Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer

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S. Gadkari

Core Messages

Eales’ disease is essentially a clinical entity, presenting as a recurrent vitreous hemorrhage in young adult males

The clinical picture is one of an idiopathic retinal vasculitis (periphlebitis) and its sequelae

Bilateral involvement in an economically productive age group makes it an important ophthalmic health care issue in South Asia

25.1.1 History

Henry Eales, a British ophthalmologist, described this condition almost 125 years ago [14, 15]. Eales’ original description was of recurring retinal and vitreous hemorrhages along with epistaxis, headaches, variation in peripheral circulation, dyspepsia, and chronic constipation in young men. He felt it was a vasomotor neurosis, wherein constriction of the alimentary vessels resulted in compensatory dilatation of the vessels in the head, leading to bleeding. Though Eales was honored with the eponym for this disease, Wadsworth was the first to describe the presence of retinal inflammation, 5 years later [37]. Duke Elder considered Eales’ disease to be a clinical manifestation of many diseases.

25.1.2 Epidemiology

One in 200 – 250 general ophthalmic patients in India are affected, ten times more than in North America or Europe, where today it is a diagnosis of exclusion. The male preponderance is marked – almost 90 % [10]. Bilateral affection has been reported in 50 – 90 % of cases, depending on the study [26]. Most present in the 3rd decade of life (15 – 45 years). There is a definite predilection for the poor socioeconomic class and most patients come from rural communities. While the disease was reported globally at the beginning of the last century, improved sanitary conditions and standard of living have seen a gradual

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Its exact etiopathology has evaded explanation, though the role of Mycobacterium tuberculosis, oxidative stress and immunological mechanisms have been studied

Visual results with retinal laser treatment in patients with neovascularization and of vitrectomy in eyes having vitreous hemorrhage are good, if timely treatment is available

Periodic follow-up is important given the progressive nature of the disease

decrease in Europe and North America. Interestingly, Murphy et al. from the USA did not note a male preponderance in their series of 55 cases in America

[27].Today most cases are reported from Asia.

25.1.3Clinical Features

Eales’ disease is an idiopathic, usually peripheral, invariably bilateral retinal vasculitis resulting in peripheral non-perfusion and neovascularization in a young otherwise healthy male population.

The presenting symptoms in most patients are the presence of floaters and painless diminished vision of varying degrees. On most occasions patients have had many such episodes. These are usually self-limit- ing in the initial phase, as reabsorption takes place when the bleed is small. Visual loss usually takes place due to recurrent vitreous hemorrhage and rarely due to vascular ischemia.

Clinical signs are mainly restricted to the posterior segment; rarely a patient may show the presence of minimal anterior chamber reaction. The presence of anterior chamber flare or cells is usually the first indicator of the development of rubeosis iridis, as the presence of new vessels is difficult to visualize in dark brown irides.

Clinically, the various features of Eales’ disease can be divided into signs of inflammation, signs of ischemia, and signs of neovascularization and its sequelae. In the normal course, they occur in this order; however, features from different stages may be

present in the same patient. Given the bilateral tendency of this condition, careful examination of the fellow eye almost always shows peripheral sheathing.

It is important to emphasize that the diagnosis of Eales’ disease is essentially clinical: no immunological, pathological or biochemical tests are available to

25 III make a diagnosis.

25.1.3.1 Signs of Inflammation

Peripheral periphlebitis or vasculitis is the hallmark of this disease. Perivascular exudates result in sheathing of the involved segment of the blood vessels. This can be localized, which can be referred to as cuffing (Fig. 25.1.1b) or involving a large segment of the vessels, called sleeving (Fig. 25.1.1a, c). Vessels with active vasculitis take up fluorescein (FA) dye, showing typical staining. It is important to note the extent of involvement of a vessel on FA far exceeds the ophthalmoscopic picture (Fig. 25.1.1d). Sometimes the vasculitis may involve one of the larger

venous branches, resulting in a secondary branch retinal vein occlusion (Fig. 25.1.2a, c). Such secondary venous occlusions are characterized by sheathing of the involved vessels. Associated superficial retinal hemorrhages and edema occurring in this condition are often seen to cross the horizontal midline raphae temporally, which is not seen normally in branch retinal vein occlusion (BRVO) (Fig. 25.1.2b, c) [27]. Though not common, some eyes do show the presence of patches of fresh or old chorioretinitis, against the backdrop of retinal vasculitis (Fig. 25.1.3a–c).

25.1.3.2 Signs of Ischemia

Retinal ischemia due to vessel closure manifests in the same way as in other retinal vascular diseases [16, 35]. Superficial retinal hemorrhages in the nerve fiber layer are often seen in the area of sheathed vessels (Fig. 25.1.4). Interestingly, dot blot hemorrhages are rarely seen. In response to ischemia, venous changes such as beading and reduplication are seen (Fig.

25.1.5a, b). In an attempt to correct the ischemic changes, collaterals or venovenous shunts are common (Fig. 25.1.5c). These represent a stabilization of the vasculature, and are not an indication for scatter laser treatment. These can be differentiated from

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Fig. 25.1.4. Superficial retinal hemorrhages seen in the vicinity of a vessel with periphlebitis due to retinal ischemia

a

c

new vessels on FA as they do not leak dye (Fig. 25.1.5d). Areas of retinal edema are seen especially in the early stage of the disease because of the hemodynamic disturbance caused by the closure of inflamed vessels (Fig. 25.1.6). Macular edema, however, is not common as it is in diabetic retinopathy. Areas of non-perfusion can be well identified on FA and are peripherally located in the distribution of the involved vessels (Fig. 25.1.7a–d). The posterior pole and macula are rarely involved, except in cases where advanced disease and severe ischemia exist.

25.1.3.3Signs of Neovascularization and Its Sequelae

Since most patients present after bleeding into the vitreous cavity, as many as 80 % have neovascularization. Since ischemia most commonly occurs in the retinal periphery, new vessels arise at the junction of the vascular and avascular retina, usually in the typical sea fan pattern (Fig. 25.1.8a). As in other retinal vascular diseases, the new vessels occur in intraretinal, preretinal and intravitreal locations progressive-

b

d

ly. Some workers have tried to show that the temporal periphery is more commonly affected. Sometimes the new vessels develop in the mid periphery, or just outside the arcades (Fig. 25.1.8b, c). They may radiate spider like from a common point. In more advanced disease with global ischemia, NVD may develop. The commonest sequela of neovascularization is vitreous hemorrhage (Fig. 25.1.9a), the others being traction retinal detachment (Fig. 25.1.9b, c) and combined retinal detachment. Vitreous hemorrhage occurs from new vessels and is rarely due to sudden occlusion of a large vessel. Most bleeds are intragel and small. Retrohyaloid hemorrhages, which are de rigueur in proliferative diabetic retinopathy, are rarely seen here. Most eyes show multiple bleeds in various stages of absorption, before they become dense enough to completely obscure vision. In Eales’ disease, traction retinal detachments rarely affect the posterior pole and hence do not significantly affect vision. However, contraction of the fibrous component of the fibrovascular tissue laid down during neovascularization can cause retinal tears, resulting in a combined retinal detachment. These tears are usually linear and are related to contracted glial tissue (Fig. 25.1.9d).

25.1.3.4 Central Eales’

Central Eales’ has been referred to inconsistently in the literature. Some studies place the prevalence of this at 6 % in the case of Eales’ disease [32]. This presents as a papillophlebitis or a non-ischemic central retinal vein occlusion (CRVO) (Fig. 25.1.10a, b). Good vision is usually present and a good response has been noted to corticosteroids or immune suppression (Fig. 25.1.11a–c).

a

25.1 Eales’ Disease 619

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a

b

Fig. 25.1.11. a Central Eales’ with disk edema, sheathing and extensive hard exudates over the macula. b Response to systemic steroids in a fortnight showing decreased venous fullness, disk edema and reduction of hard exudates.

b

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c

Fig. 25.1.11. c Marked improvement 8 weeks after systemic steroids. Lamellar macular hole noted in area of cleared exudates

25.1.4 Natural Course

The natural course of Eales’ disease is variable. Some spontaneously remit after a single episode of bleeding while others gradually progress to end stage disease [20]. Retinal vasculitis causes retinal ischemia, which in turn promotes neovascularization and fibrovascular proliferation. This results in vitreous hemorrhage and/or retinal detachment. End stage eye disease (Fig. 25.1.12) is marked by neovascular glaucoma, proliferative vitreoretinopathy (PVR), cataract and ectropion uvea. Some patients may insidiously progress to a burnt out state with severe ischemia and disk pallor.

Eales Disease has to be differentiated from other causes of retinal vasculitis/retinitis

CMV retinitis: immune compromised patients, clear vitreous, granular retinal opacification, brushfire like progress, frosted branch angiitis like sheathing

Beh¸cet’s: hypopyon, aphthous and genital ulcers

Sarcoid: female preponderance, candle wax dripping, hilar adenopathy, serum ACE levels

Leukemia: peripheral smear, cotton-wool spots (CWS) and preretinal hemorrhages

Syphilis: serological tests, genital ulcers/scars, lymphadenopathy

Tuberculosis: focal chorioretinitis, nodule formation, systemic features

Multiple sclerosis: optic neuritis, systemic features Pars planitis: snow banking, vitritis, macular edema

Toxoplasma: necrotizing central retinochoroiditis, overlying vitritis, serology

Toxocara: usually unilateral, granuloma formation, ELISA Systemic lupus erythematosus: systemic and skin signs, CWS Lyme borreliosis: systemic disease, spirochetal, response to

tetracycline

Eales Disease has to be differentiated from other retinal vascular diseases

Sickle cell disease: black sunburst appearance, salmon patch, sea fans with autoinfarction, Hb electrophoresis

Coats’ disease: vascular abnormalities, lipid exudation, unilateral

Branch vein occlusion: no sheathing hemorrhages and exudates do not cross horizontal midline raphae

Central retinal occlusion: non-ischemic type difficult to differentiate from central Eales’

Diabetic retinopathy: hyperglycemia, dot blot, hemorrhages, maculopathy, no vasculitis

Retinopathy of prematurity: history, age of presentation, no vasculitis

Fig. 25.1.12. End stage eye with severe neovascularization

25.1.5 Differential Diagnosis

Today, cytomegalovirus (CMV) retinitis is an important differential diagnosis due to the common patient profile.

25.1.6Systemic Associations Described in Eales’ Disease

The involvement of the CNS and vestibulocochlear apparatus [31] show that the pathology of Eales’ is not confined to the eye. In the CNS it is thought to cause:

Acute or subacute myelopathy [34] Multifocal white matter abnormality [25] Ischemic infarction of the brain [7]

and therefore manifests as:

–Focal neurological signs and demyelination

–Abnormalities of the peripheral vestibular system

–Bilateral sensorineural hearing loss

–Hemiplegia and paraparesis

–Internuclear ophthalmoplegia

–Psychosis

Over the years various attempts have been made at classification. Charmis et al. [9] suggested a classification system based on evolution and progress of the disease. The classification divided the disease into four stages:

Stage I: mild periphlebitis of peripheral retinal capillaries

Stage II: widespread periphlebitis of the venous system

Stage III: new vessel formation and vitreous hemorrhage

Stage IV: end result of multiple hemorrhages – retinitis proliferans

A more complete classification was suggested [11], which can be used to study the response to treatment. In addition to the lesions seen, it also noted the number of clock hours involved (Table 25.1.1).

In 2004, Saxena et al. suggested a new system of classification which first divides the disease into central and peripheral types [32], the latter being further subdivided into:

Stage 1 is periphlebitis of small (1a) and (1b) large caliber vessels with superficial retinal hemorrhages

Stage 2a denotes capillary non-perfusion and 2b neovascularization (NVE/NVD)

Stage 3a is classified as fibrovascular proliferation and 3b vitreous hemorrhage

Stage 4a is traction/combined retinal detachment whereas 4b is rubeosis iridis, NVG, cataract, optic atrophy

This classification addresses the issue of central and peripheral disease and also accommodates end stage disease.

Histopathology of the epiretinal membranes (ERM) in Eales’ disease can be performed after harvesting the sample during vitrectomy. Studies have been performed using light microscopy and even with immunohistochemical stains [4]. These show several neo-

vascular channels with glial cells, macrophages, III 25 fibrocytes and lymphocytic infiltration. Majji et al. histologically compared ERM harvested from pa-

tients with vaso-occlusive conditions (other retinal vascular diseases) and from Eales’ (vasoinflammatory group). The ERMs from both groups were similar except for the presence of inflammation in the latter. The presence of mast cells and eosinophils was also noted [23].

25.1.9 Etiopathology

More than 125 years since its description by Eales, this entity has evaded an exact explanation of its etiopathology. While it appears to be multifactorial -immununological, molecular biological, and biochemical studies have indicated the role of HLA antigens, autoimmunity, mycobacterial genome and oxidative stress mechanism.

The controversy of whether it is due to an immunological response to mycobacterial antigens, or due to the actual presence of the acid fast bacilli, seems to be getting unraveled using the latest investigative modalities. Laboratory studies have showed statistically significant higher phenotype frequencies of HLA B5, DR1 and DR4 among patients with Eales’ disease compared to controls [6]. Since the most favored etiologies were tuberculosis or hypersensitivity to tuberculoprotein, Mantoux testing and lymphocyte proliferation assay to purified protein derivative (PPD) was performed on patients with Eales’ against age and gender matched volunteers with normal fundus findings. No significant difference was found between the two groups [5]. Polymerase chain reaction (PCR) was applied using IS 6110 primers to