Eales disease (Dr. Pradeep Bastola, Assistant Professor, GMC)

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Special thanks: Prof. D.N. Shah Prof. O.K. Malla Prof. P.C. Karmacharya Prof. M.P. Upadhyaya Associate Prof. S.N. Joshi Dr. Deepak Khadka

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Introduction to Clinical Medicine Eales Disease (Ophthalmology) : 

Introduction to Clinical Medicine Eales Disease (Ophthalmology) Dr. Pradeep Bastola MD, Ophthalmology Assistant professor Gandaki Medical College

Introduction: : 

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.

Slide 3: 

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”.

Hall marks : 

Hall marks Idiopathic obliterative perivasculitis Unknown etiology Healthy young adult (97.6%) of Indian subcontinent Extensive retinal nonperfusion Perivascular sheathing Neovascularization of disc and retina

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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.

Aetiopathogenesis: : 

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.

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Idiopathic Nontuberculous Mycobacteria M. fortuitum and M. chelonae Isolated from classical Eales’ disease pt’s aqueous and ERM (J. Biswas) Higher phenotype frequency of HLA B5, DR1 and DR 4 Probably this HLA predisposition could be responsible for the Presence of sequestered mycobacterium

Systemic disease associated with Eales’ disease: : 

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

Tuberculosis: : 

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.

Tuberculosis: cont…d : 

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)

Hypersensitivity to tuberculoprotein: : 

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.

Hypersensitivity to tuberculoprotein: cont…d : 

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.

Pathophysiology : 

Pathophysiology Mostly unknown primary, noninflammatory disorder of the walls of peripheral retinal vessels, namely the shunt vessels vascular occlusions, peripheral neovascularization, and vitreous hemorrhage

Pathophysiology : 

Pathophysiology The microvascular abnormalities are seen at the junction of perfused and nonperfused zones of the retina. Although associations with tuberculosis and multiple sclerosis have been suggested, these findings have not been substantiated in other studies

Physical Findings : 

Physical Findings The physical findings mostly involve the retina and vitreous. Vascular sheathing with adjacent nerve fiber layer hemorrhages is seen in most patients. The sheathing can manifest as thin white lines, limiting the blood column on both sides of the sheathed vessel to heavy exudative sheathing that can cause vascular occlusion. Although believed to affect primarily the retinal veins, others have reported the same prevalence of both venules and arterioles.

Clinical features : 

Clinical features The anterior chamber may exhibit cell and flare with keratic precipitates. Vitreous debris and cells often are seen, even in the absence of vitreous hemorrhage. Macular edema can occur in eyes with vascular sheathing, and it often is cystoid in nature. Epiretinal membranes with or without macular edema can compromise visual acuity. The etiology of the macular edema is thought to be associated with low-grade inflammation

Peripheral nonperfusion : 

Peripheral nonperfusion Peripheral nonperfusion is a typical feature of Eales disease The temporal retina is affected most commonly, often in a confluent area The surrounding vasculature is tortuous with microvascular abnormalities, which include the following: microaneurysms, arteriovenous shunts, venous beading, hard exudates, and cotton-wool spots. Fine solid white lines occasionally can be seen, representing obliterated larger vessels

BRVO : 

BRVO Branch retinal vein occlusion (BRVO) can be seen in patients with Eales disease and may be limited to one area or may be multifocal. BRVO alone can be differentiated from BRVO in the presence of Eales disease by the more extensive peripheral retinal involvement in Eales disease. BRVO alone usually is confined to a single affected quadrant. BRVO alone also respects the anatomical distribution of the horizontal raphe, unlike Eales disease.

BRVO : 

BRVO

BRVO : 

BRVO

Neovascularization : 

Neovascularization Neovascularization of the disc (NVD) or neovascularization elsewhere (NVE) in the retina is observed in up to 80% of patients with Eales disease. The NVE usually is located peripherally, at the junction of perfused and nonperfused retina. The neovascularization often is the source of vitreous hemorrhage in these eyes, compromising vision. Rubeosis iridis or neovascularization of the iris can develop and may lead to neovascular glaucoma. Fibrovascular proliferation on the surface of the retina may accompany retinal neovascularization. These eyes have associated anteroposterior traction that could lead to retinal detachment.

Cystoid macular edema : 

Cystoid macular edema Cystoid macular edema can occur in patients with Eales disease due to increased capillary permeability. Associated with significant vision loss.

Cystoid macular edema : 

Cystoid macular edema

PVD : 

PVD A posterior vitreous separation has been reported in 27% of patients with Eales disease Several patients have been found to have concomitant macular holes. Macular hole surgery may effectively repair this abnormality and lead to significant visual improvement similar to that seen in patients with idiopathic macular holes.

Systemic association : 

Systemic association Systemic abnormalities have been reported in association with Eales disease, mostly neurologic findings. Myelopathy, ischemic stroke, hemiplegia, and multifocal white matter abnormalities have been reported. A higher incidence of vestibuloauditory dysfunction is seen in patients with Eales disease when compared to the general population of the same age. It is presumed that a similar mechanism of vascular occlusion and hypoxia leads to these systemic findings.

PCR : 

PCR In the retrospective study, 70% ERM samples were positive for one or more Mycobacterium spp. Tested by snPCR. M.fortuitum and M. chelonae were isolated from two VFs, which were also positive by snPCR in the prospective study. Statistical evaluation of the results of both retrospective and prospective investigations showed a statistically significant association of Mycobacterium spp. With eales’ disease. Study by Dr J biswas, Dr Madhavan

Slide 28: 

PCR

M. chelonae : 

M. chelonae

Association of mycobacteria with eales’ : 

Association of mycobacteria with eales’

Systemic disease: : 

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.

Immunological studies in Eales’ disease: : 

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.

Immunological studies in Eales’ disease: cont…d : 

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)

Newer classification system for Eales disease : 

Newer classification system for Eales disease

Biochemical studies in Eales’ disease: : 

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).

Stages of Eales’ disease : 

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.

Slide 37: 

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

Slide 38: 

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

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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

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

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Sea fan–like neovascularisation of the retina.

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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.

Clinical features: : 

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)

Slide 45: 

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.

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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.

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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.

Slide 48: 

Proliferative stage

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Vitreous hemorrhage

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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

Slide 51: 

Healed perivasculitis with anastomotic arteriovenous shunt

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Fibrovascular proliferation causing tractional retinal detachment

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Healed perivasculitis with sclerosed vein and multiple chorioretinal atrophic patches

Fundus fluorescein angiography : 

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.

Slide 58: 

FFA following laser photocoagulation of neovascular frond

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Multiple veno venous shunts in late AV phase

Pathology: : 

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.

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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.

Diagnostic studies performed on patients with Eales’ disease : 

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

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

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

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Sarcoidosis Wegener Granulomatosis III. Radiological tests:

Differential diagnosis:Vasculitis mimicking Eales’ disease : 

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

Proliferative vascular retinopathy mimicking Eales’ disease: : 

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

Sarcoidosis : 

Sarcoidosis Sarcoid nodules Bilateral hilar lymphadenopathy

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Candle wax dipping

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Vitritis and snowball Peripheral neovascularisation

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leukemia

Sickle cell retinopathy : 

Sickle cell retinopathy Seafan neovascularisation

Behcet disease : 

Behcet disease Aphthous ulceration Erythema nodusum like lesions

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Dermatographism Hypopyon

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Occlusive vasculitis Retinal exudation and vascular occlusion

Treatment: : 

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.

Treatment of Eales’ disease: : 

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

Observation: : 

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.

Medical therapy: : 

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.

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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.

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

Photocoagulation: : 

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.

Photocoagulation : 

Photocoagulation

Persistant vitreous hamorrhage with traction : 

Persistant vitreous hamorrhage with traction

Pars plana vitrectomy : 

Pars plana vitrectomy

Vitrectomy, traction release and endolaser : 

Vitrectomy, traction release and endolaser

Anti VEGF : 

Anti VEGF Establishment of vascular endothelial growth factor as the primary mediator for neovascularization in the eye has led to the emergence of a number of drugs for treating various neovascular ocular disease Bevacizumab (Avastin) is a humanized monoclonal antibody that inhibits VEGF and is currently emerging as an effective treatment for neovascular age related macular degeneration, macular edema secondary to CRVO and PDR 0.05 ml (1.25mg) bevacizumab intravitreally may eliminate the need for further laser photocoagulation as per one study Rapid regression of disc and retinal neovascularization in a case of Eales disease after intravitreal bevacizumab have been reported.

FFA showing NVD and NVE : 

FFA showing NVD and NVE

1 month after bevacizumab : 

1 month after bevacizumab

Slide 92: 

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

Slide 93: 

FFA following laser photocoagulation of neovascular frond

Vitreoretinal surgery: : 

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.

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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.

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Tractional radial retinal fold after vitrectomy

Summary and conclusions: : 

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.

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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.

References: : 

References: Retina and vitreous –AAO (2004-2005) Prospective study on idiopathic retinal vasculitis (Joshi S.N) Clinical ophthalmology- 5th edition (Jack J Kanski) Retina 3rd 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

Good Luck : 

Good Luck