Eales Disease

Etiology

Eales disease was considered a form of vasomotor neurosis by Sir Henry Eales, but it was Wardsworth, in 1887, who explained the disease's association with retinal inflammation.[4]

The etiology of Eales disease still stands to be controversial and, to date, is very poorly understood. Its etiology is purportedly multifactorial in origin. It is presumed that Eales disease is an immunological reaction in response to an exogenous agent.[5] No specific cause has been elucidated till now, and the disease is still considered largely idiopathic.[6] Exposure to tuberculosis and hypersensitivity to tuberculoprotein is considered to be related to the disease.[4][7][8][9] The association between Eales disease and tuberculosis has been proposed in several studies.[10][11][12][13][14][15][16]

One study hypothesized that Mycobacterium chelonae and M. fortuitum, which are rapidly growing nontuberculous mycobacteria (RGNTM), are associated with Eales disease.[10] M. fortuitum has been isolated from the aqueous humor of a patient with Eales disease.[10] This study was undertaken to determine the presence of the DNA of M.tuberculosis and RGNTM in the vitreous humor of patients having Eales disease.[10] Semi-nested polymerase chain reactions (SnPCRs) were used to detect DNA on epiretinal membranes (ERMs) and vitreous humor of patients with Eales disease and in control patients.[10] Routine investigations for mycobacteriological profile were also done. 70% of samples of the epiretinal membrane tested positive for one or more species of Mycobacteria.[10] Vitreous humor samples also yielded M. chelonae and M. fortuitum.[10] A statistically significant association between the Eales disease and Mycobacteria was shown by this study.[10]

A highly immunogenic protein is translated by the MPT64 gene in M. tuberculosis.[17] PCR (polymerase chain reaction) for this gene has been diagnostically used successfully. 

Another prospective case-control study was done on 65 patients (31 with Eales disease and 34 controls).[17] Patients with macular edema, neovascular proliferation, proliferative diabetic retinopathy, tractional retinal detachment, and premacular fibrosis were taken as control patients. Polymerase chain reaction (PCR) was used to detect the MPT64 gene of M. tuberculosis in patients having Eales disease. The results of polymerase chain reaction (PCR) were compared using the clinical symptoms of patients, their erythrocyte sedimentation rate (ESR), and tuberculin skin test (TST) values. In patients having Eales disease, the PCR positivity was 38.7%. There was a strong corroboration between the PCR positivity and high TST and ESR values. Interestingly, 6 from 34 control vitreous samples were also PCR positive for MPT64.[17]

Another study reported the presence of Mycobacteria in the vitreous humor of patients having Eales disease.[11] Eighty-eight patients were enrolled in the study and were divided into 3 separate groups: Group A had 28 patients with Eales disease, Group B had 30 control patients having specific uveitis syndromes, and Group C had 30 negative control patients. A polymerase chain reaction assay was done on the vitreous humor samples for the detection of the MPB64 gene of M. tuberculosis (MTB).[11] Results showed 57.14% of vitreous humor samples in group A, 1 sample in group B, and none of the samples in group C tested positive for the genome of Mycobacterium tuberculosis.[11]

Enucleated eyes were subjected to a nested polymerase chain reaction for the detection of the M. tuberculosis genome, and positive results were noted, suggesting a possible correlation between the Eales disease and tuberculosis.[18]

Nested polymerase chain reaction utilized for the demonstration of the genome of M. tuberculosis in the epiretinal membranes of many patients having Eales disease underlines the possible association between Eales disease and tuberculosis.[16]

Eales disease may be associated with ocular tuberculosis, which may show its signs in the late stages of Eales disease.[19] Cases have been reported with manifestations of ocular tuberculosis, like choroidal tuberculoma, several years after Eales disease was diagnosed.[19]

It is quite possible that patients having Eales disease may not carry viable organisms, or they may just be having the DNA of M. tuberculosis. The role of tuberculosis in the pathology of Eales disease is still questionable. It is postulated that the incidence of Eales disease is low in western countries, possibly due to the low prevalence of tuberculosis in those countries. Mantoux positivity has been reported in a significant number of patients having Eales disease in several studies. However, one case-control study in India concluded that there isn't any statistically significant difference as far as Mantoux positivity is concerned between the cases and the controls.[17] Moreover, Mantoux positivity is also seen in many healthy Indian adults. Eales disease is also prevalent amongst people who happen to be Mantoux-negative. These studies make the role of tubercular hypersensitivity in Eales disease highly debatable.

Neurological manifestations have been reported in some cases of Eales disease.[20] Transient ischemic attacks, cerebral stroke, and myelopathy are rarely described and are attributed to leptomeningeal vasculitis. Multifocal white-matter abnormality, multiple sclerosis, spastic paraparesis, and internuclear ophthalmoplegia have also been reported.Factor V Leiden mutation, focal sepsis, and hematological disorders like acanthocytosis may cause thrombosis of retinal vessels and could possibly be associated with Eales disease.

Experimental studies have demonstrated other immunity-related mechanisms, like the predominant involvement of T-cells in the disease etiology. HLA B5, DR1, DR4, and several autoimmune diseases have been thought of as playing a role in the etiology of Eales disease.[21] Oxidative stress, like growing levels of lipid peroxide and carboxymethyl lysine, a decrease in the levels of glutathione, and vitamins C and E, is also supposed to be a causative factor. A complex of haptoglobin, complement C3, and galectin-1, which is an 88-kDa protein, might be playing a vital role in the etiology of Eales disease.[22] 

Levels of haptoglobin and galectin-1 in the serum may be used as biomarkers of Eales disease. Retinal neovascularization is supposed to be because of increased vascular endothelial growth factor (VEGF).[23] Various studies have revealed the involvement of peptide growth factors, like vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), transforming growth factor (TGF), urokinase and several metalloprotease enzymes, in neovascularization of eye. Yet their roles still remain to be established in Eales disease.

Epidemiology

Eales disease is largely reported in Asia, especially the Indian subcontinent. Eales disease is very rarely reported in the western world. It more commonly affects males than females. Males are generally afflicted by the disease at 20-40 years of age.[23] In 90% of the patients, Eale disease is bilateral, with the rest 10% being unilateral. Asymmetric bilateral presentation is not very uncommon.[24]

The pediatric population may also be afflicted by Eales disease, though it is uncommon.[25]

Pathophysiology

The pathophysiology of Eales disease involves retinal periphlebitis, retinal ischemia, and neovascularization.[5] Initially, the blood vessels of the retinal periphery get inflamed.[26] This vasculitis manifests as sheathing of blood vessels. This vasculitis leads to obliteration of the lumen of the blood vessel.[24] This obliteration leads to ischemia of that part of the retina perfused by the affected blood vessel. Vascular endothelial growth factor (VEGF) production is increased by persistent ischemia. Increased levels of VEGF lead to neovascularization. This neovascularization could be at or within one disc diameter of the optic disc, or it could be present anywhere else in the retina. Rubeosis of the iris may rarely develop, which may eventually give rise to neovascular glaucoma. New vessels are fragile and bleed easily. The fragility of these new blood vessels leads to recurrent vitreous hemorrhages.[4] 

Vitreous hemorrhages generally resolve in 3 to 6 months. If they happen to persist beyond this duration, the probability of membrane formation in the vitreous increases with increased chances of tractional retinal detachment. Eales disease follows a very variable course of progression. Some patients may show spontaneous regression of new blood vessels, and others may have relentless vitreous hemorrhages.[27]

Eales disease was classified by Charmis into the following stages:[27][28] 

• Stage I: This stage has mild periphlebitis. It is detected by ophthalmoscopy, and peripheral small retinal capillaries are affected.
• Stage II: Large veins are affected, and perivasculitis is present in large parts of the retina.
• Stage III: Neovascularisation with abundant vitreous and retinal hemorrhages.
• Stage IV: This stage is characterized by repeated vitreous hemorrhages and is the end-stage disease. Tractional retinal detachment may be present with vitreous hemorrhage.

The above-mentioned classification is no longer popular and is seldom used now.Recently, a new classification has been suggested by Saxena and Kumar.[1][29] The new system helps in gauging how advanced the disease is in a particular patient and also helps in classifying it. This classification is as follows:      

• Stage 1: superficial retinal hemorrhages with inflammation (periphlebitis) of small (1a) and large (1b) caliber vessels
• Stage 2a: capillary non-perfusion, 2b: neovascularization of disc/elsewhere
• Stage 3a: fibrovascular proliferation, 3b: vitreous hemorrhage;
• Stage 4a: tractional/combined rhegmatogenous retinal detachment and 4b: neovascularization of iris, neovascular glaucoma, complicated cataract, and optic atrophy.''[29]

 So far, no classification system has been adopted as standard and accepted universally.

History and Physical

History

In the initial stages of Eales disease, patients may not be having any symptoms. Mostly young males present with cobwebs floating in front of the eye called floaters with or without associated diminution of vision and photopsia.[4] Diminution of vision is mostly painless. Complaints are mostly in both eyes. Even those who have an initial unilateral presentation eventually go on to involve both eyes.[6] Three pathologic changes in the retina lead to the clinical manifestations of the disease: a) inflammation (peripheral vasculitis), b) ischemia (peripheral capillary non-perfusion) c) Neovascularisation of the optic disc and elsewhere.[24]

Physical Examination

1. Visual acuity - Since the disease predominantly affects the peripheral retina and spares the macula, visual acuity at presentation is generally 20/40 or better. Although vision may be poor in cases with vitreous hemorrhage or cystoid macular edema. No perception of light may be reported in cases with long-standing retinal detachment and in neovascular glaucoma leading to optic atrophy.
2. Anterior segment - Anterior uveitis is uncommonly seen, and if at all present, it is non-granulomatous. Granulomatous uveitis, if seen, should point in the direction of sarcoidosis.[30] Hypopyon, if present, would make Behcet disease a more probable diagnosis. Later stages of the disease may have iris neovascularization.
3. Vitreous - Vitritis is uncommon. Mild vitreous haze may be observed over areas of vasculitis. Late stages may have a recurrent vitreous hemorrhage. Dense vitreous hemorrhage will preclude the view of the fundus. Hemorrhage in the vitreous is usually because of delicate proliferating new blood vessels.[23]
4. Optic nerve - Neovascularisaton may develop in the late stages. Optic disc pallor usually develops in cases of neovascular glaucoma.
5. Retina

Early (Inflammatory) Stage

The hallmark of this stage is periphlebitis.[26] Veins are more affected, though arterioles may also be involved. It may be present concurrently in multiple quadrants. Perivascular exudates (cuffing, whitish fuzzy infiltrates along the vessel) and venous dilatation may be noted in active inflammation. Exudation is associated with superficial hemorrhages. Healed vasculitis may be seen as sheathing of veins, sclerosis of venules, pigmentation along venules, the irregular caliber of veins, or abnormal vascular anastomosis. The involvement of blood vessels is usually in the equatorial region and retinal periphery. Predominant central involvement should prompt one to hunt for other diagnoses. Macular edema is most commonly seen as central involvement in Eales disease. Sub-hyaloid hemorrhage, epiretinal membrane, subretinal fibrosis, and macular hole are less common examples of central involvement.[5]

Middle (Ischemic) Stage

Capillary ischemia is characteristic of this stage. Veno-venous shunts and venous beadings may be noted. Ischemia leads to increased production of VEGF, which may lead to macular edema or the proliferative stage.

Late (Proliferative) Stage

Neovascularisation occurs at the boundary of the non-perfused and perfused retina. This neovascularization may lead to repeated hemorrhages in the vitreous, which may or may not be associated with retinal detachment.[2] Optic disc neovascularization is less commonly noted compared to neovascularization elsewhere. Late-stage also involves neovascularization of the iris. Tractional or combined (tractional and rhegmatogenous) retinal detachment may be seen.

Evaluation

Diagnostic Procedures 

1. Fundus fluorescein angiography (FFA) - FFA is an important tool to diagnose Eales disease. A delayed venous filling is seen in case of venous obstruction. The early venous phase shall show the staining of inflamed vessel walls, while the late phase may show extravasation of the dye. Sclerosed vessels may show capillary nonperfusion. In cases of neovascularization, the early arteriovenous phase shall show hyperfluorescence, while in the late venous phase, leakage shall be noted. The ischemic stage shall highlight venovenous shunts and areas of capillary closure. Capillary non-perfusion areas will show up as hypofluorescent areas.[31] FFA helps the clinician in tailoring the treatment for the patient. The presence of neovascularization and capillary non-perfusion areas should prompt one to go ahead with laser photocoagulation. FFA on follow-up visits helps in assessing the adequacy of laser photocoagulation. The presence of macular edema may warrant intravitreal or periocular steroids. However, conventional fundus angiography visualizes only 30 to 50 degrees of the retina and misses out on the peripheral retina, where maximum disease activity usually lies.[31] This limitation has been overcome by wide-field angiography, which images greater than 150 degrees of the retina.[32] Peripheral imaging improves with a better focus and quality with wide-field angiography.[31][33] Wide-field fluorescein angiography enables better follow-up of peripheral ischemic areas than that is usually possible with conventional fluorescein angiography.[33] Ultra wide-field (UWF) angiography has helped in the quantification, localization, and better documentation of capillary non-perfusion areas.[32] One UWF imaging system images up to 82% of the retina in a single attempt. It uses red light for imaging the choroid and green light for the retina, providing us with pseudo-color UWF images. It utilizes confocal scanning laser ophthalmoscopy for acquiring high-resolution FFA images.[32]
2. B-scan (ultrasound) - When the fundus view is precluded by vitreous hemorrhage, B-scan is useful to know whether retinal detachment is present or not. Variable echo density is seen in cases of vitreous hemorrhage. Ultrasound also reveals the presence of posterior vitreous detachment, vitreoretinal attachment (neovascularization), sub-hyaloid hemorrhage, vitreoschisis, and membranes in the vitreous cavity.
3. Optical coherence tomography (OCT) - Macular edema may be quantitated with the help of OCT. Its resolution on serial follow-ups with treatment may also be seen on OCT.[5] Macular involvement is not uncommon in Eales disease. Features on OCT include intraretinal fluid, subretinal fluid, vitreoretinal traction, and macular epiretinal membrane.

Laboratory Investigations 

Other diseases causing vasculitis need to be ruled out with appropriate laboratory investigations before making the diagnosis of Eales disease. To rule out leukemia and other hematological diseases, a complete blood count is needed. Erythrocytic sedimentation rate (ESR), blood sugar, and coagulation profile may be ordered. High-resolution computed tomography (HRCT) chest or chest X-ray and Mantoux test are needed to account for tuberculosis. HRCT chest is considered the highest diagnostic value in pulmonary tuberculosis.[34] 

Hemoglobin electrophoresis is done to rule out sickle cell retinopathy. To rule out sarcoidosis, serum angiotensin-converting enzyme and HRCT chest is required. Serum antinuclear antibody test may be needed to rule out systemic lupus erythematosus (SLE); however, arterioles are more involved (in Eales disease, veins are predominantly involved), and systemic lupus erythematosus has multiple soft exudates (cotton wool spots) around the optic disc or whitish retinal patches causing Purtscher-like retinopathy. Venereal Disease Research Laboratory test (VDRL) and Treponema pallidum hemagglutination (TPHA) test are required for syphilis.[26] 

In patients with associated retinitis or other suggestive features, HIV serology should also be done.

Treatment / Management

The stage of the Eales disease determines the management. Management options include - observation, medical therapy, laser photocoagulation, and vitreoretinal surgery. Both eyes of the patient may have different stages of the disease, so more than one mode of treatment modalities may be required.

Observation

Patients who do not have active peripheral vasculitis should be kept under observation with follow-ups at 6 to 12 monthly intervals. Those with a new vitreous hemorrhage with an attached retina need to be reviewed after every 2 to 6 weeks. Such vitreous hemorrhages usually clear in about 6 weeks. 

Medical Therapy

Steroids (systemic and/or periocular) are the first line and mainstay of treatment in the inflammatory stages.[35] Oral steroids are used to treat bilateral vasculitis. Subtenon/intravitreal triamcinolone/intravitreal sustained-release dexamethasone implants may be used as adjuvants, especially when macular edema is present due to ocular inflammation.[36][37][38] The local use of steroids avoids the systemic side effects but has the risk of glaucoma.(B3)

Oral prednisolone is given in the dose of 1 mg/kg body weight and is tapered by 5 to 10 mg per week, over a duration of 6-8 weeks. A maintenance dose of 15 to 20 mg per day for a duration of up to 2 months may be needed in some patients. Generally, response to corticosteroids is extremely good in Eales disease. Thus, Eales disease seldom requires cyclosporine and other immunosuppressive drugs. Cyclosporine or azathioprine may be required in patients who have unacceptable side effects due to systemic corticosteroids or do not respond to them.[1]In patients with active perivasculitis and a positive Mantoux test with an occasional healed presumably tubercular lesion in the lung, oral corticosteroids and empirical anti-tubercular therapy (ATT) may be considered together.[4] However, ATT's role in Eales disease remains debatable. The ATT schedule includes rifampicin 450 mg and isoniazid 300 mg, once daily for 9 months[4]. ATT itself can cause multiple side effects, caution should be exercised, and risk/benefit analysis must be done before starting ATT. Usually, ATT is reserved for severe cases with 'massive infiltration along veins with obliteration of large segments of the vein.'[4]Intravitreal anti-VEGF injections may be tried in cases with retinal neovascularization not responding to scatter laser; however, they may cause vitreoretinal traction.[39][40] Laser photocoagulation, along with anti-VEGF injection, may be required to combat neovascularization in patients with complicated Eales disease.[41] (B3)

In some cases, systemic therapy may be much less effective, and in order to halt the disease progression and for reducing the recurrence, an intravitreal sustained-release dexamethasone implant may be needed in such cases.[42] (B3)

Cases with vitreous hemorrhage, precluding a view of the fundus, require serial follow-ups with B-scan ultrasound 2 to 6 weekly to rule out retinal detachment, which needs urgent surgery. The role of vitamin C and E in fighting oxidative stress is controversial.Laser Photocoagulation It is the treatment of choice in Eales disease with the proliferative stage.[27][43] Photocoagulation is suggested in the case of gross capillary nonperfusion.[44] Argon green laser or frequency-doubled green YAG laser (532nm) is most frequently used, though, in cases with hazy media like significant cataract or hemorrhage in the vitreous, red krypton laser may be put into use. The laser may be done either using a slit-lamp or by using an indirect ophthalmoscope delivery system. On the operating table, following a vitrectomy, the laser may be done using either an endolaser probe or using an indirect ophthalmoscope. The aim of Photocoagulation is to decrease the formation of vasoproliferative factors, thus regulating the circulation by diverting the blood from hypoxic areas to the healthy retina. The spot size used is 400 to 500 micrometers, as is used in pan-retinal photocoagulation. The time duration suggested is 0.15 to 0.2 seconds, with an interval of 0.15 to 0.3 seconds between two laser spots. Sectoral scatter laser photocoagulation is suggested for gross capillary nonperfusion.[27] (B2)

Optic disc neovascularization mandates the need for pan-retinal Photocoagulation. Some minor complications may arise because of laser photocoagulation. Retinal hemorrhages may occur in some cases with very high laser power, but major bleeding is rarely seen if the selection of laser parameters is done properly. Retinal gliosis due to regressing new vessels following laser may lead to contraction and may give rise to complications, like retinal tear resulting in retinal detachment. The laser is not advised in the active inflammatory stage since there are chances of worsening macular edema or inflammation after the laser. After the inflammation has subsided with medications/ subtenon or intravitreal steroids, laser photocoagulation may be done.

Surgery

Pars plana vitrectomy is indicated in cases with persistent vitreous hemorrhage with/without retinal detachment(tractional/rhegmatogenous/combined).[3][27] Vitreous hemorrhage is initially observed, and these patients are asked to keep their head end elevated while asleep. This helps in the settling down of the hemorrhage. Hemorrhage generally clears between 6 to 8 weeks. Ultrasonography should always be done to rule out the presence of retinal detachment. Non-resolving vitreous hemorrhage, which obscures central vision for 3 months, might require vitrectomy.[1] 

However, with recent advances and the safety of vitreoretinal surgery, some surgeons may plan earlier interventions depending on the patient's visual demand. Early vitrectomy may be considered in cases of extensive vitreous membranes, epimacular membranes, or tractional retinal detachment. Vitreous surgery may be straightforward if a complete posterior vitreous detachment is present beforehand. Vitrectomy clears the vitreous opacities and allows the evaluation of the fundus. Laser photocoagulation may be done using an endolaser or by an indirect laser delivery system. Compared to proliferative diabetic retinopathy, vitrectomy in Eales disease is easier. Posterior vitreous detachment and clearing of subhyaloid blood are required. After vitrectomy, epimacular membranes may be peeled off. After vitrectomy in Eales disease, visual results are generally very good.[44][43][45] Complications following vitrectomy include repeated vitreous hemorrhage, retinal detachment, neovascularization of the iris, cataract, and neovascular glaucoma. (B2)

Anterior retinal cryoablation (ARC)Primary ARC can be done in neovascular glaucoma where the visual prognosis is poor and in cases with hazy ocular media, which may be due to cataracts, after cataracts or vitreous hemorrhage, and in cases with a small non-dilating pupil. With current advances, laser photocoagulation has almost replaced ARC in most cases.

Differential Diagnosis

The stage of the disease determines the differential diagnosis of Eales disease and includes the following entities:

• Vascular: branch retinal vein occlusion, Bechet syndrome, granulomatosis with polyangiitis (Wegener granulomatosis)
• Infectious: syphilis, Lyme disease, cytomegalovirus retinitis
• Autoimmune: sarcoidosis, frosted branch angiitis.
• Idiopathic: Coats disease.
• Neoplastic: leukemia.
• Congenital: familial exudative vitreoretinopathy, sickle cell retinopathy[46]
• Endocrine: diabetic retinopathy.

Branch retinal vein occlusion generally occurs in hypertensives, and the site of occlusion is invariably an arteriovenous junction; meanwhile, in Eale disease, the site of occlusion could be anywhere along the course of the vein. Branch retinal vein occlusion (BRVO) is usually seen in a single quadrant, while Eales disease affects multiple quadrants generally. Vasculitis in the Eales disease predominantly involves the veins.[1] Other entities in which vasculitis largely affects the veins include tuberculosis, sarcoidosis, Lyme disease, and multiple sclerosis; therefore, these diagnoses need to be excluded.[47] Sarcoidosis, tuberculosis, and syphilis generally have active or healed lesions of choroiditis along with vasculitis.Pars planitis patients present with peripheral retinal periphlebitis close to pars plana exudation. Vitritis, snowballs, snowbanks, and cystoid macular edema are prominent features.

Features of PCR-positive tubercular retinal vasculitis include:[14]

• Age: 11 to 32 years
• Predominant male involvement (around 70% of patients)
• Bilaterality (54% of patients)
• Vitritis (100% eyes)
• vitreous snowballs (90% eyes)
• Retinal new vessels (around 60% of eyes)
• Retinal hemorrhages (53%)
• Neuroretinitis (53% eyes)
• Focal choroiditis (around 50%)
• Vitreous hemorrhage or preretinal hemorrhage (26%)
• Serous retinal detachment (16%)

Prognosis

Eales disease carries a good prognosis with proper treatment.[35] Severe vision loss is rare, and blindness is caused due to retinal detachment and neovascular glaucoma.

Complications

Complications of Eales disease include:

1. Recurrent vitreous hemorrhage
2. Neovascular glaucoma
3. Retinal detachment
4. Macular edema
5. Epiretinal membrane
6. Choroidal neovascularization[48]