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Year : 2007  |  Volume : 55  |  Issue : 2  |  Page : 95-102

Eales' disease: Oxidant stress and weak antioxidant defence

Biochemistry Research Department, Sankara Nethralaya, Vision Research Foundation, Chennai, India

Date of Submission15-Jun-2006
Date of Acceptance27-Oct-2006

Correspondence Address:
S Ramakrishnan
Biochemistry Research Department, Sankara Nethralaya, Vision Research Foundation, 18, College Road, Chennai - 600 006
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0301-4738.30701

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Eales' disease (ED) is an idiopathic retinal periphlebitis characterized by capillary non-perfusion and neovascularization. In addition to the existing system, a new staging system has been proposed by Saxena et al . Immunological, molecular biological and biochemical studies have indicated the role of human leucocyte antigen, retinal S antigen autoimmunity, Mycobacterium tuberculosis genome, free radical damage and possibly hyperhomocysteinemia in its etiopathogenesis, which appears multifactorial. Oxidant stress has been shown by increase in the levels of thiobarbituric acid reactive substances (lipid oxidation) in the vitreous, erythrocytes, platelets, and monocytes. A decrease in vitamins E and C both in active and healed vasculitis, superoxide dismutase, glutathione, and glutathione peroxidase showed a weakened antioxidant defence. Epiretinal membrane from patients of ED who underwent surgery showed, by immunolocalization, presence of carboxy methyl lysine, an advanced glycation end product formed by glycoxidation and is involved in angiogenesis. OH• free radical accumulation in monocytes has been directly shown by electron spin resonance spectrometry. Free radical damage to DNA and of protein was shown by the accumulation of 8 hydroxy 2 deoxyguanosine (in leucocytes) and nitrotyrosine (in monocytes), respectively. Nitrosative stress was shown by increased expression of inducible nitric oxide synthase in monocytes in which levels of iron and copper were increased while those of zinc decreased. A novel 88 kDa protein was found in serum and vitreous in inflammatory condition and had antioxidant function. Platelet fluidity was also affected. Oral, methotrexate in low dosage (12.5 mg/week for 12 weeks) as well as oral vitamin E (400 IU) and C (500 mg) daily for 8 weeks are reported to have beneficial effects.

Keywords: Beneficial therapy, decreased antioxidant defence, Eales′ disease, increased oxidant stress

How to cite this article:
Ramakrishnan S, Rajesh M, Sulochana K N. Eales' disease: Oxidant stress and weak antioxidant defence. Indian J Ophthalmol 2007;55:95-102

How to cite this URL:
Ramakrishnan S, Rajesh M, Sulochana K N. Eales' disease: Oxidant stress and weak antioxidant defence. Indian J Ophthalmol [serial online] 2007 [cited 2022 Dec 7];55:95-102. Available from: https://www.ijo.in/text.asp?2007/55/2/95/30701

Lowered oxidative stress on antioxidant supplementation in Eales’ disease

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Lowered oxidative stress on antioxidant supplementation in Eales’ disease

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Sequence of 28 amino acids from N terminus of 88
kDa protein in Eales’ disease

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Sequence of 28 amino acids from N terminus of 88
kDa protein in Eales’ disease

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Glycoxidation of glucose and glycoproteins in Eales’
disease and formation of dicarbonyls and advanced
glycation end products (AGE)

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Glycoxidation of glucose and glycoproteins in Eales’
disease and formation of dicarbonyls and advanced
glycation end products (AGE)

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Eales' disease (ED) is an idiopathic retinal periphlebitis characterized by capillary non-perfusion and neovascularization. It was first described by Henry Eales in 1880[1],[2] as a primary perivasculitis that predominantly affects the peripheral retina. In recent years, immunological, molecular biological and biochemical studies have indicated the role of human leucocyte antigen, retinal S antigen autoimmunity, Mycobacterium tuberculosis genome, free radical damage, and possibly hyperhomocysteinemia in the etiopathogenesis of this disease. Thus its etiology appears to be mutlifactorial.[3]

While other aspects of the disease have been covered extensively in the form of reviews, so far there is no review on the oxidant insult and antioxidant defence. As a significant number of papers have come out in this field, it is desirable to have a review in this aspect in detail.

  Pathophysiological changes Top

Clinical manifestations of this disease are due to three basic pathological changes:

Inflammation (peripheral retinal perivasculitis) ischemic changes (peripheral retinal capillary non perfusion) and neovascularization of the retina or disc, which often leads to vitreous hemorrhage.[3]

The disease observed more commonly in the Indian subcontinent than in the rest of the world,[4] occurs in healthy adult males[5] initially presenting as retinal periphlebitis and later as retinal ischemia that may lead to neovascularization. Bilateral involvement is evident in 50-90% of the patients.[3] There is no known mortality associated with ED.[6]

Patients are often asymptomatic in the initial stages of retinal perivasculitis. Once the disease progresses, the clinical findings are characterized by vascular areas in the retinal periphery followed posteriorly by micro-aneurysms, dilatation of capillary channels, tortuosity of neighbouring vessels and spontaneous choroido-retinal scars.[6] There is perivascular phlebitis, non-perfusion, and neovascularization [Figure - 1][Figure - 2][Figure - 3][Figure - 4][Figure - 5][Figure - 6]. Some patients may develop black spots or floaters, blurring of vision, even gross diminution of vision, due to massive vitreous hemorrhage. Recurrent vitreous hemorrhages with or without retinal detachment are the common sequelae.[3],[6],[7],[8]

  Staging of ED Top

Charmis[9] has classified ED into 4 stages. They are:

Stage I: Very early in evolution and characterized by mild periphlebitis of small peripheral retinal capillaries, arterioles, and venules detected by ophthalmoscopy.

Stage II: Perivasculitis of the venous capillary system is widespread, larger veins are affected as are the arterioles lying by the side of affected veins, vitreous haze is manifested.

Stage III: New vessel formation with abundant hemorrhage in the retina and vitreous is observed.

Stage IV: End result is massive and recurrent vitreous hemorrhages with retinitis proliferans and traction retinal detachment.

Recently Saxena et al .[10] have given a new staging system. It is as follows:

Stage I is periphlebitis of small (1a) and large (1b) caliber vessels with superficial retinal hemorrhages. Stage IIa denotes capillary non-perfusion and IIb neovascularization elsewhere/of the disc. Stage IIIa is classified as fibrovascular proliferation and 3b vitreous hemorrhage. Stage IVa is traction/combined rhegmatogenous retinal detachment whereas IVb is rubeosis iridis, neovascular glaucoma, complicated cataract, and optic atrophy.

The new system, according to the authors is useful in classifying and assessing the severity of the disease.

  Etiopathogenesis Top

The association of tuberculosis with ED has been proposed by several investigators, but the results are not conclusive. In a clinical study of 1005 patients of pulmonary and extra pulmonary tuberculosis, no case of ED was found.[11] In a molecular biological study of vitreous samples of ED patients who underwent vitrectomy for vitreous hemorrhage or retinal detachment, five out of 12 samples (41.7%) showed Mycobacterium tuberculosis complex DNA by polymerase chain reaction.[12] In another study 11 out of 23 epiretinal membranes removed from eyes with ED showed Mycobacterium tuberculosis genome by nested polymerase chain reaction technique.[13] However, culture of vitreous specimens did not show any growth of Mycobacterium tuberculosis .[3]


Lymphocyte infiltration into epiretinal and subretinal membrane predominantly with T cells has been demonstrated.[14],[15] Recently, Saxena et al .[16] studied lymphocyte proliferative response against retinal S-antigen, its uveito pathogenic peptides, yeast histone H3 peptide and uveito-pathogenic fragments of inter photoreceptor retinoid binding protein (IRBP). Six out of 24 ED patients showed significant proliferative response against retinal S-antigen, its uveitogenic fragments, and IRBP.[3] However, such cellular immune response has been seen in some other ocular diseases and is not specific to ED.[3]

Biochemical findings

Many biochemical findings in ED have been reported. They are elevated a 2 globulin and decreased albumin levels in the serum,[17] a protein of mol. wt. of 23 kD,[18] raised a 1 acid glycoprotein[19] some peptide growth factors like platelet - derived growth factor, insulin- like growth factor, epidermal growth factor, transforming growth factors a and b, vascular endothelial growth factor, urokinase and metalloprotease enzymes.[3]

  Free radicals and oxidant stress Top

Oxidative stress has been shown to play an important role in the pathogenesis of several human inflammatory diseases including ocular inflammatory diseases. It is Rao et al .[20] who first demonstrated the damage inflicted in the ocular tissue in uveitis due to reactive oxygen species (ROS) released by phagocytic cells, polymorphonuclear leucocytes (PMN), and macrophages. Armstrong et al .[21] also demonstrated elevated lipid peroxides in retinal neovascularization in diabetic retinopathy. They proposed a mechanism whereby lipid peroxides induced the synthesis of cytokines and growth factors in the retina during vascularization.

ROS consists of superoxide anion (O 2•-), hydrogen peroxide (H 2 O 2 ), hydroxyl free radical (OH·) and the lipid free radicals produced by OH· [Figure - 7]. They are measured as thiobarbituric acid reactive substances (TBARS) and are quenched by antioxidants, superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), catalase, ceruloplasmin, vitamins E and C.

Strong evidence is accumulating on free radical damage and diminished antioxidant defence in ED. As Rao et al .[20] have shown in uveitis, a similar disease, free radicals can be released in ED also with inflammation by PMN, leucocytes and macrophages. In addition, the free radicals could be generated by the oxidation of homocysteine (Hcy) to homocystine as hyperhomocysteinemia (HHcy) has been found in patients with ED.[22] It is very interesting to note that this HHcy has been reported to be greater in males than in the females[23],[24] and affects young subjects.[25]

It is brought about by the deficiency of folate and vitamin B12 quite common in Indian subcontinent.[25] It is shown that Indian Asians had 6% higher levels of Hcy in their blood compared to Europeans.[26] Hence it appears that homocysteinemia also could be one of the etiological factors for ED.

Erythrocytes and plasma

The first report on oxidative stress in patients of ED was from Bhooma et al.[5] Thirty three patients with active perivasculitis with inflammation and 19 with healed perivasculitis were examined. There was a 4.6 to 5.6 - fold increase in the levels of TBARS in the erythrocytes of patients with active perivasculitis and a two-fold increase in patients in healed condition when compared with controls. In the same patients, the levels of antioxidants were decreased to 75-76% of vitamin E in serum and 34-40.9% of vitamin C in plasma. In healed condition, the decrease was less: 43.5-56% of vitamin E and 12.5-26.8% of vitamin C. As vitamin E had decreased, Vitamin A levels also decreased in consequence due to oxidation; 67-72.8% and 49.4-50.5% in active and healed conditions, respectively. Activities of the antioxidants SOD, GPx, and the levels of GSH were also decreased by (%) 81.6, 65, and 56.6, respectively, in patients with active vasculitis and (%) 22, 46.4, and 19.2 in healed condition.

Vitreous samples

Vitreous is a repository of biochemical waste of retinal metabolism and changes in vitreous composition of metabolites could give a closer biochemical picture of the retinal disorders compared to erythrocytes. TBARS levels were increased six-fold in the vitreous of ED patients compared with the samples from patients with vitreous hemorrhage in diabetics with a reciprocal reduction of SOD by 9.9% and GSH by 84.2%.[27] These findings in vitreous confirm oxidative stress and lowered antioxidant defence in ED. Increased TBARS levels are suggestive of oxidation of lipids by free radicals.

Oxidative stress and glycoxidation: epiretinal membrane

Studies have been extended to epiretinal membrane in respect to advanced glycation end products (AGE) in ED. Immunolocalization revealed the presence of carboxy methyl lysine (CML) in surgically excised epiretinal membranes from patients with ED[28] [Figure - 8]. CML could not be found in ERM of non-diabetics as controls. AGEs trigger the production of vascular endothelial growth factor (VEGF) by binding to receptors for advanced glycation end products in vascular endothelial cell membrane.[29] VEGF in its turn causes angiogenesis, thrombogenesis and atherogenesis.[30] Hence the finding of AGE in epiretinal membrane is important as it could explain angiogenesis in ED.

AGE can be formed by glycoxidation of glucose in alkaline medium by Fe 3+sub and O 2 and the formation of ROS and dicarbonyls. The dicarbonyls form AGE [Table - 1].


Direct confirmation of the increased formation of OH· free radical was reported through work on monocytes. The monocytes separated from the peripheral blood of patients of ED were stimulated with phorbol 12-myristate acetate. OH· free radical levels analyzed quantitatively with electron spin resonance spectrometer[31] were increased. SOD and TBARS were decreased[31] [Figure - 9].

Oxidative stress leucocytes - DNA

Another confirmation of the increased production of OH•- in ED patients is the presence of 8 hydroxy 2 deoxy guanosine in the leucocytes detected by gas chromatographic mass spectrometric technique [Figure - 10]. The compound is formed by the attack of OH· on DNA. Thus, it is shown that oxidative stress affected the DNA also.[32]

Oxidative and nitrosative stress monocytes: Proteins

In addition to oxidative stress there was also nitrosative stress. The finding of activation of inducible nitric acid synthase (iNOs)[33] is very significant [Figure - 11][Figure - 12][Figure - 13] as there is increased production of NO and ONO-2 (Peroxy nitrite free radical) through NO.

Nitric oxide in physiological amounts is needed for vasodilatation and inhibition of platelet adhesion.[34],[35] But peroxy nitrite radical would react with proteins and nitrate the tyrosine residues to nitrotyrosine. NO and ONO-2 are called reactive nitrogen species (RNS).

NO + O.-2          → ONOO- [33]

Protein - tyrosine → Protein nitrotyrosine[33]

Increased production of 3 nitrotyrosine [Figure - 14] indicated nitration of protein tyrosines by ONOO-.

ONOO- can also get protonated with H+ and form ONOOH, which can give rise to OH• free radical in an iron -independent reaction.

ONOO¯ + H+ → ONOOH[36]

ONOOH         → OH• + NO 2

Thus ONOO could aggravate oxidative stress through OH• free radical. iNOs protein expression was assessed by Western Blot and 3 nitrotyrosine by reverse phase HPLC (RP-HPLC). The authors in this study have shown elevation of TBARS, iron, and copper and a decrease of SOD and zinc in the monocytes.

Oxidant stress: Platelets

Saxena et al.[37] have reported enhanced oxidative stress in ED. Significant increase in malondialdehyde levels in platelets and decreased SOD activity were reported suggesting involvement of free radicals. They also showed that levels of glutathione in ED[38] were decreased. An important demonstration of free radical damage was shown by the same group of workers who studied the platelet membrane fluidity and highlighted the photoreceptor damage.[39]

Srivatsava et al.[40] found elevation of TBARS levels in the platelets of patients with ED. As was shown in erythrocytes by other workers, increase in TBARS levels in proliferative ED supports the view that lipid peroxides may be associated with retinal neovascularization. Saxene et al.[41] have also shown impaired antioxidant defence and enhanced oxidative stress in central ED.

A novel acute phase protein of mol wt 88 kDa with antioxidant function[42]

Identification, purification, and characterization of a new protein from the serum of patients with ED have been done.[4] The protein was purified using preparative electrophoresis and HPLC. It resolved in a 2 globulin region. The purified protein had a retention time of 9.2 min in RP-HPLC. The molecular weight as determined by gel permeation chromatography was 88 kDa. Hence, the protein is referred as 88 kDa protein. Periodic acid Schiff's staining revealed it as a glycoprotein. It was completely denatured above 70ºC. Its isoelectric pH was 5. The protein was present in the vitreous and ERM of ED patients and the blood of patients with systemic diseases like tuberculosis, leprosy and rheumatoid arthritis, but was absent in diabetic retinopathy and healed vasculitis of ED, as in the latter there is no inflammation. Hence 88 kDa protein is an acute phase protein produced in inflammatory conditions. The protein of different sources and diseases was immunologically the same.

The N terminal amino acid sequence by automated Edman's degradation chemistry is given in [Table - 2]

The sequence of three internal peptides was as follows

As the protein is expressed in inflammatory conditions with accumulation of ROS O 2. -, H 2 O 2 , OH. , it was predicated that the 88 kDa protein expressed in inflammation might have antioxidant function. Protein purified from both serum and vitreous exhibited antilipid peroxidation effect on erythrocytes when added during in vitro assay of TBARS. The antiTBARS activity was completely inhibited by 0.1 mm concentration of para chloro mercuric benzoate (PCMB) and 5,5' dithio bis (2/nitro) benzoic acid (DTNB). Inhibition by PCMB suggested the presence of thiol groups (-SH), which may be involved in antioxidant function. On analysis, the protein was found to contain 8% thiols by mass. It also oxidized ferrous ion to ferric ion and is a ferro oxidase. As such, by removing ferrous ion, the protein could arrest the Fenton's reaction and Haber-Weiss-Fentons' reaction, which produce free radicals. Therefore, it is a preventive antioxidant like ceruloplasmin, which is also a ferro oxidase and arrests the Fenton's reaction and the Haber-Weiss-Fentons' reaction. By virtue of its 8% thiol content, it can also quench the oxygen free radicals directly like metallothioneins. In this respect, it could function as a protective antioxidant by removing the oxygen free radicals after their formation thereby protecting from oxidation by ROS and even by RNS.

The protein and DNA database search revealed no match to 88 kDa protein. The molecular weight, sequence of N-terminal amino acids, functions as a preventive and protective antioxidant certify that the 88 kDa protein is a novel protein different from other antioxidant or iron-sequestering proteins like transferrin, hemopexin, haptoglobins, ceruloplasmin metallothioneins and retinal pigment epithelial protective protein (RPP). It is expressed to offer natural defence against oxidant assault during inflammation.[42]

  Medical therapy Top

Corticosteroids remain the mainstay of the therapy in the active perivasculitis stage of ED. It is oral or systemic depending on the severity of inflammation[3] (quadrants of retina). In patients who do not respond to systemic corticosteroids, use of immunosuppressive agents like cyclosporin is recommended.[3] As many investigators believe that hypersensitivity to tuberculoproteins plays a role in the etiology of ED (mantoux positive) antitubercular treatment by way of refampicin and isoniazid is given for a period of 9 months.[3] Photocoagulation is also recommended.[3]

Bali et al.[43] have investigated the response time and safety profile of pulse oral methotrexate therapy in ED. They conclude that low dose oral methotrexate pulse therapy at a dose of 12.5 mg/week is clinically effective within 4 weeks and is associated with an acceptable safety profile.

Antioxidant therapy for Eales' patients

Saxena et al.[44] have given oral antioxidant supplementation in ED. Nineteen consecutive cases with ED and 19 disease-free controls were studied. Antioxidant supplementation (vitamin E, C, A, beta carotene, Cu, Zn and Se) was given for 3 months. Statistically significant differences were observed in TBARS, SOD and GSH but not catalase [Table - 3].

The conclusion from the work was that mean indices of oxidative stress were adversely affected by 25-40% in patients with ED but antioxidant supplementation was associated with more than 50% improvement in them.

Ramakrishnan and Biswas have completed the trials of giving oral vitamins E and C to ED patients and have found that there is increase in the total antioxidant capacity (TAC) and decrease of VEGF (Personal communication).

Recommendation for beneficial therapy

The observations recorded above show clearly that there is oxidative thrust with a deficiency of antioxidant vitamins E, C; even after healing, the oxidant insult is found to continue though to a minor degree. So, it is necessary that, so long as TBARS are found to accumulate, the patients should take antioxidants such as vitamins E and C till TBARS levels are normalized. So, in addition to steroid therapy, the patients should take oral vitamin E (400 IU; 1.47 IU = 1 mg) and C (500 mg of Vitamin) daily.[45],[46],[47],[48],[49]

The levels of TBARS and vitamin-antioxidants have to be monitored. As vitamin E deficiency would affect the bioavailability of vitamin A, it is preferable to take vitamin A also daily (5000 IU).[50] The antioxidant therapy should continue till there is no realizable oxidant insult to the patients. If the antioxidant defence is built up, the oxidants will be gradually eliminated and the patients may not go to the stages of vitreous hemorrhage and retinal detachment.

If hyperhomocysteinemia is found in the patients, it could also cause oxidant assault.[51] In such cases a daily dose of folate (1-2 mg)[52] and vitamin B12 (500 micrograms) orally[52] will be beneficial and be continued till homocysteine levels are normalized.

  Conclusions Top

In this review on ED, definition, pathophysiology, clinical manifestations, staging, etiopathogenesis, immunopathology, biochemical findings, oxidative, and nitrosative stress, a novel protein of molecular weight 88 kDa and therapeutic aspects have been discussed. Results of different parameters of oxidant-insult such as TBARS, OH·, AGE, iNOs, nitrotyrosine, 8-hydroxy 2-deoxy guanosine, homocysteine, and antioxidant vitamins E and C, vitamin A, SOD and glutathione peroxidase, iron, copper, and zinc in different groups have been highlighted. Erythrocytes, plasma, vitreous, epiretinal membrane monocytes, leucocytes, and platelets were the specimens analyzed by the workers. Antioxidant therapy also with oral vitamins E, C, A supplements has been described. Statistics taken for individual studies is reported to be significant. If different groups had published many papers on each aspect, the results would be more authoritative. However, two groups of scientists one each from Chennai and Lucknow have got convincing results independently on oxidant insult, diminished antioxidant defence and beneficial effects of oral supplementation of vitamins E, C, and A in patients of ED. Recommendation for daily oral supplements of vitamins E, C, A, folate, and B12 has been made. For such a therapy, further trials on large number of patients have to be made. However, the above workers have given a lead for the same.

  Acknowledgement Top

The authors thank Dr. S. S. Bardinath, Chairman, Dr. Lingam Gopal, Dr. H.N. Madhavan, Dr. S. B. Vasanthi and Dr. J. Biswas for constant encouragement.

  References Top

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  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9], [Figure - 10], [Figure - 11], [Figure - 12], [Figure - 13], [Figure - 14]

  [Table - 1], [Table - 2], [Table - 3]

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