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Dr.Manpreet Brar,Dr.MANSI SHARMA,Dr.Dilraj S Grewal,Dr.Grewal S P S

Comparison of Widefield Swept Source Optical Coherence Tomography Angiography and Fundus Autofluorescence in Chorioretinitis

Introduction: Introduction of OCTA in patients with uveitis is an important step towards integrating this advanced novel technology in the routine clinical environment.[1] OCT angiography (OCTA) has emerged as a noninvasive imaging method to detect the presence or absence of blood flow signal in the retina[2] however its major drawback was its inability to visualize the peripheral retina. Further advancement in the technology has led to the emergence of widefield OCTA and its utilization has been studied in patients with diabetic retinopathy.[3,4] Also, most currently available OCTA devices use spectral domain (SD) OCT technology. Unfortunately, diseases of the choroid and choriocapillaris are difficult to study with SD technology because of RPE attenuation of the 840-nm central wavelength used in this imaging method.[5] Despite this limitation, SD-OCTA has identified flow voids in the choroid of patients with placoid chorioretinal diseases such as acute posterior multifocal placoid pigment epitheliopathy.[6]  Swept-source (SS) OCT and OCTA use a longer central wavelength (1050 nm) that provides improved signal penetration through the RPE and produces high-resolution images of the choriocapillaris and choroidal vessels.[7,8] Swept-source OCTA has the potential to provide the benefits of noninvasive vascular imaging to identify and monitor diseases that are believed to originate in the choriocapillaris. In this study, we sought to examine the usefulness of widefield SS-OCTA to detect choriocapillaris involvement in patients with chorioretinitis. Furthermore, we compared SS-OCTA with other standard imaging methods FAF to determine their relative usefulness in characterization of active and quiescent chorioretinal lesions.

Methods:

We recruited patients with clinical diagnosis of chorioretinitis at Grewal Eye Institute, Chandigarh in this prospective, cross-sectional study. Complete ophthalmic examination was performed, and uveitis was categorized according to Standardization of Uveitis Nomenclature criteria.[9]

Excluded were individuals with media opacities that precluded imaging. Also excluded from the original cohort were individuals with high myopia or hyperopia (spherical equivalent >6 diopters [D]), AMD, or diabetic retinopathy, as these conditions have been associated with choroidal abnormalities.[10-12] The study was approved by the Institutional Review Board and written informed consent was obtained from each study participant. The study adhered to the tenets of the Declaration of Helsinki for research involving human subjects.

Imaging instruments: The commercially available OCTA platform known as the swept-source (SS) OCT PLEX Elite 9000® (Carl Zeiss Meditec, Dublin, CA) uses a swept-source, tunable laser centered at 1060 nm and operating at a scan speed of 100,000 A scans per second with an axial resolution of 6.3 μm. This device utilizes optical micro angiography complex (OMAGc) algorithms to visualize microvasculature and wider OCTA scan protocols (i.e., 9 × 9 mm and 12 × 12 mm OCTA scan protocols). The OCTA can take 12 × 12 mm fields (Fig. 1) and get the wider images by five changes of visual fixation. OCT angiography images of the choriocapillaris slab (measured from 15 to 35 mm below the RPE best-fit line) were studied. Lesions were determined manually by one expert grader with fellowship training in both medical retina and uveitis (M.B) and were graded according to the level of inflammatory activity as done in the previous report [13] into 3 different groups. Type 1: hypo areas of flow void (active); Type 2: hypo areas admixed with few areas of visible choroidal vessels -stippled hyper area with hypo border (healing); Type 3: Discrete hyper areas with underlying prominent medium to large choroidal vessels visible (healed)(figure 2).

FAF: Autofluorescence was acquired with a standardized protocol using the Topcon TRC-50DX system (Topcon Medical Systems, Inc. Oakland, NJ ), set at 558 with a minimal automatic real time (ART) setting of 30. Trained retina and uveitis specialist (MB), masked to clinical data, graded the presence of autofluorescence abnormalities as previously reported by Carreno et al and others.[14,15]

Active inflammation is characterized by ill-defined predominantly hyperautofluorescent lesions (type 1). Later the lesions appear more defined with a stippled mixture of hypo-AF and hyper-AF (type 2). When the lesion evolves, inactive inflammation is characterised by FAF images of lesions that are dark i.e hypoautofluorescent revealing complete loss of fluorophores, with very sharp borders (type 3)(figure 2). Isolated FAF abnormalities smaller than 0.5 mm in diameter were considered to be not clinically relevant and were not recorded. During evaluation of the FAF and OCTA, fovea-centered image, the ETDRS macular grid was used to identify these areas: within the central 1-mm circle (termed central circle), between the 1 and 6-mm circle (termed pericentral-macular ring, superior, supernosal, nasal, inferonasal, inferior,inferotemporal,temporal,superotemporal), and extramacular (outside the 6-mm circle- superior/nasal.inferior/temporal) were identified and recorded as per each quadrant (figure 1). The obtained wide-field FAF images of each study eye were evaluated and compared with wide-field OCTA images.

Patients were diagnosed with chorioretinitis clinically and evaluation for infectious and inflammatory causes that included a careful uveitis review of systems and laboratory testing with a complete blood count, ESR, serum ACE, levels,Treponema pallidum immunoglobulin (Ig) G and M for syphilis, an interferon-G release assay for tuberculosis (QuantiFERON-TB Gold, Qiagen, Hilden, Germany), and a chest radiograph and mantoux skin test. A complete ophthalmic examination was performed, and uveitis was categorized according to Standardization of Uveitis Nomenclature criteria.[9] Initial treatment consisted of an oral tapering course of corticosteroid with concomitant immunosuppressive treatment and antibercular treatment or antibiotic treatment consistent with expert consensus recommendations.

Results: Included in the study were 31 affected eyes of 21 individuals with chorioretinitis (focal or multifocal) of various etiologies. 17 eyes had infectious cause (toxoplasmosis- 4, tuberculosis- 13) and 14 eyes had a non infectious cause. 22 eyes had multifocal chorioretinitis , 5 had focal chorioretinis and 4 had serpigenious type. Median age of participants was 38.95 years (Range 17–61 years); 6 (28.6%) were females and 15 (71.4%) were males. Clinical diagnosis of active chorioretintis was present in 10 eyes and 21 healed chorioretinitis . At the time of enrollement 8 patients were on oral steroids. 8 patients were continuing ATT.

FAF findings: An abnormal well demarcated hypoautofluorescent lesions (type 3) identified at the posterior pole were 104, 18 lesions were at the healing stage (type 2) and 31 were classified as active chorioretinal lesions (type 1). Table 1 summarizes FAF findings by pattern and region. In the retinal periphery i.e outside 6mm ETDRS circle, 117 type 3 lesions, 35 type 2 and 46 type 1 lesions were identifiable.

OCTA montage findings: An abnormal hypo flow void lesions (type 1) identified at the posterior pole were 36, 17 lesions were type 2 (healing) and 84 were classified into type 3 (inactive). Table 1 summarizes OCTA findings by pattern and region. In the retinal periphery i.e. outside 6mm ETDRS circle 34 type 1,34 type 2, 86 type 3 lesions were identifiable.

In total, number of lesions identified on fundus autofluorescence were 351 (posterior pole lesions, n=153 and peripheral lesions n=198) and on widefield OCT angiography were 291 (posterior pole lesions, n=137 and peripheral lesions n=154). Active chorioretinal lesions were comparable on two machines (n=77 ,n=70 on FAF and OCTA respectively) ;whereas healed lesions were better identified on FAF as compared to OCTA (n=221,n= 170 on FAF and OCTA respectively). Pearson correlation test was performed to find the correlation between the FAF and OCTA values. Pearson’s coefficient was found to be 0.88 for healed lesions, 0.76 for active lesions and 0.45 for healing leasions, showing positive correlation.

Discussion: FAF imaging has been extensively used to study a variety of inflammatory eye diseases, including multifocal choroiditis and panuveitis syndrome, punctate inner choroidopathy, serpiginous choroiditis, multiple evanescent white dot syndrome, and Vogt- Koyanagi-Harada disease.[16-20] In many conditions, FAF imaging reveals areas of disease activity that are more widespread than would be suspected by other imaging techniques or by clinical investigation, suggesting its potential value in the clinical assessment of patients with these disorders. Reznicek et al Compared wide-field FAF images with wide field color fundus photographs and observed in 42.3% of the study eyes a higher number or larger involvement of chorioretinal abnormalities with clearer demarcation lines seen on FAF images.[21] Chorioretinal infiltrates or scars affect the RPE layer and result in RPE alterations, including RPE atrophy or hyperpigmentation, changes that cannot always be seen to such an extent in fundus ophthalmoscopy or composite color fundus imaging wide-field composite color fundus images and hence established widefield FAF as a better non invasive tool to confirm disease activity. Hence in our present study we have used FAF widefield images to study the disease activity in chorioretinitis and we further compared it with widefield OCT angiography images. Our study suggested that OCTA could also pick up chorio retinal lesion activity in a similar manner as FAF does and hence with the advantage of wider field of view possible with the use of 12mm x 12mm OCT A montage the use of invasive testing like FFA and ICGA is not absolutely necessary in each and every case. We defined 3 different stage of clinical activity as studied on both FAF and OCTA images (figure 2). Our results on the use of OCTA were in agreement with a recent small study of 6 eyes on SS-OCTA in serpigeneuous chorioretintis.[22]

However this report suggests that FAF imaging may not be as sensitive of a noninvasive imaging marker of acute disease as OCTA. but in our study we demonstrated that FAF and OCTA images were comparable to detect active lesions, rather on FAF healed inactive lesions were better delineated and easily identified (figure 4). The most significant strength of fundus autofluorescence (FAF) imaging is the capability to assess the integrity of the RPE/photoreceptor complex.[23] One of the most important roles of the RPE is to digest, by lysosomal action, the tips of the outer segments of the photoreceptors that are phagocytosed on a daily diurnal basis. A fraction of these phagocytosed outer segments is chemically incompatible for degradation and therefore accumulates in lysosomes of the RPE as lipofuscin. Accumulation of fluorescent material in the RPE reflects the level of metabolic activity, which is largely determined by the quantity of photoreceptor outer segment turnover. Abnormally high levels of FAF in an active inflammatory lesions may be the result of an abnormal metabolic load that cannot be properly processed by the RPE. As the lesions heal, the RPE is sequentially affected following the death of photoreceptor cells, may lead to unmasking of the underlying normal RPE autofluorescence and thus healed lesions appearing hypoautofluorescent.[24,25]

Even if OCTA does not possess the capability to detect disruption of the RPE secondary to active inflammation, it may provide other meaningful information. Our findings in chorioretinits implicate the choriocapillaris as the primary site of pathologic features. Our data suggest that lesions seen on the choriocapillaris slab represent flow voids rather than blockage because of the consistent signal penetration to deeper structures in regions and the absence of shadowing on the B scans used to generate the en face slabs. These findings, in conjunction with delayed damage identified on FAF to overlying RPE, suggest an ischemic event at the level of the choriocapillaris rather than inflammatory infiltrate, which would block light signal at deeper levels. However, slow blood flow beyond detection limits could not be differentiated from complete lack of flow with current technology used in this study. Despite this, our data also suggest that the most acute lesions appear as flow voids on OCTA and may have the potential for rapid and complete resolution when treatment is instituted promptly. However, when outer retinal changes develop and particularly when RPE damage causes FAF changes, permanent scars may be more likely to develop (figure 3,4). Our patient has tubercular chorioretinitis (figure 3) and there were two active lesions identifiable on both FAF and OCTA and following treatment with steroids there is a rapid healing, but FAF showed hypofluorescent lesion suggestive of RPE damage as a result of healing. We also demonstrated that lesion starts to heal from the center as seen on FAF as hypo spot in the center and hyper active edge and also on OCT A active edge still appears flow void as compared to the central area (figure 2).

Limitations of this study include the small number of patients, limited follow-up, and limited comparison of OCTA imaging with the traditional standard of ICGA imaging. It is likely that ICGA would detect some or all of the lesions found on SS-OCTA [26,27] however, because of the risks associated with an invasive test, it was not performed. when the treating clinician at our institution believed that management would not change. Future studies should seek to validate SS-OCTA against traditional ICGA with a prospective study design. Artifacts have been identified in previous studies using SD-OCTA[28] and have the potential to influence imaging and quantitation of the deeper choroidal structures. Shadowing from overlying retinal structures could lead to false attribution of choroidal flow voids.

To summarize, our study validates use of widewield OCTA as another non diagnostic tool to identify the disease activity in chorioretinitis. By comparing findings on OCTA with data obtained from traditional FAF we are gaining essential information on the pathogenesis of various inflammatory conditions, developing more optimal and reliable followup protocols in a non-invasive way, and more accurately and objectively assessing the response to treatment in uveitis.

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