**3. Retinitis forms due to parasites**

#### **3.1 Ocular toxoplasmosis**

Ocular toxoplasmosis is one of the most frequent causes for infectious uveitis globally, typically presenting as rather unilateral posterior uveitis with chorioretinal lesions and vitritis [19].

### *3.1.1 Pathogen*

The ubiquitously distributed protozoon of the phylum Apicomplexa, *Toxoplasma (T.) gondii* is an obligate intracellular parasite, which invades host cells of a wide range of vertebral species including humans via an apical complex. Specific *T. gondii* genotypes are likely associated with higher prevalence and development of ocular toxoplasmosis [20]. Infection and transmission by *T. gondii* are possible in various stages of the parasitic life cycle. Soil-borne, water-borne, or food-borne uptake of oocysts containing infectious sporozoids and inoculation by tissue cysts containing tachyzoits with undercooked or raw meat, free tachyzoits in milk and eggs are the most common infectious routes besides vertical transmission, organ transplantation, and blood transfusion. *T. gondii* primary infects intestinal epithelial cells, circulates via the blood stream, performs extravasation by forming cysts [21, 22], and develops into different parasitic stages such as free infectious tachyzoits after intracellular replication and cell lysis or rather dormant and inactive encysted bradyzoits. The cell-invading and immune-escaping capacity of *T. gondii* is actively mediated by complex host-parasite interactions via surface ligands. Altered cytokine profiles of targeted macrophages, dendritic, and tissue cells, by intracellular *T. gondii* are the key to immune evasion, organ tropism, and the well balanced pro- and anti-inflammatory signaling of the targeted cells. These mechanisms consequently lead to a constant destructive and protective host tissue and parasite interaction in immunocompetent persons [23].

### *3.1.2 Epidemiology*

Toxoplasmosis is widely spread with an approximately 30% human infection rate and wide geographical variation of seropositive rates up to 80% within certain populations [20, 24, 25]. Recent studies elucidated that endemic *T. gondii* strains play a major role in ocular toxoplasmosis prevalence. Archetypal strains I, II, III are dominant in Europe and North America, and non-archetypal strains are a minority but nevertheless cause the majority of ocular toxoplasmosis cases, approximately 1**–**2%, in immunocompetent seropositive individuals. In South America and Brazil, non-archetypal strains are dominant, and the ocular toxoplasmosis prevalence is up to 10**–**20% in the seropositive population [26, 27]. Other important factors related to the endemic seroprevalence of *T. gondii* are climate and socioeconomic factors such as access to clean and not contaminated water, public and institutional surveillance,

hygiene and control of parasitic prevalence in life stock and related food products, blood products, and individual host-dependent factors such as food consumption habits, age, and the host's immunocompetence.

Although seroprevalence in populations is rather high, the majority of infected people do not develop symptoms due to immunological parasite-host interactions. Ocular toxoplasmosis can occur month or years after postnatal or congenital infection and might be the first sign of a systemic toxoplasmosis. Therefore, all seropositive individuals are at risk to develop an ocular toxoplasmosis in their lifetime. Age over 40, time of infection, and immunosuppression are risk factors for onset, recurrence, and severity of ophthalmic toxoplasmosis [23].

#### *3.1.3 Clinical peculiarities*

In patients with ocular toxoplasmosis, retinochorioditis is the most typical finding. Active intraocular inflammation often presents as focal necrotizing granulomatous retinitis with reactive granulomatous choroiditis and vitritis. The clinical image contains active lesions, often close to a pigmented or atrophic scar, described as whitish foci with obscure borders. Vasculitis can appear close or distant to the lesions and presents mainly as phlebitis and less frequent as arteritis eventually with hemorrhages [28]. In rare cases, Kyrieleis arteritis, a type of arteriolitis with intravascular nodular-like white plaques, can be found [29, 30]. Usually, the active lesions tend to heal within 2**–**4 month in immunocompetent patients by leaving an atrophic area gradually turning into a hyperpigmented scar due to disruption of retinal pigment epithelium. New active lesions are frequently close to old scars as a sign of recurrence [31]. Especially in immunocompromised patients, the differential diagnosis to other pathogens may be difficult [32].

Nonetheless, there are many atypical and unusual presentations related to the anatomical region of inflammation including anterior uveitis [28] with complication of rise in intraocular pressure, punctate outer retinal toxoplasmosis (PORT) with risk for secondary optic neuropathy and significant visual loss [23], neuroretinitis, and other unspecific features such as scleritis [33], which may delay a timely diagnosis [34] with risk of permanent vitreous opacities, deterioration in visual acuity or even vision loss in case of macular or optic nerve involvement. Recurrences with inflammatory reaction may occur at any time post primary infection resulting from ruptured intraretinal cysts.

Complications are associated with intraocular inflammation and are correlated with older age, retinal lesions larger than one disc size, and extra-macular lesions. Vasculitis-associated complications are proliferative tractional bands, vitreoretinopathy, and retinal vasculitis, which can contribute to tractional retinal detachment and hemorrhages and vascular occlusions. Especially immunocompromised patients with large necrotic areas are at higher risk for retinal cracks and retinal detachment [23].

#### *3.1.4 Diagnostics*

Typical ocular toxoplasmosis usually is diagnosed by characteristic clinical findings and serological detection methods. However, imaging technics help to estimate severity of clinical signs, diagnosing atypical ocular toxoplasmosis patterns and surveil the clinical course and treatment efficacy. The diagnostic work-up usually is composed of basic ophthalmological assessments, imaging techniques such as ultrasound, fundus color photography, optical coherence tomography, optical coherence tomography angiography, confocal scanning laser ophthalmoscopy, fundus autofluorescence,

#### *Retinitis Due to Infections DOI: http://dx.doi.org/10.5772/intechopen.107394*

fluorescent angiography, indocyanine green angiography, and direct and indirect *T. gondii* detection tests in case of uncertainty after fundus imaging. Therefore, serological methods, immunohistochemical methods, specific PCR methods are commonly used. High sensitivity and specificity of PCR-based assays and detection of specific antibodies from vitreous and aqueous fluid have gained remarkable diagnostic value in diagnosing ocular toxoplasmosis [23]. PCR is the main detection method for determining *T. gondii* infection in ocular inflammation, congenital infections, and immunocompromised patients including HIV-infected patients. Real-time PCR and nested-PCR show consistently good results in detecting parasite DNA in ocular fluids of patients with toxoplasmosis including immunocompromised with high sensitivity and specificity. Detection works best during the first weeks of onset of symptoms.

Serological laboratory tests routinely help to determine whether an infection is recently acquired or chronic according to individual course of IgM, IgG, and IgA titers and IgG avidity patterns. Additionally, serology helps to rule out toxoplasmosis if suspected. Low IgG und absence of IgM antibodies are the regular finding in immunocompetent individuals with typical ocular toxoplasmosis. This highlights that only positive IgG titers are not suitable to confirm the diagnosis. However, solely immune enzyme assays are useful in diagnosing active ocular toxoplasmosis by supporting clinical findings in up to 96% of typical and atypical ocular toxoplasmosis by indicating positivity and significant increase of specific antibodies titers [35]. The approach of combined PCR and antibody detection from aqueous humor has strong predictive power in confirming the clinical diagnosis of ocular toxoplasmosis especially in immunocompromised individuals and atypical cases [36]. Interferon-γ release assays from whole blood for specific *T. gondii* T-cells show reliable results in detecting toxoplasmosis with 96% sensitivity and 91% specificity in seropositive adults with acute or chronic infection and in 94% and 98% for infants with congenital infection by mothers who acquired infection during pregnancy [37, 38].

#### *3.1.5 Therapy*

When deciding whether to treat active retinochorioiditis, considerations should include the mostly benign natural course, patients' characteristics (pregnancy, newborns, allergies, etc.) toxicity of potential drugs, the individual clinical course and immune status, presentation of active lesions, visual acuity and vitreous opacity, complications such as vascular occlusion and edema of macular or optic disc. Treatment regimens are combinations of antimicrobial drugs (control of parasite replication) and topical and systemic corticosteroids for 4–6 weeks. The role of treatment in chronic toxoplasmosis remains unclear due to lack of evidence in efficacy against tissue cysts [39]. The main goals of treatment are size reduction of lesions and prevention of adverse complications of active ocular toxoplasmosis. All first-line regimens have no significant effect on recurrences although trimethoprimsulfamethoxazole might have [40] if substituted for sulfadiazine. Close monitoring of drug-related gastrointestinal, dermatological, and hematological (leukocytopenia, thrombocytopenia) adverse events and allergic side effects is recommended. Weekly blood tests should be performed and depending on the chosen treatment regimen substitution of folic acid is required.

First-line regimens are: (I) pyrimathamine, sulfadiazine, folic acid, and prednisone; (II) pyrimethamine, clindamycin, folic acid, and prednisone; (III) pyrimethamine, sulfadiazine, clindamycin, folic acid, and prednisone "quadruple therapy." Selected alternative regimens are: (IV) trimethoprim-sulfamethoxazole and prednisone; (V) clindamycin, spiramycin, prednisone; (VI) clindamycin, sulfadiazine, prednisone; (VII) pyrimethamine, azithromycin, folic acid, prednisone. Other alternative combinations include atovaquone or tetracycline derivates [41, 42].

The first-line treatments or called classical treatments show better reduction of duration of posterior pole retinitis in comparison to alternative regimens and are more fitting for foveal adjacent and fovea lesions [43]. Systemic corticosteroid therapy usually starts 3 days after and stops 10 days before antimicrobial therapy and is only recommended in immunocompetent individuals [23].

Another therapeutic approach is the intravitreal application of clindamycin and dexamethasone, which show larger lesion size reductions in IgM-positive patients compared with the classic treatment or no treatment. Additional advantages of intravitreal drug application are less systemic side effects what might be beneficial in pregnancy. One of the disadvantages is the risk of fulminant systemic disease in immunocompromised patients. Other supportive measurements include steroid eye drops, mydriatics, and local hypotensive agents to prevent and manage complications of active ocular toxoplasmosis [44]. For immunocompromised or pregnant patients, modified treatment strategies are available, which mostly aim at prevention of severe complications of active ocular toxoplasmosis and toxoplasmosis in general with indications to treat at low thresholds and close treatment supervision by a multidisciplinary team [23].

#### *3.1.6 Prognosis*

The prognosis and course are mainly dependent on the timely and appropriate diagnosis and management of active ocular toxoplasmosis, complications, and the frequency of individual recurrences associated with personal and environmental risk factors over time.

### **3.2 Ocular toxocariasis**

Ocular toxocariasis or ocular larva migrans is a worldwide prevalent common zoonotic helminthic infection caused by roundworms, which might cause severe vision impairment or loss.

## *3.2.1 Pathogen*

Toxocara species mainly *T. canis* (dog) and *T. cati*/*mystax* (cat) are helminths (common ascaris roundworms), which can follow a direct life cycle by infecting definite hosts who shed unembryonated eggs, which become infectious (third-stage larvae, L3) in the environment. Alternatively, they follow indirect life cycles by infecting paratenic hosts where migrating L3 larvae form tissue cysts might finally be inoculated by a definite host. Humans are accidental hosts (L3 larvae cannot complete the life cycle and therefore do not breed eggs) and get infected by accidentally ingesting infectious eggs with contaminated food or water or by consumption of undercooked and raw meat of paratenic hosts containing L3 larvae cysts. After ingestion, L3 larvae penetrate the small intestinal mucosa and circulate via blood to different organs and tissues where the larvae start migrating causing local immunological and inflammatory reactions, which might lead to symptoms. The majority is asymptomatically infected. Symptomatic presentations are either visceral or ocular larva migrans. Severity is a function of parasitic load.

## *3.2.2 Epidemiology*

Toxocariasis is worldwide distributed. The majority of ocular larva migrans infections are related to *T. canis* and less frequent reported by *T. cati/T. mystax*. Seroprevalence rates for Toxocara antibodies vary from approximately 3 to over 70% [45] with lower rates in industrialized countries and higher rates in low- and middleincome countries related to lower standards in water, sanitation and hygiene and public surveillance, prevention, and control. Exceptions are reported, which mostly are related to habitual food consumption than low hygiene standards [45, 46].

Ocular larva migrans affects children and adults with mean age at onset ranging from 6.4 [47] to 51.7 [48, 49] years and is a significant cause for visual impairment during childhood. The age at presentation with symptoms may vary from 1 to 77 years [48**–**51].
