Eales' disease is an idiopathic inflammatory retinal vasculitis that primarily affects young males in India. It involves peripheral retinal perivasculitis and ischemia leading to neovascularization and recurrent vitreous hemorrhage. While its exact etiology is unknown, it has been associated with tuberculosis and hypersensitivity to tubercular proteins. Treatment involves corticosteroids to reduce inflammation, laser photocoagulation to ablate new vessels and reduce hemorrhage risk, and vitrectomy for non-resolving hemorrhage or retinal detachment.

1. Eales’ Disease Dr Gyanendra Lamichhane, Dr I. Kansakar Lumbini Eye Institute Bhairahawa,Nepal

2. References: Retina and vitreous –AAO (2004-2005) Prospective study on idiopathic retinal vasculitis (Joshi S.N) Clinical ophthalmology- 5 th edition (Jack J Kanski) Retina 3 rd edition (Stephen J Ryan) Atlas of ophthalmology (R.K. Parrish) Principle and practice of ophthalmology (Peymen) Eales disease – An update Major Review (J. Biswas) Survey of ophthalmology 2002

3. Introduction: In 1880 and 1882, Henry Eales - “primary recurrent retinal hemorrhage”. Similar conditions of retinal and vitreous hemorrhage were described under the name of Eales’ Disease. Eales didn’t mention any inflammatory signs preceding or accompanying the hemorrhages.

4. In 1887 Wadsworth reported on signs of inflammation of the retinal vasculature - Eales’ disease and periphlebitis Elliot initially suggested that the disease be called “periphlebitis retinae”.

5. Currently, Eales’ disease is considered to be an idiopathic inflammatory venous occlusion that primarily affects the peripheral retina. Retinal changes include perivasculitis, mainly periphlebitis, and peripheral non-perfusion. This inflammation induced vascular occlusion can lead to a proliferative vascular retinopathy, with sequelae such as recurrent vitreous hemorrhage and traction retinal detachment.

6. Aetiopathogenesis: Recognized as primary vasculitis of unknown etiology occurring in young adults. Retinal vasculitis and peripheral retinal neovascularisation associated with various systemic and ocular disease could mimic Eales’ disease.

7. Systemic disease associated with Eales’ disease: Systemic disorders associated with Eales’ disease: Tuberculosis Hypersensitivity to tuberculoprotein Thromboangitis obliterans Neurologic disease Hematological abnormalities

8. Tuberculosis: The assumption of tubercular aetiology is based on active or healed tuberculosis in some patient with Eales’ disease. Ophthalmoscopic evaluation in patient with active or healed TB showed 1.3% had Eales’ disease .

9. Tuberculosis: cont…d Presence of Tubercular bacilli DNA in epiretinal membrane (Madahavan et al) 2010 eyes with active pulmonary or extra pulmonary TB – no Eales’ disease (Biswas J et al) 32 patient with Eales’ disease were followed up for 37 years, only one patient had active tuberculosis (William et al)

10. Hypersensitivity to tuberculoprotein: Allergic reaction to tuberculosis has been reported by many authors till date. Positive Mantoux reaction which is as high as 90% in some series.

11. Hypersensitivity to tuberculoprotein: cont…d Ashton – retina sensitized against tuberculoprotein and re-exposure leads to retinal vasculitis. Eales’diease has been reported in Mantoux negative patients and mantoux test positive in 67-90% of healthy individuals.

12. Systemic disease: Several studies have shown association between neurological and hematological disease. bilateral hearing loss 48% (Renie et al) , 25% (William et al). 2 pt with Eales’ disease had progressive worsening of neurological deficit (Rodier G). Myelopathy with Eales’ disease has been described by many.

13. Immunological studies in Eales’ disease: Immune mediated mechanism has been suggested by many authors as a possible cause of Eales’ disease. Acute onset, steroid responsiveness, lymphocytic infiltration and abnormal immunological parameters all indicate an immunological basis of disease.

14. Immunological studies in Eales’ disease: cont…d Altered immune response of type III and/or IV reaction to an infectious agent (Muthukaruppan et al). Raised IgG and IgA levels (Johnson et al) , elevated levels of circulating immune complexes and antiretinal antibody (Kasp et al) , immunophenotyping predominant T cell CD4 Higher frequencies of HLA B5(B51), DR1 and DR4 (Biswas et al)

15. Biochemical studies in Eales’ disease: Raised alpha-globulins and reduced albumin levels in the serum samples. PDGF, IGF1, EDF, TGFa and TGFb play a key role in neovascularisation. Raised serum alpha1 acid glycoproteins in 27 patients of Eales’ disease (Sen et al).

16. Stages of Eales’ disease Stage I (inflammatory stage) Localized areas of peripheral retinal edema with sheathing of the smaller caliber vascular branches. Minute retinal hemorrhages as well as minute vascular brackets or hooklets connecting two adjoining vessels. active periphlebitis with subhyaloid hemorrhage over the macula.

17. Active periphlebitis with tortuosity of veins as well as multiple superficial retinal hemorrhage

18. Montage fundus photograph showing an active perivasculitis involving predominantly the peripheral retina of an Eales disease patient.

19. Stage II (ischemic stage) Involvement of larger vessels and extend more posteriorly Veins as well as arterioles may be sheathed Widespread retinal hemorrhages and vitreous looks hazy

20. Stage III (stage of neovascularisation) Peripheral new blood vessels with numerous vitreous and retinal hemorrhages. The hemorrhages frequently recurs.

21. Sea fan–like neovascularisation of the retina.

22. Stage IV (complicated stage) Massive retinal proliferans associated retinal and massive vitreous hemorrhage. With this advanced disease the neovascular frond can cause tractional rhegmatogenous retinal detachment.

24. Clinical features: Usually occurs in young , healthy people, with a peak incidence between the ages of 30 and 40 years. It occurs more frequently in males 80-90%. 75% cases it presents before 49 years. Can be unilateral or bilateral.90% bilateral (Duke Elder) 56.14% had bilateral retinal vasculitis ( O.K Malla and coworkers)

25. Vitreous floaters or blurring of vision, symptoms attributable to recurrent vitreous hemorrhages. 80% between the age of 20-40 years and 95% were male (O.K Malla and co workers) 54.34% between 20-30 years and 94.73% male Rare in more developed countries.

26. More commonly reported from Indian subcontinent. The reported incidence in India is 1 in 200-250 patient Anterior uveitis/Vitritis Active perivasculitis with exudates around the veins in one or more quadrants. Arterioles may be affected.

27. Healed perivasculitis as sheathing of the veins Macular changes uncommon Peripheral retinal neovascularisation reported in 36-84% of cases Recurrent vitreous hemorrhages, the hall mark of the disease Some vitreous hemorrhages resolve, some do not ( organize with multiple VR adhesions & RRD/TRD) Some patient specially with multiple sclerosis are asymptomatic.

28. Proliferative stage

29. Vitreous hemorrhage

30. Eales’ disease Exacerbations and remissions quiescent Rubeosis iridis Hemorrhagic glaucoma cataract Loss of eye Tractional RD Macular distortion Detachment Cystoid macular degeneration and Macular holes Tractional retinal breaks and Rhegmatogenous RD

31. Healed perivasculitis with anastomotic arteriovenous shunt

32. Fibrovascular proliferation causing tractional retinal detachment

33. Healed perivasculitis with sclerosed vein and multiple chorioretinal atrophic patches

36. Fundus fluorescein angiography To delineate areas of capillary nonperfusion, peripheral retinal nonperfusion is present in all patients with Eales’ disease. Retinal or disc neovascularisation Macular edema Helps in monitoring the regression and disappearance of new vessels during treatment and follow up.

38. FFA following laser photocoagulation of neovascular frond

39. Multiple veno venous shunts in late AV phase

40. Pathology: Patchy perivascular or intramural infiltration of lymphocytes or granulation tissue sometimes with or without giant cells Plasma cells are occasionally present. Veins are primarily affected The vascular changes are usually seen on retinal periphery.

41. Hyalinization and thinning of vein wall Narrowing and obstruction of the lumen Endothelial cell proliferation Thrombosis and rupture of the vein Intravitreal new vessel formation and Marked thickening of internal limiting membrane have been reported.

42. Diagnostic studies performed on patients with Eales’ disease To rule out leukemia and hematological condition: Hemoglobin and hematocrit Total RBC count Total WBC and Differential count

43. II. Others tests: Platelet count ESR Reticulocyte count Blood sugar Stool analysis Mantoux test Basic coagulation test Sickle cell preparation

44. Hemoglobin Electrophoresis VDRL and TPHA test Anti nuclear antibody Serum ACE Lysosome

45. Sarcoidosis Wegener Granulomatosis III. Radiological tests:

46. Differential diagnosis: Vasculitis mimicking Eales’ disease Systemic Ocular Behcet’s disease Birdshot retinochoroidopathy Leukemia Coat’s disease Lyme Borreliosis Pars planitis Multiple sclerosis Viral retinitis Sarcoidosis Systemic lupus erythematosus Toxocariasis Toxoplasmosis Tuberculosis Wegener’s granulomatosis

47. Proliferative vascular retinopathy mimicking Eales’ disease: Systemic Ocular Diabetes mellitus BRVO Sarcoidosis CRVO Sickle cell disease Coats’ disease Pars planitis ROP

48. Sarcoidosis Sarcoid nodules Bilateral hilar lymphadenopathy

49. Candle wax dipping

50. Vitritis and snowball Peripheral neovascularisation

51. leukemia

52. Sickle cell retinopathy Seafan neovascularisation

54. Behcet disease Aphthous ulceration Erythema nodusum like lesions

55. Dermatographism Hypopyon

56. Occlusive vasculitis Retinal exudation and vascular occlusion

57. Treatment: Symptomatic treatment. Treatment aim reducing retinal perivasculitis and associated vitritis ; reducing risk of vitreous hemorrhage from new vessels by retinal ablation and surgical removal of non resolving vitreous hemorrhage and/or vitreous membranes.

58. Treatment of Eales’ disease: Observation. Medical Corticosteroids Antituberculosis drugs Immunosuppressive drugs. Retinal ablation Photocoagulation cryotherapy Surgical vitrectomy

59. Observation: Patient with inactive retinal vasculitis Follow up 6 months to 1 year interval. Patient with fresh vitreous hemorrhage if retina is found to be attached. Such vitreous hemorrhage usually clears by 6 to 8 weeks.

60. Medical therapy: Corticosteroids are mainstay of therapy in active perivasculitis stage of Eales’ disease. Majority of cases 1mg/kg body weight, tapered to 10mg/week over 6 to 8 weeks. Maintenance 15 to 20mg/day for 1 to 2 months. Periocular depot steroid injection may be added for associated macular edema.

61. Systemic and Periocular steroid useful in patient having 3 quadrants involvement with macular edema. Systemic steroid only if less than 3 quadrant involvement. No difference in response between Mantoux positive and negative cases.

62. Immunosuppressive therapy in patient unresponsive or have unacceptable side effects. (Azathioprine and cyclosporine) Some investigators have recommended ATT (Rifampicin and Isoniazid) for 9 months.

63. Photocoagulation: Mainstay of therapy in proliferative stage of Eales’ disease. The aim Regulate the circulation To obliterate surface neovascularisation and Close leaking intraretinal microvascular abnormalities.

64. Sectoral laser for capillary non perfusion and PRP for neovascularisation of disc. Occasional massive hemorrhage can occur. After laser, regressing neovascularisation can cause macular distortion and retinal tear. Laser not advised in active inflammatory stage

65. FFA following laser photocoagulation of neovascular frond

66. Vitreoretinal surgery: Vitrectomy alone or combined with other vitreoretinal surgical procedures is often required. Nonresolving vitreous hemorrhage with obscuration of central vision of 3 mo duration may be subjected to vitrectomy.

67. Vitrectomy done between 3 to 6 mo has better results than done after 6 months (Kumar et al). Early vitrectomy in patient with TRD, extensive vitreous membranes or epimacular membranes. Endolaser can be given along with vitrectomy.

68. Tractional radial retinal fold after vitrectomy

69. Summary and conclusions: Characteristic clinical findings and angiographic pattern. Mimic several ocular or systemic disease presenting as retinal vasculitis or proliferative retinal vasculopathy. Hypersensitivity to tubercular protein has been considered a prime cause of Eales’ disease .

70. Probable multifactorial etiology. HLA, retinal autoimmunity, mycobacterium genome, free radical mediated damage. Corticosteroids in active disease and laser photocoagulation in ischemic and proliferative stage. Results of vitrectomy in non resolving vitreous hemorrhage with or without retinal detachment are satisfactory.

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