Eales’ disease revisited: Current understanding of etiopathogenesis, multimodal imaging, and treatment strategies

Eales’ disease is an idiopathic occlusive retinal vasculitis, first described by Sir Henry Eales in 1880, that primarily affects healthy young adults in their second to fourth decades of life, with a predilection for males and populations in tuberculosis (TB), endemic regions such as the Indian subcontinent, and Southeast Asia.[1,2] Clinically, it is characterized by peripheral retinal periphlebitis progressing through stages of ischemia and proliferative neovascularization [Fig. 1a-d], culminating in recurrent vitreous hemorrhage, tractional retinal detachment [Fig. 2], and potentially irreversible visual loss.[1] Although bilateral involvement occurs in up to 80–90% of cases over time, the disease is often unilateral at presentation, a fact that can delay diagnosis.Figure 1: Representative fundus photographs depicting the four clinical stages of Eales’ disease. (a) Stage I (Inflammatory Phase), (b) Stage II (Ischemic Phase), (c) Stage III (Proliferative Phase), and (d) Stage IV (Advanced Tractional band)Figure 2: Color fundus image of a patient with long-standing Eales’ disease demonstrating florid neovascularization of the optic disc (NVD). These findings represent the proliferative stage of disease, associated with a high risk of vitreous hemorrhage and tractional complicationsThe label “idiopathic” has become increasingly untenable in light of compelling molecular, immunological, and epidemiological evidence implicating Mycobacterium tuberculosis (MTB) DNA as the principal immunological trigger.[3–5] Yet, the heterogeneity of clinical presentations, overlapping features with other inflammatory vasculitides, and the variable predictive value of TB immunological tests across endemic and nonendemic settings continue to challenge the clinician. This editorial aims to provide a pragmatic, stage-based clinical framework for the diagnosis and management of Eales’ disease, synthesizing current evidence into actionable decision-making tools for the practicing ophthalmologist. Current Understanding: A Nonidiopathic, Immune-Mediated Vasculitis Eales’ disease is now best understood as a hypersensitivity response to MTB antigens in genetically susceptible individuals, rather than a primary infectious or truly idiopathic condition.[4,5] Mantoux positivity is reported in up to 83% of patients, and seminested PCR has detected MTB DNA in up to 70% of epiretinal and vitreous samples, yet direct bacterial invasion of ocular tissue is conspicuously absent.[4] This paradox supports a type-IV hypersensitivity mechanism, wherein sensitised T-lymphocytes (predominantly CD4+ and CD8+) mount an aberrant immune response to retinal antigens sharing molecular mimicry with mycobacterial epitopes, particularly retinal S-antigen and interphotoreceptor retinoid-binding protein. Immunogenetic associations with HLA-B5 (B51), DR1, and DR4 further underscore heritable susceptibility. At the molecular level, innate immune activation via CD16+ monocytes with upregulated TLR-2 expression drives a proinflammatory cascade characterized by elevated TNF-α and IL-6, which promote endothelial activation and upregulate matrix metalloproteinase-9 (MMP-9), facilitating extracellular matrix breakdown and angiogenesis. Concurrently, a significantly elevated vitreous VEGF/PEDF ratio shifts the retinal milieu decisively toward neovascularization.[6–8] Clinicians should view these molecular perturbations not as disease-specific hallmarks but as shared downstream pathways that amplify once ischemia and inflammation are established, justifying both anti-inflammatory and anti-angiogenic therapeutic strategies. Diagnostic Challenges: Differentiating Eales’ Disease from Mimics The diagnosis of Eales’ disease remains one of exclusion. Three conditions warrant particular scrutiny in everyday clinical practice. First, tubercular retinal vasculitis (TRV) typically manifests with accompanying choroiditis, multifocal retino-choroidal lesions, or necrotising retinitis and is supported by angiographic evidence of discrete choroidal hypofluorescent lesions with late staining. Critically, positive MTB immunological tests in TRV carry a different interpretive weight; they indicate active or reactivating ocular infection rather than the mere sensitisation seen in Eales’ disease. Ocular fluid PCR positivity and radiological evidence of active or healed pulmonary TB on HRCT favor TRV. Second, sarcoid vasculitis presents with granulomatous anterior uveitis, pathognomonic “candle-wax” perivenous exudates, and mixed arteriovenous involvement, contrasting with the predominantly venous and peripheral periphlebitis of Eales’ disease. Bilateral hilar lymphadenopathy, elevated serum ACE or soluble IL-2 receptor, and systemic organ involvement are discriminating features. Skin or lymph node biopsy may be required for confirmation. Behçet’s retinal vasculitis is characterized by explosive panuveitis, necrotizing vasculitis with prominent arterial involvement, and widespread early capillary nonperfusion (CNP) on angiography, a fulminant picture distinct from Eales’ indolent peripheral phlebitis. The systemic context of recurrent oral and genital ulceration, skin lesions, and pathergy positivity is diagnostic. A critical point for clinicians in TB-endemic regions is that a positive Mantoux or IGRA frequently reflects prior sensitization and does not, in isolation, establish either TRV or a tubercular etiology for Eales’ disease. The diagnostic weight of these tests rises substantially in nonendemic settings. In endemic regions, a positive immunological test must be corroborated by HRCT chest findings (apical scarring, healed granulomas, nodules), angiographic features of peripheral occlusive phlebitis without granulomatous choroiditis, and clinical course before attributing the disease to TB hypersensitivity or initiating antitubercular therapy (ATT). Role of Multimodal Imaging: Clinically Relevant Utilities Imaging in Eales’ disease serves three practical purposes: staging the disease, identifying therapeutic targets, and monitoring response [Fig. 3a-d]. Ultra-widefield fluorescein angiography (UWF-FFA) images over 200°, detects additional areas of active vasculitis in up to 56% of visits compared with conventional FFA, and is indispensable for staging, mapping CNP for laser planning, and detecting early neovascularization [Fig. 4a-d].[9,10]Figure 3: (a) Montage of widefield color fundus photographs showing peripheral to mid-peripheral periphlebitis involving multiple quadrants, with evident venous dilation, perivascular exudation, and retinal hemorrhages—hallmarks of the inflammatory stage of Eales’ disease; (b) Ultra-widefield fundus image of the same eye provides enhanced visualization of the peripheral vasculitic changes and associated ischemia; (c) Color fundus photograph of a 21-year-old male presenting with dense vitritis and exudative, segmental, hemorrhagic periphlebitis with vascular tortuosity involving the posterior pole. The hazy media and posterior pole involvement are suggestive of tubercular retinal vasculitis; (d) Post-treatment image of the same patient following systemic anti-tubercular therapy and corticosteroids, demonstrating significant resolution of vascular inflammation and hemorrhage, confirming a favorable response to TB-targeted immunosuppressive therapyFigure 4: Widefield fluorescein angiography images demonstrating hallmark features of proliferative Eales’ disease. (a) Presence of veno-venous shunts indicating chronic retinal ischemia; (b) Mid-peripheral areas of capillary nonperfusion (CNP), reflecting retinal ischemia and driving neovascular stimuli; (c) Neovascularization of the retina with florid leakage in the late phase, representing active angiogenesis; (d) Macular leakage indicating posterior pole involvement and risk of vision impairment. Multiple central hypofluorescent spots with hyperfluorescent rings are consistent with laser photocoagulation marks administered to ischemic retina. UWF-FA allows superior visualization of the peripheral retina compared to OCT angiography (OCTA), enabling a more comprehensive assessment of peripheral vascular pathology and ischemia in Eales’ diseaseOCT Angiography (OCTA) noninvasively delineates deep capillary plexus dropout, foveal avascular zone distortion, and perifoveal ischemia correlating with visual acuity loss, findings that FFA may underestimate [Fig. 5a and b]. Swept-source OCTA (SS-OCTA) montages enable comprehensive macular and peripheral capillary bed assessment and can detect early epiretinal neovascularization. OCTA is particularly valuable for serial monitoring when fluorescein dye is contraindicated.[11]Figure 5: Superficial capillary plexus montage (12 × 12 mm) obtained using widefield swept-source OCTA in a patient with Eales’ disease. (a) Extensive areas of capillary nonperfusion and disorganized vascular architecture are seen, indicative of widespread retinal ischemia; (b) Pathologic neovascularization is visualized as irregular, fine vascular networks beyond the foveal avascular zone, confirming proliferative disease. The SS-OCTA montage enables detailed assessment of both macular and temporal peripheral capillary beds, surpassing traditional OCT in delineating microvascular dropout and vascular remodelingPlain chest radiograph is insufficiently sensitive for latent TB-related changes. HRCT chest detects apical scarring, healed granulomas, and miliary nodules with far greater sensitivity, findings that meaningfully influence the decision to initiate ATT in TB-seropositive patients with otherwise normal radiology.[12] B-Scan ultrasonography is essential when media opacity from dense vitreous hemorrhage precludes fundus visualization. B-scan identifies retinal detachment, vitreoretinal traction, and fibrovascular membranes, directly informing the decision for surgical intervention. En-face OCT and fundus autofluorescence add incremental value in assessing RPE health, retinal layer disorganisation, and macular structural integrity, particularly during long-term follow-up. Stage-Based Management Management of Eales’ disease demands a stage-specific, multimodal, and individualized approach. The two algorithmic frameworks below synthesize current evidence into practical decision pathways. Stage-based management algorithm STAGE I – INFLAMMATORY (Periphlebitis, Mild Vitritis) Systemic oral prednisolone (1 mg/kg/day), tapered over 6–8 weeks, remains the mainstay. In unilateral disease or systemic contraindications, periocular triamcinolone or intravitreal dexamethasone implant. If TB-positive (IGRA/Mantoux) with supporting HRCT or PCR, initiate 4-drug ATT (HRZE) concurrently with corticosteroids. Adjunctive antioxidants (Vitamins C, E) and folate pathway support (folic acid, B12) should be added. STAGE II – ISCHEMIC (Capillary Nonperfusion, No Active Neovascularization) Continue corticosteroids if active vasculitis persists; taper if quiescent. Pan-retinal photocoagulation (PRP) to be done in areas of CNP, perform only after inflammation is controlled (active vasculitis is a contraindication to laser). Serial UWF-FFA and OCTA monitoring at 3–6-month intervals to detect progression to Stage III. STAGE III – PROLIFERATIVE (Neovascularization, Vitreous Hemorrhage, Fibrovascular Bands) Complete PRP, if not previously performed. Intravitreal anti-VEGF (aflibercept) for active neovascularization or persistent vitreous hemorrhage. Anti-VEGF in eyes with established fibrovascular proliferation carries a real risk of tractional retinal detachment (TRD) from rapid membrane contraction. A randomized controlled trial (Patwardhan et al.)[13] confirmed that bevacizumab did not accelerate vitreous hemorrhage clearance or reduce vitrectomy rates, reinforcing selective use. Dexamethasone intravitreal implants are to be used for refractory macular edema. Consider steroid-sparing immunosuppressants (azathioprine, methotrexate 7.5 mg weekly, or cyclosporine) for recurrent or steroid-dependent disease. STAGE IV – ADVANCED/COMPLICATED (TRD, Dense VH, Neovascular Glaucoma) Early pars plana vitrectomy (PPV) is recommended for nonclearing vitreous hemorrhage or TRD; it also eliminates vitreous scaffold for fibrovascular proliferation and enables concurrent intraoperative endolaser. 27-gauge microincision vitrectomy (MIVS) is preferred as it reduces postoperative inflammation, faster recovery, and better access to peripheral fibrovascular tissue, which is typically more anteriorly located in Eales’ disease than in diabetic retinopathy.[14–16] Diagnostic vitrectomy with vitreous MTB PCR is valuable in diagnostically uncertain or treatment-refractory cases. Adjunctive procedures as needed: phacovitrectomy (coexisting cataract), trabeculectomy or glaucoma drainage device (neovascular glaucoma), or scleral buckling (rhegmatogenous component). Refractory cases need biologic agents including TNF-α inhibitors (adalimumab, infliximab) and IL-1 receptor antagonists (anakinra) and represent an emerging frontier for severe, treatment-resistant retinal vasculitis. Evidence remains limited to small series and case reports, and their use should be restricted to subspecialty centers with appropriate infectious disease and rheumatology collaboration.[14,17–19] TB decision-making algorithm STEP 1: Immunological Testing Perform Mantoux/IGRA (QuantiFERON-TB Gold) in all patients. In endemic regions (India, Southeast Asia), a positive result frequently reflects prior sensitization. Do not initiate ATT on immunological positivity alone. In nonendemic regions, a positive IGRA/Mantoux carries higher specificity and warrants stronger consideration of a TB-related etiology. STEP 2: Radiological and Vitreoretinal Correlation Order HRCT chest (not plain X-ray) in all IGRA/Mantoux-positive patients. Identify apical scarring, healed granulomas, or nodules consistent with latent or healed TB. Correlate with angiographic features like predominant peripheral occlusive phlebitis without granulomatous choroiditis that favors Eales’ disease (TB hypersensitivity). Reserve aqueous/vitreous PCR for MTB for atypical, diagnostically uncertain, or treatment-refractory cases. STEP 3: ATT Decision Initiate ATT (4-drug regimen: HRZE) when[4] IGRA/Mantoux positive and HRCT show latent/healed TB lesions, ocular fluid PCR is positive for MTB, paradoxical worsening after corticosteroids (suggesting IRIS from reactivated latent MTB), and/or recurrent steroid-responsive but steroid-dependent periphlebitis with positive TB serology. Avoid ATT when immunological tests are positive but HRCT is normal in an endemic region, and angiographic features are atypical for TRV. Alternative diagnosis (sarcoidosis, Behçet’s, pars planitis) is more consistent with the clinical phenotype. ATT is always combined with corticosteroids to suppress paradoxical IRIS when initiated. Key Clinical Controversies Is Eales’ disease truly TB-related? The association is strong but circumstantial, supported by immunological positivity, PCR data, and response to ATT in selected patients, but not by consistent direct bacterial evidence. Until robust prospective data emerge, the disease should be regarded as a TB-hypersensitivity vasculitis in endemic populations and as an idiopathic or other-etiology vasculitis in nonendemic ones.[4,5] Overuse of ATT in India is also common. Real-world data indicate ATT is initiated in 30–60% of patients in TB-endemic regions whenever immunological tests are positive, an approach that may expose a substantial proportion to unnecessary drug toxicity without confirmed benefits. A positive IGRA or Mantoux, in isolation, does not mandate ATT; the threshold must incorporate HRCT findings, angiographic phenotype, and clinical course.[12,18–20] Risks of anti-VEGF therapy: While intravitreal anti-VEGF effectively regresses active neovascularization, its use in eyes with established fibrovascular proliferation carries a well-documented risk of precipitating TRD through rapid membrane contraction. Clinicians must assess the fibrovascular burden before injection and have a low threshold for early vitrectomy planning in such eyes.[12,18] There is growing consensus that early PPV, rather than prolonged conservative management of nonclearing vitreous hemorrhage, reduces disease burden, facilitates laser delivery, induces protective posterior vitreous detachment, and prevents structural complications. The advent of 27-gauge MIVS has lowered the risk–benefit threshold for surgical intervention in this population.[15] Conclusion Eales’ disease is no longer the ophthalmological enigma it once was, but it remains a condition where the gap between emerging knowledge and real-world clinical practice can be costly. The evidence base firmly supports a structured, stage-based approach: controlling inflammation in early disease with corticosteroids (with or without ATT based on a rigorous TB workup), ablating ischemia with timely laser photocoagulation before neovascularization supervenes, and intervening surgically early in advanced disease. Anti-VEGF agents and immunosuppressants have a defined but circumscribed role, governed by disease stage and individual risk profile. Equally important is the need for individualized treatment: The TB interpretation must be calibrated to regional epidemiology, laser must not be applied over active vasculitis, anti-VEGF must be used with caution in fibrovascular disease, and vitrectomy should not be deferred when the clinical picture demands it. Ultra-widefield imaging and OCTA have transformed our ability to stage, target, and monitor; clinicians should leverage these tools at every decision point. With a disciplined, multimodal approach guided by staging and validated by imaging, the majority of patients with Eales’ disease can achieve meaningful, sustained visual rehabilitation.