**4. Endogenous spirochete endophthalmitis**

Spirochetes are unique bacteria with distinct long helically coiled cells. Members of the phylum Spirochaetes include *Leptospira, Borrelia burgdorferi,* and *Treponema pallidum,* all of which are known to cause various systemic and intraocular inflammatory manifestations.

*Treponema pallidum* is the causative pathogen for the sexually transmitted infection syphilis. A recent report by the Centers for Disease Control and Prevention (CDC) has revealed that rates of syphilis are on the rise, particularly among HIV-positive patients and men who have sex with men [79, 80]. This rise in syphilis cases also correlates with an increase incidence of ocular syphilis, which is often the presenting feature of the disease [81–83]. The CDC considers a patient to have ocular syphilis if he/she has been diagnosed with syphilis, regardless of the stage, and any symptoms or ocular signs consistent with syphilis. Syphilis, also known as the "great imitator," can affect any ocular structure, including the cornea, sclera, uvea, retina, and optic nerve, and is often bilateral, and should be treated as a tertiary syphilis [84, 85].

The most common ocular manifestation of syphilis is generally agreed to be posterior uveitis followed by panuveitis, although some report granulomatous iridocyclitis as being most common [83, 86, 87]. Isolated intermediate and anterior uveitis can also occur [88]. Ocular syphilis can also present with necrotizing retinitis that can mimic acute retinal necrosis (ARN) or progressive outer retinal necrosis (PORN). However, these viral entities tend to progress quickly and are unresponsive to penicillin, whereas necrotizing retinitis secondary to syphilis tends to be slower and responsive to penicillin [89]. Moreover, retinal vasculitis can occur with occlusive manifestations [89, 90]. Patients with ocular syphilis may have several distinct retinal findings that could assist in diagnosis, such as creamy white

preretinal precipitates that can migrate over time [91]. In addition, retinal lesions can heal with minimal retinal pigment epithelium involvement [23]. Acute syphilitic posterior placoid chorioretinitis is also a distinct and rare retinal manifestation of ocular syphilis characterized by discrete oval lesions of the outer retina and the inner choroid [83]. It is believed that these lesions occur secondary to inflammation from direct invasion of *Treponema pallidum* of the choriocapillaris, deposition of immune complexes, or a combination thereof [90]. Nevertheless, ocular syphilis is uncommon and constitutes a small percentage (1%–5%) of ocular inflammation cases in tertiary referral centers [80, 88, 92, 93].

One study examining 453 patients in an HIV clinic found incidence of syphilis to be 7.3%, of which 9% had ocular manifestations [94]. HIV-positive patients also showed higher rates of concurrent ocular syphilis at a younger age than immunocompetent patients [84, 88, 95]. Moreover, several studies have demonstrated that HIV-positive patients are more likely to have isolated anterior uveitis than HIVnegative patients [88, 96]. Therefore, the CDC recommends that all patients with HIV should be screened for syphilis, and all patients with syphilis should be screen for HIV. Screening for other common sexually transmitted diseases such as gonorrhea and chlamydia should also be performed. HIV-positive patients are more likely to present with acute, bilateral uveitis with more aggressive ocular involvement than HIV-negative patients [84, 85]. However, the CD4 count has not been shown to affect the frequency of ocular syphilis in HIV-positive patients [97].

Diagnosis of syphilis is achieved by nontreponemal and treponemal tests. Nontreponemal tests include Venereal Disease Research Lab (VDRL) and rapid plasma reagin (RPR) tests, which are commonly used for screening. These tests are sensitive but not specific; therefore, a positive result must be confirmed with a treponemal test such as fluorescent treponemal antibody absorption test (FTA-ABS),*T. pallidum* particle agglutination test (TPPA), or microhemagglutination-*T. pallidum* test (MHA-TP) due to their high specificity [98]. In very early or late stages of the infection, RPR can be negative, therefore, a more sensitive test such as enzyme immunoassay (EIA) or chemiluminescence immunoassays (CIA) can be used instead [99].

Ocular syphilis is categorized as a subtype of neurosyphilis and should receive prompt treatment, as delay in treatment may result in visual loss. Only 12% of patients diagnosed with neurosyphilis were found to have ocular involvement, and syphilitic meningitis does not always accompany ocular syphilis [97, 100]. Nevertheless, the CDC recommends a lumbar puncture to be performed on all patients with syphilis and ocular complaints, even in the absence of clinical neurological findings. Commonly, CSF-VDRL is the initial test followed by CSF-FTA-ABS if the former test is positive [101].

The recommended treatment by CDC for ocular syphilis includes intravenous aqueous crystalline penicillin G, 18 to 24 million units per day administered as 3 to 4 million units every four hours or continuous infusion over 10 to 14 days. An alternative regimen, if patient compliance is guaranteed, is 2.4 million units of intramuscular procaine penicillin G once daily in addition to 500 mg oral probenecid four times a day, both for 10 to 14 days.

*Borrelia burgdorferi*, the culprit behind Lyme disease, is another spirochete known to affect ocular structures. Like syphilis, Lyme disease progresses through different stages. Follicular conjunctivitis occurs in the early stage of the disease (7–11% of patients), while keratitis, episcleritis, uveitis, and neuroretinitis tend to occur in the second and third stages [93, 102, 103]. Anterior, intermediate, posterior, and panuveitis have all been reported to occur in Lyme disease, with the intermediate form being the most common one [104, 105]. Retinal vasculitis is also a common presentation in patients with uveitis [104, 106, 107]. Exudative retinal

#### *Endogenous Endophthalmitis: Etiology and Treatment DOI: http://dx.doi.org/10.5772/intechopen.96766*

detachment and macular edema can also occur, along with involvement of the optic nerve such as papillitis and optic neuritis. However, Lyme-associated uveitis is rare. One study conducted in France found Lyme disease to be causative of uveitis in only 7 out of 1,006 cases [104]. Diagnosing Lyme-associated uveitis can be challenging, and it can be difficult to ascertain whether positive serologic testing was incidental in patients with uveitis. A study looking at 430 patients with uveitis found the incidence of positive Lyme serology to be similar to the general population [108]. Serology for Lyme disease without clinical suspicion (presentation of specific Lyme symptoms, tick bite, and/or presence in a *Borrelia burgdorferi*-endemic area) is discouraged due to high false positive rates [109]. The CDC currently recommends a two-step approach to establish the diagnosis [110]: ELISA, to be confirmed with western blot if positive or equivocal. Direct identification of intact spirochetes has also been reported in the vitreous post-vitrectomy [111]. Cultures and PCR of both vitreous samples and urine specimens have also been applied [112–114]. *Borrelia burgdorferi* is highly susceptible to systemic antimicrobial treatment. Oral doxycycline, amoxicillin, and ceftriaxone are routinely used in systemic treatment of Lyme disease [103, 104]. Intravenous ceftriaxone was observed to be more efficacious in treatment of uveitis compared to oral doxycycline, perhaps due to better penetration across the blood– brain barrier [104]. However, an optimal treatment regimen for uveitis remains elusive, and recurrences of uveitis after successful treatment are common. The etiology of such recurrences is unclear, but they are thought to be either a reinfection, relapse of the original infection (due to antibiotic resistance) or an autoimmune reaction. Steroids can be used as adjunct treatment and, in some cases, can be sufficient when used alone [104]. Intravitreal triamcinolone has been used to treat macular edema in Lyme disease [115].

Leptospirosis, caused by the spirochete *Leptospira,* is a common infection in tropical and subtropical areas such as the Caribbean, Central and South America, the Pacific Islands and Southeast Asia [116, 117]. The most common ocular manifestations include subconjunctival hemorrhage, chemosis, and conjunctival hyperemia. Uveitis, retinal vasculitis, retinal hemorrhages, and papillitis can also occur [118]. It is believed that 4–7 days after the onset of leptospirosis bacteremia, the immune system rapidly clears the pathogen from all host tissues except the eye and the brain, as they are somewhat immunologically privileged, resulting in uveitis 3– 6 months post-systemic infection [119, 120]. The exact incidence of uveitis is unclear (3–92%) but can vary from anterior uveitis to panuveitis [119, 121]. Inflammation can be intense, leading to a formation of hypopyon. In fact, hypopyon secondary to leptospiral uveitis is the most common cause of hypopyon in tropical counties [119, 120]. Vitritis has been reported to occur in 76% of cases. Snow banking and vitreous precipitates can also occur in a linear pattern resembling the "string of pearls" that is characteristic of sarcoidosis [122]. The microscopic agglutination test is the gold standard for the diagnosis of leptospirosis; however, other tests such as PCR, ELISA, *Leptospira* dipstick test, and microscopic slide agglutination tests have been routinely used [123]. Intravenous penicillin G is typically reserved for severe infections, while oral doxycycline suffices for milder cases [124]. Topical, periocular and systemic steroids have also been used in the treatment of leptospiral uveitis [122].
