Chapter 165 – Syphilitic Uveitis
PRAVIN U. DUGEL
ALLEN B. THACH
• A complex series of infectious and immunologically mediated intraocular inflammation initiated by Treponema pallidum.
• Intraocular inflammation.
• Systemic manifestations.
• Latent intraocular and/or systemic manifestations.
• Chancres and gummatous involvement of the conjunctiva.
• Secondary episcleritis or scleritis.
• Interstitial keratitis.
• Congenital and acquired cataracts.
• Secondary glaucoma.
• Argyll Robertson pupil.
The ophthalmic manifestations of syphilis are protean and consist of inflammation and its sequelae. New clinical signs have been recognized in patients who also are infected with human immunodeficiency virus (HIV).
EPIDEMIOLOGY AND PATHOGENESIS
Syphilis is caused by the bacterium Treponema pallidum (Tr. pallidum). It is primarily a sexually transmitted disease but can be spread by transfusion of fresh blood or by accidental contact with an infected lesion. This disease has been a source of social stigma, morbidity, and mortality for centuries. Not until the widespread availability of penicillin after World War II was an appreciable decline in its incidence seen. However, penicillin alone is not the cure. Increasing bacterial resistance, socioeconomic factors, increased high-risk sexual activity, and devastating diseases that result in permanent immunodepression have contributed to a resurgence of syphilis. 
Perhaps syphilis is one of the difficult infectious diseases to understand and treat because it modulates the host immune system. Once infection takes place, immunity does occur, but it does not confer absolute protection. Humoral antibodies are protective only partially. Cell-mediated immunity, on the other hand, confers some resistance but, more important, may be a key factor in the development of late complications in humans.
Socioeconomic factors along with high-risk sexual behaviors and the HIV infection have resulted in an increased incidence of syphilis. It is therefore recommended that tests for both syphilis and HIV be carried out in patients who test positive for either disease. Because immunomodulation has a significant role in the development of clinical manifestations of syphilis, patients who have the acquired immunodeficiency syndrome (AIDS)
Figure 165-1 Ocular retinitis. This developed in a 38-year-old man who had a positive serology for syphilis.
present a new and formidable challenge in the diagnosis and management of syphilis.
Nonspecific iritis and iridocyclitis are the most commonly associated forms of uveitis and may be the predominant finding in secondary syphilis. The anterior uveitis, however, is nonspecific and may be granulomatous or nongranulomatous. Dilated iris capillaries (roseola) during the second stage of syphilis have been described as a distinctive feature. Some authorities speculated that treponemal emboli may cause secondary vascular tortuosity and dilatation.
The clinical manifestations of syphilis chorioretinitis are diverse. All forms of posterior uveitis have been described—vitritis, vasculitis with or without vascular occlusion, macular edema, stellate maculopathy, disciform macular detachment, pseudoretinitis pigmentosa, retinal detachment, uveal effusion, central retinal vein occlusion, subretinal neovascular membrane formation, retinal necrosis, big blind spot syndrome, and neuroretinitis ( Figs. 165-1 to 165-3 ).      In HIV-positive individuals, the posterior intraocular inflammation includes large macular or juxtapapillary placoid lesions at the level of the retinal pigment epithelium. These lesions are yellowish or gray with atrophic centers and are flat with no fluid or hemorrhage. The fluorescein angiogram shows early hypofluorescence and late staining in a pattern described as a “leopard spot” hypofluorescence, which is thought to be a distinguishing finding; the condition is named acute syphilitic posterior placoid chorioretinitis. HIV-positive patients may also present with a dense vitritis and no other signs of posterior uveitis ( Fig. 165-4 ). 
Other ocular manifestations arise from involvement of the conjunctiva, cornea, sclera, optic nerve, and central nervous system.
Involvement of the conjunctiva may occur in all three stages of syphilis. The chancre of primary syphilis is very similar to that seen systemically. It consists of an ulcerative conjunctival lesion with a rounded edge and surrounding conjunctival injection; no discharge occurs. This chancre is usually asymptomatic, but irritative
Figure 165-2 Syphilitic chronic choroiditis.
symptoms have been described. The nonspecific conjunctivitis of secondary syphilis is usually mild and often overlooked. It consists of a primary papillary reaction and may be a harbinger of underlying scleritis, which is a more ominous sign. Tertiary syphilis may result in a granulomatous conjunctivitis with secondary necrosis and gumma formation, which can be quite painful with a significant infiltration of lymphocytes and plasma cells. Clinically, a necrotizing conjunctivitis with intense inflammation and pain is found.
Scleritis or episcleritis as part of conjunctivitis is a relatively common finding in secondary syphilis, but isolated episcleritis or scleritis is uncommon at any stage of the disease. When scleritis or episcleritis does occur, it is entirely nonspecific and usually does not progress to necrosis. The involvement of the sclera or episclera may be secondary to an immune complex reaction.
Corneal manifestations of congenital and acquired syphilis are probably the best known of all ocular manifestations. Syphilitic interstitial keratitis usually results from congenital infection but occasionally may be acquired. As there is a delay in the clinical manifestation of congenital infection, the cause of interstitial keratitis is often presumed and not apparent. It is also not clear whether inflammation arises from direct infection or from an immune complex reaction.
Clinically, acquired active interstitial keratitis consists of stromal inflammation, particularly in the peripheral cornea. Marginal infiltrates of the anterior stroma may be seen, which usually occur in association with a secondary anterior uveitis. As the uveal inflammation subsides, corneal scarring develops. Stromal neovascularization, just anterior to Descemet’s membrane, is a distinctive feature of interstitial keratitis. However, in inactive interstitial keratitis, ghost vessels may lie within areas of stromal scarring and are difficult to visualize. Inactive interstitial keratitis is usually the clinical presentation of presumed congenital syphilis. Another clinical feature that has been described as being characteristic of interstitial keratitis is alteration in Descemet’s membrane with the development of ridges, webs, or thick scrolls.
Cataracts have been described in association with congenital as well as acquired syphilis but are not distinctive. It is not known whether cataract is a direct manifestation of syphilis or a secondary result of intraocular inflammation.
Although numerous types of glaucoma have been described in association with syphilis, the type most often seen is secondary to uveitis and can occur in either congenital or acquired syphilitic iridocyclitis. It is thought that patients who develop interstitial keratitis early in infancy, be it congenital or acquired, may not develop a mature anterior segment and angle. This maldevelopment may cause narrow-angle glaucoma in later life.
The classical pupillary finding in syphilis is the Argyll Robertson pupil, which is most commonly seen in late syphilis
Figure 165-3 Extensive chorioretinal damage with hyperplasia of retinal pigment epithelium. The patient has syphilis.
Figure 165-4 Acute syphilitic retinitis. This individual is infected by the human immunodeficiency virus. Note that the media is hazy from collections of inflammatory cells in the vitreous.
but may be seen in early neurosyphilis as well. The pupils are unequal in size, irregular, and miotic, with light-near dissociation (the last may also occur with a normal pupillary size). Interruption of fibers from the Edinger-Westphal nuclei that connect to the pretectal nuclei is thought to result in the light-near dissociation.
The neuro-ophthalmic manifestations of early neurosyphilis are diverse. Early neurosyphilis results in vasculitis and vascular compromise, which often presents as a stroke-like clinical finding. Therefore, any of the cranial nuclei and their pathways may be affected, which results in isolated as well as complicated palsies of the third, fourth, and sixth cranial nerves. Abnormalities of the saccadic systems and smooth pursuit systems may also occur. Other neuro-ophthalmologic manifestations that have been described include the superior orbital fissure syndrome that arises from focal gummas, brainstem infarction, basilar meningitis, homonymous hemianopia, chiasmal syndrome with bitemporal hemianopia, cortical blindness, lateral medullary plate syndrome, Horner’s syndrome, and internuclear ophthalmoplegia. Late neurosyphilis may cause a general paresis and tabes dorsalis.   
Syphilis is the great masquerader. Therefore, diagnosis requires a high level of clinical suspicion combined with the appropriate laboratory tests. The demonstration of live organisms using dark-field microscopy or an immunofluorescent technique may confirm the diagnosis of syphilis before seroconversion occurs 10–20 days after contact. Although these tests are highly specific, they may not be very sensitive. However, serological tests are the
mainstay of diagnosis. Serological tests can be divided into two groups—those that detect antibody to cardiolipin (lecithin) cholesterol antigen (nontreponemal tests) and those that detect antibodies against treponemal antigens (treponemal tests). Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests are the nontreponemal tests used most commonly. Of the treponemal tests, fluorescent treponemal antibody absorption tests (FTA-ABS), hemagglutination treponemal test for syphilis, hemagglutination assay for Tr. pallidum, and microhemagglutination tests are used most commonly. The selection and interpretation of a specific test must take into account its diagnostic sensitivity and specificity at each stage of syphilis as well as the population in which it is being used. For instance, a nontreponemal test may be suited best for general screening (in a population that shows a low prevalence of disease), and any positive results are confirmed using a treponemal test. However, when the likelihood of syphilis is high (such as in patients who have one or more of the systemic and/or ocular manifestations discussed herein), an initial treponemal test is best. Treponemal tests are at least as sensitive as and more specific than nontreponemal tests. Nontreponemal tests may be used to monitor treatment effectiveness, as the titers decrease with appropriate treatment.
In a clinically suspected case of syphilitic uveitis, a screening test such as VDRL or RPR is performed to obtain a quantitative measure of antibody production. An FTA-ABS or hemagglutination assay for Tr. pallidum is also obtained, either to confirm a positive screening test or to document a case of tertiary or latent syphilis, in which VDRL or RPR is often negative.
In individuals infected by HIV, both treponemal and nontreponemal tests may be unreliable, and in some patients a normal serological response to syphilis infection may be found. However, a false-negative test may occur because of insufficient antibody production or decreased immunoreactivity. False-positive tests may be encountered, particularly with nontreponemal tests, most likely because of the polyclonal B-cell activation that occurs with HIV infection. In addition, nontreponemal test titers may fail to decline after adequate therapy because of the polyclonal B-cell stimulation. 
The Centers for Disease Control and Prevention recommends the use of the cerebrospinal fluid (CSF)–VDRL test to establish the diagnosis of neurosyphilis when serological tests are positive. The role of CSF–FTA-ABS in the diagnosis of neurosyphilis is controversial, as it may be too sensitive. However, no absolute test exists for the diagnosis of neurosyphilis. A CSF leukocytosis and elevated CSF protein concentration present for more than 1 year in a patient at any stage of syphilis who has neurological symptoms are consistent with a diagnosis of neurosyphilis. Such patients are treated accordingly even if the CSF-VDRL test is negative. The advantage of CSF-VDRL is seen in the evaluation of patients who have suspected neurosyphilis when the possibility of previously treated disease cannot be excluded. In this situation, CSF-VDRL is superior to CSF–FTA-ABS in the differentiation of currently active neurosyphilis from past syphilis.
The ocular manifestations of syphilis in general are nonspecific. Therefore, the diagnosis always requires serological confirmation when a high index of clinical suspicion exists. The differential diagnosis of uveitis includes sarcoidosis, tuberculosis, and autoimmune uveitis. The most important conditions to rule out in the diagnosis of acute syphilitic posterior chorioretinitis are acute posterior multifocal placoid pigment epitheliopathy and atypical serpiginous choroidopathy.
It must be emphasized, however, that eventual diagnosis always requires serological confirmation. The great masquerader, however, can be uncovered only if a high degree of clinical suspicion exists.
The systemic manifestations of syphilis have been divided arbitrarily into three clinical stages, which overlap. The primary stage is characterized by an ulcerative lesion called a chancre, which occurs in the site where Tr. pallidum penetrates the skin or mucous membrane. The organism enters the lymphatics and blood stream and disseminates shortly after contact. Only rarely is primary dissemination associated with flu-like systemic symptoms. The mean incubation period is approximately 3 weeks, within a range of 3 days to 3 months. The primary lesions heal spontaneously within 2–8 weeks.
The systemic treponemal load is largest in the secondary stage, which usually occurs 2–12 weeks after contact. This stage is characterized by fever, malaise, lymphadenopathy, and mucocutaneous lesions. Clinically apparent secondary syphilis occurs in 60–90% of patients, and one third of patients who have secondary syphilis may have the primary chancre as well. Central nervous system infection may be demonstrated in nearly one fourth of patients who have early syphilis (early syphilis includes primary, secondary, and early latent stages and is usually of less than 1 year’s duration). The secondary stage of syphilis resolves in weeks to months but can recur, usually within 1 year and rarely as long as 4 years later.
The tertiary stage of syphilis refers to its late sequelae. Complications include vaso vasorum of the aorta or the central nervous system. Focal inflammatory lesions, known as gummas, may affect any organ. Approximately one third of untreated patients develop tertiary syphilis, and less than 1% develop clinical neurosyphilis. A quaternary stage of syphilis was described occasionally in the older literature, and the term has been revived for a necrotizing encephalitis that occurs in patients who have AIDS. It is useful to differentiate this aggressive form of neurosyphilis (quaternary syphilis) from the tabes dorsalis and general paresis of tertiary syphilis.
The clinical manifestations of congenital syphilis may occur at any time throughout life. An arbitrary division between early and late onset of congenital syphilis has been selected as 2 years of age. The incidence of congenital syphilis may increase as HIV infection permeates into the heterosexual population.
Diffuse or focal lymphocytic infiltration, particularly around the blood vessels, is seen in the iris, ciliary body, or choroid. A chronic granulomatous inflammation contains epithelioid histiocytes and multinucleated giant cells. In selected cases, conjunctival biopsy obtained from patients who have granulomatous anterior uveitis may reveal a granulomatous conjunctival inflammation. In such cases, special stains for spirochetes may reveal organisms consistent with Tr. pallidum ( Fig. 165-5 ).
Penicillin G (benzylpenicillin) is the drug of choice for the treatment of all stages of syphilis. However, the duration of treatment required for various stages of syphilis remains a topic of much debate. It is accepted that early syphilis (primary, secondary, or latent of less than 1 year’s duration) in immunocompetent patients may be treated effectively with one intramuscular injection of 2.4 million units of benzathine penicillin G. For patients with a penicillin allergy other antibiotics can be used; however, no other antibiotic is as effective as penicillin, and penicillin skin testing and desensitization are recommended over the use of other antibiotics. Doxycycline (100?mg twice a day for 14–28 days) and tetracycline (500?mg four times a day for 14–28 days) have been used.
For patients who have failed primary treatment and for patients who have syphilis of more than 1 year’s duration and no evidence of central nervous system involvement, three doses of
Figure 165-5 Syphilis. A, The biopsied nodules show numerous granulomas under the conjunctival epithelium (CE, surface conjunctival epithelium; GR, granulomatous reaction in substantia propria). B, A special stain, Dieteria, demonstrates spirochetes (S) within the inflammatory infiltrate. (Case reported in Spektor FE et al. Ophthalmology. 1981;88:863.)
2.4 million units of benzathine penicillin G intramuscularly at weekly intervals are recommended. Whether such patients need a routine lumbar puncture with examination of the CSF in the presence of a normal neurological examination is not known—asymptomatic neurosyphilis has been described in such a setting. However, the number of patients who fall into this category is not known. Risk factors for asymptomatic neurosyphilis that may justify examination of the CSF include evidence of aortitis, visceral gummas, ocular inflammation, and serum nontreponemal titers greater than 1:32.
The recommended treatment for neurosyphilis consists of intravenous aqueous penicillin G 2–4 million units every 4 hours for 10–14 days. An alternative regimen consists of daily intramuscular procaine penicillin G 2.4 million units plus oral probenecid (500?mg four times a day) for 10–14 days. No alternative to penicillin has proved scientifically effective in the treatment of neurosyphilis.
Congenital syphilis has been treated with a 10- to 14-day regimen of either intravenous aqueous penicillin G or procaine penicillin G. Ceftriaxone and ampicillin have also been used as alternative antibiotics. No known optimal treatment exists for congenital syphilis.
Although no specific treatment is known for ocular syphilis, any patient who presents with ocular findings must be evaluated for neurosyphilis. Thereafter, the treatment is as described previously. However, benzathine penicillin G fails to cross the blood-brain barrier, and presumably the blood-ocular barrier, and does not consistently provide measurable levels in the CSF. Patients may need higher doses and longer duration of therapy if the eye is involved.
Treponema pallidum is thought to take a particularly aggressive course in patients who are immunocompromised by HIV. Abnormalities of CSF are known to be present in 40–60% of HIV-infected patients who do not have syphilis. Therefore, the diagnostic evaluation of the CSF in HIV-infected patients is a challenge. In this setting, HIV-infected patients who have syphilis are treated aggressively with a course sufficient to cure neurosyphilis, irrespective of the CSF examination. Certainly, overtreatment of some patients is justified by the prevention of the morbidity and mortality that often occur in immunocompromised patients.
In immunocompetent patients, treatment effectiveness may be evaluated clinically and serologically. Clinical manifestations often improve after effective treatment. Seroconversion or stable low titers of nontreponemal tests also indicate effective treatment. The well-published criteria of fourfold and eightfold decreases in nontreponemal titer that should occur by 3 and 6 months, respectively, in early syphilis may be too stringent. However, evaluation of treatment effectiveness in patients who are affected simultaneously with HIV is difficult if not impossible. Given the inaccuracy of serological tests, resolution of clinical findings is most important. The inability to monitor treatment effectiveness is another reason for aggressive treatment in such patients.
Adjunctive corticosteroid therapy may be useful for some forms of ocular inflammation related to syphilis. Topical steroids are useful in patients with stromal keratitis and anterior uveitis. Prolonged treatment may be necessary to prevent a recurrence. Oral corticosteroids may be useful for scleritis, posterior uveitis, and optic neuritis. Corticosteroids should not be used without concomitant antibiotics.
COURSE AND OUTCOME
Prompt diagnosis and treatment with antimicrobial agents usually result in full visual recovery. Syphilitic intraocular inflammation untreated with penicillin or other appropriate antibiotics may lead to chronic progressive intraocular inflammation. Such an inflammatory process may lead to secondary glaucoma, chronic vitritis, retinal necrosis, and optic atrophy.
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