viral exposure [7]. Recently, several studies have focused on the classification of PIC as well as choroidal neovascularization (CNV), an associated complication of CNV. Essex et al. [2] have described both typical and atypical PIC lesions, which were considered to be different spectrums of a single disease. In contrast, Zhang et al. [8] have reported a five-stageprogression of PIC, including the focal elevation of the RPE with sparing of the choroid and Bruch’s membrane (BM) [9]. These alterations corresponded with disruption of the ellipsoid region of the inner segment ellipsoid zone (EZ), formerly known as the inner segment/outer segment boundary [10]. If the lesion progresses to a hump-shaped chorioretinal nodule, or loss of the photoreceptor layer and inner choroid occurs, the atrophy lesion expands to the final stage of the disease [8]. Atrophic lesion has been observed to be stable for years or enlarge with time [11]. Similarly, Richard et al. considered the consistent appearance of elevation of RPE as active lesions. On the other hand, autofluorescence (AF) imaging showed a corresponding spot of absent AF in cases of dehiscence of RPE. In contrast, the infiltrative changes in the outer retina extended both above and laterally from the apex of the ruptured RPE elevation [12]. It has been reported that acute lesions can develop into punched-out atrophic lesions within three months [11]. These clinical features approximately divide the disease course into an active phase and an atrophic phase, primarily based on the stage of the majority of the lesions in the fundus. In addition, Olsen et al. [13] also proposed five stages in the progress of bridging CNV associated with PIC, involving the disruption and atrophy of RPE. Taken together, changes of RPE may play an important role in the duration of PIC toward the endpoint of this disease, characterized by atrophic lesions. Therefore, monitoring PRE atrophy lesions in PIC is of critical importance for predicting the prognosis of PIC. AF imaging can identify extensive histopathological changes of PIC beyond the clinically apparent spots. AF findings highlight the areas of corresponding anatomic disruption of the photoreceptor—RPE complex [14]. Acute lesions are associated with slight hyperfluorescence unless dehiscence with central absent AF is observed [12]. In addition, AF can also be employed to monitor and predict the
R. Hua et al. responses to mycophenolate mofetil therapy, which aims to decrease PIC recurrence [15]. To the best of our knowledge, the Region Finder software included in the Heidelberg Eye Explorer suite can significantly facilitate the quantification of RPE atrophy. Direct operation of this software ensures correct image scaling and alignment within a follow-up series, simultaneously excluding any transcription errors. This software has been successfully used in monitoring geographic atrophy (GA) lesions [16,17], and semi-automated AF imaging may currently represent the most precise method for the measurement of GA [16]. In the present study, we analyzed the outcomes of PIC using AF imaging and investigated the progression rate of RPE atrophy lesions in PIC using confocal scanning laser ophthalmoscopy (CSLO) and Region Finder. Our methods may prove useful to noninvasively predict the progress of PIC.
Methods Patients This retrospective study was conducted in the ophthalmology outpatient clinic of the first hospital of China Medical University based on 22 eyes of 14 PIC cases and 21 eyes of 21 non-proliferative diabetic retinopathy (NPDR) cases with non-perfusion area/diabetic macular edema (DME). The 14 PIC and 21 NPDR subjects consisted of 20 males and 15 females with a median age of 20 years (16—45 years). The mean best corrected visual acuity (BCVA) of PIC and NPDR cases was 0.6 (0.4—1.0) and 0.5 (0.3—0.8), respectively. The NPDR cases that received yellow laser retinal coagulation for more than one year were included as controls in this study. The laser retinal coagulation was conducted according to the Early Treatment Diabetic Retinopathy Study (ETDRS) standards [19], with a mean laser intensity of 210 mW (150—300 mW). Patients with systematic diseases were excluded from this study, including hypertension, systemic lupus erythematosis, anemia, and leukemia. Patients with other ocular diseases such as central retinal vein occlusion, multifocal choroiditis with panuveitis, diffuse subretinal fibrosis, multiple evanescent white dot syndrome, and pathologic myopia were also excluded from this study. In our previous study, we observed retinal structural changes and gradual expansion of laser scars without inflammation after conventional laser photocoagulation based on AF and SD-OCT [18]. Therefore, NPDR cases which received retinal coagulation were selected as a control in this study. These NPDR cases did not receive intravitreal therapy of antivascular endothelial growth factor (anti-VEGF) or steroid for the treatment of DME that disappeared when AF and EDI-OCT were conducted. PIC patients were diagnosed and classified according to previous studies [8,12], based on multiple, punctate, and yellow-white lesions and atrophic scars in the posterior pole, early hyperfluorescence of acute lesions in the FA images, the absence of vitreous cells regardless of the lesion size and the status of lesion whether (active or inactive). This study adhered to the tenets of the Declaration of Helsinki and was approved by the Medical Research Ethics Committee of First Hospital of China Medical University.
Progression rate of atrophy lesions in punctate inner choroidopathy
567
Figure 1 Results of AF analysis (A: PIC, B: NPDR post retinal coagulation) were documented in a report form including the size of individual atrophic patch with color coding. Ancillary data such as date of the analysis were also automatically displayed. In cases of multifocal atrophy, the Region Finder software was used for rapid assessment of the total size of atrophy.
Written informed consent was obtained from all participants.
Imaging acquisition AF (excitation 488 nm, emission 500—700 nm) was conducted using high-speed mode CSLO (Spectralis HRA plus OCT; Heidelberg Engineering, Heidelberg, Germany). The field of view was set at 30◦ × 30◦ and was centered on the macula. At the same time, EDI-OCT was performed at 30◦ with Eye Tracking software (Heidelberg Engineering, Heidelberg, Germany). Sections were obtained from a line scan across the RPE atrophy lesion center with 100 averaged B-scans per image and a dense volume scan encompassing an area of clustered lesions with 30 averaged B-scans per image. EDI-OCT and AF were recorded at each visit once after diagnosis for PIC patients or mean 1.2 year (1.0—1.5 year) after retinal coagulation for NPDR patients.
Image analyses Semi-automated atrophy detection and quantification were independently performed by two readers (RH and LML) using customized software (Region Finder, version 1.5.0; Heidelberg Engineering) according to the methods of S. Schmitz-Valckenberg et al. [16] The AF intensity of each picture element (pixel) is assigned a certain gray value. Given the digital image resolution of 768 × 768 pixels in a 30◦ × 30◦ frame, one pixel roughly corresponds to 11 m. After imaging all atrophic areas, grading reports for each visit were automatically generated, including time of analysis, total size of atrophy, number and sizes of spots, and disease progression rate. The follow up period was up to 18 months. PIC patients did not receive any local or
systemic therapy during or before the study period, and no eye developed CNV. Two reviewers (R.H. and L.M.L.) separately assessed all images. Discrepancies were referred to a fundus specialist (L.C.) for final determination (Fig. 1).
Statistical analyses Statistical analyses were performed using SPSS, version 16.0. The data were expressed as the median (minimum—maximum). Atrophy progression rates were calculated by subtracting the total size of atrophy at month 18 from baseline (assuming a linear growth rate). Mann—Whitney—Wilcoxon tests were used to analyze the differences of progression rate of atrophy lesions between PIC and NPDR patients. A P value
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/pdpdt
Evaluation of the progression rate of atrophy lesions in punctate inner choroidopathy (PIC) based on autofluorescence analysis Rui Hua, Limin Liu, Lei Chen ∗ Department of Ophthalmology, First Hospital of China Medical University, Shenyang, China Available online 18 July 2014
KEYWORDS Punctate inner choroidopathy; Retinal pigment epithelium atrophy; Progression rate; Autofluorescence; Enhanced depth imaging optical coherence tomography
Summary Purpose: To investigate the autofluorescence (AF) characteristics of punctate inner choroidopathy (PIC) and to evaluate the progression rate of retinal pigment epithelium (RPE) atrophy lesions in PIC using confocal scanning laser ophthalmoscopy. Methods: Twenty-two eyes of 14 PIC cases and 21 eyes of 21 non-proliferative diabetic retinopathy (NPDR) cases which received retinal coagulation as a control group were enrolled in this study. Enhanced depth imaging optical coherence tomography (EDI-OCT) and AF were recorded from all patients at 18 months follow-up. The RPE atrophy areas of PIC and laser scars in NPDR were analyzed using the Region Finder software of the Heidelberg Eye Explorer. This software allows direct export of AF images from the database and semi-automated detection of atrophic areas by shadow correction, vessel detection, and selection of seed points. Results: At baseline, both hyperfluorescence and hypofluorescence were observed in the lesions of PIC eyes with a focal elevation of RPE and corresponding disruption of the ellipsoid region of the inner segment ellipsoid zone (EZ). In contrast, hypo-AF was detected when there was a lack of RPE. The mean progression rate of RPE atrophy in PIC and NPDR were 3.735 mm2 /year (0.056—0.545) and 0.127 mm2 /year (0.015—0.466), respectively. Compared with the atrophy area in the last visit, the progression rate in PIC was significantly greater than that in NPDR (Z = 5.615, P < 0.0001). Conclusions: The results of AF reflect the status of PIC and the progression rate of RPE atrophy in PIC, which can be used to predict the progress of PIC noninvasively. © 2014 Elsevier B.V. All rights reserved.
∗ Corresponding author at: Department of Ophthalmology, First Hospital of China Medical University, No. 155, Nanjingbei Street, Heping District, Shenyang, Liaoning Province, China. Tel.: +86 13840583355; fax: +86 24 83282630. E-mail address: [email protected] (L. Chen).
http://dx.doi.org/10.1016/j.pdpdt.2014.07.002 1572-1000/© 2014 Elsevier B.V. All rights reserved.
566
Introduction Punctate inner choroidopathy (PIC) is an idiopathic inflammatory disorder of the inner choroid under the retinal pigment epithelium (RPE). This disease was initially described and named by Watzke et al. in 1984 [1]. Specially, PIC was defined as the presence of multifocal, pale, and atrophic lesions at the level of the RPE and inner choroid without any sign of inflammation elsewhere in the eye [2]. Ongkosuwito et al. [3] also reported that PIC eyes, with a clinical appearance identical to that of presumed ocular histoplasmosis syndrome (POHS), are often observed in non—Histoplasma-endemic areas. It has been hypothesized that the pathogenesis of PIC was related to ‘‘common nondisease specific genes’’ predisposed to autoimmune disease in general, and the major histocompatibility complex (MHC) may also be involved [4—6]. No clear association was found between PIC and herbal supplements, intake of coffee, tea, soda, or alcohol, cigarette smoking, sexual orientation, or immediate viral exposure [7]. Recently, several studies have focused on the classification of PIC as well as choroidal neovascularization (CNV), an associated complication of CNV. Essex et al. [2] have described both typical and atypical PIC lesions, which were considered to be different spectrums of a single disease. In contrast, Zhang et al. [8] have reported a five-stageprogression of PIC, including the focal elevation of the RPE with sparing of the choroid and Bruch’s membrane (BM) [9]. These alterations corresponded with disruption of the ellipsoid region of the inner segment ellipsoid zone (EZ), formerly known as the inner segment/outer segment boundary [10]. If the lesion progresses to a hump-shaped chorioretinal nodule, or loss of the photoreceptor layer and inner choroid occurs, the atrophy lesion expands to the final stage of the disease [8]. Atrophic lesion has been observed to be stable for years or enlarge with time [11]. Similarly, Richard et al. considered the consistent appearance of elevation of RPE as active lesions. On the other hand, autofluorescence (AF) imaging showed a corresponding spot of absent AF in cases of dehiscence of RPE. In contrast, the infiltrative changes in the outer retina extended both above and laterally from the apex of the ruptured RPE elevation [12]. It has been reported that acute lesions can develop into punched-out atrophic lesions within three months [11]. These clinical features approximately divide the disease course into an active phase and an atrophic phase, primarily based on the stage of the majority of the lesions in the fundus. In addition, Olsen et al. [13] also proposed five stages in the progress of bridging CNV associated with PIC, involving the disruption and atrophy of RPE. Taken together, changes of RPE may play an important role in the duration of PIC toward the endpoint of this disease, characterized by atrophic lesions. Therefore, monitoring PRE atrophy lesions in PIC is of critical importance for predicting the prognosis of PIC. AF imaging can identify extensive histopathological changes of PIC beyond the clinically apparent spots. AF findings highlight the areas of corresponding anatomic disruption of the photoreceptor—RPE complex [14]. Acute lesions are associated with slight hyperfluorescence unless dehiscence with central absent AF is observed [12]. In addition, AF can also be employed to monitor and predict the
R. Hua et al. responses to mycophenolate mofetil therapy, which aims to decrease PIC recurrence [15]. To the best of our knowledge, the Region Finder software included in the Heidelberg Eye Explorer suite can significantly facilitate the quantification of RPE atrophy. Direct operation of this software ensures correct image scaling and alignment within a follow-up series, simultaneously excluding any transcription errors. This software has been successfully used in monitoring geographic atrophy (GA) lesions [16,17], and semi-automated AF imaging may currently represent the most precise method for the measurement of GA [16]. In the present study, we analyzed the outcomes of PIC using AF imaging and investigated the progression rate of RPE atrophy lesions in PIC using confocal scanning laser ophthalmoscopy (CSLO) and Region Finder. Our methods may prove useful to noninvasively predict the progress of PIC.
Methods Patients This retrospective study was conducted in the ophthalmology outpatient clinic of the first hospital of China Medical University based on 22 eyes of 14 PIC cases and 21 eyes of 21 non-proliferative diabetic retinopathy (NPDR) cases with non-perfusion area/diabetic macular edema (DME). The 14 PIC and 21 NPDR subjects consisted of 20 males and 15 females with a median age of 20 years (16—45 years). The mean best corrected visual acuity (BCVA) of PIC and NPDR cases was 0.6 (0.4—1.0) and 0.5 (0.3—0.8), respectively. The NPDR cases that received yellow laser retinal coagulation for more than one year were included as controls in this study. The laser retinal coagulation was conducted according to the Early Treatment Diabetic Retinopathy Study (ETDRS) standards [19], with a mean laser intensity of 210 mW (150—300 mW). Patients with systematic diseases were excluded from this study, including hypertension, systemic lupus erythematosis, anemia, and leukemia. Patients with other ocular diseases such as central retinal vein occlusion, multifocal choroiditis with panuveitis, diffuse subretinal fibrosis, multiple evanescent white dot syndrome, and pathologic myopia were also excluded from this study. In our previous study, we observed retinal structural changes and gradual expansion of laser scars without inflammation after conventional laser photocoagulation based on AF and SD-OCT [18]. Therefore, NPDR cases which received retinal coagulation were selected as a control in this study. These NPDR cases did not receive intravitreal therapy of antivascular endothelial growth factor (anti-VEGF) or steroid for the treatment of DME that disappeared when AF and EDI-OCT were conducted. PIC patients were diagnosed and classified according to previous studies [8,12], based on multiple, punctate, and yellow-white lesions and atrophic scars in the posterior pole, early hyperfluorescence of acute lesions in the FA images, the absence of vitreous cells regardless of the lesion size and the status of lesion whether (active or inactive). This study adhered to the tenets of the Declaration of Helsinki and was approved by the Medical Research Ethics Committee of First Hospital of China Medical University.
Progression rate of atrophy lesions in punctate inner choroidopathy
567
Figure 1 Results of AF analysis (A: PIC, B: NPDR post retinal coagulation) were documented in a report form including the size of individual atrophic patch with color coding. Ancillary data such as date of the analysis were also automatically displayed. In cases of multifocal atrophy, the Region Finder software was used for rapid assessment of the total size of atrophy.
Written informed consent was obtained from all participants.
Imaging acquisition AF (excitation 488 nm, emission 500—700 nm) was conducted using high-speed mode CSLO (Spectralis HRA plus OCT; Heidelberg Engineering, Heidelberg, Germany). The field of view was set at 30◦ × 30◦ and was centered on the macula. At the same time, EDI-OCT was performed at 30◦ with Eye Tracking software (Heidelberg Engineering, Heidelberg, Germany). Sections were obtained from a line scan across the RPE atrophy lesion center with 100 averaged B-scans per image and a dense volume scan encompassing an area of clustered lesions with 30 averaged B-scans per image. EDI-OCT and AF were recorded at each visit once after diagnosis for PIC patients or mean 1.2 year (1.0—1.5 year) after retinal coagulation for NPDR patients.
Image analyses Semi-automated atrophy detection and quantification were independently performed by two readers (RH and LML) using customized software (Region Finder, version 1.5.0; Heidelberg Engineering) according to the methods of S. Schmitz-Valckenberg et al. [16] The AF intensity of each picture element (pixel) is assigned a certain gray value. Given the digital image resolution of 768 × 768 pixels in a 30◦ × 30◦ frame, one pixel roughly corresponds to 11 m. After imaging all atrophic areas, grading reports for each visit were automatically generated, including time of analysis, total size of atrophy, number and sizes of spots, and disease progression rate. The follow up period was up to 18 months. PIC patients did not receive any local or
systemic therapy during or before the study period, and no eye developed CNV. Two reviewers (R.H. and L.M.L.) separately assessed all images. Discrepancies were referred to a fundus specialist (L.C.) for final determination (Fig. 1).
Statistical analyses Statistical analyses were performed using SPSS, version 16.0. The data were expressed as the median (minimum—maximum). Atrophy progression rates were calculated by subtracting the total size of atrophy at month 18 from baseline (assuming a linear growth rate). Mann—Whitney—Wilcoxon tests were used to analyze the differences of progression rate of atrophy lesions between PIC and NPDR patients. A P value
