Difference between revisions of "Eales Disease"

From EyeWiki
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{{Article
 
{{Article
|Authors=Andreas.K.Lauer
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|Authors=Monique Munro
 
|Category=Retina/Vitreous
 
|Category=Retina/Vitreous
 
|Assigned editor=Pooja.Bhat
 
|Assigned editor=Pooja.Bhat
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= Authors =  
 
= Authors =  
'''Kristen Ann Mendoza, MD;  Andreas Lauer, MD'''
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'''Monique Munro MD, Kristen Ann Mendoza, MD;  Andreas Lauer, MD'''
  
 
== Disease  ==
 
== Disease  ==
  
Eales disease is an idiopathic peripheral retinal vasculopathy characterized by inflammation, ischemia, retinal neovascularization and is hallmarked by recurrent vitreous hemorrhages.
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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
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==Epidemiology==
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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
  
 
== Etiology  ==
 
== Etiology  ==
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No definite cause for Eales disease has been found to date and it is considered idiopathic.
 
No definite cause for Eales disease has been found to date and it is considered idiopathic.
  
== Risk Factors ==
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== Pathophysiology ==
  
Eales disease has been reported predominantly in India, although it has been found in North America and Europe (rare in the modern era).   Eales disease tends to occur in males in their second decade and has been related to tuberculosis exposure and hypersensitivity to tuberculoprotein. Less commonly, it has been linked to CNS pathology (stroke, demyelination, intranuclear ophthalmoplegia), hematological abnormalities (abnormal red blood cell morphology), vestibuloauditory dysfunction, and focal sepsis.
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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
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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
  
== General Pathology  ==
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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
 
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Eales disease was originally described as a combination of recurrent intraocular hemorrhages in young men with constipation, epistaxis, and headache.  More recently, it has been found to be a process that progresses through retinal periphlebitis, ischemia, and neovascularization. Specifically, peripheral retinal vessels first become inflamed and sheathed, then become occluded. The loss of perfusion leads to retinal neovascularization that causes recurrent vitreous hemorrhages. Eales is considered a bilateral disease in up to 90% of patients, although symptoms often present unilaterally.
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== Pathophysiology  ==
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The exact pathological mechanisms in Eales disease are largely unclear despite several basic science and clinical studies.  Immunologic mechanisms have been proposed.  T-cell lymphocytic infiltration has been found in the epiretinal and subretinal membranes associated with Eales. There have also been associations made with the retinal S-antigen and HLA B5, DR1, DR4 and patients with autoimmune disease.  Support has been found for oxidative stress, as increased accumulation of lipid peroxide, increased carboxy methyl lysine, decreased glutathione, and decreased vitamins C and E has been found.  Similarly, increased vascular endothelial growth factor (VEGF) results in retinal neovascularization.
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== Primary prevention  ==
 
== Primary prevention  ==
  
There are no preventative measures for Eales disease.
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There are no known preventative measures for Eales’ disease.
  
= Diagnosis =
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==Diagnosis==
  
 
Eales disease is a clinical diagnosis of exclusion.
 
Eales disease is a clinical diagnosis of exclusion.
  
== History  ==
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==Signs and Symptoms==
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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
  
Those with Eales disease typically present as young males living in India.  Patients may have other associated risk factors as mentioned above.  A history of a systemic disorder can point away from the diagnosis of Eales.
 
  
 
== Physical examination  ==
 
== Physical examination  ==
* Visual acuity: Two-thirds of patients have vision 20/40 or better as the disease tends to spare the macula and predominantly affects the peripheral retina.  In patients with vitreous hemorrhage or more severe disease, the vision may be very poor. No perception of light may result from optic atrophy secondary to neovascular glaucoma, chronic retinal detachment, and other causes.
 
* Anterior segment: cell and flare, rubeosis irides (late finding), neovascular glaucoma (late finding), nongranulomatous uveitis (rare finding).
 
* Vitreous: cells and debris (early finding), hemorrhage (late finding); dense vitritis is uncommon.
 
* Optic nerve: edema, neovascularization.
 
* Retina: perivascular sheathing and exudate, vessel tortuosity, venous obstruction, capillary non-perfusion, neovascularization, retinal detachment, epiretinal membrane, macular edema.
 
  
== Signs  ==
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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
* Eales is initially asymptomatic, but then progresses through general stages of the disease. While there is no standardized classification of Eales due to clinical overlap of early and late signs of the disease, three phases are typically recognized:
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• 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.
* Early (inflammatory) Stage: periphlebitis is hallmark and may be found in various stages and in various quadrants concurrently; venous dilation and perivascular exudates can be found as well.
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• Anterior segment: nongranulomatous uveitis may occur from posterior spill over (less common), rubeosis iridis, neovascular glaucoma/neovascularization of the angle.
* Middle (ischemic) Stage: characterized by capillary ischemia; demarcation between perfused and nonperfused zones is marked by veno-venous shunts, venous beadings, and micro-aneurysms.
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• Vitreous: cells and debris, vitreous hemorrhage; dense vitritis is uncommon.
* Late (proliferative) Stage: neovascularization occurs at the junction between perfused and non-perfused retina that leads to recurrent vitreous hemorrhages with or without retinal detachment.
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• 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).  
* Eales disease tends to occur peripherally, but macular edema and disc neovascularization may occur.
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• Optic nerve: edema, neovascularization (0.9% eyes).4
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• Choroid: not involved.
  
== Symptoms  ==
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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
  
Patients may present with decreased vision, photopsia, and floaters unilaterally or bilaterally.
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== Signs  ==
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Due to clinical overlap with Eales’ disease findings, there is no standardized staging; however, three phases are typically recognized:
  
== Clinical diagnosis  ==
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• 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.
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• Intermediate Stage (Ischemic): characterized by retinal capillary ischemia. Demarcation between perfused and nonperfused retina is marked by arteriovenous shunts, venous beadings, and micro-aneurysms.
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• 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.
  
Eales disease is a diagnosis of exclusion. Peripheral retinal inflammation and recurrent vitreous hemorrhages in the absence of other systemic conditions are important defining features.
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Based of the above findings, Saxena et al.13 propose the following stages:
  
== Diagnostic procedures  ==
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Stage Findings
* Fluorescein angiography (FA): leakage of sheathed vessels, retinal vascular tortuosity and telangiectasias, shunt vessels, venous stasis, capillary non-perfusion and sharply demarcated areas of non-perfusion, retinal neovascularization
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I         Peripheral phlebitis of small (Ia) and large (Ib) caliber vessels with retinal hemorrhage
* Inflammation correlates to venous insufficiency.  In the inflammatory stage, extravasation of dye indicates active inflammation. Venous staining without leakage indicates sclerosed vessels or resolved inflammation.
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IIa         Capillary nonperfusion
* Ultrasonography: useful for detecting retinal detachment when vitreous hemorrhage obscures view of the fundus.
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IIb         Revascularization elsewhere/of the disc
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IIIa         Fibrovascular proliferation
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IIIb Vitreous hemorrhage
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IVa Traction/combined rhegmatogenous retinal detachment
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IVb Rubeosis iridis, neovascular glaucoma, complicated cataract, and optic atrophy
  
== Laboratory test  ==
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==Diagnosis==
  
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.  As Mycobacterium tuberculosis DNA has been found in the vitreous of patients with Eales disease, the Mantoux test and a chest x-ray may be helpful.  Hemoglobin electrophoresis can assess for sickle cell retinopathy, serum angiotensin converting enzyme and a chest x-ray can point to sarcoidosis, the Venereal Disease Research Laboratory test (VDRL) is useful for syphilis, and anti nuclear antibody (ANA) can indicate systemic lupus erythematosus (SLE).
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Eales’ disease is a diagnosis of exclusion and requires evaluation for ocular and systemic conditions associated with retinal periphlebitis, neovascularization and recurrent vitreous hemorrhage.  
  
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).
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==Differential Diagnosis==
  
== Differential diagnosis  ==
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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
* Vasculitides and retinopathies comprise the differential for Eales disease.
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* Vascular: retinopathy of prematurity, branch retinal vein occlusion, Bechet’s syndrome, radiation retinopathy, coagulopathy,  granulomatosis with polyangiitis (formerly Wegener's).
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* Infectious: lyme disease, syphilis.
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* Autoimmune: frosted branch angiitis, ulcerative colitis, multiple sclerosis, sarcoidosis, Birdshot retinochoroidopathy.
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* Idiopathic: serpiginous choroiditis, central serous retinopathy, idiopathic hypereosinophilia, Coat’s disease, idiopathic retinal vasculitis aneurysms and neuretinitis, Susac disease.
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* Neoplastic: leukemia.
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* Congenital: sickle cell retinopathy, incontinentia pigmenti, familial exudative vitreoretinopathy.
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* Endocrine: diabetic retinopathy
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* Choroiditis or hypopyon are not present in Eales disease.
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= General treatment & Management  =
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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:
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• Autoimmune-related causes of retinal phlebitis: sarcoidosis, frosted branch angiitis, multiple sclerosis, pars planitis, Bechet’s disease, human immune deficiency virus (HIV).
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• 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.
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• Vascular disease: diabetic retinopathy, sickle cell retinopathy, branch retinal vein occlusion, radiation retinopathy, coagulopathies, and retinopathy of prematurity.
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• Infectious retinal vasculitis: syphilis, tuberculosis, Lyme disease.
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• Idiopathic: IRVAN, Susac disease, idiopathic hypereosinophilia, Coat’s disease.
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• Neoplastic: leukemia.
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• Congenital: incontinentia pigmenti, familial exudative vitreoretinopathy.
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.
  
Observation is warranted in patients with inactive vasculitis or new vitreous hemorrhage in the setting of an attached retina for 6 months and 6 weeks, respectively.
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== Diagnostic procedures  ==
 +
• Fluorescein angiography (FA): leakage of dye surrounding veins indicates active inflammation. Venous staining without leakage indicates sclerosed vessels or resolved inflammation.
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• Wide-field FA: enables assessment of peripheral areas with better quality and allows peripheral observation of the above findings.15
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• Ultrasonography: allows detection of retinal detachment when vitreous hemorrhage obscures view of the fundus.
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• 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.
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• OCT-angiography (OCT-A): may detect neovascularization depending on location of involvement.
  
== Medical therapy  ==
 
  
Steroid (systemic and or local/periocular) is the mainstay of treatment for the inflammatory stage. Whether isolated/ incidentally detected localized area of retinal vasculitis (asymptomatic or not causing vision loss) requires therapy is controversial. However, in the presence of vasculitis threatening vision or causing cystoid macular edema treatment is needed.
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== Laboratory test ==
  
Bilateral vasculitis may be treated with oral steroid and or sequential subtenon triamcinolone/intravitreal triamcinolone/intravitreal ozurdex/ other intravitreal steroid implants.
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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.
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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.
  
Intravitreal or periocular steroid in unilateral disease avoids the systemic side effects of steroid.
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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).
  
In inflammatory stage, usually oral prednisone (1 mg/kg tapered over 6-8 weeks) is used. In some patients a maintenance dose (15-20 mg per day for up to 2 months) is needed.   
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= General treatment & Management  =
  
"Efficacy of systemic or periocular corticosteroids in the inflammatory stage of Eales disease was studied in a nonrandomized clinical trial where systemic steroid (1mg/kg of body weight) and posterior sub-tenon injection of steroid (triamcinolone acetonide 40 mg/ml) were found beneficial if there was involvement of three quadrants with cystoid macular edema. Systemic corticosteroids alone were helpful when there was two quadrant involvement. In the case of one quadrant involvement, periocular corticosteroids were administered. However, the natural course of Eales disease remained unaltered in spite of steroid therapy. There was no difference in response to treatment in the Mantoux-positive and Mantoux-negative groups of patients." (Biswas J, Sharma T, Gopal L, Madhavan HN, Ramakrishnan S. Eales disease – an update. Surv. Ophthalmol. 2002;47(3):197-214.)
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General Treatment
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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
  
Non-steroidal immunosuppressive agents are reserved for those in whom steroids are ineffective or contraindicated. With vascular non-perfusion and retinal neovascularization, intravitreal anti-VEGF therapy may be successful, however its effects may cause vitreoretinal contraction. In patients with exposure to tuberculosis, anti-tubercular therapy can be given for 9 months, but this is reserved for patients with massive infiltration, nodule formation, and venous obliteration.
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Medical Treatment
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Corticosteroids
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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
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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
  
== Medical follow up  ==
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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
  
Ultransonographic surveillance of the retina when allowing vitreous hemorrhage to clear spontaneously is useful. Use of supplemental antioxidants such as vitamins C and E to help fight oxidative stress on the retina has been advocated in the past but is less commonly recommended in recent times.
 
  
== Surgery  ==
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Anti-Vascular Endothelial Growth Factor (Anti-VEGF)
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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
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Tuberculosis Treatment
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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
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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
  
For patients with later stage disease where retinal neovascularization is present, laser scatter photocoagulation (peripheral pan retinal photocoagulation) in the areas of retinal non-perfusion induces regression of neovascularization.  Moderately strong, 200-500 micrometer, overlapping laser spots are applied to the areas of retinal non-perfusion and direct photocoagulation of new and underlying feeder vessels is suggested.  When optic disc neovascularization is present, panretinal photocoagulation laser is recommended.  For nonresolving vitreous hemorrhage and/or retinal detachment (whether tractional, rhegmatogenous, or combined), pars plana vitrectomy is necessary, with or without other vitreoretinal surgical procedures.  Endolaser treatment may be applied at the time of surgery.  Vitrectomy for nonresolving vitreous hemorrhage should be performed no later than 6 months following onset of hemorrhage.
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Photocoagulation
  
When access to vitrectomy is not possible and the view to the peripheral retina is compromised by vitreous hemorrhage, trans-scleral anterior retinal cryoablation may be use alone or in conjunction with photocoagulation of ophthalmoscopically visible non-perfused retina.
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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.
  
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Surgical Treatment
  
== Surgical follow up  ==
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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
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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
  
Since subsequent ischemia develops often, further photocoagulation is typically required.
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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.
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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 ==
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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
  
Post-operative complications include choroidal neovascularization, retinal, choroidal or vitreous hemorrhage, retinal detachment, epiretinal membrane, glaucoma and cataract.
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Prognosis
 
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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.
== Prognosis ==
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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, blindness is rare, and vision less than 20/200 occurs in less than 1% of patients.  
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= References  =
 
= References  =
  
1. Das T, Pathengay A, Hussain N, Biswas J. Eales’ disease: diagnosis and management. Eye (Lond). 2010;24(3):472-82.
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1. Eales H. Primary retinal haemorrhage in young men. Ophthalmic Rev. 1882;1: 41.
 
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2. Biswas J, Ravi RK, Naryanasamy A, Kulandai LT, Madhavan HN. Eales' disease - current concepts in diagnosis and management. J Ophthalmic Inflamm Infect. 2013;3(1):11.
2. Agrawal S, Agrawal J, Agrawal TK. Intravitreal triamcinolone acetonide in Eales disease. Retina. 2006;26(2):227-9.
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3. Das T, Pathengay A, Hussain N, Biswas J. Eales’ disease: diagnosis and management. Eye (Lond). 2010;24(3):472-82.
 
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4. Biswas J, K R R, Pal B, Gondhale HP, Kharel Sitaula R. Long-Term Outcomes of a Large Cohort of Patients with Eales' Disease. Ocul Immunol Inflamm. 2018;26(6):870‐876.
3. Biswas J, Sharma T, Gopal L, Madhavan HN, Ramakrishnan S. Eales disease – an update. Surv. Ophthalmol. 2002;47(3):197-214.
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5. Ishaq M, Karamat S, Niazi MK. HLA typing in patients of Eales disease. J Coll Physicians Surg Pak. 2005 May; 15(5):288-90.
 
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6. Rajesh M, Sulochana KN, Coral K, et al. Determination of carbonyl group content in plasma proteins as a useful marker to assess impairment in antioxidant defense in patients with Eales' disease. Indian J Ophthalmol. 2004;52(2):139-144.
4. Fraunfelder FT, Roy FH. Current Ocular Therapy. 5th edition. Philadelphia: W.B. Saunders Company; 2000. 609-11.
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7. Saxena S, Rajasingh J, Biswas S, Kumar D, Shinohara T, Singh VK. Pathobiology. 1999; 67(1):39-44
 
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8. Madhavan HN, Therase KL, Gunisha P, Jayanthi U, Biswas J . Polymerase chain reaction for detection of Mycobacterium tuberculosis in epiretinal membrane in Eales’ disease. Invest Ophthalmol Vis Sci. 2000; 41: 822–825.
5. Roy FH, Fraunfelder FW, Fraunfelder FT. Current Ocular Therapy. 6th edition. Elsevier; 2008. 624-5.
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9. Therese KL, Deepa P, Therese J, Bagyalakshmi R, Biswas J, Madhavan HN: Association of mycobacteria with Eales’ disease. Indian J Med Res. 2007, 126: 56–62.
 
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10. Singh R, Toor P, Parchand S, Sharma K, Gupta V, Gupta A: Quantitative polymerase chain reaction for Mycobacterium tuberculosis in so-called Eales’ disease. Ocul Immunol Inflamm. 2012,20(3):153–157.
6. Gupta SR, Flaxel CJ. The use of a vascular endothelial growth factor inhibitor (ranibizumab) in macular edema due to eales disease. Retin. Cases Brief Rep. 2012;6(1):122-4.
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11. Muthukkaruppan VR, Rengarajan K, Chakkalath HR, Namperumalsamy P . Immunological status of patients of Eales’ disease. Indian J Med Res. 1989; 90: 351.
 
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12. Saxena S, Kumar D. Visual outcome of patients with central Eales disease. Ann Ophthalmol. 2001;33(4):300–302.  
7. Patwardhan SD, Azad R, Shah BM, Sharma Y. Role of intravitreal bevacizumab in Eales disease with dense vitreous hemorrhage: a prospective randomized control study. Retina. 2011;31(5):866-70.
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13. Saxena S, Kumar D: A new staging system for idiopathic retinal periphlebitis. Eur J Ophthalmol. 2004,14(3):236–239.
 
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14. Abu El-Asrar AM, Herbort CP, Tabbara KF. Differential diagnosis of retinal vasculitis. Middle East Afr J Ophthalmol. 2009;16(4):202‐218. doi:10.4103/0974-9233.58423
8. Sen A, Paine SK, Chowdhury IH, Mukherjee A, Choudhury S, Mandal LK, Bhattacharya B. Assessment of gelatinase and tumor necrosis factor-alpha level in the vitreous and serum of patients with Eales disease: role of inflammation-mediated angiogenesis in the pathogenesis of Eales disease. Retina. 2011;31(7):1412-20.
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15. Cruzado-Sánchez D, Tellez WA, Barriga-Salaverry G, Luglio-Valdivieso H, Luján-Najar S. Wide-field angiography for diagnosis and follow-up of Eales disease: a case series. Arq Bras Oftalmol. 2019;82(4):339‐344. Published 2019 May 20.
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16. Goel N, Kumar V, Arora S, Jain P, Ghosh B. Spectral domain optical coherence tomography evaluation of macular changes in Eales disease. Indian J Ophthalmol. 2018;66(3):433‐438.  
 +
17. Agrawal S, Agrawal J, Agrawal TK. Intravitreal triamcinolone acetonide in Eales disease. Retina. 2006;26(2):227-9.
 +
18. Patwardhan SD, Azad R, Shah BM, Sharma Y: Role of intravitreal bevacizumab in Eales disease with dense vitreous hemorrhage: a prospective randomized control study. Retina. 2011, 31: 866–870.
 +
19. Chanana B, Azad RV, Patwardhan S: Role of intravitreal bevacizumab in the management of Eales’ disease. Int Ophthalmol. 2010, 30: 57–61.
 +
20. Ishaq M, Niazi MK: Usefulness of laser photocoagulation in managing asymptomatic eyes of Eales disease. J Ayub Med Coll Abbottabad. 2002,14(4):22–25.
 +
21. Gopal L, Abraham C. Efficacy of photocoagulation in Eales’ disease. Trans Asia-Pacific Acad. 1985; 10: 689
 +
22. Das TP, Namperumalsamy P . Photocoagulation in Eales’ disease. Results of prospective randomised clinical study. Presented in XXVI Int Cong Ophthalmol, Singapore, 1990.
 +
23. Selvi R, Angayarkanni N, Biswas J, Ramakrishnan S: Total antioxidant capacity in Eales’ disease, uveitis & cataract. Indian J Med Res. 2011,134(1):83–90.
 +
24. Saxena S, Srivastava P, Khanna VK: Antioxidant supplementation improves platelet membrane fluidity in idiopathic retinal periphlebitis (Eales' disease). J Ocul Pharmacol Ther. 2010,26(6):623–626
 +
25. Ramakrishnan S, Rajesh M, Sulochana K N. Eales Disease: Oxidant stress and weak antioxidant defence. Indian J Ophthalmol. 2007;55:95-102
 +
26. Shukla D, Kanungo S, Prasad NM, Kim R: Surgical outcomes for vitrectomy in Eales’ disease. Eye. 2008, 22: 900–904.
 +
27. Asghar A, Niazi JH: Role of vitrectomy in the management of Eales’ disease. Pak J Ophthalmol. 2007,23(1):1–5.

Revision as of 19:09, September 23, 2020


Eales Disease


Disease Entity

Eales Disease

Authors

Monique Munro MD, Kristen Ann Mendoza, MD; Andreas Lauer, MD

Disease

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

Epidemiology

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

Etiology

No definite cause for Eales disease has been found to date and it is considered idiopathic.

Pathophysiology

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

Primary prevention

There are no known preventative measures for Eales’ disease.

Diagnosis

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


Physical examination

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

Signs

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

Diagnosis

Eales’ disease is a diagnosis of exclusion and requires evaluation for ocular and systemic conditions associated with retinal periphlebitis, neovascularization and recurrent vitreous hemorrhage.

Differential Diagnosis

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. .

Diagnostic procedures

• 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 test

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

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.

Surgical 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.


References

1. Eales H. Primary retinal haemorrhage in young men. Ophthalmic Rev. 1882;1: 41. 2. Biswas J, Ravi RK, Naryanasamy A, Kulandai LT, Madhavan HN. Eales' disease - current concepts in diagnosis and management. J Ophthalmic Inflamm Infect. 2013;3(1):11. 3. Das T, Pathengay A, Hussain N, Biswas J. Eales’ disease: diagnosis and management. Eye (Lond). 2010;24(3):472-82. 4. Biswas J, K R R, Pal B, Gondhale HP, Kharel Sitaula R. Long-Term Outcomes of a Large Cohort of Patients with Eales' Disease. Ocul Immunol Inflamm. 2018;26(6):870‐876. 5. Ishaq M, Karamat S, Niazi MK. HLA typing in patients of Eales disease. J Coll Physicians Surg Pak. 2005 May; 15(5):288-90. 6. Rajesh M, Sulochana KN, Coral K, et al. Determination of carbonyl group content in plasma proteins as a useful marker to assess impairment in antioxidant defense in patients with Eales' disease. Indian J Ophthalmol. 2004;52(2):139-144. 7. Saxena S, Rajasingh J, Biswas S, Kumar D, Shinohara T, Singh VK. Pathobiology. 1999; 67(1):39-44 8. Madhavan HN, Therase KL, Gunisha P, Jayanthi U, Biswas J . Polymerase chain reaction for detection of Mycobacterium tuberculosis in epiretinal membrane in Eales’ disease. Invest Ophthalmol Vis Sci. 2000; 41: 822–825. 9. Therese KL, Deepa P, Therese J, Bagyalakshmi R, Biswas J, Madhavan HN: Association of mycobacteria with Eales’ disease. Indian J Med Res. 2007, 126: 56–62. 10. Singh R, Toor P, Parchand S, Sharma K, Gupta V, Gupta A: Quantitative polymerase chain reaction for Mycobacterium tuberculosis in so-called Eales’ disease. Ocul Immunol Inflamm. 2012,20(3):153–157. 11. Muthukkaruppan VR, Rengarajan K, Chakkalath HR, Namperumalsamy P . Immunological status of patients of Eales’ disease. Indian J Med Res. 1989; 90: 351. 12. Saxena S, Kumar D. Visual outcome of patients with central Eales disease. Ann Ophthalmol. 2001;33(4):300–302. 13. Saxena S, Kumar D: A new staging system for idiopathic retinal periphlebitis. Eur J Ophthalmol. 2004,14(3):236–239. 14. Abu El-Asrar AM, Herbort CP, Tabbara KF. Differential diagnosis of retinal vasculitis. Middle East Afr J Ophthalmol. 2009;16(4):202‐218. doi:10.4103/0974-9233.58423 15. Cruzado-Sánchez D, Tellez WA, Barriga-Salaverry G, Luglio-Valdivieso H, Luján-Najar S. Wide-field angiography for diagnosis and follow-up of Eales disease: a case series. Arq Bras Oftalmol. 2019;82(4):339‐344. Published 2019 May 20. 16. Goel N, Kumar V, Arora S, Jain P, Ghosh B. Spectral domain optical coherence tomography evaluation of macular changes in Eales disease. Indian J Ophthalmol. 2018;66(3):433‐438. 17. Agrawal S, Agrawal J, Agrawal TK. Intravitreal triamcinolone acetonide in Eales disease. Retina. 2006;26(2):227-9. 18. Patwardhan SD, Azad R, Shah BM, Sharma Y: Role of intravitreal bevacizumab in Eales disease with dense vitreous hemorrhage: a prospective randomized control study. Retina. 2011, 31: 866–870. 19. Chanana B, Azad RV, Patwardhan S: Role of intravitreal bevacizumab in the management of Eales’ disease. Int Ophthalmol. 2010, 30: 57–61. 20. Ishaq M, Niazi MK: Usefulness of laser photocoagulation in managing asymptomatic eyes of Eales disease. J Ayub Med Coll Abbottabad. 2002,14(4):22–25. 21. Gopal L, Abraham C. Efficacy of photocoagulation in Eales’ disease. Trans Asia-Pacific Acad. 1985; 10: 689 22. Das TP, Namperumalsamy P . Photocoagulation in Eales’ disease. Results of prospective randomised clinical study. Presented in XXVI Int Cong Ophthalmol, Singapore, 1990. 23. Selvi R, Angayarkanni N, Biswas J, Ramakrishnan S: Total antioxidant capacity in Eales’ disease, uveitis & cataract. Indian J Med Res. 2011,134(1):83–90. 24. Saxena S, Srivastava P, Khanna VK: Antioxidant supplementation improves platelet membrane fluidity in idiopathic retinal periphlebitis (Eales' disease). J Ocul Pharmacol Ther. 2010,26(6):623–626 25. Ramakrishnan S, Rajesh M, Sulochana K N. Eales Disease: Oxidant stress and weak antioxidant defence. Indian J Ophthalmol. 2007;55:95-102 26. Shukla D, Kanungo S, Prasad NM, Kim R: Surgical outcomes for vitrectomy in Eales’ disease. Eye. 2008, 22: 900–904. 27. Asghar A, Niazi JH: Role of vitrectomy in the management of Eales’ disease. Pak J Ophthalmol. 2007,23(1):1–5.