Evaluation of the retinal, choroidal, and nerve fiber layer thickness changes in patients with toxic anterior segment syndrome

Purpose To evaluate changes in choroidal, retinal, and nerve fiber layer (NFL) thickness following toxic anterior segment syndrome (TASS). Methods Macular and peripapillary choroidal thickness was measured using enhanced depth imaging (EDI) optical coherence tomography (OCT) on the day of the diagnosis and on three follow-up exams (months 1 to 4). A similar OCT analysis of central retinal and NFL thickness was performed. Results Thirteen TASS patients were included. Average age was 72.8 ± 8.7 years. Macular choroidal thickness in the superior, subfoveal, and nasal macula in the study eye was larger than the control eye and decreased at months 2–4. This was statistically significant only for the superior macula (p = 0.004). Peripapillary choroidal thickness was larger in the study eye at baseline compared with the control eye—significantly so in the nasal (p = 0.026) and inferior (p = 0.033) locations. Peripapillary choroidal thickness peaked at the baseline or 1st month exam and decreased thereafter. Retinal thickness increased significantly with time, peaking at the 2nd month and decreasing thereafter. No changes were found in the NFL. Conclusions TASS may have a transient effect on the choroid. Changes in retinal thickness are probably a normal transient postoperative response and not a result of TASS.


Introduction
Cataract surgery is one of the most common surgeries performed worldwide, with a high rate of success. Toxic anterior segment syndrome (TASS), a term coined by Monson et al. in 1992 [1], is a postoperative complication reported in increasing numbers. It is a sterile, postoperative inflammation occurring early after anterior segment surgery, generally appearing within 12-48 h [2]. It may result in damage to various intraocular tissues.
Typically, TASS presents acutely, but rarely can have a delayed onset. Symptoms include blurry vision, discomfort, and minimal pain. Signs include eye redness, fibrin formation with or without hypopyon, inflammatory membranes, and diffuse corneal edema secondary to endothelial damage. In addition, potential damage to the iris and trabecular meshwork may occur. The inflammation is limited to the anterior segment. TASS can present sporadically or in outbreaks [3], possible causes are numerous [4], but in many of the cases the cause is not identified. The outcome of topical steroidal drops and close monitoring in the management of TASS is excellent [5]. However, severe complications, such as irreversible visual loss, permanent endothelial damage, corneal decompensation, a permanently dilated pupil, or glaucoma due to permanent damage to the trabecular meshwork, may occur [2,6].
TASS has many similarities to other postoperative inflammatory processes, such as uveitis and endophthalmitis [7,8]. However, it can be distinguished from endophthalmitis as it seems to be limited to the anterior segment [2].
In the past, choroidal thickness could not be accurately measured. Recent advancements in optical coherence tomography (OCT) with the use of enhanced depth imaging (EDI) allow more accurate evaluation of choroidal thickness in a reproducible manner, as shown in previous studies [9][10][11]. In the field of inflammatory eye diseases, this technique has been used to demonstrate changes in choroidal thickness in Vogt-Koyanagi-Harada panuveitis subjects [12]. The inflammatory process seen in TASS influences anterior uveal structures. Our aim was to investigate whether these inflammatory changes have an effect on the posterior uvea and retina and whether subtle choroidal and retinal changes, which cannot be noticed clinically, exist.

Materials and methods
This prospective study adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board (IRB) of the Tel Aviv Medical Center. Informed consent was obtained from all patients.

Participants
Thirteen eyes of 13 subjects, consecutively diagnosed with TASS following cataract surgery, were enrolled.
A diagnosis of TASS was established based on the clinical findings of a postoperative anterior chamber inflammatory response with fibrin formation in either the anterior chamber, the pupillary aperture, or just anterior to the posterior chamber intraocular lens. All subjects had no clinical evidence of posterior segment involvement (no vitreous inflammation and no acute retinal findings on a dilated fundus examination). Following a clinical diagnosis of TASS, a complete ophthalmological examination was performed including visual acuity (VA), slit-lamp examination, Goldmann applanation tonometry, and fundus examination. In addition, a baseline spectral domain OCT (SD-OCT) scan was performed.
Subjects underwent repeat biomicroscopic and SD-OCT examinations, performed on month 1 (first follow-up), month 2 (second follow-up), and a final follow-up exam performed at months 3 or 4 (third follow-up).

Spectral domain optical coherence tomography
All participants were examined using Heidelberg Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany), which achieves an axial resolution of 7 μm. The retinas of both eyes were first scanned by a horizontal high-speed raster scanning protocol of a 20°X20°quadrangular area, and central macular thickness (CMT) was obtained. Glaucoma retinal NFL protocol scan was then performed, and inferior, superior, nasal, and temporal NFL thickness measurements were recorded. In addition, in order to demonstrate choroidal thickness changes, EDI technique [10,11] was used. The choroid was scanned with 20°horizontal and vertical single crosssection EDI scans through the center of the fovea and by a circular EDI NFL scan protocol at the peripapilary region. To ensure high quality and noise reduction, the eye tracking system and averaging technique was employed. Each choroidal scan consisted of 100 averaged OCT frames. Images were converted to white on black grayscale to sharpen the contrast and allow a more accurate measurement. Choroidal thickness was measured by a single investigator, with an SD-OCT software electronic caliper. Choroidal thickness was defined as the vertical distance between the outer margin of the hyperreflective retinal pigment epithelium layer and the chorioscleral interface. Choroidal thickness was measured at five macular locations: subfoveal (an average of two subfoveal measurements-one from the horizontal and the other from the vertical cross-section) and 2.5 mm nasal, temporal, inferior, and superior to the foveal center (Fig. 1a). Similar measurements were performed in the peripapillary region in four different locations: 1.75 mm superior, temporal, inferior, and nasal to the optic disc center (Fig. 1b).
The follow-up acquisition mode, unique to this SD-OCT device, was used in all follow-up visits and automatically placed follow-up scans in precisely the same anatomic location as previous scans.
Two analyses of OCT measurements were performed: The first compared measurements of the study eye with measurements of the fellow eye, while the second analysis examined measurement changes in the study eye over time.

Choroidal thickness measurement correction
Previously published data demonstrated that choroidal thickness is influenced by axial length [13]. There is an inverse relationship between axial length and choroidal thickness. Therefore, choroidal thickness measurements were corrected according to the difference in axial length between the study and fellow eye. The correction coefficient used to compensate for axial length differences between the study and fellow eye was based on previously published literature [14]-for every 1 mm difference in axial length, choroidal thickness was reduced by 22 μm.
There was no need for age-related adjustments of choroidal thickness because all comparisons were performed either in the same eye or with the fellow eye of the same patient with no inter-patient comparisons.

Axial length
Axial length measurements were obtained from the patient's medical records (standard measurements performed prior to a cataract surgery). Measurements were performed using the IOLMaster (Carl Zeiss, Oberkochen, Germany) biometer. In cases of media opacities, interfering with the biometer measurements, axial length was measured using an A-scan 10-MHz transducer with minimal corneal compression and with the use of topical anesthesia. The recorded value was the mean of six reliable measurements.

Exclusion criteria
Exclusion criteria included cystoid macular edema of any etiology, history of endophthalmitis or other infectious process in the study eye, history of idiopathic or autoimmuneassociated uveitis in either eye, history of any posterior segment operation prior to the cataract procedure in either eye, any procedure, but for uneventful cataract surgery, patients receiving steroidal treatment (systemic or topical) prior to the cataract surgery, and media opacities preventing OCT imaging of the retina or choroid.

Statistical analysis
Data was recorded using Microsoft Excel and analyzed using SPSS version 21 (SPSS Inc., Chicago, IL, USA). Because of the small sample size, non-parametric tests were used. The Friedman test was used to compare overall difference in measurements over time (including baseline exam and the three follow-up exams) or difference between the choroidal thickness measurement locations.
Pairwise comparison of two time-point or measurement locations was analyzed by the Wilcoxon Matched-Pairs Signed-Ranks Test. All tests were two-tailed, and the threshold for statistical significance was defined as a p value <0.05.

Patients and procedures
Thirteen participants were included in the study-nine women and four men. The average age was 72.8±8.7 years (range 57-89 years). There were three left study eyes and 10 right study eyes. Two patients had bilateral epiretinal membrane with no evidence of macular edema, and one patient had a history of branch retinal vein occlusion in his control eye with no evidence of macular edema prior to or following surgery. All patients had undergone uneventful cataract extraction surgeries.
Twelve of 13 patients had normal findings at the routine 1day postoperative exam and have been diagnosed with TASS at the routine 1-week postoperative exam (mean 8.1 days). They did not seek earlier ophthalmologic consult prior to the routine 1-week exam. One patient presented at the clinic 3 days following surgery, with TASS-related complaints and was then diagnosed. All TASS cases resolved under topical steroidal treatment (in 10 of 13 eyes, a mydriatic agent was also administered). One patient had residual posterior iris synechiae, one patient developed pseudophakic CME (diagnosed 8 weeks following TASS diagnosis), and a third patient had both residual synechiae and mild pseudophakic CME (diagnosed 10 weeks following TASS diagnosis). The remaining 10 patients had no stigmata following TASS resolution. Average follow-up times (post TASS diagnosis) for the first, second, and third follow-up exams were: day 10.5±5.6, day 35±7.7, and day 95.2±23.8, accordingly. Follow-up exams included clinical evaluation and OCT exams.
Subfoveal and nasal macular choroidal thickness increased at baseline and 1st month exams and decreased at the 2nd and 3rd/4th month exams. These differences were not statistically significant (both for comparison with the control eye and comparison with baseline thickness in the study eye). Only one significant difference was shown in nasal choroidal thickness between study and controls eye at the 2nd month exam (see Fig. 2b and c). No specific pattern was shown in temporal and inferior macular thickness (see Fig. 2d and e).

Peripapillary choroidal thickness measurements
Mean peripapillary choroidal thickness±SD at the superior, temporal, nasal, and inferior locations was 181±63, 170±74, 150±,60 and 128±53 μm, respectively. All differences between peripapillary choroidal thickness locations were statistically significant (p<0.001), except for the difference between temporal and nasal measurements (p=0.081).  Table 3. Superior, temporal, nasal, and inferior baseline thickness in the study eye were 187±61, 183±84, 166±71, and 149±61 μm, respectively. These were larger than control eye measurements which were 180±66, 151±63, 143±56, and 116 ± 59 μm, respectively. The differences were Temporal, e Inferior). Only significant p-values are shown. p1, p-value for comparison with baseline measurements in the study eye. p2, p-value for comparison with fellow eye measurements statistically significant for the nasal (p=0.026) and inferior (p=0.033) locations. In the superior (187±61 μm) and nasal (166±71 μm) locations maximal thickness was at the baseline exam. In the temporal (183±84 μm) and inferior (149± 61 μm) locations maximal thickness was at the 1st month exam. These differences were not statistically significant (Table 3). Peripapillary thickness decreased thereafter (Fig. 3). Differences were not statistically significant when compared with baseline measurements in the study eye (Table 3).  Mean CMT at baseline was 288±48 μm, compared with 271± 38 μm in the control (fellow) eye. This difference of 17 μm was not statistically significant (p=0.382). Changes in CMT at the 1st, 2nd, and 3rd/4th month exams are shown in Fig. 4. Difference in CMT between the study and control eyes was statistically significant only at the 2nd month exam (a difference of 44.2 μm, p=0.036) (Fig. 4). Peripapillary NFL thickness did not change significantly in any location and showed no specific pattern (Table 4).

Discussion
In this study, we evaluated quantitatively possible changes in choroidal, retinal, and nerve fiber layer thickness following an occurrence of TASS. Few studies have used EDI-OCT to evaluate inflammatory-related changes in choroidal thickness. Published studies evaluated diseases with a known chorioretinal involvement, such as Vogt-Koyanagi-Harada [12,15]. and Multiple Evanescent White Dot Syndrome (MEWDS) [16]. We attempted to discover subtle inflammatory changes in the choroid, resulting from an acute anterior segment inflammatory process, with no clinical evidence of posterior segment involvement.
Macular choroidal thickness in the superior, subfoveal, and nasal macula did increase and was larger than the fellow eye. This was statistically significant only for the superior macula. Peripapillary choroidal thickness was larger in the study eye at baseline compared with the control eye. This difference was statistically significant for the nasal (p=0.026) and inferior (p=0.033) locations. There appeared to be a pattern in all peripapillary choroidal locations, showing a peak thickness at the baseline or 1st month exam with a decrease thereafter. However, these changes were not statistically significant. There are no previous publications examining choroidal thickness changes following TASS. Two recent publications examined changes in subfoveal choroidal thickness following uneventful cataract extraction and had conflicting results. The first paper found a significant increase in subfoveal choroidal thickness following cataract surgery in   [17]. The second paper analyzed both subfoveal and peripapillary choroidal thickness measurements and found no significant change following cataract extraction [18]. Therefore, the trend found in our study may be attributed to the TASS, but evidence in the literature regarding choroidal changes following cataract extraction are inconclusive.
Measurements of retinal CMT showed an increase in retinal thickness, peaking at the 2nd month (statistically significant) and decreasing thereafter. The changes can be attributed to a transient subclinical macular inflammatory response to the cataract procedure and not to the TASS itself. Such changes following cataract surgery have been previously demonstrated in the literature [18,24,25]. Two patients developed CME during follow-up. In both cases, CME was not evident at the 2nd month follow-up and appeared later. Therefore, it did not seem to be a major contributor to the peak CMT change seen at month 2. No significant change in NFL thickness was observed.
In conclusion, TASS may have a transient effect on the choroid. Retinal changes observed may be related to the cataract procedure itself as previously described. We acknowledge some limitations of the study, which include a small sample size and a lack of OCT measurements prior to the occurrence of TASS. Choroidal measurements were corrected for inter-eye axial length differences, but compensating for the known diurnal variation in choroidal thickness [26,27] was not feasible in the outpatient clinic setting.
The novel use of EDI-OCT enabled accurate imaging and quantification of choroidal changes. This study demonstrated that a significant inflammatory reaction involving the anterior uvea, such as TASS, might also have an effect on the posterior uvea. Further studies are needed to corroborate this. The continued use of EDI-OCT will help prove or refute theories of choroidal involvement in different pathologies and provide better understanding of disease processes and etiologies.
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