Key Multimodal Fundus Imaging Findings to Recognize Multifocal Choroiditis in Patients With Pathological Myopia

Myopia represents a major socioeconomic burden with an increasing prevalence worldwide. Pathologic myopia refers to myopic patients with structural changes in the posterior pole including different patterns of chorioretinal atrophy, choroidal neovascularization (CNV) and vitreomacular tractional diseases. Multifocal choroiditis (MFC) is one of the most frequent noninfectious posterior uveitis, and epidemiologically typically affects young myopic females. Acute and chronic chorioretinal atrophic changes are the hallmark feature of MFC, with CNV developing in almost one third of cases. Thus, differentiation of inflammatory lesions due to MFC or neurodenegerative lesions due to pathologic myopic is key in order to establish a particular prognosis, follow-up schedule, and therapeutic approach. The aim of the present manuscript is to summarize and illustrate the main multimodal imaging features of these diseases.


INTRODUCTION
Myopia is a medical condition characterized by blurred distance vision because of images of distant objects focusing in front of the retina, what is mostly due to excessive elongation of the eye. The sociosanitary impact of myopia is increasing worldwide with an estimated overall prevalence of 2.5 billion cases, comprising 10-30 % in the adult population in many countries and 80-90% in young adults in some parts or East and Southest Asia (1,2).
The term pathologic myopia is usually used to describe patients with myopia and structural changes in the posterior pole (3), including vitreoretinal tractional changes, choroidal neovascularization (CNV) and chorioretinal atrophy (2,4,5).
Focusing on chorioretinal atrophic changes related to pathologic myopica we can divide them into fundus tessellation, diffuse chorioretinal atrophy, and patchy chorioretinal atrophy (PCA). PCA can be observed as whitish well-defined lesions of various shapes and configurations, probably related to complete closure of the choriocapillaris. PCA may develop from lacquer cracks (Lc), within areas of advanced diffuse chorioretinal atrophy, and along the border of posterior staphyloma (6,7).
Idiopathic Multifocal Choroiditis (MFC) and Punctate Inner Choroidopathy share clinical, structural and prognostic insights. Thus, both terms are generally used indistinctly and a consensus to differentiate both entities remains undetermined. They represent a form of non-infectious posterior uveitis characterized by a chronic, recurrent and usually bilateral disease (8)(9)(10). Acute inflammatory lesions appear as single or multiple yellow-grayish spots that may evolve progressively into punched-out atrophic scars, with a variable degree of pigmentation. Also, MFC may eventually associate inflammatory choroidal neovascularization in about one third of cases through the follow-up (8,(11)(12)(13).
Thus, the ability of clinicians to differentiate findings suitable for pathologic myopia or MFC is key to provide an accurate prognosis and follow-up plan for patients, and thus to consider the addition of immunosuppressive therapy in cases with visual threatening atrophic and neovascular changes. The aim of the present manuscript is to summarize the key multimodal imaging findings in cases with MFC and the main helpful tips to differentiate these from those of PCA and myopic CNV.

CHORIORETINAL ATROPHIC CHANGES
Ruiz-Medrano et al recently published a simplified classification of retinal atrophic patterns associated with high myopia (2). The authors define category A0 in the absence of any particular atrophic change in the fundus examination; category A1 for cases with fundus tessellation; category A2 for cases with diffuse chorioretinal atrophy; category A3 for patients with PCA; and category A4 for cases with complete macular atrophy (Figure 1).
The differentiation of PCA due to pathologic myopia, and chorioretinal atrophic lesions due to MFC may be challenging. However, this should be carefully addressed by physicians given the relevant prognostic implications of the origin of atrophic lesions.
PCA consists in well-defined, grayish white lesion(s), mainly localized within the macular area and around the optic disk. The size may vary between one or several choroidal lobules (14). The appearance of myopic PCA lesions developed within areas of diffuse chorioretinal atrophy is usually elliptical, whereas those developed from Lc exhibit oval configurations; on the other hand, PCA related to posterior staphyloma develops along the edge of this posterior wall morphologic change (6,15,16). In stereoscopic fundus image, is possible to appreciate the excavation of the area compared to surrounding diffuse atrophy, due to the complete loss of choriocapillaris. Sometimes there is pigment clumping, especially along the margin or along large choroidal vessels that are often visible within the area of PCA. In advanced cases it is possible to observe the sclera and even the retrobulbar vessels by transparence (14). OCT reveals disruption of outer retinal layers and retinal pigment epithelium (RPE); therefore, choroidal hypertransmission is the tomographic hallmark feature of RPE atrophy. PCA appears typically hypoautofluorescent on fundus autofluorescence (FAF) images, and early hyperfluorescent (window defect) on fluorescein angiography (FA) images (14).
Mechanical fissures in the retinal pigment epithelium and Bruchs's membrane-choricapillaris complex lead to the formation of Lc; these can be observed as fine, irregular, yellowish longitudinal lines, often branching and crisscrossing located mostly on the posterior pole (radiating from the optic disc, at the papillomacular bundle, through and around the macula), but their usually difficult detection depends on their stage and the surrounding atrophy (14,17,18). Lc are usually too narrow to be appreciated on OCT, but macular choroidal thinning is frequently observed. ICGA is the best approach to detect Lc, showing linear hypofluorescence in the late phase. On FA, they are hyperfluorescent due to window defect by the atrophic overlying RPE, but the latter develops months after the onset of the rupture, being difficult to demonstrate LC at their early stages. Presumably, this fact could be explained by the leakage from surrounding normal choriocapillaris along with the yet not atrophic overlying RPE. On FAF, LC appear as hypoautofluorescent lines, but this approach has a low detection rate, maybe because of the presence of a continuous RPE-BM overlying line (19). PCA lesions enlarge with increasing age and may also coalesce with other focal atrophic areas. Enlargement of PCA lesions depend on the location and origin, with those related to posterior staphyloma growing toward the macula, and those with onset within the macular region enlarging in all directions (6,7,20).
Chorioretinal atrophy is also included in the MFC spectrum. When acute inflammatory lesions subside, they may evolve progressively into punched-out atrophic scars, with a variable degree of pigmentation (21). Their atrophic legacy seems to depend on the degree and duration of inflammation and the resilience of the RPE, retina and choroid to the inflammatory injury. Their particular size, usually smaller than one disc area, the random distribution throughout the posterior pole and the midperipheral retina, and the lack of relationship  between their location and the retinal vessels or the posterior staphyloma may be helpful to differentiate them from typical PCA and LC lesions. Also, new peripheral lesions spreading centripetally and sparing the macular area may develop with an eventual progression of the disease, leading to chorioretinal zonal or diffuse atrophy (22-24) (Figure 2). Curvilineal streaks may develop in the mid or far peripheral retina in cases with MFC, representing a hallmark feature of the disease, originally described by Nozik and Dorsch (25). This finding is commonly known as Schlaegel streaks according to the description of this author in patients with presumed ocular histoplasmosis syndrome (26). Curvilinear streaks result from coalescence of atrophic lesions along longitudinal lines (Figure 3).

INFLAMMATORY CHORIORETINAL CHANGES
MFC acute inflammatory lesions can be observed as single or multiple yellow-grayish spots (21, 22). The typical OCT signs include (21-24): transient mild thickening of the underlying choroid; multifocal abrupt elevation of the RPE layer with disruption in the apex, leading to choroidal hypertransmission of the tomographic signal; subretinal hyperreflective material with various configurations but in close topographical relationship with the RPE changes; eventual presence of posterior vitreous inflammatory cells (Figure 4). During the acute inflammatory stage of MFC, FAF images usually evidence two distinguished features: on the one hand, concrete small hypoautofluorescent   observed as hyperreflective subretinal material overlying an intact RPE layer (Figure 6). Subretinal bleeding usually are self-limited and absorb spontaneously with no need to perform any therapeutic approach.

CHOROIDAL NEOVASCULARIZATION
The early identification of early choroidal neovascularization (CNV) signs in patients with pathologic myopia or MFC is key to optimize the final visual outcome by prompting intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors. CNV represents a leading cause of significant visual impairment in patients with pathologic myopia and MFC.
Myopic and inflammatory CNV develop as type 2 neovascular lesions, growing from the choriocapillaris through an eroded RPE into the subretinal space (27). These neovascular lesions typically lead to high density subretinal exudation and intraretinal fluid. FA shows early hyperfluorescence with subsequent leakage given the vascular nature of the subretinal lesion, suitable with a predominantly classic pattern. However, inflammatory lesions in MFC may also lead to early hyperfluorescence secondary to the window defect due to the RPE erosions described.
Thus, the differentiation of neovascularization and inflammation by FA might be challenging (21). The pitchfork sign is a distinctive finding in CNV with inflammatory etiology (28), described as the presence in OCT structural images of multiple finger-like projections arising from the area of CNV into the outer retina (Figure 7). Optical coherence tomography angiography (OCT-A) is an essential tool to differentiate accurately between inflammation and neovascularization in cases with subretinal exudation (Figure 8) by ruling out or confirming the presence of flow signal within the structural abnormality (21, 29).

OVERLAP BETWEEN PATHOLOGIC MYOPIA AND MULTIFOCAL CHORODITIS
MFC is more common in myopic female patients. This opens the possibility to find structural fundus changes related to both the refractive condition and the inflammatory disorder. The overlap between atrophic myopic and MFC is more frequent in patients after the fifth decade of life that may develop chorioretinal atrophic changes in association with previous MFC healed lesions (Figure 9).

THERAPEUTIC APPROACH
There is a significant lack of evidence-based guidelines for the management of the inflammatory activity of MFC cases. Oral prednisone at doses >10 mg/day have been proven to decrease the risk of structural complications (30) so in the presence of vision threatening complications this approach should be considered. The response is typically rapid in terms of symptoms improvement and structural recovery of lesions (Figure 10). However, as in many other intraocular inflammations, the prolonged and repeated use of steroids is associated with a significant risk of secondary effects. Therefore, the use of immunosuppressant steroid-sparing agents should be considered in the presence of inflammatory recurrences with visual threatening. The most commonly one used is mycophenolate as mofetil (CellCept, Roche, Basel, Switzerland) or sodium (Myfortic, Novartis, Basel, Switzerland) although no randomized clinical trial has been performed (31, 32). Thus, the dosage and duration of this treatment is completely empirical, but the general reported use coincides overall in doses of 500-1,000 mg twice per day (mofetil), or 360-720 mg twice per day (sodium).
On the other hand, inflammatory and myopic CNV need intravitreal anti-VEGF drugs to induce regression of exudative  manifestations related to the neovascular process. The general consensus about the protocol to use with anti-VEGF in inflammatory CNV indicates to perform a first intravitreal treatment followed by observation afterwards. The addition of intraocular or periocular steroid injection might not be helpful to improve the response or the visual prognosis compared with monotherapy with anti-VEGF, but instead increasing the adverse events with intraocular pressure rise or cataract formation.

CONCLUSION
Atrophic or neovascular changes present in myopic patients should always include MFC as a potential underlying etiology. The number, shape and distribution of atrophic lesions makes possible to distinguish PM and MFC in a conventional fundus examination, but multimodal analysis with OCT and FAF imaging may add valuable information to perform such distinction. The sudden onset of visual loss and complaint might be related to inflammatory events, choroidal neovascularization or spontaneous subretinal hemorrhage. The present manuscript details the most relevant structural changes that OCT and FAF can highlight related to these distinct processes. The management, prognosis and follow-up schedule should be adapted to a comprehensive and thoughtful approach in patients with atrophic or neovascular lesions, considering MFC as a potential underlying diagnosis in patients with myopia.

AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.