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
Slide 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.
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.
Slide 7: 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.
Slide 39: 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
Slide 40: Stage III (stage of neovascularisation)
Peripheral new blood vessels with numerous vitreous and retinal hemorrhages.
The hemorrhages frequently recurs.
Slide 41: Sea fan–like neovascularisation of the retina.
Slide 42: 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.
Slide 46: 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.
Slide 47: 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
Slide 49: Vitreous hemorrhage
Slide 50: 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
Slide 52: Fibrovascular proliferation causing tractional retinal detachment
Slide 53: 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
Slide 59: 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.
Slide 61: 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
Slide 63: II. Others tests:
Platelet count
ESR
Reticulocyte count
Blood sugar
Stool analysis
Mantoux test
Basic coagulation test
Sickle cell preparation
Slide 64: Hemoglobin Electrophoresis
VDRL and TPHA test
Anti nuclear antibody
Serum ACE
Lysosome
Slide 65: 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
Slide 69: Candle wax dipping
Slide 70: Vitritis and snowball Peripheral neovascularisation
Slide 71: leukemia
Sickle cell retinopathy : Sickle cell retinopathy Seafan neovascularisation
Behcet disease : Behcet disease Aphthous ulceration Erythema nodusum like lesions
Slide 75: Dermatographism Hypopyon
Slide 76: 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.
Slide 81: 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.
Slide 82: 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.
Slide 95: 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.
Slide 96: 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.
Slide 98: 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