Hindawi Case Reports in Ophthalmological Medicine Volume 2021, Article ID 1056659, 6 pages https://doi.org/10.1155/2021/1056659

Case Report Eales’ Disease: When the Rare Sounds Frequent

Beatriz Oliveira Lopes ,1 Margarida Sena Brízido ,1 Ana Isabel Reis ,2 Margarida Maria Miranda ,1 and Susana Morais Pina 1

1Department of Ophthalmology, Beatriz Ângelo Hospital, Loures, Portugal 2Department of Medicine, Beatriz Ângelo Hospital, Loures, Portugal

Correspondence should be addressed to Beatriz Oliveira Lopes; [email protected]

Received 14 April 2021; Accepted 22 July 2021; Published 10 August 2021

Academic Editor: Takaaki Hayashi

Copyright © 2021 Beatriz Oliveira Lopes et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Eales’ disease is a peripheral occlusive retinal phlebitis, with an unclear pathogenesis. The classic association with hypersensitivity to Mycobacterium tuberculosis protein infers that immunologic disturbance may be involved. Here, we described three cases of Eales’ disease. All patients are Caucasian men aged 27-58 years and presented with vitreous hemorrhage and/or peripheral venous vasculitis. Tuberculin skin sensitive test (Mantoux screening test) and interferon-gamma release assay (IGRA) were positive in all patients. Therapeutic approach included antituberculosis therapy and systemic steroids, associated or not to immunosuppressive therapy, and retinal scatter photocoagulation in all cases. Antivascular endothelial grow factor (VEGF) intravitreal injections were also required in two cases. Since various retinal diseases can resemble this presentation, Eales’ disease is considered a diagnosis of exclusion. Early diagnosis and appropriate therapeutic approach are both essential to accomplish disease control and reduce ophthalmologic complications.

1. Introduction Although the pathophysiology is poorly clarified, litera- ture suggests that there is a clear association between Eales Eales’ disease is a primary idiopathic peripheral obstructive disease and Mycobacterium tuberculosis [2,4,5]. retinal vasculopathy, reported in 1880 by Henry Eales for Different therapeutic approaches are suggested for Eales’ the first time [1]. A relation to ocular inflammation was disease, depending on its clinical stage [3, 5]. The typical described few years later [2, 3]. Healthy young men are the usually requires treatment with systemic most affected by this disease, which is more prevalent in steroids in combination with complete antituberculosis ther- India and the Middle East [1]. In recent years, more cases apy for a minimal period of 9 months. Steroid- paring immu- affecting older adults have been described. nosuppressive agents, like methotrexate, cyclosporine, and The clinical findings of Eales’ disease include perivascu- azathioprine, are usually reserved for cases which corticoste- lar phlebitis and secondary proliferative retinopathy with roids are not sufficient, need to be discontinued, or are , recurrent vitreous hemorrhages, and contraindicated. Peripheral retinal scatter photocoagulation possible tractional [1, 2]. Other signs and anti-VEGF intravitreal injections are also essential ther- of ocular inflammation as vitritis and anterior chamber cell apeutic approaches in cases of proliferative disease and reaction may also be present. The clinical course of Eales’ important retinal [2, 5]. In case of secondary ocular disease is highly variable, presenting itself with gradual pro- complications such as tractional retinal detachment and/or gression in few cases and temporary or even permanent persistent vitreous hemorrhage, pars plana vitrectomy sur- remission in others [4]. gery may improve visual prognosis [2]. 2 Case Reports in Ophthalmological Medicine

Table 1: Description of the presented cases. Abbreviations: OD: right eye; OS: left eye; FA: fluorescein angiography; SD-OCT: spectral domain optical coherence tomography; ERM: ; CME: cystoid ; CT: computed tomography; IGRA: interferon- gamma release assay; VEGF: antivascular endothelial grow factor.

Case 1 Case 2 Case 3 Sex Male Male Male Age (years) 27 49 58 Laterality Unilateral Bilateral Bilateral Progressive blurred vision Acute bilateral decrease in the left eye over Clinical presentation in the right eye visual acuity and floaters the previous 6 months Anterior segment evaluation Low-grade iridocyclitis Unremarkable Unremarkable Bilateral peripheral hemorrhages, Vitritis, optic disc edema, venous Bilateral vitritis, vitreous vascular remodeling, vasculitis, and perivascular hemorrhage, retinal vasculitis, Fundus features neovascularization, vitreous haemorrhages in nasal quadrants hemorrhages in all retinal hemorrhage, and macular edema (OD) quadrants, and macular edema (OS) FA: bilateral venous vasculitis FA: bilateral occlusive venous Ophthalmology multimodal FA: venous vasculitis with with peripheral ischemia, vasculitis with retinal ischemia evaluation retinal ischemia neovascularization SD-OCT: bilateral CME SD-OCT: ERM+ CME (OS) Tuberculin skin sensitive Positive Positive Positive and IGRA test Cisural micronodule with Unspecific small bilateral Apical reticular pattern, residual Thorax TC a 4 mm ganglion hilar ganglia fibrotic, and retracted changes Systemic evaluation Negative Negative Negative Quadruple antitubercular Quadruple antitubercular Quadruple antitubercular treatment, prednisolone treatment, prednisolone treatment and prednisolone Systemic treatment (1 mg/kg/day) with progressive (1 mg/kg/day) with progressive (1 mg/kg/day) with progressive withdrawal, and methotrexate withdrawal, and methotrexate withdrawal (20 mg/week) (20 mg/week) Topical prednisolone Scatter laser photocoagulation Scatter laser photocoagulation and Ocular treatment and bromofenac and intravitreal anti-VEGF in intravitreal anti-VEGF in both eyes Sectorial laser photocoagulation both eyes Time on follow-up 2 years 2 years 4 years Clinically stable, under Clinically stable with no Clinically stable with no methotrexate (20 mg/week) and need for therapy Follow-up need for therapy prednisolone (2.5 mg/day) Significant visual Complete visual acuity recovery Significant visual acuity recovery, acuity recovery restriction of visual field

2. Clinical Cases Initial investigation included hemogram, platelet count, hepatic and renal function, erythrocyte sedimentation rate, 2.1. Patient 1. A healthy 27-year-old Caucasian male pre- human leukocyte antigen (HLA) B51, antinuclear antibody, sented with progressive blurred vision in the right eye (OD) lysozyme, angiotensin-converting enzyme (ACE), and infec- (Table 1). He denied ocular pain, headaches, and other ocular tious serologic analysis. No suspicious lesions indicating or systemic symptoms. Best corrected visual acuity (BCVA) active tuberculosis or were found in the com- was 10/10 in both eyes. Anterior segment evaluation showed puted tomography (CT) of the thorax; although, it showed low-grade iridocyclitis in the OD. Dilated ocular fundus a cisural micronodule with a 4 mm ganglion (Table 1). A examination revealed moderate vitritis, optic disc edema, further systematic review was unremarkable. Tuberculin skin vascular tortuosity, and venous vasculitis with perivascular sensitive test and IGRA test (5.59) were positive, and Eales’ hemorrhages mainly in the nasal quadrants of the OD disease was considered the likely diagnosis. (Figure 1). Fluorescein angiography showed severe venous Besides topical therapy, corticoid therapy (1 mg/Kg/day vasculitis with important retinal ischemia in the correspon- oral prednisolone) with slow progressive withdrawal was dent quadrants of the same eye (Figure 1 and Table 1). started, associated with quadruple antituberculosis therapy Unilateral panuveitis with retinal vasculitis, prompted for (ethambutol, rifampicin, pyrazinamide and isoniazid). Oral the search of an etiology study while topical therapy with methotrexate (15 mg/week) was introduced two months prednisolone and bromofenac, was implemented. later, keeping slow progressive corticosteroids withdrawal Case Reports in Ophthalmological Medicine 3

(a) (b)

Figure 1: Retinography and fluorescein angiography evidencing (a) active venous vasculitis with perivascular hemorrhages and retinal ischemia in the nasal quadrants OD in patient 1and (b) after medical treatment and scatter laser photocoagulation.

(a) (b)

Figure 2: Image of ocular fundus showing (a) active venous vasculitis with hemorrhages in all retinal quadrants in both eyes in patient 2 and (b) after treatment, including scatter laser photocoagulation and intravitreal anti-VEGF therapy. with clinical improvement (Table 1). Sectorial laser photoco- for nine months, associated with oral corticoid therapy agulation of the ischemic nasal quadrants of the retina was (prednisolone 1 mg/Kg/day) with slow progressive with- performed after vasculitis remission (Figure 1). drawal and subsequent introduction of oral methotrexate Two years after diagnosis, having completed one year of (20 mg/week) in order to achieve control of the disease. Serial antitubercular and two years of immunosuppressive treat- treatment regime with anti-VEGF vitreous injections was ment, the patient remains clinically stable, with no signs of also performed in both eyes (in a total of 11 in each eye). active vasculitis and no need for further therapy. Laser photocoagulation was also required in both eyes over four sessions (Figure 2 and Table 1). This therapeutic 2.2. Patient 2. A healthy 48-year-old Caucasian male came to approach allowed progressive clinical improvement. the emergency room with acute bilateral decrease visual acu- After two years of follow-up, the patient maintains ity and floaters (Table 1). He denied ocular pain, fever, immunosuppression with oral methotrexate (20 mg/week) anorexia, and other systemic symptoms. BCVA in OD was associated with prednisolone (2.5 mg/day) and achieved 6/10 and in OS was 5/10. Biomicroscopic examination was almost complete visual acuity recovery for 10/10 in both eyes, unremarkable in both eyes. Dilated ocular fundus examina- although with significant restriction of visual field, induced tion showed vitritis, vitreous haemorrhage, and extensive by both severe retinal ischemia and photocoagulation retinal venous vasculitis with haemorrhages in all retinal (Table 1). quadrants and macular edema (Figure 2). Fluorescein angi- ography showed bilateral severe occlusive venous vasculitis 2.3. Patient 3. A 58-year-old Caucasian male with known associated with paramacular, midperipheral, and peripheral medical history of dyslipidemia, diabetes mellitus type 2 for retinal ischemia (Figure 3), and spectral domain optical 15 years, and ischemic stroke 15 years before presented to coherence tomography (SD-OCT) revealed cystoid macular the emergency room with complaints of floaters in his left edema (CME) in both eyes (Table 1). eye over the previous 6 months (Table 1). At presentation, Investigation of the etiology included hemogram, inflam- BCVA was 8/10 OD and 5/10 OS. Anterior segment evalua- matory markers (C-reactive protein and erythrocyte sedi- tion was unremarkable. Fundoscopy revealed peripheral ret- mentation rate), human leukocyte antigen (HLA) B51, inal hemorrhages in both eyes and irregular macular reflex, lysozyme, angiotensin-converting enzyme (ACE), infectious inferior vitreous hemorrhage, vascular remodeling, and neo- serologic testing and hemoglobin electrophoresis, coagula- vascularization in OS (Table 1). Fluorescein angiography tion, and prothrombotic evaluation that were all unremark- showed retinal venous vasculitis with peripheral ischemia able, except for tuberculin skin sensitive test (20 mm) and and neovascularization in both eyes, with no suggestive IGRA (>10) which were positive. X-ray and CT scan of the appearance of diabetic retinopathy (Figure 4). Patient also thorax also revealed unspecific small bilateral hilar ganglia performed SD-OCT which revealed epiretinal membrane (Table 1). (ERM) with CME in the OS (Table 1). Eales’ disease was suspected, and patient started complete Detailed clinical history and thorough systemic examina- quadruple antituberculosis treatment, which was maintained tion including serologic analysis, hemogram, inflammatory 4 Case Reports in Ophthalmological Medicine

(a) (b)

Figure 3: Fluorescein angiography showing (a) retinal venous vasculitis, perivascular hemorrhages, and severe retinal ischemia in both eyes in patient 2 and (b) after treatment, including scatter laser photocoagulation.

Table 2: Disease severity classification system [13].

Stage Description Periphlebitis of small caliber vessels with Ia superficial retinal hemorrhages Periphlebitis of large caliber vessels with Ib superficial retinal hemorrhages Figure 4: Fluorescein angiography showing significant occlusive IIa Capillary nonperfusion vasculitis associated with peripheral ischemia, hemorrhages, and IIb Neovascularization elsewhere/of the disc neovascularization in both eyes in patient 3. IIIa Fibrovascular proliferation IIIb Vitreous hemorrhage IVa Traction/rhegmatogenous retinal detachment markers, protein, and hemoglobin electrophoresis were unre- , neovascular , markable. X-ray and CT scan of the thorax evidenced pulmo- IVb nary parenchyma with apical reticular pattern and residual complicated cataratac, and optic atrophy fibrotic and retracted changes (Table 1). Once other causes of vasculitis and infections have been ruled out and tubercu- lin skin sensitive test (41 mm) and IGRA (2.77) were positive, in the middle stage which contributes to retinal ischemia with Eales’ disease was considered. increased vascular endothelial growth factor [2]. Neovascu- Patient started a complete quadruple antituberculosis larization seen at the boundaries between perfused and non- treatment associated with oral corticoid therapy (predniso- perfused zones of the retina is observed consequently in the lone 1 mg/Kg/day) with progressive withdrawal. Scatter laser late proliferative stage. It can happen up to 80% of the cases photocoagulation and three anti-VEGF vitreous injections [1, 2], unlike disc neovascularization, which is rare [2]. were also performed in both eyes (Table 1). Although poor Recently, it has been created a new 4 stage-grading classifica- patient’s compliance, clinical improvement with complete tion in order to facilitate assess severity and functional prog- regression of vasculitis and neovascularization was achieved. nosis of the disease [1, 2] (Table 2). Almost 4 years after diagnosis, patient remains clinically Eales is a bilateral condition in approximately 90% of stable and had significant visual acuity recovery (BCVA was patients. However, due to the inherent asymmetry, it can 10/10 OD and 8/10 OS), maintaining close follow-up and manifest itself unilaterally, as observed in patient 1, as sudden no need for treatment. blurring of vision or floaters, caused by vitreous hemorrhage [1]. Sometimes, this presentation may difficult the correct 3. Discussion diagnosis. In our case series, neovascularization associated with vitreous hemorrhages was present in patients 2 and 3. Defined as a primary idiopathic disorder of peripheral retinal We speculated that in the first patient, the diagnosis was vessel, Eales’ disease pathophysiology is still poorly under- made sooner at an earlier stage, which allowed preventing stood. This disease classically progresses in sequential stages this serious complication. involving retinal inflammation, occlusion, and neovasculari- Immunologic mechanisms, mainly cell-mediated, have zation [2, 5]. Early inflammatory stage presents with retinal been proposed for Eales’ etiology [3, 5]. From the various periphlebitis, which manifests as sheathing of blood vessels, causes suggested, Mycobacterium tuberculosis is the most primarily venous. This vasculitis leads to capillary occlusion common reported. Although the role of this antigen is not Case Reports in Ophthalmological Medicine 5 completely determined, several studies propose that Eales and , visual prognosis is generally good. Recurrent disease is strongly related to both tuberculin protein hyper- vitreous hemorrhages are the most frequent cause of visual sensitivity and previous exposure to tuberculosis [2, 5]. loss, which is transitory most of the time, as observed in Indeed, the Mycobacterium tuberculosis genome had been our patients. Therefore, patients with Eales’ disease can have detected through polymerase chain reaction studies in epiret- a hopeful prognosis, being mainly affected by early diagnosis, inal membranes and vitreous samples of several Eales prompt treatment, and regular long-term follow-up. patients with tuberculin skin test positivity [6, 7]. Our case series intend to draw attention to this rare entity In our case series, tuberculin skin sensitive test as well as which has become more frequent in the western world and IGRA test was positive in all patients, supporting the possible between older adults. In this way, clinical suspicious and etiologic role of Mycobacterium tuberculosis in the pathogen- knowledge of the appropriate therapeutic management of esis of this entity and contributing to the diagnosis as well. the disease are essential to prevent clinical progression and However, the diagnosis of Eales’ disease requires exclusion the onset of ocular complications, as we accomplished with of several other ocular or systemic inflammatory and nonin- our patients. flammatory diseases which can easily resemble its features [5]. Branch retinal vein occlusion, proliferative diabetic reti- Data Availability nopathy, Coats disease, and are all retinal entities which manifest with similar peripheral retinal non- Data are available within the article. perfusion that must be ruled out [1, 5]. It is also important to exclude systemic infections and noninfectious diseases Consent such as syphilis, sarcoidosis, toxoplasmosis, systemic lupus erythematosus, or Behçet disease [5, 8]. 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