O R I G I N A L A R T I C L E

ANN OPHTHALMOL. 2000;32(1):60–6260

Eales disease is an idiopathic, obliterative vascu-lopathy that affects primarily the peripheral reti-

na of adults.1 Retinal changes include perivasculitis,peripheral nonperfusion, and neovascularization.Visual loss is characteristically caused by recurrentvitreous hemorrhages.2 Immune-mediated mecha-nisms have been proposed in the etiopathogenesis ofthis condition.3 Isoelectric focusing of the serum hasrevealed several unique proteins in these patients.4 Itis possible that altered immune reactivity to an extra-neous agent may play a role in the pathogenesis ofEales disease.5 Raised titers of antiretinal S-antibodieshave been detected in these patients.6

Light microscopic and immunohistochemical stud-ies have demonstrated predominant T-cell involve-ment in the lymphocytic infiltration of epiretinal andsubretinal membranes. Evidence of T-cell involve-ment suggests that treatment should be directed tothe down-regulation of the activated T cells.7,8

Methotrexate is a folic acid antagonist. The drugreduces the synthesis of DNA by acting on the enzymedihydrofolate reductase. It has a marked effect onrapidly proliferating cells and causes B-cell and T-cellsuppression.9

A tertiary care center-based prospective study wasundertaken to evaluate the therapeutic efficacy of oralmethotrexate pulsed therapy in Eales disease. To our

Sandeep Saxena, MS, Dipak Kumar, MS, &Sangeeta Kapoor, MBBS

Efficacy of Oral MethotrexatePulsed Therapy in Eales Disease

A prospective study was undertaken to evaluate oral methotrexate

pulsed therapy in 6 cases of Eales disease presenting with perivas-

culitis. Methotrexate was administered (7.5 mg weekly) for 3

months. The therapy was tolerated well, and retinal perivasculitis

subsided in all cases. Five patients achieved excellent visual acu-

ity—6/6 (20/20) or better. Elevated titers of C-reactive protein

returned to normal after therapy. Six-month follow-up revealed no

recurrence of the disease.

Reprints:Sandeep Saxena, MS, G–19 River Bank Colony, Lucknow, Uttar Pradesh, 226018,India.

Drs. Saxena and Kumar are from the Retina Service, Department of Ophthalmology,King George’s Medical College, University of Lucknow, Lucknow, India. Dr. Kapoor isfrom the Department of Microbiology, King George’s Medical College, University ofLucknow, Lucknow, India.

AcknowledgmentSupported in part by a research grant from the Council of Scientific and IndustrialResearch, New Delhi, India.

A B S T R A C T

ANN OPHTHALMOL. 2000;32(1) 61

knowledge, this is the first report of the use of thistherapy in the management of Eales disease.

Subject & MethodsSix consecutive cases of Eales disease, presentingwith retinal perivasculitis, were included in thisstudy. Approval from the ethical committee of ourinstitution was obtained. Systemic diseases such asdiabetes mellitus, sickle cell hemoglobinopathy, blooddyscrasias, sarcoidosis, and collagen vascular disor-ders were ruled out with a careful medical history andappropriate laboratory tests. At presentation, all thepatients underwent a full ophthalmologic examina-tion, which included Snellen visual acuity, slit-lampbiomicroscopy, indirect ophthalmoscopy, and fluores-cein angiography.

Oral methotrexate pulsed therapy (7.5 mg) wasstarted on a weekly basis for 3 months, after weobtained informed consent. All the cases were keptunder the strict supervision of an internal medicinephysician, and twice-weekly blood cell counts weremonitored. After completion of the therapy, patientswere followed up for 6 months.

Each patient’s visual outcome was assessed interms of changes in visual acuity at the end of the fol-low-up period. Visual acuity grades were determinedaccording to the method of Palmer et al10 and areshown in Table 1. A successful visual outcome wasdefined as either maintenance of visual acuity of 6/12(20/40) or better or improvement by 1 or more grades,as determined at the last clinical examination.Patients who did not fulfill these criteria were definedas having a poor visual outcome.11,12

Titers of C-reactive protein (CRP), an acute-phasereactant, were estimated by the latex agglutinationmethod before and after therapy.

ResultsAll 6 cases of Eales disease included in this study weremen aged between 22 and 30 years, with a median ageof 25 years. Visual acuity grades at the start of therapyand at the end of 6 months of follow-up are shown inTable 2. Following therapy, retinal perivasculitis sub-sided in all the cases, and visual acuity improved in 5of 6 cases (Figs l and 2).

All the patients, who were CRP positive before initi-ation of therapy, became CRP negative at the end ofthe therapeutic regimen (Table 3). During the 6-monthfollow-up, neither any fresh episodes of retinal perivas-culitis nor any side effects of the drug were observed.

DiscussionVasculitis may be a good target for immunotherapy.The vascular endothelium may provide a more acces-sible target for biological reagents. The uniqueimmunologic environment within the eye may facili-tate the reestablishment of regulatory immune cir-cuits following therapy.13

Low-dose methotrexate therapy has been shown tobe effective in ocular inflammatory diseases.14 A

“pulse” differs from chronic moderate-dose therapy inits ability to “reset” an aberrant immune response.Inhibition of the proliferating lymphocyte clones, thetemporary removal of recirculating T lymphocytesfrom the blood and eye, and the profound suppressionof peripheral inflammation all occur simultaneously.Antigens exposed by viral, bacterial, or autoimmuneinjury are perpetuated by the inflammatory response.In such a system, a pulse may abolish the source of theantigen at the same time as it suppresses the immuneresponse. When memory T lymphocytes recirculate,the disease falters in the absence of the antigen.15

Certain proteins in the plasma, collectively termed“acute phase proteins,” increase in concentration to

T A B L E 1Grades of Visual Acuity (VA)

Grade

Grade I (excellent)

Grade II (good)

Grade III (fair)

Grade IV (poor)

Metric VA

6/6 or better

6/9–6/12

6/18–6/36

6/60 or worse

English VA

20/20 or better

20/30–20/40

20/60–20/120

20/200 or worse

T A B L E 2Visual Acuity (VA) Before and AfterOral Methotroxate Pulsed Therapy

PatientNo.

1

2

3

4

5

6

Age (years)/Sex

25/M

30/M

22/M

25/M

27/M

24/M

InitialVA

6/12 (20/40)

6/6 (20/20)

6/36 (20/120)

6/9 (20/30)

6/12 (20/40)

6/6 (20/20)

FinalVA

6/6 (20/20)

6/5 (20/15)

6/12 (20/40)

6/6 (20/20)

6/6 (20/20)

6/5 (20/15)

Fig 1.—Pretreatment 50-degree fluorescein angiogram of 25-year-old patient withEales disease showing leakage of dye from areas of retinal vasculitis (arrows).Patient’s visual acuity is 6/9 (20/30).

ANN OPHTHALMOL. 2000;32(1)62

early alarm mediators, released as a result of infectionor tissue injury. C-reactive protein is a highly sensitiveacute-phase reactant, which is the fastest rising andwhich returns to normal after successful therapies. Ingeneral, these proteins are thought to subserve defen-sive roles.16

In the present study, all the patients responded pos-itively to the therapy. Retinal perivasculitis subsided,and five patients achieved excellent visual acuity. Theelevated CRP titers returned to normal after successfultherapy. Oral methotrexate pulsed therapy was foundto be effective in the management of Eales disease.

References1. Gieser SC, Murphy RP. Eales disease. In: Ryan SJ, ed. Retina. Vol

2: Medical retina. St Louis, Mo: Mosby-Year Book; 1994:1503–1507.2. Kumar D, Saxena RC, Saxena S. Vitreous hemorrhage in Eales

disease. Afro-Asian J Ophthalmol. 1995;13:109–112.3. Saxena S, Kumar D, Singh VK, Rajasingh J. Immunological stud-

ies in Eales disease: a review. Afro-Asian J Ophthalmol. 1995;13:19–22.

4. Rengarajan K, Muthukkaruppan VR, Namperumalsamy P. Bio-chemical analysis of serum proteins from Eales’ patients. CurrEye Res. 1989;8:1259–1269.

5. Muthukkaruppan VR, Rengarajan K, Chakkalath HR, Namperu-malsamy P. Immunological status of patients of Eales’ disease. IndJ Med Res. 1989;90:351–359.

6. Sawhney R, Gupta A, Bansal RK, et al. Eales’ disease: an autoim-mune retinal disorder. Proc All India Ophthalmol Soc. 1992;50:461–464.

7. Biswas J, Rao NA. Epiretinal membranes in Eales’ disease andother vascular retinopathies. Invest Ophthalmol Vis Sci. 1990;31(suppl):369.

8. Badrinath SS, Biswas J, Sharma T, et al. Immunophenotyping ofinflammatory infiltrates in epiretinal (ERM) and subretinal (SRM)membranes in Eales’ disease. Invest Ophthalmol Vis Sci. 1992;33(suppl):857.

9. Chauber BA, Allegra CJ, Curt GA, Calabresi P. Antineoplasticagents. In: JG Mardman, Limbird LE, eds. Goodman andGilman’s The Pharmacological Basis of Therapeutics. 9th ed. NewYork, NY: McGraw-Hill; 1996:1233–1282.

10. Palmer HE, Stanford MR, Sanders MD, Graham EM. Visual out-come of patients with idiopathic ischaemic and non-ischaemicretinal vasculitis. Eye. 1996;10:343–348.

11. Stanford MR, Graham EM, Kasp E, et al. A longitudinal study ofclinical and immunological findings in 52 patients with relapsingretinal vasculitis. Br J Ophthalmol. 1988;72:442–447.

12. Howe LJ, Stanford MR, Edelsten C, Graham EM. The efficacy ofsystemic corticosteroids in sight-threatening retinal vasculitis.Eye. 1994;8:443–447.

13. Isaacs J, Dick A. Short term immunosuppressive therapy andlong term immunoregulation: promises and problems [commen-tary]. Br J Ophthalmol. 1996;80:1035–1036.

14. Shah SS, Lowder CY, Schmitt MA, et al. Low-dose methotroxatetherapy for ocular inflammatory disease. Ophthalmology. 1992;99:1419–1423.

15. Meyer PA, Watson PG, Franks W, Dubord P. Pulsed immunosup-preasive therapy in the treatment of immunologically inducedcorneal and scleral disease. Eye. 1987;1:487–495.

16. Mime CA, Playfair JHL, Roitt IMR, et al. The innate defenses ofthe body. In: Medical Microbiology. St Louis, Mo: Mosby-YearBook; 1993:4.1–4.14.

Fig 2.—Post-treatment 30-degree fluorescein angiogram of same patient as in Fig 1showing absence of leakage of dye due to resolution of retinal vasculitis (arrows).Patient’s visual acuity is now 6/6 (20/20).

T A B L E 3C-reactive Protein (CRP) in Patients

with Eales Disease (n = 6)

CRPTiter

1:0.6

1:1.2

1:1.8

1:2.4

No. of Patients

Before Treatment

4

1

0

1

After Treatment

0

0

0

0