Infectious Causes of Retinal Vasculitis: Causes, Presentation, Differentiation, and Therapy

Retinal vasculitis (RV) is an inflammatory condition of the retinal blood vessels, which may manifest in an isolated manner or in association with ocular or systemic diseases [1]. The gold standard for diagnosing any systemic vasculitis is the histopathological demonstration of infiltration by inflammatory cells of the vessel wall [1, 2]. Given the infeasibility of performing a retinal biopsy for proving inflammatory retinal vessel wall involvement, diagnosis of RV is based on clinical findings at fundus examination and fluorescein angiography [2]. Fundus findings suggestive of RV comprise perivascular sheathing or cuffing, preretinal or intraretinal hemorrhages, cotton-wool spots, vascular occlusion, and retinal neovascularization [3, 4]. Angiographic findings consistent with RV include staining of the retinal vessel walls or leakage beyond them, due to breakdown in the inner-blood retinal barrier [2, 3].

Systemic vasculitis was classified at Chapel Hill Consensus Conference by its vascular size in large, medium, or small vessel vasculitis [1]. RV is mainly a disease of small vessels [1].

Diverse categorizations have been proposed in order to group RV [1, 2, 4]. They have been classified according to clinical appearance (occlusive or nonocclusive), type of vessel predominance (arteriolar or venular), or etiology (infectious or noninfectious) [3, 4]. Recently, Datoo O’Keefe et al. [1] proposed four categories: (1) RV associated with primary systemic vasculitis; (2) RV associated with systemic infectious and noninfectious diseases; (3) organ-limited vasculitis; (4) RV from a putative identifiable trigger [1]. RV of infectious etiology was included in categories 2 and 3. Inflammatory vascular manifestations occur frequently in infectious uveitis. Usually, RV of infectious etiology is associated with retinal or choroidal involvement. Some of them manifest specific signs that lead to their suspicion. The purpose of this review was to describe the main characteristics of the infectious RV, with an emphasis on its associated specific clinical manifestations.

A literature search was performed in PubMed/Medline database to identify original articles, reviews, and case reports using the following keywords: “retinal vasculitis,” “infectious uveitis,” “viral,” “virus,” “parasitic,” “parasite,” “bacterial,” “bacteria,” “fungal,” “fungus,” “fungi,” “ocular tuberculosis,” “ocular syphilis,” “Bartonella,” “Rickettsia,” “Borrelia,” “ocular toxoplasmosis,” “ocular toxocariasis,” “herpes simplex virus,” “varicella zoster virus,” “Epstein Barr virus,” “cytomegalovirus,” “HTLV-1,” “human immunodeficiency virus,” “arbovirus,” “Dengue virus,” “West Nile virus,” “chikungunya,” “SARS-CoV-2,” “Candida,” and “Aspergillus.” Boolean operators AND and OR were used as appropriate to optimize the sensitivity of the search. All publications included were peer-reviewed and in English. We excluded gray literature from this review. The search covered the period from January 1994 to January 2024. Notwithstanding, some historic articles were included when necessary. All selected full-text publications were thoroughly reviewed by the authors to extract the most relevant information on the clinical presentation, diagnosis, and management of the different etiologies of infectious RV.

RV may be caused by bacterial, viral, fungal, or parasitic infection. Table 1 shows the specific etiologies associated with infectious RV [1, 3‒5].

RV prevalence and the spectrum of etiologies show geographical variations. In a retrospective cohort study of 2,200 patients in Singapore, 48 (2.2%) patients were identified to have RV. The most common etiology was idiopathic (25 patients, 52.1%), followed by infectious vasculitis (15 patients, 31.3%), including presumed tuberculosis (12 patients, 25%), Rickettsia (1 patient, 2.1%), syphilis (1 patient, 2.1%), and toxoplasmosis (1 patient, 2.1%) [5].

A prospective study which aimed at describing the spectrum of etiologies and clinical characteristics of uveitis in a single center in India found that 4.7% (47 out of 980 patients) of the patients had RV. However, there was no description about the etiologies associated with this subgroup [6].

In Northern Taiwan, in a retrospective single-center study that included 487 patients with uveitis, 90 (18.5%) patients were associated with RV. Among the RV patients with definite diagnosis, 30 (38.5%) patients were of infectious origin. The most prevalent infectious condition associated with RV was cytomegalovirus (CMV) retinitis (9 patients, 30.5%), followed by acute retinal necrosis (ARN) (5 patients, 16.7%), toxoplasmosis (5 patients, 16.7%), tuberculosis (3 patients, 10%), syphilis (3 patients, 10%), and HTLV-1 (2 patients, 6.7%).

In a retrospective case series of patients diagnosed with RV from Thailand, 10 out of 47 (21%) patients were of infectious origin. Tuberculosis was identified as the most prevalent infectious etiology [7].

In a multicenter retrospective case series study from Egypt that reviewed the spectrum of etiologies in patients diagnosed with RV, a total of 101 out of 618 (16.3%) patients with RV were found to have an infectious etiology. The most prevalent diagnosis was tuberculosis (59 patients, 58.4%), followed by toxoplasmosis (20 patients, 19.8%), herpes infection (6 patients, 5.9%), syphilis (5 patients, 5%), brucellosis (5 patients, 5%), human immunodeficiency virus (HIV) infection (3 patients, 3%), and CMV infection (3 patients, 3%) [8].

A retrospective study assessed the clinical manifestations, diagnosis, and treatment of 70 patients with RV in the eastern region of India. Although 30% (21 out of 70) of the patients were positive for Mantoux test, only 5.71% (4 out of 70) were diagnosed with tuberculosis. Notwithstanding, the authors concluded that all the included patients had primary RV [9].

In Japan, a retrospective case series of 283, which included only those patients with a definite infectious and noninfectious diagnosis, compared the frequency of signs of retinal vascular involvement between both etiologies [10]. Ischemic areas were observed more frequently in patients with infectious uveitis (28/95 patients, 29.5% vs. 18/188 patients, 9.6%), as well as arterial occlusion (21/95 patients, 22.1% vs. 7/188 patients, 3.7%), arteritis (55/95 patients, 57.9% vs. 21/188 patients, 11.2%), and inflammatory arterial sheathing (32/95 patients, 33.7% vs. 0%). Inflammatory retinal venous involvement was also more prevalent in infectious uveitis, with a more frequent occurrence of vein sheathing (29/95 patients, 30.5% vs. 1/188 patients, 0.5%) and vein occlusion (18/95 patients, 18.9% vs. 10/188 patients, 5.3%). Only capillary vasculitis was more prevalent in noninfectious uveitis (54/95 patients, 56.8% vs. 138/188 patients, 73.4%). Based on these results, the authors concluded that inflammatory retinal vascular involvement in active uveitis and occlusion, in particular of retinal arteries, strongly suggests an infectious etiology [10].

Tuberculosis, a chronic granulomatous infectious disease caused by Mycobacterium tuberculosis, remains as a worldwide health problem (Table 2). Ocular tuberculosis is an infrequent location of this systemic infection, with a prevalence ranging from 1.4% to 18% [11, 12]. The prevalence of ocular tuberculosis varies widely among tertiary care uveitis services, depending on their geographic location, ranging from 0.2% to 2.7% in non-endemic regions to 5.6–10.5% in highly endemic areas [13].

Non-Retinal Vasculitic Manifestations: Posterior uveitis is the most common presentation of ocular tuberculosis. Among posterior segment manifestations, choroidal involvement is the most prevalent [70]. Tuberculous choroidal inflammation may manifest itself as serpiginous-like choroiditis, multifocal choroiditis, focal choroiditis, and tuberculoma [71]. Anterior, intermediate, and panuveitis may also occur.

Retinal Vasculitic Manifestations: Tuberculous RV is also a frequent feature of ocular tuberculosis [70]. It may involve the veins, or occasionally the arteries, and associated systemic disease may occur [11].

In a retrospective study, which included 251 patients from 25 multinational centers, a majority of the patients (115 out of 185, 61.1%) had features of occlusive RV. However, Caucasian patients had a low prevalence of occlusive RV (11 out of 39, 28.6%). Regarding anatomical location of uveitis associated with RV, 127 (50.59%) patients had posterior uveitis and 124 (49.40%) had panuveitis. Inflammatory signs that accompanied tubercular RV included vitreous haze (93 out of 229 patients, 40.6%), snow balls (25 out of 244 patients, 10.2%), snow banking (11 out of 243 patients, 4.5%), disk hyperemia/edema (70 out of 243 patients, 28.8%), and macular edema (68 out of 242 patients, 28.1%) [72].

Typically, RV presents with moderate vitritis, severe vascular sheathing with infiltrates, and extensive peripheral retinal ischemia (Fig. 1), which leads to peripheral or peripapillary retinal neovascularization. Nearly half of the patients have active or healed choroiditis foci located near the retinal vessels. Occasionally, vitreous snow balls are present, located inferiorly in the vitreous cavity. Tuberculous vasculitis associated with neuroretinitis was also described [73]. Frosted branch angiitis is a rare manifestation of tubercular RV that has been described in several publications [74]. Complications besides the above-mentioned retinal neovascularization, include tractional retinal detachment, epiretinal membrane, macular edema, macular ischemia, neovascular glaucoma and iris rubeosis [75]. Retinal neovascularization can be treated with laser photocoagulation, based on fluorescein angiography, and intravitreal injections of anti-vascular endothelial growth factor [4]. Vitrectomy may be needed in case of non-resolving vitreous hemorrhage or tractional retinal detachment secondary to retinal neovascularization [73].

Diagnosis: Ocular tuberculosis is difficult to diagnose due to its paucibacillary nature, and the limited usefulness of polymerase chain reaction in the detection of the M. tuberculosis, because of its low sensitivity and the lack of standardization [13]. Therefore, diagnosis mainly relies on clinical manifestations and immunologic investigations. These techniques are used to reach a presumptive diagnosis, which has limitations regarding sensitivity and specificity. In this context, only in those cases where there is a strong clinical suspicion should the initiation of antituberculosis treatment be considered [13].

Treatment: Antitubercular therapy (ATT) is recommended in those patients with active RV with positive immunological (tubercular skin test and interferon gamma release assay) and radiological tests in endemic regions [32]. Systemic corticosteroids are usually administered, either concomitantly with or soon after the ATT administration [4, 13]. There is also a limited experience with the use of intravitreal dexamethasone implant in case of corticosteroid intolerance, macular edema, paradoxical worsening of uveitis despite ATT, and active RV. Isntravitreal dexamethasone implant has proven effective in the resolution of macular edema, vitreous haze, and choroidal lesions [76].

Uveitis is the most common ocular finding in secondary and tertiary stages of the syphilitic infection (Table 2) [77].

Non-Retinal Vasculitic Manifestations: Syphilis may affect all of the structures of the eye, with a wide variety of presentations such as anterior uveitis, interstitial keratitis, chorioretinitis, retinitis, perineuritis, papillitis, retrobulbar neuritis, optic atrophy, and optic nerve gumma [77, 78]. Therefore, syphilis testing should be included in the investigation of any type of ocular inflammation [79].

In particular, posterior segment involvement was found as the most prevalent location of ocular syphilis in many studies [79‒84]. Posterior segment syphilitic manifestations include intermediate uveitis [79, 82, 85, 86], intraocular involvement of the optic nerve [87‒91], RV [81, 82, 92‒95], necrotizing retinitis [15, 96‒101], choroidal granuloma [102, 103], and involvement of outer retina, and/or choriocapillaris [104‒107].

Retinal Vasculitic Manifestations: Although RV is predominantly arterial (Fig. 2), it may also involve vein and capillaries. Additionally, occlusive RV has also been reported [108]. Saccular dilation [109] and paravenous pigmentary epitheliopathy [110] has been described in association with RV. RV may be the only manifestation of the posterior segment inflammation [83, 95, 108, 109, 111‒116], or it may accompany acute syphilitic posterior placoid chorioretinitis [83, 106, 115, 117‒122], necrotizing retinitis [83, 108, 115, 117, 118, 123], punctate inner retinitis [97, 101], syphilitic outer retinopathy [118, 119], neuroretinitis [124], optic disc edema [108, 115, 121, 122], or scleritis [123]. There is also a case report of a frosted branch angiitis associated with neuroretinitis and paracentral acute middle maculopathy secondary to syphilis [124]. Syphilitic frosted branch angiitis was also reported associated with anterior uveitis [125]. Peripapillary or retinal neovascularization has been reported as complications of syphilitic vascular retinitis, whether associated with retinal ischemia or not [109, 111‒113, 126‒128]. Macular edema may develop as a consequence of syphilitic RV [4].

Diagnosis: Serologic tests have a pivotal role for the diagnosis and assessment of the treatment response in this infectious disease. Non-treponemal tests, such as Venereal Disease Research Laboratory and rapid plasma reagin, are useful to identify recent or active syphilis. Specific treponemal tests, such as fluorescent treponemal antibody absorption, automated agglutination enzyme immune, or chemiluminescence assays, are positive from secondary syphilis, and remain so throughout the life of the infected individuals, whether they are treated or not [79].

Treatment: Intravenous penicillin G at a dose of 4 million units every 4 h for 10–14 days is the treatment of choice for ocular syphilis. In cases of unavailability or in the presence allergies to penicillin, intravenous ceftriaxone at a dose of 2 g appears to be a useful alternative [4, 129].

Cat-scratch disease, a worldwide zoonosis, is caused by Bartonella henselae, a Gram-negative hemotropic bacteria that infects erythrocytes and endothelial cells [127, 128].

Non-Retinal Vasculitic Manifestations: The most common anterior segment manifestation of this infectious disease is Parinaud oculoglandular syndrome, characterized by preauricular, upper cervical, or submandibular lymphadenopathy, follicular conjunctivitis, and conjunctival granulomas [18, 130]. In the eye, bacillary angiomatosis has been reported to occur in the eyelids, orbit, conjunctiva, and retina [131‒135]. Several posterior segment manifestations were reported, including intermediate uveitis, optic neuritis, neuroretinitis, focal or multifocal retinitis or choroiditis, granulomas, exudative retinal detachment, macular exudation with macular star formation, angiomatous lesions, and acute endophthalmitis [18, 130, 19].

Cat-scratch disease is the most prevalent etiology of neuroretinitis [136]. Furthermore, neuroretinitis is its most frequent manifestation in posterior segment involvement [19] (Fig. 3).

Retinal Vasculitic Manifestations: When RV is present, it is predominantly occlusive in nature. Branch retinal artery occlusion, and to a lesser extent, branch retinal vein occlusion, have also been reported in association with this infectious disease [19, 137].

Diagnosis: Diagnosis of cat-scratch disease is made based on the patient’s history (young age, cat-related trauma or contact with a cat), the systemic and ocular clinical manifestations, and laboratory tests. Serological investigation for B. henselae immunoglobulin M (IgM) and G (IgG) titers (enzyme-linked immunosorbent assay [ELISA] or indirect immunofluorescence assay [IFA]) is the most commonly used test. IgM positivity confirms recent infection and supports the diagnosis. When IgM is negative, IgG titers should be higher than 1:256 to confirm acute infection. When IgG titers are lower, between 1:64 and 1:256, retesting after 10 days is required. Titers of 1:64 or less are suggestive of inactive infection [138].

Treatment: Doxycycline, azithromycin, rifampin, and co-trimoxazole are the systemic broad-spectrum antibiotics usually used to treat this infectious disease. Corticosteroids are usually administered only in conjunction with the aforementioned antibiotics [4].

Lyme disease is a tick-borne infectious multi-systemic disorder [136, 137] caused by the spirochete Borrelia burgdorferi (Table 2).

Non-Retinal Vasculitic Manifestations: Ocular involvement is usually asymptomatic or may cause redness and tearing. In early Lyme disease, 7–11% of patients develop a transient, nonspecific follicular conjunctivitis [20, 22]. In the second and third stages, the disease may develop a variety of ocular inflammatory manifestations, such as orbital/adnexal inflammation, episcleritis, anterior or posterior scleritis, nummular nonstaining corneal opacities, peripheral ulcerative keratitis, anterior, intermediate, posterior or panuveitis, endophthalmitis, exudative retinal detachment, and neuro-ophthalmological manifestations [23]. Intermediate and posterior uveitis are the most common types of ocular inflammatory involvement. Multifocal choroiditis has been observed, and the choroidal lesions are small and punched-out, associated with a variable grade of vitreous haze [4].

Retinal Vasculitic Manifestations: RV frequently occurs in Lyme disease and is nonocclusive mainly. It has been described to be associated with vitritis and pars planitis, choroiditis, macular edema, and optic disc edema. Retinal branch vein and arterial occlusion have also been reported [20, 139, 140].

Diagnosis: For the diagnosis of Lyme disease-associated uveitis, the following criteria are required: (1) positive ELISA and immunoblot serology, (2) exclusion of other causes through various tests, (3) control of inflammation with antibiotics after previous resistance to steroid treatment administered alone, and (4) evidence of possible exposure (tick bite, endemic area, walks in forests, summer season) along with compatible systemic symptoms [20].

Serology is considered positive if ELISA results are positive for IgM and/or IgG, accompanied by a positive immunoblot for IgM and/or IgG. Syphilitic serology is always performed to exclude cross-reactivity [20].

Treatment: Oral amoxicillin or doxycycline is indicated for early Lyme disease or erythema migrans, while ocular or neurologic manifestations should primarily involve intravenous antibiotics (mainly ceftriaxone or penicillin G), with the exception of isolated unilateral seventh nerve palsy. Systemic or local corticosteroid is added with the concomitant use of antibiotics [4, 139].

The genus Rickettsia is divided into three groups: (1) the Spotted fever group, (2) the typhus group, and (3) the scrub typhus group. Within the first group, Rocky Mountain spotted fever and Mediterranean spotted fever (MSF) are the most prevalent human infections (Table 2) [23].

Rocky Mountain Spotted Fever Non-Retinal Vasculitic Manifestations: Rocky Mountain spotted fever may involve almost every part of the eye, including manifestations such as petechial conjunctivitis, anterior uveitis, ischemic or inflammatory optic disc edema, retinitis, neuroretinitis, and orbital edema [23, 141, 142]. Inflammatory vascular involvement may be present in the conjunctiva, iris, ciliary body, retina, and choroid [22, 143].

Rocky Mountain Spotted Fever Retinal Vasculitic Manifestations: Retinal hemorrhages, cotton-wool spots, retinal vascular engorgement and tortuosity, vascular sheathing, intraretinal hemorrhages and exudates, branch retinal arterial or vein occlusion, and cystoid macular edema were reported with this infectious disease [23, 141, 142].

MSF Non-Retinal Vasculitic Manifestations: Ocular manifestations include conjunctivitis, conjunctival hyperemia, oculoglandular Parinaud syndrome with or without marginal ulcers, dacryoadenitis, infectious keratitis, endogenous endophthalmitis, endogenous panuveitis with chorioretinitis, vitreous inflammation, retinitis, and bilateral disc edema [23, 25]. In the acute stage, the typical finding is focal or multifocal cotton-wool spot-like retinitis, ranging from 0.5 to 3-disc diameters in size, located at the posterior pole, along the vascular arcades, and around the disc, sometimes accompanied by macular or disc edema and a few hemorrhages [144].

MSF Retinal Vasculitic Manifestations: RV, retinal arterial or venous branch occlusion, retinal venous engorgement and tortuosity, and sectoral retinal hemorrhages were described in different reports [23, 25]. In a series of 34 patients diagnosed with MSF, arterial and venous RV was found in 19 patients (55.9%). Inflammatory venous involvement was the most prevalent in this study [145]. Khairallah et al. [25] described a series of 30 patients (60 eyes) with serologically proven MSF. Focal or multifocal white retinal lesions were found in 60% (18 out of 60) of the eyes, ranging in size from 150 to 3,000 µm in diameter. Retinal lesions were juxtavascular in location, with 53.3% (16 out of 30 retinal lesions) involving the posterior pole and 46.7% (14 out of 30 lesions) involving the peripheral retina. In fluorescein angiography, retinal vascular leakage was observed in 45% (27 out of 60) of the eyes, with 20% (12 out of 60 eyes) involving the retinal capillaries, 18.3% (11 out of 60 eyes) involving the retinal veins, 1.7% (1 out of 60 eyes) involving the retinal arteries, and 5% (3 out of 60 eyes) involving both arteries and veins. Vascular leakage mostly involved the peripheral vessels (70.4%) (19 out 27 eyes).

Diagnosis: Serologic testing with IFA, immunohistochemical detection of the infectious agent in a skin biopsy or PCR amplification of rickettsial DNA from a tissue specimen are among the different procedures that can be used to diagnose the disease, along with suggestive systemic and ocular manifestations [24].

Treatment for Rickettsial Infections: Treatment with oral doxycycline at a dose of 100 mg daily for 10–14 days constitutes the primary treatment. Corticosteroids are added in cases of severe ocular inflammation [146].

Ocular toxoplasmosis is caused by Toxoplasma gondii (Table 2) and may be present in 2–20% of infected individuals, depending on the geographic location [27]. Toxoplasmic ocular involvement is the most frequent etiology of posterior uveitis, comprising 20–60% of patients [147].

Non-Retinal Vasculitic Manifestations: Typically, a whitish focus of retinochoroiditis with indistinct borders can be observed, associated (recurrent) or not (primary), with a pigmented retinochoroidal scar in either eye [148]. Atypical presentations of retinochoroidal lesions may occur in elderly or immunocompromised patients or due to an infection with virulent parasitic strains [149, 150]. A variety of atypical lesions have been described, including extensive lesions that, in some patients, mimic ARN, as well as multifocal and bilateral retinochoroiditis, serous retinal detachment, optic disc granuloma, scleritis, and uveitis involving different parts of the eye – ranging from anterior to intermediate, posterior, and panuveitis – in the absence of apparent retinochoroiditis [150, 151]. A variety of inflammatory signs may accompany the active episode, including anterior chamber cells, stellate, granulomatous or non-granulomatous keratic precipitates, vitreous inflammation, and RV [150]. Intraocular pressure may be elevated in 10–38% of patients with active retinochoroiditis [150, 152]. Usually, vitreous inflammation overlies the active retinochoroidal lesion, giving the appearance of “a headlight in the fog” [151].

Retinal Vasculitic Manifestations: RV can be observed either near of distant from the retinochoroidal lesion (Fig. 4a). It predominantly involves veins, while arteries may also be compromised, occasionally leading to vascular occlusion [1, 151]. A few case reports described the occurrence of frosted branch angiitis associated with ocular toxoplasmosis [153, 154] (Fig. 4b). Yellowish Kyrieleis plaques (KyP) may present in inflammatory arterial involvement. KyP are confined to the vessel wall and have a glistening, calcific-like appearance. As a counterpart, frosted branch angiitis and vascular sheathing extend outside the vessel wall [155]. Angiographic features help differentiate KyP from perivascular sheathing and frosted branch angiitis. KyP are hypofluorescent in early frames, with increasing hyperfluorescence in later frames, affecting only arteries. On the other hand, frosted branch angiitis and sheathing may involve arteries or veins and show extensive leakage of fluorescein dye [155]. Active retinochoroiditis, in early frames, blocks fluorescence, with gradual staining in the later frames of the involved area, starting from its borders [156] (Fig. 4c–f).

Infrequently, retinal neovascularization may occur due to inflammatory occlusive vascular damage secondary to retinochoroiditis lesions. In a recent study from Argentina, the prevalence of retinal neovascularization was 3.16% (19 out of 550 patients) [157]. There are a few reports in the literature that have shown positive outcomes after laser photocoagulation of the ischemic retina caused by this vascular damage [157‒159]. Intravitreal bevacizumab appears to achieve only partial regression of this complication [157].

Diagnosis: Diagnosis of ocular toxoplasmosis relies on the finding of a focal necrotizing retinochoroiditis with or without a pigmented retinochoroidal scar. However, the occurrence of atypical retinochoroidal manifestations may require the collection of an intraocular fluid sample, primarily aqueous humor, to investigate the presence of Toxoplasma DNA by polymerase chain reaction (PCR), or to detect local production of specific antibodies using ELISA, and to compare the local and systemic immune profiles (Goldmann-Witmer coefficient). Positive serum anti-Toxoplasma Gondii IgG antibodies do not confirm a toxoplasmic etiology; however, a negative result excludes the diagnosis in an immunocompetent patient [160].

Treatment: Treatment of ocular toxoplasmosis relies on a combination of antiparasitic drugs and systemic corticosteroids. The combination of sulfadiazine, pyrimethamine and folinic acid (known as classical treatment) is the most frequently employed [28]. Trimethoprim-sulfamethoxazole is a broadly accepted option in patients intolerant to pyrimethamine. Its wide availability and low cost are advantages of this therapy [4]. Moreover, there is substantial evidence that long-term administration of trimethoprim-sulfamethoxazole provides a protective effect against recurrences of active episodes of ocular toxoplasmosis [161]. In a small prospective comparative study, Bosch-Driessen et al. [162] suggested that the combination of azithromycin and pyrimethamine is equivalent to the classical treatment. Additionally, two prospective comparative studies found that intravitreal clindamycin and dexamethasone therapy showed no significant difference in visual and clinical outcomes compared to classical treatment [163, 164]. Intravitreal injections may be administered weekly or bi-weekly until the lesions are resolved [4].

Ocular toxocariasis is mainly caused by the roundworm Toxocara canis or occasionally by Toxocara catis [165].

Non-Retinal Vasculitic Manifestations: Ocular toxocariasis occurs when a single larva enters the ocular circulation at a stage when evidence of visceral larva migrans is usually absent. Children aged 3–16 years are commonly affected. Most of the ocular damage is caused by the inflammatory response developed after the death of the larva. Ocular involvement is predominantly unilateral (90% of the patients), and the inflammation primarily compromises the uveal and retinal tissues [33, 34]. Painful or sometimes painless loss of vision commonly occurs [166]. In children, leukocoria and strabismus are frequently observed [166, 167]. Anterior uveitis may be present, with granulomatous or non-granulomatous keratic precipitates, posterior synechiae, and infrequently hypopyon or pupillary seclusion [168]. The major types of presentation of ocular toxocariasis are peripheral granuloma, posterior pole granuloma, and endophthalmitis.

Peripheral granuloma, the most frequent mode of presentation of ocular disease, occurs in patients between 6 and 40 years of age [166, 169‒171]. The peripheral retina and ciliary body are involved, with retinal folds or detachment. An elevated white mass with surrounding membranes can be observed in the peripheral retina [34, 169, 171]. Occasionally, the mass may be much more diffuse and resemble a snow bank, a characteristic often observed in pars planitis [172]. A traction band may extend from the granuloma to the optic disc. This band can sometimes cause macular displacement or optic neuropathy [169, 171].

Posterior pole granuloma, the second most frequent type, occurs in patients between 6 and 14 years of age [166, 169‒171]. It presents as an elevated yellow-white mass at the posterior pole (at the macula or around the disc), ranging from 0.5 to 3-disc diameter. Frequently, it is well-defined and located in the subretinal space. When the lesion is active, however, it may manifest itself as an ill-defined mass surrounded by exudates and hemorrhages [169, 171]. Vitreous bands extend from the mass to the surrounding retina, sometimes distorting the vascular arcades [172] (Fig. 5). Complications such as the development of epiretinal membranes, retinal folds, or choroidal neovascularization may occur [169, 171].

Chronic endophthalmitis commonly presents in children aged 2–9 years [169, 171]. Visualization of the retina may be challenging in this type of presentation due to a dense cellular infiltrate in the vitreous. Occasionally, indistinct yellowish-white masses can be found through this intense vitreous haze, and secondary retinal detachment may be identified by ultrasound [172]. Anterior chamber cells and flare may be present. Occasionally, hypopyon can be observed. Complications may develop, such as cyclitic membrane, hypotony, leukocoria, strabismus, and retinal detachment [169, 171, 173]. Atypical presentations were reported, such as neuroretinitis, migrating granulomas, optic granuloma, or anterior segment involvement [165, 171, 172, 174‒178].

Retinal Vasculitic Manifestations: Toxocara granulomas can have associated RV [4]. Despreaux et al. [168] in a case series study of adult patients with ocular toxocariasis found that 57.1% (8 out of 14) of the patients had associated RV at the presentation of the ocular disease. Atypical presentations of the disease are also frequently associated with RV. Guo et al. [179] have shown that in 85.7% (6 out of 7) of the patients with atypical ocular toxocariasis who underwent fluorescein angiography, a “bristle-like” leakage pattern in small and medium branch veins in middle and late frames was observed, suggesting an increase of vascular permeability.

Diagnosis: Diagnosis of ocular toxocariasis mainly depends on suggestive clinical findings. Retinal biopsy demonstrating Toxocara larva is technically difficult and rarely performed. Serological tests such as ELISA or indirect hemagglutination can be supportive [34]. Recent studies have shown that testing intraocular fluids for Toxocara antibodies is useful for diagnosing ocular involvement in this parasitic etiology [180].

Treatment: When ocular disease is active, medical treatment is mainly with corticosteroids. Systemic and periocular corticosteroids are used with the aim of relieving vitreous haze and preventing vitreous membrane formation. In a recent retrospective comparative study [169, 181], Sun et al. [181] have shown that dexamethasone implant was better at improving visual acuity and reducing the score of vitreous haze compared to a control group without intervention. Topical corticosteroids are used when anterior chamber cells are present [169]. The role of antihelmintic drugs is controversial, as they are not proven to kill the intraocular parasite [165, 169]. However, some studies have shown favorable results with the combination between corticosteroids and antihelmintics [165, 169, 171].

In the posterior segment, two forms of herpetic involvement may occur: necrotizing and non-necrotizing (Table 2).

Necrotizing herpetic posterior uveitides causes a high rate of complications in either immunocompetent or immunocompromised patients [36]. They comprise a spectrum of disease that majorly depends on the immunological status of the host. ARN occurs more commonly in immunocompetent individuals, while progressive outer retinal necrosis and CMV retinitis are found in immunocompromised patients [37].

Acute Retinal Necrosis. ARN is caused by varicella-zoster virus (VZV), herpes simplex virus (HSV) type 1 and type 2. Although some authors have suggested that CMV and Epstein-Barr virus (EBV) might also be etiological agents of this condition, this assertion has weak supporting evidence. The prevalence of each viral agent varies depending on the age of the affected individuals. HSV type 2 tends to occur in patients with a mean age in the early third decade of life, HSV type 1 in patients with a mean age in the late third to fourth decade, and VZV in the sixth decade of life [182].

Non-Retinal Vasculitic Manifestations: Usually, ARN presents with unilateral loss of vision, photophobia,floaters, and eye pain, while bilateral involvement may develop in one-third of the patients [183]. Clinical criteria include one or more foci of full-thickness necrotizing retinitis, with discrete borders and located in the peripheral retina, rapid progression of disease in the absence of treatment, occlusive vasculopathy with arteriolar involvement, and intense vitreous and anterior chamber inflammation (Fig. 6). Additionally, other inflammatory signs such as episcleritis, scleritis, keratitis, granulomatous anterior segment inflammation, perivasculitis, arteriolar narrowing and optic neuropathy can be observed [36, 184, 185]. Rhegmatogenous retinal detachment develops in half to three-quarters of the eyes. This frequent and severe complication occurs weeks to months after the initiation of the disease [185] (Fig. 7). The detachment may progress to proliferative vitreoretinopathy in one-third of the eyes [186]. Other complications that may develop later include macular edema, optic atrophy, epiretinal membrane formation, and phthisis bulbi [185].

Retinal Vasculitic Manifestations: As mentioned above, occlusive vasculopathy and retinal arteriolitis are part of the clinical diagnostic criteria of ARN. Central retinal occlusive vasculitis may occur [187]. Unilateral or bilateral central retinal artery occlusion, as well as branch retinal vein occlusion has also been reported [188‒190]. KyP and frosted branch angiitis have been described in this condition as well [191, 192].

Treatment: Either oral valacyclovir 1–2 g or famciclovir 500 mg 3 times daily, or intravenous acyclovir 10 mg/kg every 8 h can be used to treat this clinical condition successfully. Adjunctive therapy with intravitreal foscarnet 2.4 mg/0.1 mL should be considered to accelerate the inactivation of the disease or limit its extension [193]. After the resolution of the retinal lesions, oral acyclovir 800 mg 5 times a day or valacyclovir 1 gr three times a day must be administered at least for other 6 weeks [39].

Prophylactic laser retinopexy aimed at preventing rhegmatogenous retinal detachment in ARN remains a matter of controversy. In a recent survey conducted among the members of the American Uveitis Society, the majority of respondents (63%) reported rarely or never performing this procedure, unless an extensive area of the retina had been compromised by the disease [194]. Two systematic reviews and meta-analyses have reached controversial conclusions regarding this matter. One of the reviews, which included 14 studies and 532 eyes, showed a statistically significant odds ratio of 0.43 for antiviral therapy and steroids combined with laser, suggesting a preventive effect on the occurrence of rhegmatogenous retinal detachment [195]. Conversely, the other review, which included 8 studies and 247 eyes, found a non-statistically significant odds ratio of 0.42, concluding that the current evidence did not support a preventive effect of laser retinopexy on the occurrence of rhegmatogenous retinal detachment in ARN [196].

Progressive Outer Retinal Necrosis. In immunocompromised patients, namely AIDS patients or posttransplant recipients, VZV and, to a much lesser extent, HSV [197, 198], may cause a highly destructive and rapidly progressive type of herpetic necrotizing retinitis, progressive outer retinal necrosis (PORN). The disease may present with acute or progressive loss of vision, constricted visual fields or scotoma, orfloaters; however, without pain or photophobia as opposed to ARN [36, 199].

Non-Retinal Vasculitic Manifestations: Its manifestations comprise multifocal, opacified, deep retinal lesions that rapidly coalesce over the course of days or weeks. At the same time, the lesions usually locate in the peripheral retina, up to one-third of the patients present lesions at the posterior pole. Perivenular lucency within the extensive retinal involvement (perivascular sparing) is characteristically found in these patients, giving an appearance of “cracked mud” to the fundus [40] (Fig. 8). Anterior segment and vitreous inflammation are mild and are present in a third of the patients.

Notwithstanding, Engstrom found anterior chamber cells occurring more frequently than vitreous cells [40]. The progression is more rapid than in ARN, and bilateral involvement was reported in more than 70% of the patients [37, 199]. Visual outcome is very poor. Two-thirds of the patients develop no light perception visual acuity within 1 month of the diagnosis. This profound loss of vision is not related to the extent of the retinal lesions, and also cannot be explained exclusively by the presence of retinal detachment [40].

Retinal Vasculitic Manifestations: Retinal vasculopathy, comprising vascular sheathing and occlusions, develops in the later stages of the disease and is seen in the fifth of the patients. Vascular involvement occurs only in areas within or in adjacent locations to the active retinal lesions [40, 199].

Treatment: The use of intravenous acyclovir alone is relatively ineffective in treating this disease [200]. A combination of intravenous antivirals (foscarnet and ganciclovir) achieves a better outcome [200]. Interestingly, the addition of intravitreal antivirals (foscarnet and/or ganciclovir) to this combination obtains even better visual results. Notwithstanding, the prognosis of this type of viral retinal infection is poor [201]. Even with antiviral treatment, rhegmatogenous retinal detachment occurs in 70% of eyes, either at the time of diagnosis or during the follow-up [201].

There are few reports of non-necrotizing herpetic retinitis [202‒205]. Three-quarters of the reported patients with this infrequent clinical type of posterior segment infection were caused by VZV, while the remaining cases were caused by HSV [36]. Some series reported mild or absent anterior inflammation, granulomatous anterior uveitis, iris atrophy, retinal edema, periphlebitis, intraretinal hemorrhages, papillitis, vitritis, arteriolar sheathing, and occlusive vasculitis with associated early neovascularization [202‒205]. Non-necrotizing herpetic retinitis has a good visual prognosis, with stabilization or resolution of ocular inflammation after a long-term systemic antiviral treatment [36].

CMV ocular manifestations depend on the immunological state of the patient. CMV posterior segment involvement occurs in immunocompromised hosts (Table 2) [42].

Non-Retinal Vasculitic Manifestations: Patients with CMV retinitis typically have mild anterior chamber and vitreous inflammation at presentation, occasionally associated with fine keratic precipitates [206]. Three forms of presentation have been reported: fulminant/edematous, indolent/granular, and exudative [36]. The fulminant/edematous type consists of large areas of intraretinal hemorrhage, in a large area of confluent necrotizing retinitis, giving the appearance of a “pizza pie.” This pattern of presentation typically occurs in the posterior pole. The indolent/granular type consists of granular (small dot-like) or satellite lesions with little or no hemorrhage. This variant occurs more often in the peripheral retina (Fig. 9a).

Retinal Vasculitic Manifestations: The exudative type consists of RV with an extensive perivascular sheathing, also known as frosted branch angiitis [36, 42, 206]. In patients with non-HIV-related CMV retinitis, intraocular inflammation may be more prominent, with occlusive RV and arteriolar involvement (Fig. 9b). Although the granular type of retinitis is typically observed, occasionally some manifestations resembling ARN may be found [207].

Treatment: The treatment of CMV retinitis includes the specific antiviral treatment and the reversal of the immunodeficiency. In patients with HIV/AIDS and low CD4 positive lymphocyte counts, highly active antiretroviral therapy (HAART) is part of the management, while minimization of immunosuppressive therapy is needed in iatrogenically immunocompromised patients. The oral valganciclovir induction dose of 900 mg or 5 mg/kg of intravenous ganciclovir every 12 h is the mainstay of therapy. This induction dose of antivirals is followed by a 900 mg daily of valganciclovir maintenance dose. The use of adjunctive treatments, such as intravitreal injections of ganciclovir (4 mg/0.1 mL), or foscarnet (1.2 mg/0.05 mL or 2.4 mg/0.1 mL) 1–2 times per week, is administered in patients with vision-threatening or macular disease [36, 42].

It is uncertain what role EBV plays in the development of ocular inflammation, as 20% of normal cadaver eyes show evidence of its presence identified by PCR [36]. Some case reports have described EBV-associated retinal manifestations, including retinochoroiditis, ARN, retinal phlebitis with whitish sheathing resembling frosted branch angiitis, central nervous system vasculitis, and necrotizing retinitis with extensive hemorrhage coinfected with CMV and HIV [208, 209].

Treatment: Responses to treatment have been reported with the use of corticosteroids and antivirals such as oral valacyclovir 1 g 3 times a day, acyclovir 400 mg 5 times a day, or famciclovir. The visual prognosis in most patients is good [36].

Human T-lymphotropic virus type 1 (HTLV-1) was found to cause tropical spastic paraplegia/HTLV-1 associated myelopathy (HAM) and since 1990 HTLV-1 uveitis (HU) (Table 2) [210].

Non-Retinal Vasculitic Manifestations: According to one of the largest series, panuveitis is the most frequent form of presentation, with few cells in the anterior chamber, occasionally fine keratic precipitates, and RV [44]. Intermediate uveitis is the second most common type, with moderate to severe vitreous opacities, which may cause decreased visual acuity. RV and anterior uveitis are absent in this clinical type of presentation.

Recurrences in HU can be observed in about a third of patients. In most patients, the visual prognosis is good. Notwithstanding, the development of cataract (111 out of 135 patients, 82.2%) and glaucoma (38 out of 135 patients, 28.1%) occurs frequently [44].

Retinal Vasculitic Manifestations: RV in HU has been described at ophthalmoscopy as dilation of the retinal vessels. Retinal vascular inflammation involves the posterior pole and mid-periphery. Disc hyperemia may also be seen. At fluorescein angiography, RV is identified by the presence of vessel leakage [44].

Treatment: Uveitis usually improves with topical, local, or systemic corticosteroids.

Non-Retinal Vasculitic Manifestations: In patients with ATL, infiltration is the most frequent ocular manifestation, followed by opportunistic infection. ATL cells have the potential to infiltrate the orbit, conjunctiva, lacrimal glands, cornea, vitreous humor, retina, choroid, and optic nerve. They can also accumulate between retinal pigment epithelium (RPE) and the Bruch’s membrane during intraocular infiltration. ATL cells in the vitreous tend to form multiple clusters [50].

Retinal Vasculitic Manifestations: Vasculitis lesions in these patients present with vascular sheathing, and enlargement of the caliber of the vessels. At fluorescein angiography, staining of the vascular wall and leakage may be present. Vascular lesions can be absent initially and, when present, may cause retinal ischemia and necrosis [45]. The manifestation of RV in ATL may represent a risk factor for poor prognosis, particularly if it appears early in the natural history of the disease. Recently, Dentel et al. reported a case of frosted branch angiitis that mainly affects the retinal veins, mild inflammation of the optic disc and vitreous membranes as a type of presentation of HTLV-1 ATL [211].

Ocular complications occur frequently in HIV/AIDS, affecting between 50 and 75% of patients during the course of the disease [212]. HIV is a retrovirus that is spread by sexual contact, exposure to infected blood or blood products, or perinatal transmission from an infected mother to her child [36, 54].

Non-Retinal Vasculitic Manifestations: Posterior segment manifestations in HIV patients may be caused by HIV infection itself, opportunistic infections, or drug-related reactions (e.g., immune recovery uveitis) [213]. Infectious ocular manifestations depend on the immunological status of the patient. After HAART therapy, there has been a significant decrease in opportunistic infections. Notwithstanding, the complications associated with these infections still reduce the visual prognosis.

CMV retinitis is seen in patients with less than 50 cells/mm³ CD4 with confluent centripetal necrotic retinal areas, peripheral granular retinal lesions with no or few hemorrhages and diffuse vasculitis of the frosty branch type [214]. Antiviral treatment is necessary to prevent vision loss and requires secondary prophylaxis until CD4 elevation greater than 100 cells/mm³ [214].

ARN in these patients is associated with viral reactivation. It is generally seen in patients with a mildly depressed immune status, whereas PORN is found with a high degree of immunosuppression. Progressive outer retinal necrosis presents with rapidly progressing retinal necrosis, distinctive outer retinal white lesions, and is characterized by the absence of evident RV or vitreous compromise, with a high risk of retinal detachment [214]. The latter viral retinal infections were more thoroughly described above.

In HIV-infected patients, treatment with HAART leads to an increase in the CD4+ lymphocyte count, which may cause immune reconstitution inflammatory syndrome (IRIS) in some cases. The most common ocular form of IRIS is the immune recovery uveitis (IRU) following the occurrence of CMV retinitis [213]. In a large prospective observational study carried out in a single center in India, 17.4% of patients on HAART developed IRU. The interval between the initiation of HAART and the onset of IRU ranged from 4 months to 2.5 years. Among the total of patients on HAART who developed IRU, 52% experienced its presentation when the increase in CD4+ counts was between 100 and 150 cells/mm³ [215]. In series from Singapore, the median CD4+ count at IRU diagnosis was 210 cells/mm³. Additionally, 86.7% (26 out of 30 patients) had more than 100 cells/mm³ when the IRU diagnosis was made. Younger patients seemed to develop IRU later than older patients (≥50 years old) [216]. Clinical findings may include anterior chamber and vitreous cells, panuveitis with hypopyon, as well as optic disk and macular edema (Fig. 10). Complications such as cataract, ocular hypertension, glaucoma, vitreomacular traction syndrome, neovascularization of the disk, epiretinal membrane formation, and proliferative vitreoretinopathy may occur [216, 217]. Treatment of IRU includes topical, periocular, and systemic oral corticosteroids [215].

Retinal Vasculitic Manifestations: Among manifestations attributed to HIV infection itself, microangiopathy is the most frequent form, with the presence of cotton-wool patches with feathered edges, intraretinal hemorrhages, and microaneurysms [173]. The prevalence of this microangiopathy is inversely proportional to the CD4+ count [205]. Although many of these cases resolve spontaneously or with antiretroviral therapy, secondary structural damage has been demonstrated [42]. Additionally, 2 patients with non-opportunistic HIV-associated peripheral RV have been reported [206, 207], as well as a patient with HIV-related occlusive vasculitis [208].

Among arboviral infections, dengue fever, chikungunya, West Nile virus, and zika frequently involve the eye (Table 2) [55, 56].

Diagnosis: The diagnosis of arboviral infection is made by detecting the viral genome within the first 6 days of symptoms using reverse transcriptase-polymerase chain reaction (RT-PCR). Serologic testing is also of use. Serum IgM antibodies can be detected from the 5th day and persist for about 12 weeks. IgG antibodies may be evident from the 7th day. False-positive results may occur due to cross-reactivity between Flavivirus [56].

Non-Retinal Vasculitic Manifestations: Ocular manifestations are observed in 7–40% of patients, [218] depending on the severity of the viral infection [56, 219]. Subconjunctival hemorrhage is the most frequent ocular manifestation, being observed in up to 40% of all patients. Additionally, vitreous or retinal hemorrhages, lid ecchymosis, and rarely retrobulbar hemorrhage can occur due to marked thrombocytopenia [219]. Clinical manifestations such as anterior uveitis, foveolitis, macular edema, acute macular neuroretinopathy, retinitis, unifocal or multifocal chorioretinitis, and optic disc hyperemia and edema have been described [144, 219, 220]. Foveolitis consists of yellow-orange lesions corresponding to outer retinal changes on optical coherence tomography, which is present in 28–34% of patients with dengue maculopathy [144]. Other less frequent lesions include oculomotor palsies, optic neuropathies, and neuromyelitis optica [56].

Retinal Vasculitic Manifestations: RV can be sectoral or extensive, occlusive, inflammatory, or mixed. In a series of 50 patients with dengue eye disease, retinal vascular inflammation was observed in 23.1% (15 of 65) of the eyes. It is usually associated with exudative retinal detachment and also can occur along with retinitis or retinochoroiditis. Macular infarction due to retinal ischemia or macular edema can complicate RV. Venule or arteriole sheathing is the most common feature, while retinal hemorrhages, cotton-wool spots, and perivascular exudates have also been reported. Fluorescein angiography shows early vessel blockage, mid and late wall vessel hyperfluorescence, and patchy blocked fluorescence. Retinal occlusive events have been described [221, 222].

Non-Retinal Vasculitic Manifestations: The most frequent ocular manifestation of West Nile Fever is bilateral multifocal chorioretinitis that often occurs in neuroinvasive disease. It is characterized by white-yellowish deep lesions in a linear pattern in the mid-periphery, following the choroidal vasculature [56, 57, 223]. The posterior pole is involved in two-thirds of patients, while mid-periphery is almost always affected. The streaks vary in number (from one to more than three per eye) and in length (from two to 15 mm). Chorioretinal lesions also vary in number (from fewer than 20 to more than 50 per eye) and in size (ranging from 200 to 1,500 µm) [144]. Fluorescein angiography of active lesions reveals early hypofluorescence with a rim of hyperfluorescence followed by late leakage. Inactive lesions acquire a “target like” pattern, with central hypofluorescence along with peripheral staining [56, 57, 224]. Indocyanine green angiography shows focal hypocyanescence that persists up to the intermediate phase is observed at the lesion level. Spectral domain shows a focal hyperreflective lesion extending from the RPE to the outer nuclear layer [224]. Iritis and vitritis without chorioretinitis, macular edema, atrophy or mottling of the RPE, optic disc swelling, optic neuritis, neuroretinitis and papilledema, have also been described [56, 223].

Retinal Vasculitic Manifestations: Retinal vascular involvement may manifest with retinal hemorrhages, retinal vascular sheathing, and, in the most severe cases, occlusive RV. The latter occurs mainly in elderly individuals (older than 50 years) and diabetic patients [218, 225, 226].

Non-Retinal Vasculitic Manifestations: Ocular manifestations in chikungunya infection usually occur in acute and/or severe forms of the ailment and less frequently in the chronic form. Anterior uveitis is the most frequent among the ophthalmological manifestations, which may present as granulomatous or non-granulomatous form [59, 227]. Unilateral or bilateral involvement, and occasionally hypertensive presentation have been reported [56]. Posterior segment manifestations include choroiditis, retinitis, optic neuritis, neuroretinitis, and panuveitis. The most common posterior segment is retinitis with surrounding retinal edema, vitritis and disc edema [55, 220]. Recurrence of retinitis has been reported [228]. Acute macular neuroretinopathy has also been observed [220, 229].

SD-OCT has revealed hyperreflective lesions in inner retina with shadowing in the area of the retinitis. Hyporeflective spaces corresponding to the areas of serous retinal detachment have also been described [144].

Retinal Vasculitic Manifestations: An associated occlusive RV is a common finding [55]. Fluorescein angiography, in the areas of retinitis, shows early hypofluorescence with late hyperfluorescence, and in RV, vascular leakage with or without capillary non-perfusion [144]. Severe inflammation may lead to the development of exudative retinal detachment, RV, and intraretinal hemorrhages [55, 56, 59, 220].

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first emerged in China in December 2019, and after a rapid spread, the World Health Organization declared the pandemic in March 2020, which led to the pandemic being officially recognized (Table 2).

Non-Retinal Vasculitic Manifestations: Besides conjunctival involvement, which is the most common ocular manifestation of COVID-19, there are reports of keratoconjunctivitis, nodular episcleritis, anterior uveitis, third, fourth, and sixth nerve palsy, RV, optic neuritis, papillophlebitis, Miller Fisher syndrome, and posterior reversible leukoencephalopathy [230]. Several reports also highlight the association between neuroretinitis, intermediate, posterior and panuveitis and SARS-CoV-2 infection [231‒236]. Observations of multiple evanescent white dot syndrome, punctate inner choroiditis, and ampiginous choroiditis after SARS-CoV-2 infection have been documented [237‒240].

Retinal Vasculitic Manifestations: Retinal vascular occlusions, including central retinal artery and/or vein, cilioretinal artery, and branch retinal vein or artery occlusion, have been reported. Additionally, paracentral acute middle maculopathy and acute macular neuroretinopathy were described [241]. Furthermore, ophthalmic artery occlusion has been presented as a complication of SARS-CoV-2 infection [230]. Quintana-Castañedo et al. [242] reported a case of nonocclusive RV and chilblains in an 11-year-old child, and Erdem et al. [243] described a case of isolated RV in a 37-year-old man.

Exogenous intraocular fungal infections can occur following an open globe injury or surgery. Endogenous intraocular fungal infections are rare, but they are more likely to be associated with a potentially life-threatening systemic source of infection. They are originated by hematogenous spread. Risk factors for their development include recent hospitalization or indwelling catheter or intravenous drug use, and different conditions that lead to relative immunosuppression such as malignancy, diabetes mellitus, corticosteroid or immunosuppressive treatment, and early or advanced age [64, 244].

Candida species are the most common cause of fungal endophthalmitis and belong to the yeast category [64, 65] (Table 2). Although older literature reported a greater frequency of ocular involvement, the estimated current prevalence of Candida chorioretinitis and endophthalmitis is less than 1% in patients with fungemia [66, 67].

Non-Retinal Vasculitic Manifestations: Patients may be asymptomatic or present with blurred vision,floaters, and scotomas. Both eyes can be involved, and the onset is subacute. Ocular pain, red eye, and photophobia are observed at later stages, particularly if there is significant iritis or keratitis. Posterior synechiae, cells, flare, and occasionally hypopyon may develop in the anterior segment.

In the posterior segment, vitritis and single or multiple lesions are initially found in the choroid and/or retina, appearing creamy, white, and well circumscribed. Subsequently, vitreous dissemination develops, and vitreous opacities may have a “string of pearls” or “fluffy ball” appearance, which is a very typical feature [245‒248] (Fig. 11).

Retinal Vasculitic Manifestations: In late stages, retinal hemorrhages or perivascular sheathing can occur. Occlusive RV in these patients is uncommon, and retinal hemorrhages may have a small necrotic center resembling a Roth spot. In some cases, vasculitis can precede a systemic fungal infection even in immunocompetent and asymptomatic patients, as reported by Vinekar et al. [249].

Aspergillus is the most common isolated mold and the second most common cause of fungal infection [69] (Table 2).

Non-Retinal Vasculitic Manifestations: Patients frequently have a clinical presentation with eye pain and blurred vision, along with greater involvement of the posterior pole and predominance of vitreous inflammation. Hypopyon frequently occurs in symptomatic patients. Chorioretinal infiltrates may also be present, which may be accompanied by a prominent vitritis. Unilateral or bilateral posterior pole subretinal abscesses have been reported [69].

Retinal Vasculitic Manifestations: Unlike Candida, Aspergillus invades the retinal and choroidal vasculature. The progression of the infection causes vascular occlusions, retinal necrosis, choroidal thickening (which may be painful), subretinal exudative lesions, and retinal detachment, leading to a poor prognosis [69, 246].

In conclusion, RV is a common manifestation of infections affecting the posterior segment. Recognizing the features of RV, along with associated ocular and systemic signs, patient habits, and origin, enables the physician to suspect the potential causative etiology of the condition, facilitating more effective management of affected patients.

None of the authors has conflicts of interest

No funding was received for this study

A.S., J.M., M.H., S.I., and E.M.D. contributed to the conception and design of the work, drafted and critically reviewed the content, approved the final version for publication, and are accountable for all aspects of the work.