Article

Eales Disease: A Blast From the Past

A rare but important disease to consider in patients with vasculitis.

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Eales disease is as an idiopathic inflammatory venous occlusive disease that affects the peripheral retina.1 Henry Eales first observed this condition in the 1880s manifesting as recurrent retinal hemorrhages associated with headaches, epistaxis, dyspepsia, or chronic constipation in young, otherwise healthy men. Later, in 1887, Wadsworth highlighted the condition’s association with retinal inflammation and Elliot, in 1954, subsequently described the condition as retinal periphlebitis, after noting the presence of perivascular inflammation that occurred in conjunction with retinal hemorrhages.1,2 While the condition is thought to be most likely idiopathic, several studies have proposed an association of this condition with Mycobacterium tuberculosis. Treatment is multifaceted and can include steroid therapy, antituberculous therapy, anti-vascular endothelial growth factor (anti-VEGF) agent administration, panretinal photocoagulation (PRP), and vitreoretinal surgery.1,2 Here we present a case of Eales disease and review the clinical features, theories of pathogenesis, and possible treatment modalities.

Nandini Venkateswaran, MD, and Harry W. Flynn Jr., MD, are with the Bascom Palmer Eye Institute Department of Ophthalmology at the University of Miami in Miami, Florida. Sonal B. Dave, MD, is with EyeHealth Northwest in Portland, Oregon. The authors report no related disclosures. Reach Dr. Flynn at Hflynn@med.miami.edu.
Editor’s note: This article is featured in a journal club episode of Straight From the Cutter’s Mouth: A Retina Podcast. Listen to the episode at www.retinapodcast.com .

CASE DESCRIPTION

A 23-year-old male from Honduras presented to the Bascom Palmer Eye Institute emergency department in early November 1989 with acute-onset blurred vision in his left eye. His past medical history was notable for hepatitis. His past ocular history was notable for an episode of bilateral conjunctivitis but no prior ocular trauma, surgery, or laser treatment. His family history was notable for rheumatoid arthritis in his mother, diabetes mellitus in his brother, and glaucoma in his grandfather. He was a current smoker and on no medications. His review of symptoms was overall negative.

On initial examination, his blood pressure was 140/85. Uncorrected visual acuity was 20/15-1 in the right eye and 20/20-2 in the left eye. Pupils, pressure, extraocular movements, and confrontational visual fields were all within normal limits. Anterior segment examination was normal. On posterior segment examination, the right eye showed a clear media with neovascularization of the disc, vascular sheathing, scattered intraretinal hemorrhages in the periphery, and areas of subretinal fibrosis in the macular region. In the left eye, there were multiple areas of preretinal and subhyaloid hemorrhages with neovascularization of disc and sclerosis of retinal vessels extending into the periphery (Figure 1). Fluorescein angiography showed late leakage around the disc consistent with neovascularization and staining in the areas of subretinal fibrosis in the right eye and multiple areas of late leakage consistent with neovascularization and nonperfusion of vessels extending into the periphery in the left eye (Figure 2).

Figure 1. Fundus montage photos of the right and left eyes on initial presentation in November 1989. In the right eye, neovascularization of the disc, vascular sheathing, scattered intraretinal hemorrhages in the periphery and areas of subretinal fibrosis in the macular region are present. In the left eye, multiple areas are visible of preretinal and subhyaloid hemorrhages with neovascularization of disc and sclerosis of retinal vessels extending into the periphery.

Figure 2. Fluorescein angiography images of the right eye (A) and left eye (B). In the right eye, late leakage around the disc is consistent with neovascularization and staining in the areas of subretinal fibrosis. In the left eye, multiple areas of late leakage are consistent with neovascularization and nonperfusion of vessels extending into the periphery.

A thorough medical work-up was pursued to determine an underlying cause for the patient’s presentation. His workup, which included a complete blood count, coagulation panel, comprehensive metabolic panel, infectious studies (fluorescent treponemal antibody absorption, venereal disease laboratory research, human immunodeficiency virus), inflammatory studies (erythrocyte sedimentation rate, antinuclear antibodies, lupus anticoagulant, cardiolipin antibodies, angiotensin-converting enzyme), and hematologic studies (sickle cell screen), were all negative. He did, however, have a purified protein derivative (PPD) that showed >10 mm of induration, but he had a normal chest x-ray. He reported having 2 prior PPDs that were negative in 1967 and 1983; his mother had a history of a positive PPD but a negative chest X-ray as well. He also had positive Lyme IgG antibodies and Lyme index but an indeterminate western blot. A subsequent spinal tap was unremarkable with a normal cell count and negative infectious serologies including mycobacteria, Lyme, cryptococus, and toxoplasma (Table 1).

Table 1: Medical Work-up for Eales Disease
TESTING PATIENT’S RESULTS
Complete blood count Normal
Coagulation studies Normal prothrombin time and partial thromboplastin time
Comprehensive metabolic panel Normal blood glucose, normal liver function tests
Infectious studies Fluorescent treponemal antibody absorption nonreactive
Venereal disease laboratory research nonreactive
Human immunodeficiency virus negative
Lyme IgM normal (<1.16)
Lyme IgG high (1:64)
Lyme index value positive (1.39)
Lyme western blot indeterminate
Purified protein derivative >10 mm induration
Chest X-ray normal
Cerebrospinal fluid studies (cell count, infectious cultures and antibodies all normal)
Inflammatory studies Erythrocyte sedimentation rate 4 (normal)
Antinuclear antibodies <40 (normal)
Lupus anticoagulant normal
Cardiolipin IgM <5 (normal)
Cardiolipin IgG <3 (normal)
Angiotensin-converting enzyme 30 (normal)
Hematologic studies Sickle cell screen negative

The patient had an interval worsening in visual acuity 2 weeks after his initial presentation, with a new vitreous hemorrhage in his right eye and worsening vitreous hemorrhage in his left eye. He was given a subtenon steroid injection in his left eye to treat any underlying vascular inflammation. He underwent bilateral panretinal photocoagulation (PRP) but eventually required a pars plana vitrectomy and endolaser in both eyes secondary to recurrent and nonclearing vitreous hemorrhages and membrane formation. Cultures of vitreous samples from both vitrectomies yielded no growth of organisms. He was also treated with 4 months of isoniazid for empiric antituberculous therapy for possible latent tuberculosis and 2 weeks of intravenous ceftriaxone for empiric Lyme disease coverage.

Following bilateral vitrectomies and complete PRP, he has remained remarkably stable with excellent vision. At 27-year follow-up in March 2017, the patient’s uncorrected vision was 20/20-1 in the right eye and 20/25-2 in the left eye. A minimal epiretinal membrane was present in the left but there was no evidence of hemorrhage or neovascularization (Figure 3). His only complaint is a mild reduction in night vision for driving. He will continue to be followed annually.

Figure 3. Fundus photos of the right (A) and left (B) eyes at 27-year follow-up after bilateral vitrectomy and complete panretinal photocoagulation. A minimal epiretinal membrane is present in the left eye.

CLINICAL FEATURES

In this patient, the constellation of an obliterative peripheral vasculitis associated with neovascularization and preretinal and intraretinal hemorrhages in a young male with a positive PPD raised high suspicion for Eales disease.

Eales disease classically affects young, healthy males. The condition is more prevalent in India, Pakistan, and Afghanistan, with 1 in 200 to 250 patients being diagnosed with the condition after presenting to a general eye hospital and 1 in 135 patients being diagnosed after presenting to a referral ophthalmic center in India.1 Our patient’s Honduran nationality did not fit the usual demographic of patients affected with Eales disease, and this prompted consideration of alternative diagnoses.

A review of 898 eyes of 500 patients with Eales disease characterized the condition as a frequently bilateral disease (81%) primarily affecting males (95.2%) between the ages of 20 years and 40 years (71.2%). The most common presenting complaints included floaters and an abrupt decrease in vision, likely secondary to a new vitreous hemorrhage (40%).3

Examination of patients often reveals perivascular inflammation, mainly periphlebitis and peripheral capillary nonperfusion. Inflammation-induced vascular occlusion can lead to a proliferative vasculopathy with subsequent sequelae, such as vitreous hemorrhages and tractional retinal detachments.4 Saxena et al proposed a staging system for Eales disease comprised of stages I to IVb. Stage I consists of periphlebitis of small- (Ia) and large-caliber (Ib) vessels with superficial retinal hemorrhages; stage IIa capillary nonperfusion; stage IIb revascularization elsewhere/of the disc; stage IIIa fibrovascular proliferative; stage IIIb vitreous hemorrhage; stage IVa traction/combined rhegmatogenous retinal detachment; stage IVb: rubeosis iridis, neovascular glaucoma, complicated cataract, and optic atrophy.5 In addition to the above findings, patients can present with concomitant signs of ocular inflammation. These signs can include anterior chamber cell and flare, keratic precipitates, vitreous cells, vascular sheathing, macular edema, and choroiditis.3 Macular involvement with Eales disease is uncommon, and thus, central visual acuity is often preserved despite extensive peripheral nonperfusion. When there is macular involvement, it commonly presents as macular edema and intraretinal hemorrhages, rarely with macular nonperfusion, epiretinal membrane formation, or macular hole formation.6

DIFFERENTIAL DIAGNOSIS

Ultimately, Eales disease is a diagnosis of exclusion. In a patient presenting with an obliterative peripheral vasculitis, one must consider several diagnoses. These can include retinal vascular diseases (diabetes mellitus vascular occlusions, hemoglobinopathies), collagen vascular diseases (ie, systemic lupus erythematosus, granulomatosis with polyangiitis), infectious causes (ie, tuberculosis, syphilis, Lyme disease, HIV, viral processes), inflammatory processes (ie, sarcoidosis, serpiginous choroidopathy, Behcet disease) and idiopathic causes (ie, idiopathic retinitis vasculitis aneurysms and neuroretinitis). The patient must undergo a thorough systemic work-up assessing for any alternative metabolic, hematologic, immunologic, or infectious abnormalities that could explain their pathology (Table 2).2

Table 2: Differential Diagnosis for Eales Disease
RETINAL VASCULAR DISEASE
Diabetes mellitus
Sickle cell disease
Hemoglobinopathies
Vascular occlusions (vein and arterial)
Radiation retinopathy
Leukemic retinopathy
Retinopathy of prematurity
Familial exudative vitreoretinopathy
INFECTION/INFLAMMATION
Tuberculosis
Syphilis
Lyme disease
Human immunodeficiency virus
Herpes viruses (HZV, VZV, CMV)
Sarcoidosis
Serpiginous Choroiditis
Behcet Disease
COLLAGEN VASCULAR DISEASE
Systemic lupus erythematosus
Granulomatosis with polyangiitis
IDIOPATHIC VASCULITIS
Idiopathic retinitis vasculitis aneurysms and neuroretinitis
Eales disease

Lyme disease in particular can manifest as with vitritis, retinal vasculitis, vasculitic vein occlusions, choroiditis, exudative retinal detachments, and even an obliterative proliferative vasculopathy. This patient did have positive Lyme IgG antibodies and Lyme index value but negative Lyme IgM antibodies and an indeterminate Western blot. A lumbar puncture was also performed and all Lyme antibodies were negative in the cerebrospinal fluid samples. He also had no other systemic manifestations of the disease. Given these findings, index of suspicion for an active Lyme vasculitis was low; however, the patient was treated empirically with IV ceftriaxone.

PATHOGENESIS

Several theories exist on the pathogenesis of Eales disease.1,2 Many center on an underlying infectious etiology, given the proposed association between Eales disease and Mycobacterium tuberculosis. Some believe the disease is the sequelae of a direct tuberculosis infection; 2 studies from the 1930s showed direct histopathologic evidence of tubercle bacilli in cases of Eales disease. Others believe that it is a manifestation of a hypersensitivity reaction to the tuberculin protein, as patients with the disease can have Mantoux positivity ranging from 42.1% to 98%.7 Various studies have investigated the presence of Mycobacterium tuberculosis in vitreous and epiretinal membrane samples and have found statistically significant higher percentages of positive Mycobacterium tuberculosis PCR in patients with the disease as compared with controls.7-9 Positive PCR samples from intraocular specimens suggest that eyes with Eales disease may sequester nonviable mycobacteria that can trigger inflammatory and immunopathologic changes.7-9 Additional theories include immune-mediated mechanisms, primarily T-cell-mediated mechanisms, and proposed associations to specific HLA subtypes including HLA B5, HLA DR1, and HLA DR4. Alterations in VEGF and pigment epithelial derived factor levels have been thought to drive retinal the vascular abnormalities observed in the disease.1

Eales disease has also been linked to various comorbid conditions. Reports describe the condition occurring in association with cerebellar ataxia, multiple sclerosis, cerebrovascular accidents, and myelopathy.4,10 Renie et al noted a subset of their Eales disease patients to have sensorineural hearing loss and abnormal vestibular function, which they hypothesized was secondary to widespread vascular dysfunction that led to cochlear ischemia.4

TREATMENT

The treatment of Eales disease can include various modalities, including steroid therapy, antituberculous therapy, anti-VEGF agent administration, PRP, and surgery.1,2 Steroids are considered to be the initial management in the acute perivasculitis stage or for macular edema. These can be administered orally (to doses of up to 2mg/kg, with gradual taper) or as injections into the subtenon space or intravitreally. They are administered if systemic tuberculosis is or has been treated. Steroid-sparing agents can be reserved for patients who cannot tolerate steroids or who have remained refractory to steroid therapy.1,2

Antituberculous treatment is often instituted in the acute phlebitis stage, particularly when massive infiltration, nodule formation, and complete obliteration of venous segments is observed. Per the CDC, multidrug therapy is recommended for tuberculous uveitis, typically consisting of a 4-drug regimen for 2 months and a 2-drug regimen for an additional 4 months.11 Steroids can be administered concurrently to help mitigate further inflammation.2

Vascular endothelial growth factor expression is driven by retinal ischemia and chronic inflammation and can cause neovascularization and recurrent vitreous hemorrhages, which are the most common cause of vision loss in Eales disease. Administration of anti-VEGF agents for this condition has been studied but has yielded mixed results. A small study of 2 patients with proliferative Eales disease treated with intravitreal bevacizumab showed rapid regression of retinal neovascularization and clearing of vitreous hemorrhage,12 while a larger prospective, randomized trial of 20 patients treated with either intravitreal bevacizumab or observation showed that injections neither hastened the resolution of vitreous hemorrhages nor reduced the need for vitrectomy.13

Panretinal photocoagulation can be considered in the management of the proliferative phase of the disease. However, several questions remain regarding its utility in the inflammatory stage of the disease, the role of segmental vs complete laser therapy, and the benefit of prophylactic laser therapy. Magargal et al found that PRP administered to all ischemic zones as well as in a sectoral fashion permitted full regression of vascular proliferation at 70 months of follow-up.14 Ishaq et al interestingly found that prophylactic PRP allowed for statistically significant improvements in visual acuity and decrease in persistence of disease.15

Ultimately, patients with more advanced disease may require surgical intervention for nonclearing vitreous hemorrhages, tractional and/or rhegmatogenous retinal detachments, and epimacular proliferations. Vitrectomies have been shown to improve visual acuity by 60% to 100% in different studies. Shanmugam et al found that in patients treated with vitrectomy, 45.3% had a postoperative visual acuity of 6/6 to 6/12 at 60 months of follow-up as compared with poor preoperative visual acuities of hand motions and light perception. They also recommended performing intraoperative endolaser at the time of vitrectomy to ischemic retina to reduce additional vascular sequelae.1,16

CONCLUSION

Eales disease should remain on the differential diagnosis of a peripheral occlusive vasculopathy found in otherwise young, healthy males with suspected tuberculosis exposure; however, it is important to note that a thorough work-up is required before arriving at this diagnosis of exclusion. The patient presented here had an extended course of bilateral retinal neovascularization and vitreous hemorrhages but remains stable with remarkably good vision after bilateral vitrectomies and full PRP at 27 years of follow-up. RP

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