Ocular syphilis Anthony J. Aldave, MD,* Julie A. King, MD,† and Emmett T. Cunningham, Jr., MD, PhD, MPH* Although the annual incidence of primary and secondary Epidemiology syphilis has dropped to the lowest rate recorded, syphilis The last national epidemic of primary and secondary remains an important cause of ocular disease. Uveitis is the syphilis reached its peak in 1990. Since that time, the most common ocular manifestation of syphilis in both annual incidence of primary and secondary syphilis has HIV-positive and HIV-negative patients, and the diagnosis declined steadily to the lowest annual rate reported in should prompt an analysis of the cerebrospinal fluid to exclude the United States [1,2] (Fig. 1). In 1999, 6,657 cases of associated neurosyphilis. Newer modalities such as enzyme primary and secondary syphilis were reported in the immunoassays and genomic amplification using the United States, an annual incidence of 2.5 cases per polymerase chain reaction may prove to be useful techniques 100,000 population. This figure was down 87% from the to detect Treponema pallidum in intraocular specimens. The 50,578 cases reported in 1990, corresponding to an an- preferred treatment for all stages of syphilis remains parenteral nual incidence of 20.3 cases per 100,000 population [1,2]. penicillin G, although the preparation, dose, route of Most of this decline is attributed to lower rates of infec- administration, and duration of therapy are dictated by the tion in blacks, in whom the rate of infection is still 30 stage of disease and various host factors. All patients times that of whites. The number of syphilis cases in diagnosed with ocular syphilis should be tested for HIV, homosexual men has increased during this time, how- because the presence of a primary genital chancre increases ever [2–5]. The increase in reported cases among men the risk of acquiring or transmitting HIV, and because risk who have sex with men, many of whom are coinfected factors for the two diseases are similar. Curr Opin Ophthalmol 2001, with HIV, is thought to be related to an increase in high- 12:433–441 © 2001 Lippincott Williams & Wilkins, Inc. risk sexual behavior in this era of highly active antiret- roviral treatment and to decreased concern over acquir- ing or transmitting HIV [5–7]. The annual incidence of congenital syphilis, closely re- *Francis I. Proctor Foundation for Research in Ophthalmology, University of lated to the incidence of primary and secondary syphilis California, San Francisco, California, USA; and †Department of Ophthalmology, Loma Linda University, Loma Linda, California, USA. in the preceding year, also has shown a significant de- cline over the last decade [8,9]. From 1991 through 1999, Correspondence to Emmett T. Cunningham, Jr., MD, PhD, MPH, Vitreous-Retina-Macula Consultants of New York, 519 East 72nd St., Suite 203, the average annual decrease in the rate of congenital New York, NY 10021, e-mail: [email protected] syphilis was 22%, to a rate of 14.3 cases per 100,000 live Current Opinion in Ophthalmology 2001, 12:433–441 births in 1999 [9]. Most the reported cases, 81%, occurred because the mother failed to receive adequate penicillin Abbreviations treatment before or during pregnancy [8]. CDC Centers for Disease Control and Prevention VDRL Venereal Disease Research Laboratory test for syphilis ISSN 1040–8738 © 2001 Lippincott Williams & Wilkins, Inc. To ensure the continued decline in the incidence of primary and secondary syphilis, the U. S. Centers for Disease Control and Prevention recently have launched a National Plan to Eliminate Syphilis from the United States, with the goal of reducing the annual number of primary and secondary cases nationwide to less than 1,000, equal to 0.4 cases per 100,000 population, by the year 2005 [10]. Classification Syphilis may be transmitted transplacentally to the fetus or acquired postnatally by sexual contact. Congenital syphilis may be divided into an early stage, which de- velops before age 2 years and corresponds to the second- ary stage of acquired syphilis, and a late stage, which develops after age 2 years and is analogous to the tertiary 433 434 Ocular manifestations of systemic disease Figure 1. Incidence of primary and secondary syphilis over The most common ocular manifestation of secondary time syphilis is uveitis [11]. Even without treatment, the signs and symptoms of sec- ondary syphilis tend to resolve in all patients, although relapses may occur in as many as 25% of untreated pa- tients [13]. During the period of early latent syphilis, the first year after infection, relapses are most common, al- though between relapses, no overt clinical manifesta- tions are noted. The late latent stage may span decades, either remaining stationary or progressing to tertiary syphilis [13]. As in secondary syphilis, uveitis is the most common ocular finding of tertiary syphilis, occurring in approxi- mately 2.5 to 5% of the 30% of untreated patients who Since 1990 the annual incidence of both primary and secondary syphilis has declined dramatically in the United States and is now at its lowest reported progress to this stage [11,13,14]. The most commonly annual rate. encountered clinical manifestations of tertiary syphilis are cardiovascular complications and neurosyphilis, which may take the form of meningitis, occlusive me- ningovasculitis, and parenchymatous degeneration in- cluding atrophy of the cerebral cortex, optic nerves, and stage of acquired syphilis. The most common features of posterior columns of the spinal cord [11]. early congenital syphilis, appearing several weeks after Clinical features birth, are mucocutaneous lesions, mainly involving the Known as the great imitator, syphilis may affect all of the buttocks and thighs; periostitis; and osteochondritis [11]. structures of the eye (Table 1). Recent publications have Uveitis is the most common ocular complication of early highlighted the prevalence and myriad clinical manifes- congenital syphilis, with associated chorioretinitis and tations of syphilitic involvement of the cornea, retina, retinal vasculitis producing a salt-and-pepper pattern of retinal vasculature, and uveal tract, both in immunocom- retinal pigmentary mottling [11]. Left untreated, a latent petent and immunocompromized people. period ensues, characterized by the development of bony and dental abnormalities including frontal bossing, Interstitial keratitis a saddle nose deformity, saber shins, peg-shaped upper In the preantibiotic era, most cases of interstitial keratitis central incisors, and abnormal first molars [11]. The most were associated with congenital syphilis. With the wide- common ocular manifestation of late congenital syphilis spread use of antibiotics, the prevalence of congenital is interstitial keratitis, which occurs most frequently be- and acquired syphilis has decreased dramatically, as has tween 5 and 20 years of age. Although treatment of af- the development of syphilitic interstitial keratitis. To fected infants in the first 3 months of life may prevent determine the most common etiologies of interstitial the development of luetic interstitial keratitis, penicillin keratitis at the end of the 20th century, Schwartz et al. administration after this point has no direct effect on the [15•] reviewed the records of 97 patients diagnosed with severity or duration of the keratitis [11,12]. interstitial keratitis. Although syphilis remained the most common cause of inactive interstitial keratitis, account- Acquired syphilis traditionally has been divided into pri- ing for 16 (38%) of 42 cases, it was responsible for only 2 mary, secondary, latent, and tertiary stages. Primary (4%) of the 55 cases of active interstitial keratitis. Over- syphilis is characterized by a chancre, which typically all, herpes simplex virus was the most common cause of appears 2 to 6 weeks after inoculation with Treponema interstitial keratitis (34 [35%] of 97 cases), including 49% pallidum. This solitary, painless ulcer often is associated of cases of active interstitial keratitis (27 of 55 cases). with nontender regional lymphadenopathy that may per- Syphilis was the third leading cause of all cases of inter- sist for months, although the chancre normally resolves stitial keratitis (18 [19%] of 97 cases). within 3 to 6 weeks [11]. Uveitis Secondary syphilis develops in almost all untreated pa- Syphilis was considered a common cause of uveitis in the tients. The most common sign is a diffuse maculopapular first half of the 20th century, although, like syphilitic rash, which typically appears approximately 6 weeks af- interstitial keratitis, the number of cases of uveitis attrib- ter the development of the primary lesion and signifies utable to syphilis dropped precipitously after the intro- hematogenous dissemination of T. pallidum [13]. Consti- duction of penicillin [16–18]. Tamesis and Foster [19] tutional symptoms such as malaise, fever, sore throat, and found that only 25 (2.45%) of 1,020 new patients seen arthralgia may accompany the cutaneous eruption [11]. over a 6-year period at a large uveitis referral center had Ocular syphilis Aldave et al. 435 Table 1. Ocular manifestations of syphilis Stage Congenital Secondary Tertiary Conjunctiva Mucous patches Papillary conjunctivitis Granulomatous conjunctivitis Sclera Limbal episcleritis adjacent to Episcleritis Scleritis IK Cornea Stromal keratitis (80% bilateral) Marginal corneal infiltrates Stromal keratitis (40% bilateral) Keratic precipitates Keratic precipitates Lens Congenital