Infectious Chorioretinal Diseases

Clinical Spectrum

The choroid is the most commonly affected structure in intraocular TB. Posterior segment uveitis is the most common form of involvement. The posterior segment manifestations include the following:

• 1.

  Multifocal choroidal tubercles

• 2.

  Solitary choroidal tuberculoma

• 3.

  Subretinal abscess

• 4.

  Serpiginous-like choroiditis, neuroretinitis

• 5.

  Retinal vasculitis

• 6.

  Endophthalmitis and panophthalmitis

The following sections describe imaging characteristics of tubercular lesions that primarily involve the choroid.

Choroidal tubercles

Choroidal tubercles represent the most characteristic clinical presentation of ocular TB and occur as a result of hematogenous dissemination of tubercle bacilli from pulmonary and extrapulmonary sites. The tubercles may be unilateral or bilateral, usually multiple (≤5 in number), discreet grayish-white to yellowish subretinal lesions with indistinct borders ( Fig. 14.1 ). The lesions are usually seen in the posterior pole but may be present in the midperiphery as well. A choroidal granuloma may clinically resemble noninflammatory conditions such as central serous chorioretinopathy, choroidal metastases, melanoma of the choroid, and age-related macular degeneration.

Fluorescein Angiography and Indocyanine-Green Angiography

On fluorescein angiography (FA), choroidal tubercles are hypofluorescent in the dye transit and become hyperfluorescent in the late frames. On indocyanine-green angiography (ICGA), choroidal tubercles may have the following appearance: early and intermediate phase hypofluorescent lesions becoming hyperfluorescent in late phase (Type 1) indicating active choroidal lesions or remain hypofluorescent (Type 2) in the late phase indicating areas of atrophy. There may be presence of numerous hyperfluorescent spots, fuzzy appearance of choroidal vessels in the intermediate phase, and late choroidal hyperfluorescence due to dye leakage which tends to regress after completion of treatment with antitubercular therapy (ATT) and corticosteroids. The ICGA changes are reversible and may be used to monitor the response to therapy.

Optical Coherence Tomography

Optical coherence tomography (OCT) is useful in confirming the presence of exudative retinal detachment associated with choroidal granulomas. A characteristic appearance on OCT has been described in tubercular choroidal granuloma with an area of localized adhesion between the choriocapillaris-retinal pigment epithelial (RPE) layer and the overlying neurosensory retina. This has been termed “contact” sign and has been attributed to inflammatory adhesions overlying the granuloma. However, this sign may not pathognomic of choroidal tuberculous granuloma, and a similar appearance may be seen in other inflammatory granulomas. Nevertheless, OCT can play a role in the differentiating tuberculous choroidal granulomas from other noninflammatory lesions with a similar clinical picture. Enhanced-depth imaging OCT (EDI-OCT) scans have shown to display visible alterations in the choroid that coincide with the ICGA lesions in patients with choroidal granulomas. Invernizzi et al . showed that all choroidal granuloma lesions generated an increased transmission of the OCT signal toward the sclera. Compared with small lesions, large granulomas were more likely to be full thickness, round shaped, with defined margins, lower reflective than the surrounding structures and with a homogenous internal pattern. Granulomas in patients affected by TB-related uveitis were more likely to have a lobulated shape and nonhomogeneous internal pattern.

Studies have reported the use of swept-source OCT to study the choroidal and retinal anatomical sequelae in patients with choroidal granulomas of noninfectious etiology, for example, sarcoidosis. These are characterized by outer retinal tubulations and loss of normal choriocapillaris in the area of healed lesions. However, there are no published studies that have validated these findings among patients with tubercular choroidal granulomas.

Choroidal tuberculoma/subretinal abscess

A large, solitary choroidal granuloma may present as an elevated yellowish subretinal mass lesion often associated with exudative retinal detachment. The lesion is a result of rapid liquefaction caseation necrosis and tissue destruction. These patients often have disseminated systemic TB. The subretinal abscesses are more yellowish in color than a small choroidal granuloma, usually have overlying retinal hemorrhages, and have a tendency to develop retinal angiomatous proliferation over a period of time ( Fig. 14.2 ).

Imaging Features

On B-scan ultrasonography, subretinal abscesses appear like an elevated mass lesion with high initial spike on A-scan and low internal reflectivity. These findings are common to elevated subretinal lesions of other uveitic etiologies as well. On FA, the lesions show early hypofluorescence and late hyperfluorescence. On ICGA, subretinal abscesses appear hypofluorescent throughout the early as well as late phase and larger in size than FA.

Serpiginous-like choroiditis

TB serpiginous-like choroiditis (TB SLC) typically affects young to middle-aged adults from TB-endemic areas. Unlike autoimmune serpiginous choroiditis, TB SLC occurs at a younger age, associated with mild vitritis and is bilateral in majority of the cases ( Fig. 14.3 ). It is thought to represent a hypersensitivity reaction to the tubercular bacilli sequestered in the RPE. This entity shows good response to combination treatment with corticosteroids and full course of antitubercular drugs.

TB SLC may have different morphological patterns:

• 1.

  Multifocal discreet lesions, yellowish-white in color, measuring about 1/4 to 1 disk diameter in size with well-defined margins and slightly raised edges which are noncontiguous initially and show a wave-like progression over a period of 1–4 weeks and gradually become confluent. On FA, the lesions are hypofluorescent in the early phase with late hyperfluorescence. As the lesions become confluent, the advancing edge shows early hypofluorescence with late hyperfluorescence. On ICGA, the lesions remain hypofluorescence from early to late phase.

• 2.

  A diffuse plaque-like lesion with an ameboid pattern and active serpiginous-like edge at the initial presentation. The edges are yellowish-white and elevated, whereas the center of the lesion is less elevated with pigmentary changes suggestive of a healing process in the center of the lesion. On FA, the center of the lesion shows mixed hyperfluorescence, whereas the advancing edge shows early hypofluorescence with late hyperfluorescence.

• 3.

  Mixed pattern with overlapping features in opposite eyes.

Optical Coherence Tomography

Studies that have assessed spectral-domain OCT imaging among patients with TB SLC have described presence of retinal atrophy in the peripapillary region, disruption of the photoreceptor layer, thinning of RPE, mild cystic changes as well as subretinal fibrosis in area of old choroidal neovascularization, and marked attenuation of the interdigitation zone in the outer retina. Features observed on high-resolution spectral-domain OCT scans and correlation with simultaneous fundus autofluorescence (FAF) in eyes with TB SLC have been described.

Acute stage of SLC: OCT B-scans passing through the hyper-autofluorescent active edge of the lesion show a localized, fuzzy area of hyperreflectivity in the outer retinal layers involving the RPE, photoreceptor outer segment tips (POST), photoreceptor inner segment–outer segment (IS/OS) junction, external limiting membrane (ELM), and the outer nuclear layer with no increased backscattering from the inner choroid.

Early healing stage of SLC: In the early stage of healing, OCT B-scans passing through the hyper-autofluorescent central part of the lesion show disappearance of the hyperreflective fuzzy areas that are replaced by irregular, hyperreflective knobbly elevations of the outer retinal layers. The RPE, POST, IS/OS junction, and the ELM cannot be distinguished at this stage. There is an increased reflectance from the choroidal layers due to attenuating RPE–photoreceptor complex.

Late healing stage of SLC: As the lesions heal further over the next 3–6 months, they show stippled pattern of predominant hypo-autofluorescence. The corresponding OCT scans show loss of RPE, POST, IS/OS junction, ELM, and increased reflectance from the choroid persists.

EDI-OCT: Infiltration of the choroid, elevation of the RPE-Bruch’s membrane complex, and focal increase in choroidal thickness have been described in patients with active TB SLC. Retinal thinning and loss of the ELM, ellipsoid and interdigitation zones, loss of visible choroidal vasculature with enhanced choroidal signaling are the findings corresponding to the atrophic inactive areas.

Paradoxical Worsening in Tubercular Serpiginous-Like Choroiditis

Paradoxical worsening following initiation of ATT has been well documented in systemic TB, more so in extrapulmonary TB, including intracranial tuberculomas, tuberculous meningeal radiculitis, and tubercular lymphadenopathy, among others. The worsening of these lesions is believed to be mediated by the host’s immune system because of a combination of factors including enhanced delayed hypersensitivity of the host, decreased suppressor mechanisms, and increased exposure to the mycobacterial antigens or a response to mycobacterial antigens such as tuberculoproteins. Paradoxical worsening has been reported in 14% of patients of intraocular TB after 2–6 weeks of initiation of ATT. These patients should continue to receive ATT despite initial worsening as it helps in reducing the number of recurrences over a long-term follow-up. This phenomenon should not be mistaken for drug-resistant tubercular SLC or other possible nontubercular etiologies.

Role of Ultrawide Field Retinal Imaging in Detecting Paradoxical Worsening

The incidence of paradoxical worsening may be higher than previously reported. With the recent introduction of ultrawide field (UWF) retinal imaging, it is possible to simultaneously document central and peripheral TB SLC lesions in one image and monitor the overall response to treatment on successive visits. Therefore, it may be superior to the conventional imaging in identifying any peripheral paradoxical worsening which may otherwise get missed due to inability of conventional imaging to capture all lesions at every visit. The finding may affect management decisions such as increasing the dose of systemic immunosuppression.

Treatment

The treatment of ocular TB consists of standard four drug regimen of isoniazid (5 mg/kg/day), rifampicin (10 mg/kg/day), ethambutol (15 mg/kg/day), and pyrazinamide (20–25 mg/kg/day) along with pyridoxine (vitamin B6). Ethambutol and pyrazinamide are stopped after a period of 2 months. The role of ATT in intraocular TB is to eliminate the bacilli and reduce the antigen load, which may prevent recurrence of the disease. ATT is usually given in combination with systemic steroids (oral prednisolone 1 mg/kg/day) which are then tapered over the next 6–12 weeks depending upon the severity of inflammation. Topical steroids may be employed in cases with anterior segment inflammation. Systemic immunosuppressants and steroid sparing agents such as azathioprine may be added as and when required.

Clinical Features

Ocular involvement can be a result of acquired infection or, more commonly, a recurrence of the congenital form of the disease. Ocular toxoplasmosis associated with congenital T. gondii infections can be apparent at birth, either as active retinal lesions or as healed retinochoroidal scars. Various clinical manifestations include the following:

• 1.

  Retinochoroiditis

• 2.

  Vasculitis

• 3.

  Vascular occlusion

• 4.

  Papillitis

• 5.

  Neuroretinitis.

Classically, lesions of Toxoplasma retinochoroiditis appear as foci of inner retinitis adjacent to an old chorioretinal scar and are accompanied by dense focal vitritis ( headlight in fog appearance) ( Fig. 14.4 ). In primary acquired disease, the retinitis is seen without the presence of any previous scar. Recurrences manifest as satellite lesions at a border of preexisting retinochoroidal scars with variable pigmentation. However, in some patients, new primary retinal lesions (defined as those not arising from retinochoroidal scars can develop far away from the preexisting scars, in areas of retina that had appeared clinically normal) may occur. Recurrences are unpredictable and can occur months to years after the resolution of the primary lesion.

The typical lesion is a yellowish–whitish area of necrotizing retinitis with poorly defined margins due to surrounding edema. The lesion is frequently located in the macula or posterior to the equator but may occur in the periphery. The edges of the lesion gradually become well-defined, and the lesion progressively heals from periphery toward the center leaving behind a scar tissue. The scar gets progressively pigmented starting at the edges. The average time for the scarring of an active lesion often appears to be related to the lesion size and immune status of the host; resolution often occurs in approximately 3–4 weeks. With prompt diagnosis and treatment, lesions may resolve more rapidly. In an immunocompromised host, the disease may have bilateral presentation and multiple foci in one eye. The lesions tend to enlarge progressively resembling viral retinitis.

Three distinct morphologic forms of Toxoplasma lesions have been described:

• 1.

  Large destructive lesions

• 2.

  Punctate inner lesions

• 3.

  Punctate outer lesions.

Vasculitis may be associated with the retinochoroiditis lesion ( Kyrieleis' vasculitis ). Periphlebitis is more frequent than arteritis; retinal hemorrhages may also be seen. In some cases with very intense inflammation, vasculitis may be present in areas distant from the primary site of retinochoroiditis. Vein or retinal vascular occlusions may also occur as a complication of ocular toxoplasmosis. Papillitis, juxtapapillary chorioretinitis, and neuroretinitis are the less common clinical manifestations of ocular toxoplasmosis.

Fluorescein Angiography

Early phase of FA shows an area of hypofluorescence corresponding to active lesions of toxoplasmosis followed by hyperfluorescence progressing from the periphery of the lesion to its center. There is hyperfluorescence of the surrounding vessel walls suggestive of active vasculitis. Pigmented scars show areas of blocked fluorescence with staining of the scar tissue in late phase. Juxtapapillary cases show progressive hyperfluorescence of the disk. Cystoid macular edema may occur in posterior pole lesions or in cases with severe inflammation. Hypofluorescent areas corresponding to ischemia may be seen in cases associated with vascular occlusions. For cases with choroidal neovascularization associated with a previous healed scar, there is a typical pattern of early lacy hyperfluorescence with progressive late leakage.

Indocyanine-Green Angiography

ICGA appears useful in assessing the extent of choroidal involvement and the evolution of Toxoplasma lesions. Choroidal hypofluorescence is seen in the area of the main lesion and may extend further away from the lesion indicating that Toxoplasma retinochoroiditis is a more widespread process than is clinically suspected as it extends beyond the visible lesions. Multiple hypofluorescent dots described as satellite dark dots have been shown to be present away from the main area of hypofluorescence ( Fig. 14.5 ). These are present in areas that appear normal on clinical examination and FA and probably represent a perilesional inflammatory reaction. They have been reported to disappear following treatment.

Optical Coherence Tomography

Spectral-domain OCT may be helpful in identifying the features, extent, and location of retinitis caused by toxoplasmosis and may be helpful in the visualization of the toxoplasmosis cyst or granuloma ( Fig. 14.5 ). In addition, OCT could be helpful in observing the progression of the disease and development of complications and provides information regarding the visual prognosis ( Fig. 14.6 ).

Active lesion: Active lesions of chorioretinitis show thickening and hyperreflectivity of the neurosensory retina, disruption of the photoreceptor IS/OS junction, choroidal shadowing, and elevation of the RPE ( Fig. 14.5 ). Choroidal thickening may occur beneath the active lesion in the acute phase, which subsequently returns to normal values as the inflammation resolves. It is also useful to detect subtle serous retinal detachment triggered by active retinochoroiditis or to detect subretinal new vessel formation.

Healed lesion: OCT through the site of healed lesion demonstrates thinning of the neurosensory retina, and disorganization of photoreceptor and RPE layer. Disruption of the photoreceptor layer can be helpful in predicting the visual prognosis ( Fig. 14.6 ).

Alwassia et al . have described sequential OCT findings in a case of toxoplasma retinochoroiditis with the following stages:

• 1.

  Initial OCT scan showing a hyperreflectivity in the inner retinal layers with mild elevation representing the area of retinitis.

• 2.

  Disruption in the IS/OS junctions of the photoreceptors.

• 3.

  Early cystic changes in the inner nuclear layer.

• 4.

  Discrete cyst in the ganglion cell layer, possibly representing toxoplasmosis tissue cyst (bradyzoite).

• 5.

  Hyporeflective cystic changes, on follow-up scans, in the previous area of retinitis with greater disruption in the photoreceptor layer and marked loss of retinal tissue and distortion of the outer retinal architecture. The development of these cystic spaces may possibly represent progression from retinitis to liquefactive necrosis.

• 6.

  As the healing progresses, the gap within the retina caused by necrosis becomes smaller with improvement in the architecture of inner and outer retinal layers.

Treatment

The most commonly employed treatment strategy for acute Toxoplasma retinochoroiditis is systemic administration of one or more antibiotics usually given for 4–8 weeks. Most agents are effective only against the active tachyzoite form of toxoplasma, and not the tissue-encysted bradyzoite form. The term, classic therapy or triple-drug therapy , refers to the combination of pyrimethamine (25–50 mg daily orally in one to two doses) and sulfadiazine along with corticosteroids and folinic acid. An alternative to classic treatment, trimethoprim–sulfamethoxazole (160–800 mg twice daily orally) is an attractive option for reasons that include low cost, wide availability, and tolerability though sulfonamide-related reactions may occur. This drug combination has a similar mode of action to pyrimethamine and sulfadiazine on tetrahydrofolate synthesis. Studies have indicated that trimethoprim/sulfamethoxazole/prednisone is an acceptable alternative to classic therapy. This combination may also have a role in the prevention of recurrent attacks of ocular toxoplasmosis. Clindamycin (300 mg orally four times daily) is a lincosamide antibiotic that interferes with translation of the apicoplast, which is an unusual plastid-like organelle found in T. gondii . The drug is often added to triple therapy, which is then referred to as “quadruple therapy.”

In conclusion, despite the common practice of treating Toxoplasma retinochoroiditis with systemic antibiotics, there are no randomized controlled trials demonstrating that antibiotic treatment improves long-term visual outcomes. Also, there is no convincing evidence to date that treatment decreases the severity of intraocular inflammation or duration of disease for all patients.

Clinical Features

Syphilitic uveitis can present as a nonspecific anterior, intermediate, posterior, or panuveitis ( great masquerader ). Uveitis in either the anterior or posterior segment is the most common presentation and can occur as early as 6 weeks after initial infection. Posterior uveitis may manifest as the following:

• 1.

  Focal/multifocal chorioretinitis

• 2.

  Acute posterior placoid chorioretinitis

• 3.

  Necrotizing retinitis and retinal vasculitis similar to acute retinal necrosis (ARN)

• 4.

  Intermediate uveitis

• 5.

  Panuveitis.

Focal/multifocal chorioretinitis: The manifestation presents as a deep-yellow-gray lesion often with a shallow serous retinal detachment and overlying vitreous inflammation. Patchy diffuse chorioretinitis with vitritis is the most common manifestation and may involve retinal hemorrhages, perivasculitis, or other manifestations of retinal vasculitis. On FA, the lesions show early hypofluorescence followed by late staining.

Posterior placoid chorioretinitis: Acute syphilitic posterior placoid chorioretinitis is an uncommon but clinically distinct manifestation of ocular syphilis. It is characterized by pale-yellowish, ill-defined, solitary, placoid subretinal lesion in the posterior pole, or midperiphery of the fundus ( Fig. 14.7 ). These lesions usually have a faded center and stippled hyperpigmentation of the RPE, and they can coalesce to become large confluent lesions. Chorioretinitis is accompanied by variable amount of vitreous inflammation and may be associated with superficial hemorrhages, retinal vasculitis, disk edema, and serous detachment of the RPE. Retinal hemorrhages and vasculitis are typically observed among the immunocompromised patients. The clinical manifestations of acute syphilitic posterior placoid chorioretinitis strongly suggest active inflammation involving the choriocapillaris-pigment epithelium retinal receptor complexes.