Eales disease

INTRODUCTION — Eales disease is a form of retinal vasculitis typified by vascular inflammation in the peripheral retina. Because of its tendency to involve veins, the disorder has also been termed "periphlebitis retinae" and "idiopathic retinal periphlebitis."

The clinical presentation, treatment, and prognosis of Eales disease are distinct from those of other inflammatory conditions that involve the retina. Eales disease must be distinguished from systemic disorders and infections, as well as from other ocular syndromes that cause retinal vasculitis.

The clinical manifestations, diagnosis, and treatment of Eales disease will be reviewed. Retinal vasculitis that occurs in association with systemic disorders, infections, and primary retinal diseases is discussed separately. (See "Retinal vasculitis associated with systemic disorders and infections" and "Retinal vasculitis associated with primary ocular disorders".)

EPIDEMIOLOGY — Eales disease was described originally in England [1,2] but is observed much more commonly on the Indian subcontinent than in any other region. Eales disease has been estimated to occur in 1 of every 135 to 250 patients evaluated at tertiary eye care centers in India [3-5].

A striking male predominance is reported in most series [6,7]. However, in one series from North America, equal numbers of females and males were reported [8]. The mean age at onset in most studies from India is between the age of 20 and 30 years, compared with approximately 40 years in America and Germany [8,9].

PATHOGENESIS AND PATHOPHYSIOLOGY

●Pathogenesis – The cause of Eales disease remains unknown. Substantial speculation has surrounded the potential association between Mycobacterium tuberculosis and Eales disease [10-14]. If any true association does exist between these entities, the relationship is likely to be a reactive type of inflammation, similar to that which occurs in the joints in Poncet disease (tuberculous rheumatism) or human leukocyte antigen (HLA) B27-associated reactive arthritis (see "Bone and joint tuberculosis", section on 'Inflammatory (Poncet disease)' and "Reactive arthritis"). Observational studies provide indirect support for the possibility of reactive inflammation in patients with Eales disease thought to be harboring nonviable tuberculosis organisms [10,11].

The precise events in the pathophysiology of Eales disease remain incompletely defined. Light microscopic and immunohistochemical studies of the epiretinal and subretinal membranes in Eales disease reveal T cell infiltration. In other ocular inflammatory diseases, the blood-retinal barrier breaks down during intraocular inflammation, followed by seepage of circulating blood into the retina. The vascular tropism of Eales disease, its predilection for veins, and its confinement to the retina remain unexplained. The presence of inflammatory mediators and vascular growth factors in the vitreous of these patients supports the theory of inflammation-mediated angiogenesis [15,16].

●Pathophysiology – The pathophysiology of Eales disease involves three basic processes [17]:

•Inflammation (peripheral retinal perivasculitis)

•Ischemic changes (peripheral retinal capillary nonperfusion)

•Neovascularization

Eales disease begins as a retinal perivasculitis that primarily affects the peripheral parts of the retina. It is not unusual to have involvement of all four quadrants of the peripheral retina by active perivasculitis and exudates surrounding retinal veins. This vasculitis can lead to obliteration of the lumen of the blood vessel. Branch retinal vein occlusion may be noted on initial examination [18]. The obliteration leads to ischemia of the part of the retina perfused by the vessel. Vascular endothelial growth factor (VEGF) production is increased by persistent ischemia, which subsequently leads to neovascularization.

CLINICAL FEATURES

Ocular symptoms and signs — The visual loss in Eales disease is painless. Patients usually present in a subacute manner because retinal changes are focused in the periphery and may not cause notable visual changes. Mild visual blurring can occur early in the disease course and some patients report floating spots or flashes in one or both eyes. Profound visual loss may develop later because of vitreous hemorrhage. Although Eales disease is often unilateral and recurrent, up to 90 percent of patients with Eales disease eventually have involvement of both eyes [18].

The duration of symptom progression can be quite variable, ranging from weeks to months. Central portions of the retina may be involved at the time of diagnosis. Eales disease may evolve in a discontinuous fashion, with apparent regression of the inflammatory process in some areas of the retina associated with signs of healing. Healed perivasculitis is represented by venous sheathing.

Superficial retinal hemorrhages often accompany the inflammation. Vitreous hemorrhage (picture 1) occasionally results from capillary rupture caused by vascular inflammation in the acute phases of the illness but more commonly stems from proliferative retinal disease that resembles diabetic retinopathy.

Peripheral retinal neovascularization in Eales disease has a characteristic "sea fan" appearance noted on clinical examination with indirect ophthalmoscopy. Recurrent vitreous hemorrhage from these lesions is a disease hallmark. Although vitreous hemorrhages may resolve spontaneously over a period of weeks, the more common scenario is that such hemorrhages lead to organization, multiple vitreoretinal adhesions, and retinal detachment.

Clinical stages — Classification systems have been developed that help define the clinical stages of the disease [19,20]. The more detailed classification system proposed in 2004 is as follows [20]:

●Stage I – Periphlebitis of small (Ia) and large (Ib) caliber vessels with superficial retinal hemorrhages

●Stage IIa – Capillary nonperfusion

●Stage IIb – Neovascularization of the disc/neovascularization elsewhere

●Stage IIIa – Fibrovascular proliferation

●Stage IIIb – Vitreous hemorrhage

●Stage IVa – Traction/combined rhegmatogenous retinal detachment

●Stage IVb – Rubeosis iridis, neovascular glaucoma, complicated cataract, and optic atrophy

DIAGNOSIS

When to suspect Eales disease — The diagnosis of Eales disease should be suspected in a younger patient who reports floaters, with or without decreased vision, in one or both eyes. When present, changes in vision are typically painless. Patients may be asymptomatic in early stages of the disease, but floaters, photopsias, and blurry vision are the most common symptoms.

Ocular examination — The initial evaluation in a patient with suspected Eales disease should focus on obtaining an expedited eye examination by an ophthalmologist. As the changes caused by the disease involve the retina, careful assessment of the retinal vasculature via indirect ophthalmoscopy is imperative to document disease pathology.

Fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) are generally performed in all patients with suspected Eales disease. B-scan ultrasound is rarely required.

●Fundus fluorescein angiography – FFA is a sensitive approach to detecting retinal blood vessel abnormalities that are consistent with Eales disease. FFA findings include aneurysms, hemorrhage, and vascular occlusions.

FFA is particularly helpful in the ischemic stage, when it can delineate areas of nonperfusion, neovascularization, and macular edema and can help guide the selection of sites for laser photocoagulation. As the pathology is predominantly in the periphery of the retina, wide-field angiography captures the retinal changes more effectively. (See 'Patients with proliferative disease' below.)

●Optical coherence tomography – OCT is a noninvasive test that offers high-resolution imaging of the retina. OCT can demonstrate regions of neovascularization, hemorrhage, and macular edema.

●B-scan ultrasound – In rare situations, ultrasonography is needed to exclude retinal detachments in eyes that have undergone vitreous hemorrhage. This imaging modality may be used when the media (vitreous) precludes adequate visualization of the retina by slit-lamp examination or indirect ophthalmoscopy.

Subsequent evaluation to exclude alternative diagnoses — Once the presence of retinal vasculitis is confirmed, a subsequent evaluation is performed to exclude the presence of a related systemic disorder or infection. Referral to a rheumatologist or other specialist may be appropriate to help with the evaluation. (See "Retinal vasculitis associated with systemic disorders and infections", section on 'Evaluation for underlying disease'.)

History and physical examination — A thorough history and physical should be performed to exclude the presence of other systemic rheumatic diseases or infectious etiologies, as described in detail elsewhere. (See "Retinal vasculitis associated with systemic disorders and infections", section on 'History and examination'.)

Additional testing — We typically obtain a complete blood count, serum chemistry profile, urinalysis with microscopy, and acute phase reactants (erythrocyte sedimentation rate [ESR] and serum C-reactive protein [CRP]) in all patients with retinal vasculitis.

For patients with suspected systemic disease, the additional serologic assays may be appropriate depending on the clinical presentation:

●Antinuclear antibody testing – Antinuclear antibody (ANA) testing is useful in the evaluation of systemic lupus erythematosus and other systemic rheumatic diseases. A strongly positive ANA assay should be followed by additional serologic testing to determine the specific disease state responsible for the ANA positivity. This additional testing may include serum complement levels (C3, C4), antibodies to double-stranded DNA, and antibodies to the Ro/SSA, La/SSB, Sm, or ribonucleoprotein (RNP) antigens. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing'.)

●Antiphospholipid antibodies – Antiphospholipid antibodies (aPL) may be associated with ocular thrombotic events that mimic Eales disease (see "Clinical manifestations of antiphospholipid syndrome"). Because not all patients with antiphospholipid syndrome (APS) have all types of aPL, performance of each of the following tests is important:

•Immunoglobulin (Ig) G and IgM anticardiolipin antibodies

•IgG and IgM anti-beta2-glycoprotein I

•Lupus anticoagulant assay (usually a Russell viper venom time)

●Rheumatoid factor – A positive rheumatoid factor assay is a nonspecific result, but extremely high titers are usually found in the setting of rheumatoid vasculitis. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis" and "Rheumatoid factor: Biology and utility of measurement".)

●Antibodies to cyclic citrullinated peptides – Antibodies to cyclic citrullinated peptides (anti-CCP antibodies) have a high specificity for rheumatoid arthritis. (See "Biologic markers in the assessment of rheumatoid arthritis".)

●Antineutrophil cytoplasmic antibodies – Antineutrophil cytoplasmic antibody (ANCA) assays are likely to be positive in patients with granulomatosis with polyangiitis, microscopic polyangiitis, or eosinophilic granulomatosis with polyangiitis (Churg-Strauss), particularly in cases associated with scleritis. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

If an immunofluorescence assay is positive in either a cytoplasmic or a perinuclear pattern (ie, C-ANCA or P-ANCA), then confirmation of the ANCA specificity, through enzyme immunoassays for antibodies to proteinase-3 and myeloperoxidase, is important.

●Spirochetal disease assays – Syphilis should be excluded with an initial screening with a nontreponemal test (eg, a Venereal Disease Research Laboratory [VDRL] test), and then confirmed if reactive with a treponemal-specific test (eg, a fluorescent treponemal antibody absorption [FTA-ABS] test). Lyme disease should be excluded with an enzyme-linked immunosorbent assay followed, if appropriate, by a Western immunoblot assay. (See "Syphilis: Screening and diagnostic testing" and "Diagnosis of Lyme disease", section on 'Serologic tests'.)

●Tuberculosis testing – We perform screening for tuberculosis, given the possible association with Eales disease and the potential need to give systemic immunosuppression for treatment. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)", section on 'Diagnostic approach'.)

The use of imaging depends upon the clinical assessment and upon the suspected underlying condition. As an example, chest radiography or computed tomography (CT) of the lungs is may be useful to exclude systemic diseases associated with retinal vasculitis, such as sarcoidosis and ANCA-associated vasculitis. (See "Overview of and approach to the vasculitides in adults", section on 'Diagnostic approach'.)

Diagnosis — The diagnosis of Eales disease is based upon the presence of characteristic clinical findings on eye examination (see 'Clinical features' above) and the exclusion of systemic disorders that may result in similar findings, such as sarcoidosis, which can exhibit similar ocular manifestations to early-stage Eales disease.

Differential diagnosis — Eales disease must be distinguished from retinal vasculitis found in primary vasculitides, connective tissue disorders, infections, and other conditions. (See "Retinal vasculitis associated with systemic disorders and infections".)

One distinguishing feature between Eales disease and other disorders associated with retinal vasculitis is that anterior uveitis seldom occurs concomitantly with Eales disease. In a small percentage of patients with Eales disease, a "spillover" uveitis occurs. This reflects spillover of inflammatory cells from the vasculitis into the uveal tract.

MANAGEMENT APPROACH — The treatment of Eales disease is largely dependent on the disease stage. There are four major treatment options: watchful waiting, medical therapy, laser photocoagulation, and vitreal surgery. Since each affected eye may be at different stages of the disease, more than one treatment approach may be required for each patient.

As this condition is suspected to represent a postinfectious inflammatory syndrome (similar to reactive arthritis) in response to exposure to tuberculosis, infectious disease referral for consideration of antimicrobial therapy should be considered.

Patients without active retinal vasculitis — For patients who do not have evidence of active peripheral retinal vasculitis, we suggest watchful waiting rather than medical therapy. Patients without active peripheral vasculitis are typically those who in whom the initial slit-lamp examination reveals only venous sheathing, a finding that is consistent with inactive vasculitis. Watchful waiting usually consists of follow-up evaluations with slit-lamp examinations and fundus fluorescein angiography (FFA) every six months.

Watchful waiting may also be appropriate in patients with fresh vitreous hemorrhage, which sometimes resolves spontaneously. Such patients should be evaluated monthly with history, ocular examination, slit-lamp examination, possibly FFA, and, if the fundus cannot be well visualized, ultrasonography.

Patients with active retinal vasculitis — Glucocorticoids (systemic and/or periocular) are the mainstay of medical therapy for patients in the inflammatory stages of Eales disease.

●Systemic glucocorticoids – For most patients with active retinal vasculitis, we suggest initial treatment with high doses of systemic glucocorticoids rather than other immunosuppressive therapies. The rationale for this approach is based on clinical experience and limited observational data, as well as extrapolation from the management of retinal vasculitis that is idiopathic or associated with other systemic diseases. Methotrexate may be a reasonable alternative in patients at risk for or who develop severe toxicity from glucocorticoids. (See "Retinal vasculitis associated with systemic disorders and infections", section on 'Management and prognosis' and "Retinal vasculitis associated with primary ocular disorders".)

In a large cohort of patients with Eales disease, patients who received oral glucocorticoids during the acute state of the disease had statistically significant better visual acuity at the final visit (mean, 0.42logMar (6/18) ± 0.723 logMar (6/30)) compared with those who did not receive glucocorticoids (mean, 0.5907logMar (6/24) ± 0.945logMar (6/48)) [21]. Data to support the use of oral glucocorticoids in patients with sight-threatening retinal vasculitis not due to Eales disease is discussed separately. (See "Retinal vasculitis associated with systemic disorders and infections", section on 'Management and prognosis'.)

We typically use an initial dose of prednisone 1 mg/kg per day (maximum of 60 to 80 mg/day of oral prednisone or its equivalent) for one month. Although there is no standard for glucocorticoid dosing and tapering regimens, the following approach is useful in many systemic and ocular inflammatory diseases:

•Prednisone tapering should begin after one month at the initial dose

•The dose is tapered by 10 mg each week until a dose of 40 mg/day is reached

•After one week on 40 mg/day, the dose is tapered by 5 mg each week until the patient reaches 20 mg/day

•After one week on 20 mg/day, the dose is tapered by 2.5 mg each week until the patient reaches 10 mg/day

•After one week on 10 mg/day, the dose is tapered by 1 mg every two weeks until the patient reaches 5 mg/day

Assuming that a patient begins prednisone treatment at 60 mg/day and remains on this dose for one month, the taper outlined above will require six months to reach a daily dose of 5 mg. If serial ocular examinations indicate that the retinal vasculitis is controlled, prednisone may be discontinued entirely by tapering in 1 mg/day decrements each week.

Additional interventions to prevent complications from high-dose prednisone use should be implemented at the beginning of treatment:

•Screening tests for tuberculosis and immunizations against influenza and pneumococcal pneumonia should be up to date. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

•Osteoporosis prevention should be pursued in selected patients. Adequate dietary calcium and vitamin D intake should be encouraged. Determination of bone mineral density near the time treatment is begun is helpful for guiding management of bone loss. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

•Prophylactic treatment to prevent Pneumocystis jirovecii pneumonia may be required for patients who are taking daily oral glucocorticoids at a dose equivalent to 20 mg or more of prednisone in addition to other immunosuppressive therapy. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Monitoring for adverse effects of systemic glucocorticoids is discussed in detail elsewhere. (See "Major adverse effects of systemic glucocorticoids", section on 'General treatment considerations and monitoring'.)

●Periocular glucocorticoid injections – Periocular glucocorticoid injections into the posterior sub-Tenon region are particularly helpful in the setting of cystoid macular edema and may be used in addition to systemic glucocorticoids [5]. The dosing is typically 1 mL of triamcinolone acetonide (40 mg/mL). For those with resistant cystoid macular edema, triamcinolone acetonide (40 mg/mL) can be injected intraocularly, typically 0.05 to 0.1 mL. In one case report of a patient with periphlebitis due to Eales disease who was unable to take systemic glucocorticoids due to peptic ulcer disease, an intraocular injection of 0.1 mL of triamcinolone acetonide (40 mg/mL) resulted in regression of disease [22].

●Methotrexate – For patients in whom the need to avoid systemic glucocorticoids is critical, limited evidence suggests that methotrexate may also be useful in the setting of active Eales disease. In a case series of 21 consecutive patients with Eales disease who were given methotrexate for 12 weeks, 86 percent achieved excellent visual outcomes [23]. Eighty percent of the patients had treatment responses by four weeks, and there were no serious adverse effects. Some experts may use mycophenolate as an alternative to methotrexate.

Patients with proliferative disease — For patients who are in the proliferative stage of Eales disease, we suggest photocoagulation rather than continued immunosuppressive therapy. Laser photocoagulation is contraindicated during periods of active inflammation, when neovascularization may be worsened by the release of angiogenic factors.

The aims of photocoagulation in Eales disease are threefold:

●To divert blood from hypoxic areas to areas of healthy retina, thereby decreasing the stimulus for vasoproliferative factors

●To destroy areas of surface neovascularization, thereby reducing the likelihood of vitreous hemorrhage

●To seal leaks from microvascular abnormalities within the retina

Evidence for the efficacy of laser photocoagulation in Eales disease is largely extrapolated from data demonstrating the efficacy of this intervention in the proliferative retinopathy of diabetes and is discussed in detail separately (see "Diabetic retinopathy: Prevention and treatment", section on 'Panretinal photocoagulation'). If applied properly, photocoagulation can help prevent the late complications of Eales disease, including recurrent vitreous hemorrhage, retinal detachment, anterior segment neovascularization, and secondary glaucoma. In a retrospective study that included 43 eyes with Eales disease complicated by neovascularization, the rate of visual acuity improved from 53 percent before treatment to 60 percent after photocoagulation treatment [24].

Intravitreal anti-vascular endothelial growth factor (VEGF) injections may also play a role as adjunctive therapy for patients with proliferative Eales disease. Anti-VEGF agents have been primarily used in patients with diseases inducing retinal and choroidal neovascularization, such as age-related macular degeneration. However, there are case reports regarding the use of intravitreal anti-VEGF injections in patients with proliferative Eales disease with favorable clinical responses (specifically bevacizumab 1.25 mg/0.05 mL) [25,26].

Patients with hemorrhage and/or retinal detachment — Pars plana vitrectomy is generally required for patients with Eales disease complicated by persistent vitreous hemorrhage with or without retinal detachment. The goal of vitrectomy is to remove vitreous opacities and to evaluate the fundus for retinal neovascularization. In some series, almost 20 percent of patients with Eales disease eventually undergo vitrectomy [4].

For patients with vitreous hemorrhage and obscuration of central vision, we suggest vitreal surgery between three and six months in patients rather than delaying beyond six months. Visual outcomes may be better in patients who undergo vitrectomy between three and six months, compared with those in whom the procedure is deferred for more than six months [27]. Earlier vitrectomy may be considered if a traction retinal detachment occurs or if there is extensive membrane formation within the vitreous or over the macula.

PROGNOSIS — Patients with Eales disease are at greatest risk when their disease remains undiagnosed until an advanced stage, when recurrent vitreous hemorrhages and retinal detachments may pose serious threats to vision. Diagnosis at an early stage, appropriate access to care, and judicious medical and surgical interventions usually lead to favorable outcomes [21].

Eales disease rarely results in blindness. In a study of 800 patients with Eales disease involving a total of 1214 eyes, only 4 eyes had vision worse than 20/200, and only 8 percent had visual acuity between 20/100 and 20/200 [7]. In another series of 135 patients, only 1 became blind in both eyes [6].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

SUMMARY AND RECOMMENDATIONS

●Definition – Eales disease is a form of vasculitis typified by venous inflammation (periphlebitis) in the peripheral retina. (See 'Introduction' above.)

●Epidemiology – Eales disease occurs more commonly on the Indian subcontinent than any other region in the world. The disorder has a tendency to affect younger males. (See 'Epidemiology' above.)

●Pathogenesis and pathophysiology – The cause of Eales disease remains unknown. Substantial speculation has surrounded the potential association between Mycobacterium tuberculosis and Eales disease. The pathophysiology involves three basic processes: inflammation (peripheral retinal perivasculitis), ischemic changes (peripheral retinal capillary nonperfusion), and neovascularization. (See 'Pathogenesis and pathophysiology' above.)

●Clinical features – Patients are usually asymptomatic in the initial stages and present in a subacute manner. Some patients report floating spots in one or both eyes. Mild visual blurring can occur early in the disease course, but painless visual loss may develop later because of vitreous hemorrhage. The duration of symptom progression can be quite variable, ranging from weeks to months. (See 'Ocular symptoms and signs' above.)

●Ocular examination – The initial evaluation in a patient with suspected Eales disease should focus on obtaining an expedited eye examination by an ophthalmologist. As the changes caused by the disease involve the retina, careful assessment of the retinal vasculature via indirect ophthalmoscopy is imperative to document disease pathology. (See 'Ocular symptoms and signs' above.)

●Subsequent evaluation – Once the presence of retinal vasculitis is confirmed, a subsequent evaluation is performed to exclude the presence of an underlying disease observed in patients with retinal vasculitis associated with systemic disorders and infections. (See 'Subsequent evaluation to exclude alternative diagnoses' above.)

●Diagnosis – The diagnosis of Eales disease is based upon the presence of characteristic clinical findings on eye examination and the exclusion of systemic disorders that may result in similar findings, such as sarcoidosis, which can exhibit similar ocular manifestations to early-stage Eales disease.

●Treatment – The treatment of Eales disease is predicated upon the patient's disease manifestations and severity. Our approach is as follows:

•For patients who do not have evidence of active peripheral retinal vasculitis, we suggest watchful waiting rather than medical therapy (Grade 2C). Watchful waiting usually consists of follow-up evaluation with slit-lamp examinations and fundus fluorescein angiography (FFA) every six months. (See 'Patients without active retinal vasculitis' above.)

•For most patients with active retinal vasculitis, we suggest initial treatment with high doses of systemic glucocorticoids rather than other immunosuppressive therapies (Grade 2C). However, methotrexate may be a reasonable alternative in patients at risk for or who develop severe toxicity from glucocorticoids. (See 'Patients with active retinal vasculitis' above.)

•For patients who are in the proliferative stage of Eales disease, we suggest photocoagulation rather than continued medical therapy or vitrectomy (Grade 2C). (See 'Patients with hemorrhage and/or retinal detachment' above.)

•Vitrectomy is generally required for patients with Eales disease complicated by persistent vitreous hemorrhage with or without retinal detachment. For patients with vitreous hemorrhage and obscuration of central vision, we suggest vitreal surgery between three and six months in patients rather than delaying surgery beyond six months (Grade 2C). (See 'Patients with hemorrhage and/or retinal detachment' above.)

●Prognosis – Eales disease rarely results in blindness, even in patients who experience vitreous hemorrhages. Early diagnosis, appropriate access to care, and judicious interventions usually lead to favorable outcomes. (See 'Prognosis' above.)