Monique Munro MD, Kristen Ann Mendoza, MD; Andreas Lauer, MD
Eales' disease was first described by British ophthalmologist Henry Eales in 1880.1 Eales’ disease is an idiopathic occlusive vasculitis involving the mid-peripheral retina that is characterized by retinal venous inflammation (periphlebitis), vascular occlusion, and subsequent retinal neovascularization.2,3 A hallmark of Eales’ disease is recurrent vitreous hemorrhage.3,4
Eales’ disease mainly affects young males in their second decade of life.3 It is more prevalent in India and Middle Eastern countries with cases observed worldwide.4 In a study by Biwas et al., a male-to-female ratio of 20:1 was observed with a mean age at presentation of 29.95 years, with a range from 11– 59 years.4
No definite cause for Eales disease has been found to date and it is considered idiopathic.
Eales’ disease presents with overlapping stages of retinal periphlebitis, ischemia, and neovascularization.2-4 The peripheral retinal veins first become inflamed with sheathing, and subsequently become occluded. The loss of perfusion may result in retinal neovascularization that leads to recurrent vitreous hemorrhage.2-4 Recent research has proposed immunological, molecular biological, and biochemical mechanisms for Eales’ disease with theorized roles of free radical-mediated damage and oxidative stress, human leukocyte antigens, retinal autoimmunity, and Mycobacterium tuberculosis.2,3,5,6 Immunologic mechanisms proposed include T-cell lymphocytic infiltration as T-cell lymphocytes has been observed in recovered epiretinal and subretinal membranes in Eales’ disease patients.3 Presently, the etiology appears to be multifactorial and is presumed to be an immunological reaction triggered by the exposure of an exogenous agent.2,7
The most prevalent etiologic theory is possible hypersensitivity to tuberculoprotein that develops after exposure to Mycobacterium tuberculosis.2,3 In a retrospective study, 47.8% of epiretinal membrane samples were positive for one or more Mycobacterium species compared to 11.1% of controls from Eales’ disease patients using polymerase chain reaction (PCR).8 This finding has been observed in other studies9 and the mycobacterium genome has also been recovered in vitreous fluid samples.10 Due to this association, Eales' disease may be a variant of tuberculosis-related vasculitis but the exact role of tuberculosis in Eales' disease has yet to be completely ascertained as Eales’ disease has also been observed in Mantoux-negative cases.2,10,11
There are no known preventative measures for Eales’ disease.
Eales disease is a clinical diagnosis of exclusion.
Signs and Symptoms
Patients with Eales disease tend to be initially asymptomatic but may present unilateral or bilateral decreased vision, photopsias, and floaters. At initial presentation, the most common complaints were found to be decreased vision (40%), floaters with decreased vision (28%), and floaters only (14%) in one study.4
Eales’ disease is bilateral in upward of 81% patients, although may present unilaterally.4 Macular involvement is uncommon in classic Eales' disease but can occur with central Eales’ disease, extensive/severe disease, and in the late stages of proliferation.2
- Visual acuity: vision tends to be spared unless vitreous hemorrhage or more severe disease occurs. Severe vision loss may result from optic atrophy, neovascular glaucoma, chronic retinal detachment or other late-stage complications. Macular edema may occur, but this is less common.
- Anterior segment: nongranulomatous uveitis may occur from posterior spill over (less common), rubeosis iridis, neovascular glaucoma/neovascularization of the angle.
- Vitreous: cells and debris, vitreous hemorrhage; dense vitritis is uncommon.
- Retina: perivascular venous sheathing and exudate, venous tortuosity, venous obstruction, capillary non-perfusion, sclerosed vessels, intraretinal hemorrhage, retinal neovascularization (73.2% of eyes).4 Neovascularization is usually located at the junction of the perfused and nonperfused retina, retinal detachment, epiretinal membrane and macula edema (less common).
- Optic nerve: edema, neovascularization (0.9% eyes).4
- Choroid: not involved.
Central Eales’, a variant of classic Eales’ disease with a similar presentation to central retinal vein occlusion and is associated with a favorable prognosis.12
Due to clinical overlap with Eales’ disease findings, there is no standardized staging; however, three phases are typically recognized:
- Early Stage (Inflammatory): peripheral to mid-peripheral periphlebitis may be found in all stages and in multiple quadrants concurrently. Venous dilation and perivascular exudate can be observed.
- Intermediate Stage (Ischemic): characterized by retinal capillary ischemia. Demarcation between perfused and nonperfused retina is marked by arteriovenous shunts, venous beadings, and micro-aneurysms.
- Late Stage (Proliferative): neovascularization occurs at the junction between perfused and non-perfused retina. Contraction and rupture of these vessels lead to recurrent vitreous hemorrhages with or without tractional retinal detachment.
Based of the above findings, Saxena et al.13 propose the following stages:
Stage Findings I Peripheral phlebitis of small (Ia) and large (Ib) caliber vessels with retinal hemorrhage IIa Capillary nonperfusion IIb Revascularization elsewhere/of the disc IIIa Fibrovascular proliferation IIIb Vitreous hemorrhage IVa Traction/combined rhegmatogenous retinal detachment IVb Rubeosis iridis, neovascular glaucoma, complicated cataract, and optic atrophy
Eales’ disease is a diagnosis of exclusion and requires evaluation for ocular and systemic conditions associated with retinal periphlebitis, neovascularization and recurrent vitreous hemorrhage.
The differential for causes of retinal periphlebitis, capillary occlusion, peripheral neovascularization and recurrent vitreous hemorrhage broadly including infectious, inflammatory/autoimmune disease and masquerades. A thorough history to exclude other causative etiologies is paramount as an identified systemic infection or other disease may require particular treatment.14
The approach to the differential may be broken into various approaches based on the constellation of findings in Eales’ disease and considerations are as follows: • Autoimmune-related causes of retinal phlebitis: sarcoidosis, frosted branch angiitis, multiple sclerosis, pars planitis, Bechet’s disease, human immune deficiency virus (HIV). • Autoimmune-related causes of retinal occlusive disease: systemic lupus erythematosus, idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN), polyarteritis nodosa, granulomatosis with polyangiitis (formerly Wegener’s granulomatosis), Bechet’s disease, Churg-Strauss syndrome, cryoglobulinemia, and Crohn’s disease. • Vascular disease: diabetic retinopathy, sickle cell retinopathy, branch retinal vein occlusion, radiation retinopathy, coagulopathies, and retinopathy of prematurity. • Infectious retinal vasculitis: syphilis, tuberculosis, Lyme disease. • Idiopathic: IRVAN, Susac disease, idiopathic hypereosinophilia, Coat’s disease. • Neoplastic: leukemia. • Congenital: incontinentia pigmenti, familial exudative vitreoretinopathy. .
• Fluorescein angiography (FA): leakage of dye surrounding veins indicates active inflammation. Venous staining without leakage indicates sclerosed vessels or resolved inflammation. • Wide-field FA: enables assessment of peripheral areas with better quality and allows peripheral observation of the above findings.15 • Ultrasonography: allows detection of retinal detachment when vitreous hemorrhage obscures view of the fundus. • Optical Coherence Tomography (OCT): while Eales’ disease predominantly involves the peripheral retina, macular involvement can be observed. In a study by Goel et al., 58.2% of eyes (n=46) had macular involvement observed on OCT.16 Macular edema was the most common feature followed by epiretinal membrane. • OCT-angiography (OCT-A): may detect neovascularization depending on location of involvement.
Laboratory tests are neither sensitive nor specific for Eales’ disease, but may be helpful in detecting systemic causes of retinal vasculitis or peripheral retinal non-perfusion. Laboratory work-up should be focused on a differential diagnosis derived from a detailed history, review of systems, and ocular and physical examination. If there are no signs or symptoms suggestive of an underlying inflammatory disease then the work-up of the patient may include a complete blood count, metabolic panel, erythrocyte sedimentation rate, syphilis testing, tuberculin skin testing/QuantiFERON Gold, antinuclear antibody, antineutrophil cytoplasmic antibody, angiotensin-converting enzyme, lysozyme, urinalysis and chest radiograph.14 Lyme disease testing in patients with suggestive symptoms may be pursued. To exclude vascular causes of retinal neovascularization, glucose levels, hemoglobin A1c, hemoglobin electrophoresis and HIV testing should be included.
A distinct protein with an isoelectric point of 5.9 and a weight of 23 kDa has been associated with Eales disease, as have increased alpha globulins, increased alpha-1 acid glycoproteins, decreased serum albumin, and increased matrix metalloproteinase 9 (MMP-9).
General treatment & Management
General Treatment The management of Eales’ disease depends upon the stage of the disease. The treatment strategy consists of medical treatment with oral corticosteroids in the active inflammatory stage and laser photocoagulation for retinal ischemia and neovascularization.2 Biwas et al. observed that the timely use of oral corticosteroid during active inflammation and use of laser ablation of areas with capillary non-perfusion had a statistically significant beneficial impact on visual outcomes during a 10-year follow-up period.4
Medical Treatment Corticosteroids Corticosteroid (systemic and/or local/periocular) is the mainstay of treatment for the inflammatory stage. It is controversial whether asymptomatic isolated or incidentally observed vasculitis requires treatment. In the presence of widespread vasculitis, vasculitis threatening vision or causing macular edema treatment is recommended.2-4 Bilateral vasculitis may be treated with oral corticosteroid and or sequential local corticosteroid treatment (subtenon/intravitreal) in patients who cannot tolerate systemic treatment. Oral prednisone (1-2 mg/kg) that is gradually tapered is typically employed.3 In some patients a low dose maintenance dose is needed.3 Intravitreal or periocular steroid in unilateral disease avoids the systemic side effects of steroid.4 In a study by Biwas et al., there was no difference in response to treatment in the Mantoux-positive and Mantoux-negative groups of patients with corticosteroid use.4 Patients on oral steroid therapy during acute stage disease had statistically significant better visual acuity at the final visit compared to those who did not take oral steroid.4
Intravitreal triamcinolone has also been utilized.17 However, secondary elevated intraocular pressure and cataract progression may limit the use of intravitreal steroids.2 As corticosteroids typically are efficacious in the acute inflammatory stage of Eales' disease, steroid-sparing immunosuppressive agents are reserved for patients for whom corticosteroids are not effective or must be discontinued and/or are contraindicated.3
Anti-Vascular Endothelial Growth Factor (Anti-VEGF) Timely regression of neovascularization is important to avoid vitreous hemorrhage and tractional retinal detachment requiring vitreoretinal surgery.2 In a recent study from India, where Eales’ disease is relatively common, the beneficial effect of intravitreal bevacizumab in a patient with presumed Eales' disease has been reported.18 Bevacizumab has been shown to be effective in regressing neovascularization and mild hemorrhage secondary to Eales disease, if given every 4 weeks, thereby hastening the process of resolution of dense vitreous hemorrhage or reduce the need for vitrectomy.19 Tuberculosis Treatment Due to the possible link between Eales’ disease and tuberculosis/hypersensitivity to tuberculoproteins; in suspect patients, antituberculosis treatment considered.3 The duration of treatment for extrapulmonary tuberculosis is a minimum of 6 months and may depend on the infectious disease specialist and patient tolerability of treatment (e.g development of transaminitis).3 Retinal periphlebitis with strongly positive tuberculin skin testing/QuantiFERON Gold test requires the use of systemic steroids and appropriate anti-tuberculous therapy even in the absence of active systemic disease to avoid reactivation of the systemic illness.2 Other Medical Therapies The roles of oxidative stress and targets in the inflammatory cascade have also been evaluated with no clear recommendations at this time.23-25
Photocoagulation is the mainstay of treatment in the proliferative stage.2 A study to evaluate prophylactic scatter photocoagulation in asymptomatic eyes of patients presenting with vitreous hemorrhage found that prophylactic photocoagulation is an effective method of controlling the secondary complications in asymptomatic eyes, especially if diagnosed early.20 In a study by Biwas et al., patients who had undergone laser therapy had statistically significant better visual acuity at the final visit compared to patients who did not receive laser treatment.2 In a prospective randomized clinical trial; photocoagulation was beneficial in stages II and III (proliferative stage with active new vessels) of Eales’ disease. Stage I disease did not require photocoagulation and stage IV (proliferative stage with massive vitreous haemorrhage or traction retinal detachment) were too advanced to benefit from photocoagulation monotherapy.2,3 Presently, good results have been found with sectoral treatment opposed to full panretinal photocoagulation with regression of retinal neovascularization in upwards of 89% of cases.3,21,22 Periodic FA aids in monitoring the response to treatment.
The main indications for vitrectomy include nonclearing vitreous haemorrhage, tractional retinal detachment threatening the macula, multiple vitreous membranes with or without tractional retinal detachment, and combined tractional and rhegmatogenous retinal detachment.3 Uncomplicated pars plana vitrectomy has shown improvement of visual acuity in majority of patients.2 Endolaser treatment may be applied at the time of surgery. The usual management is initially conservative, and vitrectomy is reserved for eyes with non-clearing vitreous hemorrhage at the end of 3 months.26 When access to vitrectomy is not possible and the view to the peripheral retina is compromised by vitreous hemorrhage, external cryotherapy may be use alone in cases requiring treatment or in conjunction with photocoagulation of the visible non-perfused retina.3
Follow up Visual outcomes are dependent on the duration of presentation, stage of presentation, treatment, complications, and regular follow-up. Recurrent vitreous hemorrhage in healthy young males is the hallmark of the disease; hence, regular follow-up is critical to allow for earlier intervention. The prognosis usually depends on the severity of vitreous hemorrhage, macular ischemia, and neovascularization.4 Recent insights and understanding of Eales’ disease has improved the diagnosis and management of Eales’ disease. For example, increased accuracy of PCR for tuberculosis detection may influence treatment8 and wide field angiography has allowed for earlier detection of phlebitis4. Periodic FA may aid in assessing for treatment response and recurrence3. Ultrasonographic surveillance of the retina when monitoring for vitreous hemorrhage to clear spontaneously is recommended at follow up appointments.
Complications The general complications, both from surgery and the natural history of untreated or severe disease, include neovascularization, vitreous hemorrhage, retinal detachment, epiretinal membrane, glaucoma and cataract.27
Prognosis With proper treatment, the overall prognosis of Eales’ disease is good. The major cause of visual loss is recurrent vitreous hemorrhages. Complications of neovascularization, such as retinal detachment and neovascular glaucoma, may contribute to significant vision loss, however, this is rare.
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