The largest series of cases with Eales’ disease reported in the literature come from India [2,3,4], Southeast Asia [4] and Germany [5]. The epidemiology of this disease in Latin America has not been reported. In our country, however, it constitutes a pathology of significant frequency, comparable with that of other countries. This epidemiologic finding becomes relevant considering the significant prevalence in populations of different racial origins, suggesting that-genetic makeup does not determine the etiology-, or the development of the disease, and reinforcing instead the most accepted theory that links the origin of this vasculopathy with an abnormal immunologic response to the antigenic fragments of Mycobacterium tuberculosis [2, 3, 6]. This finding also highlights the fact that in Bolivia, we still register a high incidence and prevalence of tuberculosis [7].

Immunology-based etiopathogenesis has been proposed, as a reaction to genetic material and the presence of non-viable Mycobacterium tuberculosis fractions, which has been supported by strong evidence. Furthermore, statistically significant portions of M. tuberculosis DNA have been detected upon vitreous PCR analysis, and in epirretinal membrane analysis form Eales’ disease patients. Moreover, other retrospective and prospective studies also found other Mycobacterium (chelonae and fortuitum) [6] using optimized seminested polymerase chain reactions, reinforcing their causal relationship and extending in to other Mycobacterium species, in addition to tuberculosis. In contrast, some authors performed RT-PCR on vitreous biopsies and found a significant Mycobacteria inoculum in at least 50% of their samples; reinforcing the possibility of vasculitis being a reaction to an active infectious agent and not just an immune response [8].

On the other hand, a possible association with autoimmune systemic disease has been reported, and neurological and hematological disorders have also been mentioned [2]. Our series showed coexisting autoimmune disease in only one patient, but no other clinical or paraclinical analysis suggested other systemic diseases.

Immunohistochemical analysis showed lymphocytic infiltration, especially T lymphocytes, consistent with type IV hypersensitivity, which is a characteristic response to tuberculin, but can also be an expression of the autoimmune mechanism triggered by retinal S-antigen [9].

Vitreous biochemical analysis showed significant increase in several growth factors, specially VEGF, in contrast to a PEDF reduction –a potent ischemia inhibitor [10]- and increased reactive substances, such as TBARS, and decreased E and C vitamins, superoxide dismutase, glutathione and glutathione peroxidase, suggesting oxidative stress [11].

Our case series demonstrates that this disease is most common in young adults and the sex distribution is equivalent, which differs from the classic descriptions of a clear male gender dominance [1, 2, 5, 12], but it matches smaller case series reflecting a more even gender distribution [13].

A total of 76.6% of patients in our study had a positive Quantiferon-TB Gold Plus test, which is of relative value, since it only demonstrates immunologic memory of Mycobacteria. Since tuberculosis is endemic in our country, our population received the BCG vaccine, which reduces the specificity of this test for the detection of active tuberculosis cases [8].

We noticed bilateral involvement in 100% of our cases. However, it is important to mention the asymmetric evolution of a significant percentage of these cases, which allowed us to intervene at the early stages of many contralateral eyes in those patients with unilateral symptoms. This fact, also reinforces our recommendation of a careful evaluation (under pharmacological dilation) looking for subtle or peripheral signs in the periphery of asymptomatic eyes.

Only one case in our series, presented with signs of anterior uveitis, primarily cell and fine keratic precipitates. In fact, anterior segment inflammation is not usually part of these patients’ presentation and in those few cases where it was present it may have been due to spillover phenomenon [12], in those cases with a severe stage IIIb inflammatory process.

The most common reason for initial consultation was a reduction in visual acuity, secondary to vitreous hemorrhage, in patients previously asymptomatic and without relevant ocular or systemic comorbidity. The clinical stages associated with vitreous hemorrhage correlated to those with retinal neovascularization, confirming the cause-effect relationship. However, despite the advanced stages of these patients, the evolution is favorable if treated in a timely manner, because it lacks other components that could exacerbate the process, such as those of diabetes. Additionally, even though they share similar clinical and evolutionary characteristics, the behavior of Eales’ disease is less aggressive than that of proliferative diabetic retinopathy. We found this phenomenon even in cases with large areas of non-perfusion and/or aggressive neovascularization, probably because Eales’ pathology does not originate from a systemic metabolic disorder, or permanent endothelial dysfunction such as diabetic retinopathy [10].

Retinal vasculitis is located in the mid periphery, post-equatorial or equatorial in 64% of cases with a central predominant component in 36%. Some cases in early stages with close follow-up of its progression or recurrence post-treatment, display new spots of vasculitis in different meridians, always in the mid-periphery or closer to the center, but not in the most peripheral sectors. However, areas of vascular shutdown, extend to the pre-equatorial and extreme periphery in some cases where neovascularization tends to develop in transition areas between perfused and ischemic retina, which is why careful clinical exploration and complementary studies, especially fluorescein angiography should be able to demonstrate the most peripheral locations up to 360°, with new wide-field techniques probably optimal for evaluation and follow-up.

Similarly, associated macular edema is less common than in other retinal pathologies, the treatment response to a timely intervention is favorable, and the results are stable over time. Spectral domain OCT is an ideal tool for the diagnosis and follow-up of macular edema as well as abnormalities in the vitreoretinal interphase that could develop. OCT-A could also be valuable to evaluate other associated phenomena, such as macular ischemia, that could easily explain visual loss in some cases [12, 14], with an added advantage of its non-invasive quality and reproducible results.

Even though the clinical characteristics of Eales’ are usually quite distinctive and match those of the series of cases, this disease remains an exclusion diagnosis, which must be considered on the basis of clinical findings since it lacks a specific, conclusive diagnostic test. Therefore, all laboratory tests and referrals to other specialties -if needed- to rule out other causes of retinal vasculitis must be carried out without delay.

There were some differences regarding clinical features in our series compared to others, 100% of our patients showed bilateral compromise, compared to 73 and 87% reported in the largest case series in Asia [2, 4] and Europe [5], however, during follow-up these numbers increased to 81 and 98% respectively, reinforcing that asymmetry is frequent and both eyes are involved at some point, responding to previously established etiopathogenic mechanisms. Also, recently developed diagnostic tools, such as ultra-wide-field angiography and retinography are able to detect this changes on early stages. Vascular features in our patients showed venous sheathing in most of the cases, associated to vascular dilatation and tortuosity, microhemorrhages, AV shunts and neovascularization in the transition areas, between perfused and ischemic retina, these changes were consistent with previous reports. However, our patients did not present telangiectasias or microaneurysms, which are the first manifestation of internal retinal-blood barrier disruption in other retinopathies, different from Eales’ disease.

As for topographic features in our series, the main difference is a significant number of centrally located clinical characteristics-up to 36%-compared to the 10% rate, stablished by previous reports [2,3,4,5]. However, we must point out, that most of our patients didn’t show disc neovascularization, compared with variable rates-between 1 and 6.2%-in other studies [2, 4], which can be attributed to the fact, that even if central compromise is common, corresponding non-perfusion and ischemic areas weren’t equivalent in extension. Additionally, we noticed that cystoid macular edema is the most frequent form of macular affection. 27% of cases showed vitreofoveal traction component and just 2% of them had epiretinal membranes; similarly to other series outcomes.

Combined treatment with anti-VEGF, systemic, periocular and/or intraocular corticosteroids, or external or intraoperatory laser photocoagulation in ischemic areas depending on the case, has shown favorable results [12, 15, 16], with structural and functional improvement. Similarly, macular edema and abnormalities in the vitreoretinal interphase, although less frequent, have been demonstrated to be treatable with the expected visual improvement.

Ocular comorbidities, such as retinal detachment, respond quite well to conventional surgical treatments, and we found that inflammation does not play a determinant role in the postoperative evolution. Obviously, the appropriate peri and postoperative control of any sign of inflammation must be taken into consideration to minimize its impact, and following surgery, once the retina is reattached, it is important to complete the ablation treatment of ischemic areas if they are present. There is still a need to establish diagnostic and therapeutic protocols that best fit the clinical stage and individual characteristics of each case (including the contralateral eye’s condition, presence of macular edema, etc.). Additionally, we will surely find more efficient applications of current technology such as angiographic studies of ultra-wide field, new generation anti-VEGF, and sustained release intraocular steroid devices, which will improve our diagnostic and therapeutic capabilities and help achieve more favorable visual outcomes.

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