Gender Differences in Birdshot Chorioretinopathy and the White Dot Syndromes: Do They Exist?

Inflammatory conditions that affect the posterior pole are diverse. Specifically, birdshot chorioretinopathy and the white dot syndromes present with multiple white dots in the fundus. These diseases appear to affect similar age groups but there is question as to whether or not a difference exists between the genders. This review summarizes the current studies on birdshot chorioretinopathy and the white dot syndromes as they are related to gender, exploring the differences, if any, which may exist between prevalence, clinical presentation, and treatment response for these diseases. Though the specific etiology of these diseases remains unclear, future treatments may be guided as to how these diseases affect the sexes differently.


Introduction
The spectrum of posterior uveitis disorders is broad. There is a specific group, called the white dot syndromes, which presents with multiple white dots in the fundus. The characteristic inflammatory changes of the choroid and retina are typically yellow-white foci beneath or in the deep retina and include birdshot chorioretinopathy (BCR), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multiple evanescent white dot syndrome (MEWDS), multifocal choroiditis with panuveitis (MFC), punctate inner choroidopathy (PIC), and acute zonal occult outer retinopathy (AZOOR). These disorders represent a range of presentations, including that of demographics, age, genetic, and gender prevalence. The etiology of these diseases is not completely understood nor is the best approach for treatment of these diseases. The purpose of this review was to assess the current scientific evidence as it is related to the possible gender differences that may exist in birdshot chorioretinopathy and the white dot syndromes. the largest reviews on birdshot chorioretinopathy, there was slight female predominance (54.1%), though there have been other studies that have shown a near equal male : female ratio and some with slight male predominance [6][7][8][9][10].
In evaluating the current literature for APMPPE, data was obtained from 3 articles ( Table 2) [26][27][28]. In PubMed, the term "acute posterior multifocal placoid pigment epitheliopathy, " using all or parts of the term, brought up 205 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those in which data was repeated, 3 reports remained. None of the reports revealed female predominance, ranging from 45.5 to 50%. When all patients from these articles were considered ( = 405), 185 patients (46%) were female. The mean of the average age was 27.1 years old, with a range from 26.2 to 28.6 years old.

MEWDS. MEWDS, first described by Jampol et al.,
presents with numerous small, discrete white lesions in the deep retina or level of the RPE and appears in the posterior pole and extends to the midperiphery [29]. Classically, the fluorescein demonstrates wreath-like lesions and granular appearance to the fovea ( Figure 3). Though usually unilateral in young, myopic women ages 20 to 45 years old, there have been bilateral cases described [30]. A preceding viral illness has been reported in approximately 1/3 of cases, and though the cause is unknown, a viral etiology has been suggested. This disease usually resolves spontaneously.
In evaluating the current literature for MEWDS, data was obtained from 3 articles (Table 3) [13,31,32]. In PubMed, the term "multifocal evanescent white dot syndrome, " using all or parts of the term, brought up 151 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those in which data was repeated, 3 reports remained. Two of the three reports revealed female predominance, ranging from 50 to 91%.  When all patients from these articles were considered ( = 77), 57 patients (74%) were female. The mean of the average age was 28.7 years old, with a range from 28-29.9 years old.

MFC.
MFC, unlike classic APMPPE and MEWDS, is more likely to have irreversible visual damage and impairment ( Figure 4). This syndrome simulates presumed ocular histoplasmosis (POHS) except that patients present with vitreous cells and inflammation. The punched-out chorioretinal scars with pigmented borders found in the posterior pole and periphery are similar to those in POHS. There is frequent development of choroidal neovascular membranes, which can cause severe vision loss [33]. This disease is usually bilateral with a predilection for patients in their third decade. Though the cause is unknown, it has been hypothesized that an exogenous pathogen may sensitize the individual, with subsequent episodes not requiring the inciting antigen. MFC tends to be a chronic disorder with, generally, a poorer visual prognosis. Some patients require systemic immunosuppression, while other treatments, such as photodynamic therapy and antivascular endothelial growth factor, are used to treat the resultant CNVM [34][35][36].
In evaluating the current literature for this review for MFC, data was obtained from 22 articles (Table 4) [33][34][35][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]. In PubMed, the term "multifocal choroiditis and panuveitis, " using all or part of the term, brought up 184 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those reports in which data was repeated, 22 articles remained. All reports revealed female predominance, ranging from 55 to 100%. When all patients from these articles were considered ( = 538), 406 patients (75%) were female. The mean of the average age was 39.2 years old, with a range from 30.2 to 57 years old.  3.5. PIC. PIC, a possible variant of MFC, was first described by Watzke et al [57]. This disease was originally described in young, myopic women with punched-out lesions of the posterior pole without ocular inflammation. Like MFC, CNVM may develop and contribute to vision loss ( Figure 5). In evaluating the current literature for PIC, data was obtained from 13 articles (Table 5) [33,[57][58][59][60][61][62][63][64]. In PubMed, the term "punctate inner choroidopathy, " using all or parts of the term, brought up 76 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those in which data was repeated, 13 articles remained. All 13 articles revealed female predominance, ranging from 64 to 100%. When all patients from these articles were considered ( = 471), 400 patients (85%) were female. The mean of the average age was 33.1 years old, with a range from 26 to 41.5 years old.
3.6. AZOOR. AZOOR, thought of predominantly in young women, includes a rapid loss of one or more large zones of outer retinal function and photopsias with minimal fundus changes. Though the cause is unknown, 28% of patients had associated autoimmune diseases, such as Hasimoto's thyroiditis and relapsing transverse myelopathy [65]. No treatment has found to be effective. In Gass' series, 78% of patients with AZOOR had stabilization of the visual field loss and 20% had improvement [65].
In evaluating the current literature for AZOOR, data was obtained from 5 articles (Table 6) [66][67][68][69][70]. In PubMed, the term "acute zonal occult outer retinopathy, " using all or part of the term, brought up 82 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those with repeated data, 5 articles remained. All articles revealed female predominance, ranging from 75 to 93%. When all patients from these articles were considered ( = 190), 150 patients (79%) were female. The mean of the average age was 38 years old, with a range from 33 to 49.1 years old.

Summary of Gender Differences in Prevalence.
A summary of the gathered data from this paper is provided in Table 7. A review of the presented data appears to demonstrate female predominance, in order from most to least, in the following diseases: PIC > AZOOR > MFC > MEWDS. There appeared to be very slight female predominance in BCR in this review. Very slight male predominance was seen in APMPPE in this review. As for age at onset, from youngest to oldest, this review revealed APMPPE > MEWDS > PIC > AZOOR > MFC > BCR. The BCR patients, on average, were twice as old as the patients of the other WDS for age of onset.

A Hormonal Difference?
Sex hormones influence the immune system, resulting in females having higher immunoglobulin levels and mounting stronger immune responses following immunizations or infections than males [75]. However, this also increases woman's susceptibility to autoimmune diseases [75]. Abnormal hormone levels may trigger disease [75]. BCR tends to involve older patients, including women who may be menopausal. This is less likely to occur in the other WDS diseases, as they tend to be younger. This may be a possible reason why the ratio is much closer in female : male involvement in BCR than such diseases as PIC, AZOOR, MFC, and MEWDS. Unfortunately, this does not explain the near equal development of APMPPE in males and females, as the patients tend to be younger and this disease usually follows a viral prodrome. Clearly, there is something more. Other factors, such as the involvement of HLA A29 factor in BCR, may influence the occurrence of disease [71].

Conclusion
In conclusion, though in this review PIC, AZOOR, MFC, and MEWD were found to have female predominance, there does not appear to be a significant difference in clinical presentation nor in the treatment of these diseases between the genders. BCR and APMPPE appear to affect both men and women equally and again, both in presentation and treatment, there does not appear to be a significant difference between the genders. Though estrogens have been implicated in the manipulations of the immune system, further work is needed to truly elicit how estrogen levels may affect prevalence, presentation, and treatment in these ocular diseases.