Eales' disease: The great masquerader

Optometry (2009) 80, 354-359

Eales’ disease: The great masquerader Jeanmarie Davis, O.D.,a Scott H. Schecter, O.D., C.S.T.,b and Joseph Sowka, O.D.a a

Nova Southeastern University College of Optometry, Ft. Lauderdale, Florida, and bRainbow Eye Center, Miami, Florida.

KEYWORDS Eales’ disease; Idiopathic retinal periphlebitis; Vitreous hemorrhage; Vasculitis; Vitritis; Vascular sheathing; Neovascularization; Retinal detachment

Abstract BACKGROUND: Eales’ disease, also known as idiopathic retinal periphlebitis, is a diagnosis of exclusion, mainly affecting men in the second through fourth decades of life. Although less common in the United States, Eales’ disease is widespread in India and certain areas of the Middle East. CASE REPORT: A healthy, 42-year-old Filipino man presented with reduced vision in the right eye of 2 days’ duration and had recently had a nonrhegmatogenous retinal detachment diagnosed. Clinical findings included angle neovascularization, posterior vitritis, intraretinal hemorrhages, and retinal vascular sheathing in that eye. Systemic evaluation did not disclose an underlying etiology. Eales’ disease was diagnosed. Treatment included topical steroids and cycloplegia, along with intravitreal triamcinolone acetonide injection, which yielded an improvement in the vasculitis and vitritis with subsequent visual improvement and stabilization. CONCLUSION: Eales’ disease should be considered as a differential diagnosis in patients with vasculitis and vitritis. Optometry 2009;80:354-359

Eales’ disease is a primary idiopathic peripheral retinal vasculopathy, mainly affecting healthy men in their second through fourth decades of life and is most prevalent in India and the Middle East.1,2 Henry Eales, a British ophthalmologist, first described this disease in the 1800s after observing recurrent vitreous hemorrhages in healthy young men.3,4 To date, the pathophysiology of Eales’ disease is poorly understood. Also referred to as idiopathic retinal periphlebitis, there is controversy as to whether Eales’ disease is a primary noninflammatory disorder of the walls of the peripheral retinal vessels or an associated epiphenomenon of another inflammatory process.5-8 Recurrent inflammation of retinal vessels in multiple quadrants, severe retinal nonperfusion, neovascularization of the anterior and posterior segment, and vitreous hemorrhage characterize Eales’ disease. Corresponding author: Jeanmarie Davis, O.D., Nova Southeastern University College of Optometry, 4842 SW 155 Terr., Pembroke Pines, Florida 33027. E-mail: [email protected]

Case report A 42-year-old Filipino man presented with a nonrhegmatogenous retinal detachment in the right eye that was recently diagnosed by an ophthalmologist in his country. His initial complaints were a sudden decrease in vision and increase in floaters, which were progressive over a 2-day period. He denied any history of ocular trauma or infection. A detailed case history indicated that he had no evidence of systemic infection, inflammatory process, or any other associated medical conditions. His family history was likewise unremarkable. He had no known allergies to medication. Uncorrected visual acuities were 20/200 in the right eye (O.D.) and 20/25 in the left eye (O.S.), with no pinhole improvement. Extraocular motilities were normal. Confrontation visual fields showed hand motion perception in all 4 quadrants O.D. and full to finger counting in the right eye (O.S.). Pupils were equal, round, and reactive to light without afferent defect in both eyes (OU). Intraocular pressure by Goldmann applanation was 9 mmHg O.D. and 12 mmHg O.S. Biomicroscopic examination found

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Figure 1

Vasculitis and vascular occlusion in the presence of vitritis.

clear corneas OU. The anterior chamber was deep and quiet O.S. but manifested an inflammatory cell and flare reaction O.D. The right iris showed florid neovascularization at the pupillary frill. No iris neovascularization was noted in the left eye. The crystalline lenses were clear OU. Gonioscopy of the right eye showed anterior chamber angles open to the ciliary body 360 without peripheral anterior synechiae, although neovascularization was present throughout the entire angle. The left anterior chamber angle was open to the ciliary body 360 without abnormalities. Dilated retinal examination of the right eye found an optic nerve that was physiologically cupped at 0.2/0.2 and perfused without pallor or neovascularization. There was peripheral vascular sheathing present with hemorrhages in all quadrants. No retinal detachment or separation was found. There was vitritis and mild vitreous hemorrhage. The left fundus examination was normal in all aspects with similar disc cupping. At this time, the patient manifested findings of posterior uveitis, retinal vasculitis with iris rubeosis, and vitreous hemorrhage O.D. (see Figure 1). Eales’ disease was considered the likely diagnosis. The patient was prescribed Pred ForteÒ (Allergan, Inc., Irvine, California) every hour and homatropine 5% 3 times daily O.D. for the anterior segment inflammation. A directed medical evaluation was ordered in an attempt to identify an underlying etiology (see Table 1). An appointment for consultation with a vitreoretinal specialist was scheduled for the next day.

On presentation to the retinal specialist, the patient had no change in ocular findings, but acuity had improved to 20/40 in the affected eye. Review of laboratory findings showed noncontributory and normal results in the majority of tests. The patient’s chest x-ray was positive for granulomatous changes on the left lobe, suggesting previous inflammation, but no active disease. Acute active cardiopulmonary pathology was not found. Ultimately, because of the granulomatous changes on x-ray, a contrast-enhanced computed tomography (CT) scan was performed, which ruled out a mass or infiltrative process. Serologic markers commonly involved in sarcoidosis, such as erythrocyte sedimentation rate (ESR), and angiotensin converting enzyme (ACE), were all normal. Additionally, this patient did not show any other signs or symptoms related to sarcoidosis, such as a dry cough, wheezing, chest pain, excessive tearing, enlarged liver, spleen or salivary glands, abnormal heart rhythm, swollen lymph nodes, or skin rash. The patient’s blood chemistry identified elevated calcium and creatine kinase levels, which were thought to be false-positives because no other supportive systemic findings indicative of sarcoidosis or myocardial infarction were found. The positive cytomegalovirus (CMV) immunoglobulin M (IGM) reflected previous exposure to cytomegalovirus with no evidence of active disease. Normal laboratory findings and lack of physical signs and symptoms for this man ruled out the diagnosis of systemic lupus erythematosus. Although a vitritis was present,

356 Table 1

Optometry, Vol 80, No 7, July 2009 Laboratory studies done in this patient

Test

Result

Chest x-ray

Positive for suggestive granulomatous changes on the left Normal Normal Negative All normal except as noted

CBC w/ differential SED rate Sickle cell screen Blood chemistry BUN, Creatinine, B/C Ratio, GGT, Total Protein, Albumin, Globulin, A/G Ratio, Phosphorous, Bilirubin Total, ALK Phos, LDH ALT (SGPT), AST (SGOT), Cholesterol, Triglycerides, Uric Acid Calcium CK Protein evaluation Total Protein, Albumin Fract, Alpha 1 Glob, Alpha 2 Glob, Beta Glob, Gamma Glob Paraprotein, Serum Protein Electrophoresis C-reactive protein Hemoglobin evaluation Angio converting enzyme RPR FTA-ABS HIV ½ AB screen Toxo IGG, IGM CMV IGG IGM

ANA DNA ds RA factor C-ANCA P-ANCA

High

High

Normal

Normal Normal Normal Non reactive Non reactive Negative Negative Negative Positive - Reflects infection with CMV at some undetermined time Negative Negative Negative Normal Normal

Abbreviations: CBC, complete blood count; SED, erythrocyte sedimentation rate; BUN, blood urea nitrogen; B/C ratio, blood urea nitrogen/creatinine ratio; GGT, Gamma-glutamyl transpeptidase; A/G ratio, albumin/gobulin ratio; ALK Phos, alkaline phosphatase; LDH, lactate dehydrogenase; ALT (SGPT), alanine aminotransferase (serum glutamic-pyruvic transaminase); AST (SGOT), aspartate aminotransferase (serum glutamic-oxaloacetic transaminase); RPR, rapid plasmin regain; FTA-ABS, fluorescent treponemal antibody adsorption test; IGG, immunoglobulin G; IGM, immunoglobulin M; ANA, antinuclear antibody test; DNA ds, double stranded DNA; RA factor, rheumatoid arthritis factor; C-ANCA, circulating anti-neutrophil cytoplasmic antibody; P-ANCA, perinuclear anti-neutrophil cytoplasmic Antibody.

additional ocular findings, such as vasculitis, perivascular sheathing, and hemorrhagic retinopathy, suggest a more complex disease process than would be found in pars planitis.

Table 2

Staging of idiopathic retinal periphlebitis7

Stage features of peripheral idiopathic retinal periphlebitis 1a. Periphlebitis of small caliber vessels with superficial retinal hemorrhages 1b. Periphlebitis of large caliber vessels with superficial retinal hemorrhages 2a. Peripheral capillary nonperfusion 2b. Neovascularization elsewhere/neovascularization of the disc 3a. Fibrovascular proliferation 3b. Vitreous hemorrhage 4a. Traction/combined rhegmatogenous detachment 4b. Rubeosis irides, neovascular glaucoma, complicated cataract, and optic atrophy

Because of the posterior inflammation, the retinal specialist performed an intravitreal injection of triamcinolone acetonide (KenalogÒ; E.R. Squibb & Sons, Middlesex, United Kingdom). All other topical medications were continued, and topical moxifloxacin (VigamoxÒ; Alcon Laboratories, Inc., Ft. Worth, Texas) was added as postinjection prophylaxis. On follow-up the next day, the patient’s visual acuity had improved slightly to 20/30 in the affected eye. There was no appreciable improvement in the fundus findings. However, intraocular pressure had risen to 32 mmHg in the affected eye, presumably because of the combined effects of topically applied and intravitreally injected steroid. At this time, cycloplegia use was discontinued, topical prednisolone acetate dose was decreased to twice daily, and brimonidine tartrate (Alphagan PÒ, Allergan, Inc.) 0.15% 3 times daily was prescribed. On follow-up the next day, visual acuity had improved to 20/25 O.D. Dilated retinal examination found decreased vitreous and retinal hemorrhage and improvement in the vasculitis. Intraocular pressure was 12 mmHg O.D. and 10 mmHg O.S. All topical medications were continued unchanged. Repeat examination the following day found stabilization of visual acuity at 20/25 O.D. Intraocular pressures were 18 mmHg O.D. and 15 mmHg O.S. Dilated retinal examination found continued improvement of perivascular sheathing, vitritis, and hemorrhage O.D. At this time, the diagnosis was Eales’ disease based on clinical findings and no identified etiology after medical evaluation. The topical steroid and brimonidine were continued, and the topical antibiotic was discontinued. At this point, the patient returned to his home country.

Discussion Eales’ disease typically occurs bilaterally in approximately 70% to 80% of healthy young men with initial symptoms of decreased visual acuity and/or floaters.9 The clinical findings of Eales’ disease include perivascular sheathing, peripheral nonperfusion, retinal neovascularization, vitreous

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Differential diagnoses for Eales’ disease

Condition

Clinical findings

Diagnostic testing

Diabetic retinopathy

Hemorrhagic, neovascular, and exudative retinopathy Common findings include anterior uveitis, retinal vasculitis, papillitis, pars planitis and choroidal granulomas16

Diagnosed thorough systemic evaluation and blood glucose testing. Can not be diagnosed by a specific test; however, the majority of patients with this disease have characteristic lymphadenopathy.17 Granulomas may be present, and the majority of sarcoid patients also have parenchymal lung disease.18 Other common, but not specific, findings may include elevated ACE, hypercalcemia, hypercalcuria, lymphocytopenia, eosinophilia, elevated ESR and hyperglobulinemia.17-19 Commonly associated with hypertension, arteriosclerosis, and diabetes.21 Common laboratory findings used to diagnose this disease include antinuclear antibody testing (ANA), chest x-ray revealing pleuritis or pericarditis, abnormal CBC, elevated ESR and abnormal serum globulin and serum protein electrophoresis. Common symptoms associated with SLE include fever, malaise, ‘‘butterfly’’ skin rash over the cheeks and bridge of the nose, joint pain and swelling.22 It has been reported that most cases are idiopathic. A number of cases are associated with sarcoidosis, multiple sclerosis, and Lyme disease.23

Sarcoidosis

Branch vein occlusion Systemic lupus erythematosus

Pars planitis

Sectoral retinal hemorrhages with possible ischemia, exudates, macular edema20 An inflammatory autoimmune disease that affects mainly women and has ocular manifestations in a significant percentage of patients with this disorder. Vasculitis and cotton wool spots are common findings.

An intermediate uveitis affecting young patients that has been suggested to be an immune mediated process. Common findings include vitritis, posterior vitreous detachment from vitritis, cystoid macular edema, and inferior aggregates of inflammatory cells (snow balls and snow banks). Behcet’s syndrome Mouth sores (oral aphthous ulcers) at least 3 times in 12 months. In addition to any 2 of the following: Recurring genital ulcers, eye lesions (uveitis or retinal vasculitis), skin lesions (red, pus-filled bumps commonly found on legs and upper torso); Positive pathergy test Almost all patients with Behcet’s disease are affected with mouth sores. Chorioretinitis Associated with syphilis with other signs such as iridocyclitis, secondary glaucoma, Hutchinson’s triad (deafness, saddle-nose deformity, and interstitial keratitis), mental retardation, and a failure to thrive.27 Tuberculosis A disease affecting the lungs causing symptoms such as weight loss, loss of appetite, night sweats, fever, fatigue, cough, hemoptysis and chest pain. This is commonly found in patients who are HIV positive.28 Toxoplasmosis Commonly presents with a characteristic whitish, yellow fuzzy raised lesion with a dense vitritis. Old retinal scars may be present.27 Wegener’s granulomatosis Other common findings include anemia, elevated white blood cell count, elevated platelet count and elevated ESR.29

A chronic multisystem disease that is difficult to diagnose, as there is no specific confirmatory test.24-26 Diagnosis is based on presence of the most common signs and symptoms associated with the disease.

Specific and nonspecific syphilis testing

Mantoux tuberculin skin test (TST)

Toxoplasmosis titers

Does not have a specific blood test; however, many patients with this disorder test positive for an antibody called ANCA (antineutrophil cytoplasmic antibody). (Continued)

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Optometry, Vol 80, No 7, July 2009 (Continued)

Condition

Clinical findings

Diagnostic testing

Birdshot (vitiliginous) retinochoroidopathy

A rare, bilateral intraocular inflammatory disease causing decreased visual acuity, nyctalopia and dyschromatopsia. Characteristic fundus appearance of round to oval cream-colored multifocal patches of RPE and choroidal depigmentation. Perifoveal vascular leakage from cystoid macular edema is a key angiographic finding.

Most patients have HLA-A29 marker present.30

Abbreviations: ACE, angiotensin-converting enzyme; ESR, erythrocyte sedimentation rate; ANA, antinuclear antibody test; CBC, complete blood count; SLE, systemic lupus erythematosus.

hemorrhage, vitritis, anterior segment neovascularization, anterior chamber reaction with keratic precipitates (which typically is a spillover reaction from vitritis), and cystoid macular edema.10,11 Neovascularization is observed in up to 80% of patients with Eales’ disease.10 A classification system to assess the severity of the disease has been created for peripheral idiopathic retinal periphlebitis, which includes 4 stages that take into account prognostic funduscopic and fluorescein angiographic variables (see Table 2).7 Fluorescein angiography is an essential diagnostic tool in treating patients who have peripheral retinal nonperfusion and neovascularization. Capillary nonperfusion is a typical feature of Eales’ disease. Retinal nonperfusion is generally confluent.8 Vascular endothelial growth factor (VEGF) is an important signal protein involved in angiogenesis through activation of protein kinase C.12,13 VEGF is important in mediating both vasoconstriction and vascular permeability in the retina. Cells that are not receiving enough oxygen produce VEGF. When a cell is deficient or deprived of oxygen, it produces hypoxia inducible factors (HIF), which stimulate the release of VEGF. Therefore, the production of VEGF usually accompanies conditions such as diabetic retinopathy or macular degeneration.14,15

Differential diagnosis Eales’ disease is a diagnosis of exclusion; therefore, other retinal diseases associated with inflammation and neovascularization must be considered first. These include diabetic retinopathy, sarcoidosis, branch vein occlusion, systemic lupus erythematosus, pars planitis, Behcet’s disease, syphilis, tuberculosis, toxoplasmosis, Wegener’s granulomatosis, and birdshot choroidopathy (see Table 3).8,9

Treatment and prognosis Prognosis for patients with Eales’ disease is guarded, mainly because many patients live in areas underserved by medical care. In locations in which medical care is available, the outcomes tend to be better with treatment. Various treatments

have been proposed for Eales’ disease. Photocoagulation is the first line of therapy in Eales’ disease patients with neovascularization and nonperfusion.31 Visual loss usually is a result of complications from neovascularization, retinal detachments, or nonclearing vitreous hemorrhage.32 Vitrectomy combined with retinal photocoagulation can be utilized for removing persistent vitreous hemorrhage secondary to neovascularization.33-35 Other procedures such as intravitreal steroids or Avastin (bevacizumab) have shown promising results, especially in patients with inflammation and macular edema.36

Conclusion Eales’ disease is a hemorrhagic, inflammatory, idiopathic retinal disorder that is a diagnosis of exclusion. Although uncommon in the United States, it must be considered in patients of the appropriate ethnic descent. It mainly affects young healthy men in the second to fourth decades of life but may also affect women of the same age group. Thorough systemic evaluation and appropriate diagnostic testing, such as fluorescein angiography, are essential to properly diagnosing and managing this condition. Early treatment has been shown to significantly improve the prognosis in these patients.32

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