Retinal vasculitis associated with primary ocular disorders

INTRODUCTION — Retinal vasculitis is characterized by inflammation of the vessels of the retina [1]. Positive findings on fluorescein examination may be diagnostic, with fluorescein angiography demonstrating vascular leakage, perivascular staining, and capillary nonperfusion.

The detection and characterization of retinal vasculitis may help in the diagnosis and management of a variety of disorders associated with ocular inflammation. These include systemic autoimmune disorders, some infectious diseases, and certain ocular processes.

The clinical features of retinal vasculitis occurring in association with ocular disorders will be reviewed here. Retinal vasculitis due to systemic autoimmune disorders and infectious agents and a classification of the vasculitides are discussed separately. (See "Retinal vasculitis associated with systemic disorders and infections" and "Overview of and approach to the vasculitides in adults".)

CLINICAL CHARACTERISTICS

Presenting features — The classic symptom of retinal vasculitis is a painless decrease in vision. Other symptoms may include a blind spot from ischemia-induced scotomas or floaters from vitritis. With macular involvement, patients may present with metamorphopsia (change in shape of an object) or abnormalities in color vision.

Retinal vasculitis can also be asymptomatic for prolonged periods of time if the macular region is not involved. However, once the macula becomes involved, visual deterioration can be rapid. Patients are often not seen when asymptomatic so it is difficult to determine how long this asymptomatic period lasts prior to presentation. The asymptomatic patients are sometimes found on routine eye examinations with unilateral visual decline (eg, under 20/40 or 0.5, which is considered poor vision and not compatible with safe nighttime driving), while the contralateral unaffected eye could retain normal visual acuity; since people function with both eyes open, a unilaterally affected eye's visual decline may not be noticed by the patient for prolonged periods.

Physical examination — Abnormalities in the retinal vessels may be observed upon physical examination. Funduscopic findings include visible accumulation of inflammatory cells along vessel walls (vascular sheathing) (picture 1). The peripheral vessels are often more involved than central arterioles and venules, and there are frequently skip areas. With certain disorders such as sarcoidosis, lesions resembling candlewax drippings or extensive perivascular inflammation may also be observed.

The retinal vascular abnormalities are better demonstrated by fluorescein angiography. One of the main changes on fluorescein angiography is perivascular staining, which reflects the increase in vascular permeability (picture 2). Cystoid macular edema and capillary nonperfusion also may be seen.

Fluorescein angiography is the gold standard for detecting retinal vasculitis, and it is designed to optimally capture the macular region. However, most retinal vasculitis is typically observed in the peripheral retina, which is not adequately visualized with standard imaging modalities. Ultra-widefield imaging and angiography is available but has yet to become the standard of care for diagnosis and is used primarily in patients with an established diagnosis to monitor during treatment and/or for recurrence. A study designed to quantify the benefits of wide field imaging versus fluorescein angiography in the management of non-infectious retinal vasculitis included 71 visits from 23 patients [2]. Based on the clinical examination alone, the decision to alter management was made in 6 percent, and an additional 4 percent of patients using fluorescein angiography. When using ultra-widefield angiography in addition to the clinical examination, management was altered in an additional 14 percent of patients with color images, and 51 percent with ultra-widefield fluorescein angiography. Combining peripheral visualization with the sensitivity of fluorescein angiography for detecting retinal vasculitis should allow for detection of earlier disease and asymptomatic reactivation of disease, resulting in improved patient care.

OCULAR SYNDROMES ASSOCIATED WITH RETINAL VASCULITIS — Retinal vasculitis can occur in association with primary ocular inflammatory disorders as discussed in the following sections.

Retinal vasculitis occurs more commonly in association with systemic autoimmune disorders or infections, which are discussed separately. (See "Retinal vasculitis associated with systemic disorders and infections".)

Idiopathic retinal vasculitis — Retinal vasculitis may be the marker for or the harbinger of a systemic disease, usually a systemic inflammatory or immune disorder or an infectious disease, or may occur in isolation or as part of an ocular syndrome such as idiopathic retinal vasculitis aneurysm neuroretinitis (IRVAN). In a study of 150 patients initially diagnosed with isolated retinal vasculitis, 40 percent continued to have local disease at 10-year follow-up [3]. (See "Retinal vasculitis associated with systemic disorders and infections".)

The frequency of progression was substantially lower in a study performed by the National Eye Institute, which evaluated 25 patients with primary retinal vasculitis, none of whom had evidence of an underlying causative systemic disorder at disease presentation [4]. At four-year follow-up, a systemic disease developed in only one patient (4 percent). A more recent retrospective study in India corroborates the National Eye Institute study. In this study, only 3 percent of 76 patients with primary retinal vasculitis developed systemic vasculitic disease [5].

Thus, if a thorough history, review of systems, and physical examination fail to uncover evidence of a systemic disease at disease presentation, the authors advise that the evaluation should generally be limited to:

●A complete blood count

●Urinalysis

●Erythrocyte sedimentation rate

●Syphilis and HIV serologies

●Chest radiograph

●Fluorescein angiography

By comparison, a "shotgun" approach to laboratory testing can be expensive and often fruitless.

Treatment — Treatment of idiopathic retinal vasculitis is usually reserved for those who develop symptomatic decline in vision or if vasculitis is encroaching on the macula. Systemic glucocorticoids, azathioprine, methotrexate, cyclosporine, and plasma exchange have been used with variable efficacy, but none has been evaluated in a randomized fashion [6-10]. One retrospective study of 29 patients with vision-threatening disease found that the administration of prednisone (initial dose 1 mg/kg per day) was associated with visual improvement in 60 percent of patients [6]. Another cohort study of 96 patients with retinal vasculitis found that treatment with immunosuppressive therapies appeared to lower the risk of visual loss, independent of a relapsing disease course (odds ratio 0.79, 95% CI 0.66-0.94) [10].

An emerging therapy for retinal vasculitis with or without identifiable etiology is the use of subcutaneous repository corticotropin injection (HP Acthar Gel) at a dose of 40 mg every three days. A multicenter phase IV study has been initiated evaluating the efficacy and safety of repository corticotropin injection in patients with posterior uveitis, including retinal vasculitis [11].

Laser therapy is reserved for complications of retinal vasculitis, such as rubeosis iridis, recurrent vitreous hemorrhage, or retinal neovascularization. Other local procedures are warranted in selected patients. Vitrectomy has been indicated in dense vitreous inflammation, vitreous hemorrhage, retinal detachment, or epiretinal membrane formation. In some patients, filtering procedures (to increase drainage of aqueous) must be performed to treat the secondary glaucoma that may accompany retinal vasculitis and ocular inflammation. Secondary glaucoma can occur because of inflammation and/or new blood vessel growth on the angle (drainage portion of the eye). In patients in whom macular edema develops, bevacizumab has been shown to reduce the edema and to improve vision [12]. For IRVAN, a single systemic dose of infliximab and ranibizumab appears to be helpful in improving vision and in suppressing complications related to this rare form of retinal vasculitis [13,14].

Pars planitis syndrome — Pars planitis is a relatively common ocular inflammatory condition (also called peripheral uveitis or intermediate uveitis) that is observed in young (typically female) adults and children; it represents one of the most common forms of uveitis [15]. Although it occurs mostly in isolation and is hence termed idiopathic, the findings of pars planitis can be also found in a patient with multiple sclerosis (MS) or sarcoidosis [16,17]. Findings of pars planitis can either predict the development of MS or be found in patients who are already diagnosed with MS. However, a majority of MS patients do not have pars planitis. Similarly, the vast majority of patients with pars planitis do not have associated systemic disease and are hence idiopathic. Clinically, idiopathic pars planitis and MS or sarcoid-associated pars planitis are indistinguishable. Because of the potential for systemic association, select patients with pars planitis syndrome should be questioned for a history of or undergo workup for possible MS or sarcoidosis. However, from a probability standpoint, the yield of such an evaluation is low. In one series, the incidence of progression to MS or optic neuritis was 20 percent at five years [16], although this rate of conversion is considered to be high based upon clinical experience. The current consensus is that the term "pars planitis" be reserved for idiopathic disease unrelated to systemic disease. (See "Uveitis: Etiology, clinical manifestations, and diagnosis".)

The major clinical findings of pars planitis are localized to the vitreous and posterior pole. One eye is usually affected more than the other, and the condition is bilateral in 80 percent of affected patients [17]. The hallmark of the disorder is the presence of preretinal exudates over the inferior pars plana, findings referred to as snow banks. Patchy, peripheral retinal vasculitis often accompanies these lesions. In addition, the vitreous cavity usually has cells, debris, and snowball opacities.

The two major causes of visual loss in pars planitis are macular edema and vitreous opacities. Cataracts are the most common complication and may result from inflammation and glucocorticoid therapy [18].

Treatment — Therapy consists of oral or intra/periocular injected glucocorticoids. External cryotherapy has also been used directly on the snowbanks [19]. If these modalities fail, systemic immunosuppression, including methotrexate, azathioprine, cyclophosphamide, and cyclosporine, has been used in some cases [7,20,21]. Severe disease can often benefit from surgery to extract a cataract and/or to remove vitreous debris.

Decisions regarding the best modality and dose of therapy should be made in conjunction with an ophthalmologist expert in this area; as a general rule, immunosuppressive dosing is similar to that used in systemic vasculitis.

Birdshot retinochoroidopathy — Birdshot retinochoroidopathy is a rare ocular condition characterized by multiple discrete, cream-colored foci of depigmentation scattered throughout the fundus (picture 3) [22]. Involvement of the anterior segment is uncommon, although occasional cells and flares may be detected. There is usually cellular infiltration in the vitreous cavity. The diagnostic hallmark is the presence of vitreous cells, choroidal spots, and the absence of snowbanks or peripheral vascular change.

Retinal vasculitis is also a common finding. In a study of 203 eyes with birdshot retinochoroidopathy, 40 percent had perivascular leakage and 62 percent had cystoid macular edema (image 1) [23].

Birdshot retinochoroidopathy is strongly associated with the human leukocyte antigen (HLA)-A29 haplotype [24]. The use of HLA-A29 testing can be used to support the diagnosis but is not necessary for making the diagnosis because of its unique clinical features [25]. Similarly, a systemic workup is generally not required.

Treatment — Treatment of birdshot retinochoroidopathy is not uniformly successful; frequently, a combination of cyclosporine, prednisone, and a third immunosuppressive agent is required for an optimal response. One study found that treatment regimens initially including low-dose methotrexate were more effective than treatment primarily with systemic glucocorticoid or without any systemic immunomodulatory therapy [26].

The use of a sustained release fluocinolone implant has also shown promise; although ocular complications could be considerable, this method avoids systemic complications [27].

Eales disease — Eales disease is a retinal vasculopathy of the peripheral retina. Patients usually present with a decrease in vision, symptoms of floaters and cobwebs, and vitreous hemorrhage on funduscopic examination (picture 4). Although the disease is typically unilateral at onset, 80 to 90 percent eventually develop bilateral disease.

Retinal vasculitis is the primary ocular manifestation of this condition. It is thought to affect retinal veins predominantly, but arteriolar involvement may also occur. Peripheral nonperfusion is commonly observed, and branch retinal vein occlusions may develop. Neovascularization, seen in up to 80 percent of affected individuals, and bleeding differentiate Eales disease from idiopathic retinal vasculitis, in which these features are generally absent.

The diagnosis and management of Eales disease is discussed separately. (See "Eales disease".)

Hemorrhagic occlusive retinal vasculitis — Hemorrhagic occlusive retinal vasculitis (HORV) has been reported after cataract surgery. The condition usually occurs after uncomplicated cataract surgery. The presenting symptoms occur a few days after the cataract surgery and results in a painless loss of vision. On examination, large hemorrhage are seen in the posterior pole and angiography demonstrates retinal vessel occlusion [28]. The use of periocular vancomycin has been implicated in the development of this condition and is generally no longer used routinely after cataract surgery [29-31].

Treatment — Postoperative HORV requires aggressive treatment which includes the use of systemic, topical, and intravitreal corticosteroids as well as anti-vascular endothelial growth factor (VEGF) therapies [29]. The prognosis for vision recovery is poor. In one case series, 61 percent had vision no better than 20/200 and 22 percent had no light perception [31].

Brolucizumab-associated occlusive retinal vasculitis — Brolucizumab is a novel intravitreal anti-VEGF injection that had received US Food and Drug Administration (FDA) approval for the treatment of exudative macular degeneration. During post-marketing use, multiple cases of occlusive retinal vasculitis were noted. In a case series of 15 eyes who developed this complication, there was variable occlusion of large or small retinal arteries, or both, and perivenular abnormalities [32]. The severity spanned from peripheral vasculitis to occlusion of large retinal arteries around the optic nerve or macula with severe vision loss.

Treatment — The patients who developed this complication were treated with systemic, topical, and intravitreal corticosteroids as well as vitrectomy surgery [32]. Despite these aggressive treatments, all patients on average had significant visual acuity decline [32]. Because of the severity of this vasculitis, an FDA label update was approved that included additional safety information regarding retinal vasculitis and retinal vascular occlusion. With this update, brolucizumab continues to be used for macular degeneration and diabetic macular edema [33].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis" and "Society guideline links: Uveitis".)

SUMMARY AND RECOMMENDATIONS

●Clinical features – Retinal vasculitis is characterized by inflammation of the vessels of the retina. The classic symptom of retinal vasculitis is a painless decrease in vision. Other symptoms may include a blind spot from ischemia-induced scotomas or floaters, metamorphopsia (change in shape of an object), and abnormalities in color vision. Retinal vasculitis can also be asymptomatic. (See 'Clinical characteristics' above.)

Abnormalities in the retinal vessels may be observed upon physical examination. Funduscopic findings include visible accumulation of inflammatory cells along vessel walls (vascular sheathing) (picture 1). Positive findings on fluorescein examination may be diagnostic, with fluorescein angiography demonstrating vascular leakage, perivascular staining, and capillary nonperfusion (picture 2). (See 'Physical examination' above.)

●Associated syndromes and systemic diseases – Retinal vasculitis may be associated with a systemic disease or may occur in isolation, this latter form being more common. The primary ocular inflammatory disorders associated with retinal vasculitis include idiopathic retinal vasculitis, pars planitis syndrome, birdshot retinochoroidopathy, Eales disease, and postoperative hemorrhagic occlusive retinal vasculitis (HORV). Each exhibits characteristic and distinctive findings on ocular examination. (See "Retinal vasculitis associated with systemic disorders and infections" and 'Idiopathic retinal vasculitis' above and 'Pars planitis syndrome' above and 'Birdshot retinochoroidopathy' above and 'Eales disease' above.)

●Evaluation – In patients in whom a thorough history, review of systems, and physical examination fail to uncover evidence of a systemic disease at disease presentation, the authors advise that the evaluation should generally be limited to a complete blood count, urinalysis, erythrocyte sedimentation rate, syphilis and HIV serologies, chest radiograph, and fluorescein angiography. (See 'Idiopathic retinal vasculitis' above.)

●Management – Treatments differ to some extent among disorders, but they usually involve systemic and sometimes intra/periocular glucocorticoids and may include other immunosuppressive agents. (See 'Idiopathic retinal vasculitis' above and 'Pars planitis syndrome' above and 'Birdshot retinochoroidopathy' above and 'Eales disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael Tolentino, MD, who contributed to earlier versions of this topic review.