Chorioretinitis is a type of uveitis involving the posterior segment of the eye, which includes inflammation of the choroid and the retina of the eye. Though the term uveitis means inflammation of the uveal tract (iris, ciliary body, and choroid), it can involve the adjacent structures like the retina, retinal vessels, vitreous, optic nerve head, and sclera. The Standardization of Uveitis Nomenclature (SUN)[1] consensus conference workshop classified uveitis into anterior (iritis, iridocyclitis, anterior cyclitis), intermediate (pars planitis, posterior cyclitis, hyalitis), posterior uveitis (choroiditis, chorioretinitis, retinochoroiditis, retinitis, and neuroretinitis) and panuveitis based on the anatomical location. Uveitis also classifies as granulomatous or nongranulomatous, acute, chronic or recurrent, insidious, or sudden, based on criteria like appearance, duration, or type of onset. Chorioretinitis is a type of posterior uveitis. The choroid is the vascular layer of the eye, which lies between the retina and the sclera. Since the choroid is responsible for the vascular support of the outer layers of the retina, inflammation of these layers can lead to vision-threatening complications.

Uveitis correlates with a wide range of underlying causes. Based on the etiology, posterior uveitis can classify as infectious or noninfectious.[2] Infection can be congenital or acquired. It can be idiopathic or associated with trauma.

Infectious causes include[3][4][5][6]:

• Toxoplasmosis
• Viruses like cytomegalovirus (CMV), herpes simplex, rubella, lymphocytic choriomeningitis virus, West Nile virus,
• HIV related eye diseases
• Tuberculosis
• Toxocara
• Syphilis
• Bartonella
• Fungal infections caused by Candida spp.
• Coccidioidomycosis[6] histoplasmosis

Noninfectious etiology with systemic association:

• Sarcoidosis
• Behcets disease 

Noninfectious etiology without any systemic association:

• Multifocal choroiditis and panuveitis
• Punctate inner choroidopathy
• Multiple evanescent white dots syndrome
• Unilateral acute idiopathic maculopathy
• Birdshot choroidopathy
• Serpiginous choroidopathy

Other conditions are malignancies like lymphoma masquerading as uveitis, cancer-associated retinopathy.[7] Sympathetic ophthalmia and Vogt Koyanagi Harada syndrome have choroidal inflammation as a part of panuveitis. Posterior scleritis may also simulate choroiditis, but posterior scleritis is associated with severe pain and on ultrasound shows subtenon fluid (T sign).

The epidemiological data from various studies showed that uveitis occurs between 52 and 341 per 100000 person-years in the US.[8][9] It is responsible for 2.8 to 10% of blindness cases in the United States.[10] Toxoplasma chorioretinitis is the most common cause of posterior uveitis worldwide. It has a higher prevalence in tropical countries with hot and humid climates. It accounts for 25% of cases of posterior uveitis in the US.[11] In the United States, antibodies to Toxoplasma are present in nearly 20% of people. It is a major opportunistic pathogen in AIDS.[12] Increased age was associated with a higher incidence of uveitis.[13] It is responsible for an estimated 30000 new cases of legal blindness annually in the USA  and accounts for about 10 to 15% of all cases of total blindness in the country.[14] Ocular inflammatory disorders affect women more than men, and the majority of affected women are of childbearing age.[15][16]

Chorioretinitis is usually due to an infectious etiology. The extent of ocular involvement varies depending on the organism. Toxoplasma gondii is the most common cause of infectious posterior uveitis worldwide. Infection usually occurs by either consumption of tissue cysts present in raw or undercooked meat or by ingesting oocysts in the feces of cats. It can be transmitted transplacentally.[17] It can cause severe infection in immunosuppressed individuals and pregnant women.

Congenital Toxoplasmosis:  In congenital toxoplasmosis, the mother is often asymptomatic or has mild constitutional manifestations. The severity of fetal involvement is related to the gestational period at which infection occurred, with more severe in early trimesters, when fetal death may result. In the first trimester rate of transmission to the fetus is around 10 to 25%, in the third trimester the transplacental transmission is approximately 60 to 80%. However, fetuses infected in early pregnancy are more likely to show clinical signs of infection.[18] The presence of chorioretinitis, intracranial calcifications, and hydrocephalus are considered the classic triad of congenital toxoplasmosis.[19] Congenital toxoplasmosis is associated with retinochoroidal lesions in 80% of infected newborns. It can be bilateral. Typical features are excavated macular lesions with associated pigmentation.

Acquired Toxoplasmosis: Most infections are thought to occur congenitally and can remain asymptomatic for several years and can become clinically evident commonly in the second through fourth decades. In the inactive stage, it can present as quiescent atrophic chorioretinal scars, which appear as pigmented lesions in clusters. In 70 to 80% of cases, it can occur as a unilateral focal chorioretinal lesion.[20] In the active phase, it occurs as necrotizing chorioretinitis with overlying vitritis. On fundoscopy, it can appear as a yellow-white lesion with indistinct margins, often described as a “headlight in a fog” appearance. The 'fog' is due to the vitritis, which causes vitreous haze, and the lesion of chorioretinitis appears as a focal area of yellow/whitish-yellow lesion ('headlight'). Lesions can be solitary, multiple, or satellite to an old chorioretinal scar. Numerous or bilateral active lesions are present in immunocompromised patients. In immunocompromised patients, it can mimic severe acute retinal necrosis (ARN).

In immunocompetent patients, the parasite can occur as a tissue cyst and can cause chronic infection. In patients with HIV, toxoplasmosis reactivation occurs when cell-mediated immunity fails. In HIV patients, with CD4 count less than 100, cotrimoxazole or dapsone and pyrimethamine can be given for six months.[21]

Congenital CMV: Cytomegalovirus (CMV) is the most common congenital viral infection in the United States. Congenital CMV infection presents with ocular manifestations like chorioretinitis, cataract, and optic atrophy along with jaundice, petechiae, hepatosplenomegaly, hearing loss, periventricular calcifications, ventricular calcifications, and microcephaly.[22][23] The majority of children with congenital CMV have asymptomatic infection. Chorioretinitis and/or optic atrophy is present in 10% of symptomatic infants with CMV.

CMV retinitis occurs in severely immunocompromised AIDS patients, with a CD4 lymphocyte count less than 50cells/micro L. CMV can cause necrotizing retinitis, retinal vasculitis, and optic neuropathy, with minimal vitritis. The characteristic fundus appearance of white retinitis lesions with hemorrhages is called "pizza-pie" appearance. It can cause anterior uveitis in healthy adults.

Ocular toxocariasis: It results from the nematodes Toxocara canis and Toxocara cati. It usually affects young patients. It is unilateral in 90% of cases. The child can have leukocoria, eye pain, strabismus, and profound monocular loss of vision.  It commonly causes chronic endophthalmitis, granulomas in the posterior pole, or peripheral retina. Tractional retinal detachment can occur in these patients. Atypically it can cause diffuse chorioretinitis. It can be diagnosed based on the history of contact with pets and the characteristic ocular features. Retinoblastoma is an important differential diagnosis to be considered, which has a similar presentation. Serological tests like ELISA for the detection of anti-Toxocara excretory-secretory antigen IgE levels can confirm the diagnosis.[24][25] The use of anti-helminthic drugs is limited. Systemic steroids are given to treat severe inflammation.

Ocular syphilis:  It has earned the name the great masquerader as the clinical presentation is diverse, with various inflammatory presentations such as iritis, chorioretinitis, vitritis, scleritis, neurosyphilis with Argyll Robertson pupil, and panuveitis. The most common presentation is iritis or iridocyclitis. In syphilis patients with HIV, placoid lesions have been described called acute syphilitic posterior placoid chorioretinitis.[26][27] It can occur in secondary or tertiary syphilis. Treatment is the same as neurosyphilis. The diagnosis should be suspected in patients with high-risk sexual behavior or with a history of other sexually transmitted diseases.

Ocular Tuberculosis (TB) is extrapulmonary tuberculosis commonly seen in endemic countries like India. The presentation can be variable, with lesions involving any layer of the eye. It can present as granulomatous anterior uveitis. Posterior segment manifestations including retinal vasculitis, multifocal serpiginous choroiditis, multifocal choroiditis, choroidal tubercles, tuberculoma, subretinal hypopyon, and subretinal abscesses are present.[28][29][30][29][28] Serpiginous like choroiditis may be associated with tuberculosis. Choroidal tubercles, tuberculoma, and choroidal abscess are generally considered as direct infection by tuberculosis bacillus. However, whether other manifestations are caused by infection (which needs antitubercular therapy/ATT) or by a hypersensitivity reaction (which is treated by steroids and/or immunosuppressive therapy) is controversial.[31] Mantoux test, interferon-gamma release assay/IGRA, polymerase chain reaction (PCR) from the intraocular specimen can suggest the diagnosis, though confirmation of direct causation by the bacteria is difficult. In most of the cases, the diagnosis is presumptive.[32] In low and middle-income countries, the World Health Organization's policy statement concluded that 'Neither IGRAs nor the TST should be used for the diagnosis of active TB disease.'[33] Ascertaining which cases need ATT, is difficult; this is important as ATT might have serious adverse effects also. Ocular tuberculosis is usually treated with ATT of at least nine months and oral steroids if needed. Healed ocular tuberculosis may be associated with a choroidal neovascular membrane, which might respond well with anti-vascular endothelial growth factor agents.[34][35]

Ocular histoplasmosis syndrome occurs in regions endemic for Histoplasma capsulatum. It can present with asymptomatic chorioretinitis, discrete oval–round whitish lesions less than 400 micrometers in diameter that may develop into classic punched out histo spots or choroidal neovascular membrane, which can cause central vision loss.[36]

Chorioretinitis has also been described in congenital infections with the Zika virus, rubella, and varicella-zoster virus.[37][38][39][40][41][40][38][42]

Zika virus is a neurotropic virus that can cross the placenta and infect the fetus. Classical findings include microcephaly, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence called arthrogryposis. Infants with the Zika virus have vision-threatening fundus abnormalities like macular chorioretinal atrophy, focal pigmentary changes, and optic nerve abnormalities. Diagnostic confirmation is by Zika RNA with PCR.

Congenital Varicella-Zoster virus infection can cause microphthalmia, chorioretinitis, and cataract in 44 to 52% of cases.[43]

EBV (Epstein Barr virus) uveitis: EBV uveitis can present as iritis, whereas posterior segment involvement may include multifocal choroiditis with punched-out areas of pigment epithelial changes and vitritis.[44] Reports exist of chorioretinitis with West Nile virus infection.[45] The chorioretinitis associated with the West Nile virus is typically linear, which might be related to the organization of the retinal nerve fiber layer.[46] 

Non-infective posterior uveitis with systemic illness:

Sarcoidosis: It is a multi-system disease characterized by noncaseating granulomas in tissues, with a high incidence reported in African American women. It can cause granulomatous anterior uveitis, periphlebitis, with candle wax drippings and yellow waxy spots, vitritis, snowball opacities, and snowbanking. Chorioretinal granulomas, placoid lesions, and optic nerve head granuloma are presenting features.

Bechet’s disease presents with recurrent anterior and posterior uveitis, recurrent oral or genital ulcers, and skin lesions. Ocular manifestation can be seen in 70% of cases of Behcets disease and is one of the main diagnostic criteria of the disease. It can cause nongranulomatous anterior uveitis. Posterior segment involvement characteristically shows by vitritis/media haze, retinal vasculitis, hyalitis, necrotizing retinitis, and chorioretinitis.[47][48]

Non-infective posterior uveitis without systemic illness (white dot syndromes)

Common non-infective posterior uveitic entities include the white dot syndromes (WDS), named according to their clinical appearance and behavior. Laboratory investigations are not routinely needed for their diagnosis. Fundus fluorescein angiogram (FFA), indocyanine green angiogram (ICGA), optical coherence tomography (OCT), and multimodal imaging are used to evaluate WDS.

Birdshot chorioretinopathy (BSCR)/vitiliginous choroiditis: More than 90% of the patients with BCR are HLA-A29 positive. The term “birdshot” is because the lesions scattered around the optic disc and radiate to the equator resembling the shotgun scatter of birdshot.[49]

Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPEE): It is a bilateral inflammatory retinal/choroidal disease characterized by a sudden loss of vision caused by the sudden appearance of multiple yellow-white, flat inflammatory lesions lying deep within the sensory retina, Retinal pigment epithelium (RPE) and the choriocapillaris. The lesions of APMPPE are unique but may be confused with viral retinitis, syphilis, serpiginous choroiditis, and toxoplasma retinochoroiditis. In APMPPE, lesions are flat, and there is no significant vitritis. Fundus Fluorescein Angiography (FFA) shows an early hypofluorescence of the white placoid lesions with late staining.

Multiple Evanescent White Dot Syndrome (MEWDS): MEWDS is an inflammatory chorioretinopathy characterized by the presence of white/gray lesions deep in the retina. It is a rare disorder seen in healthy young women. It can also demonstrate optic disc edema, mild vitritis, panuveitis, diffuse choroidal thickening. A characteristic granular appearance of the fovea is present. Contrary to other white dot syndromes, it is usually unilateral. FFA shows early and late hyperfluorescence at the lesions.

Serpiginous Choroiditis (SC): It is a rare progressive recurrent bilateral disease that affects the outer retina, retinal pigment epithelium, choriocapillaris, and inner choroid. The lesions are gray or gray-yellow areas that begin either in the peripapillary region or macula. FFA demonstrates early hypofluorescence and late hyperfluorescence of active lesions.

Multi-Focal Choroiditis/Punctate Inner Choroidopathy (MFC and PIC): They occur predominantly in myopic women, usually involving both eyes. The presence of cystoid macular edema /choroidal neovascular membrane is associated with poor visual prognosis.

Masquerade syndromes: Malignancies like intraocular lymphoma and leukemia can present with uveitis. Choroidal melanoma and cancer-associated retinopathy must be ruled out in non-resolving and atypical presentations of uveitis.[50]

Histopathologically, diffuse or focal inflammatory infiltrates appear in the retina and choroid. With active ocular toxoplasmosis, a focal retinochoroiditis with necrotizing granulomatous inflammation of the retina is present. Parasites may appear as free tachyzoites, or tissue cysts with mononuclear inflammatory infiltrates surrounding retinal blood vessels.