Biotti, Damien MD*†; Bidot, Samuel MD‡; Mahy, Sophie MD*; Buisson, Marielle MD*; Duong, Michel MD*; Grappin, Michèle MD*; Creuzot-Garcher, Catherine MD, PHD‡; Chavanet, Pascal MD, PHD*; Piroth, Lionel MD, PHD*
From the *Département d'Infectiologie CHU Dijon; †Service de Neurologie CHU Dijon; and ‡Service d'Ophtalmologie CHU Dijon
The authors thank Philip Bastable for his help in reviewing this article.
Correspondence: Lionel Piroth, MD, PhD, Département d'Infectiologie CHU. Dijon; 2 boulevard du Maréchal de Lattre de Tassigny, 21079 DIJON CEDEX BP 77908, France. E-mail: firstname.lastname@example.org.
Received for publication May 20, 2009, and accepted June 19, 2009.
Until recently syphilis was considered a rare disease. However, since 2001, a significant and sharp increase has been observed in many parts of the world.1 Moreover, syphilis is frequently found in association with HIV, with potential interactions between these two infections.2 In parallel, ocular syphilis, which was quite frequent before the era of antibiotherapy, became very rare.3–6 Since ocular syphilis seemed to be more common and severe in our ward than in published reports, we conducted a retrospective study of the cases of syphilis diagnosed during a 3-year period. The study focused on the epidemiologic characteristics, clinical presentations and outcomes.
The study population was an in-hospital cohort of 509 HIV-positive patients followed from July 1, 2005 to July 1, 2008 in the Infectious Diseases Department of the University Hospital of Dijon, France. All cases of syphilis were retrospectively collected. Syphilis was diagnosed by positive Venereal Disease Research Laboratory (VDRL), Treponem pallidum haemagglutination assay (TPHA), and fluorescent treponemal antibody (FTA) assays. Special attention was paid to the ophthalmologic examination in the context of proven ongoing syphilis (in particular angiography and puncture of the vitreous body) and to neurologic examination (including systematic lumbar puncture).
Syphilis of any stage was diagnosed and treated in 20 patients of the cohort (prevalence 3.93%, 95% confidence interval 2.2%–5.6%, annual incidence rate 1.31/100 patient-years, 95% CI: 0.03–2.30). Of these, 4 (0.79%) had ocular involvement.
Patient 1 was a 38-year-old man, HIV-positive in 2003 and followed until he was hospitalized in December, 2005 following a 3-week decline in visual acuity (8/10 on the right eye and just light perception for the left eye). He was not on antiretroviral treatment (CD4 478/mm3 and HIV viral load 4.20 log10 copies/mL). Examination of the fundus showed optic disc oedema with large retinal haemorrhages. Highly active antiretroviral therapy (HAART) was quickly introduced. Cerebrospinal fluid (CSF) examination showed 47 leukocytes/mm3 (all lymphocytes), 2 red blood cells, and normal biochemistry. Tests for toxoplasmosis, VZV, CMV and herpes in the blood, CSF and vitreous samples were negative. Whereas tests for syphilis had all been negative in the past, VDRL, FTA IgM (1/320) and TPHA (1/1280) were positive in the blood. In the CSF, specific syphilis IgM detection was also positive. A new funduscopic examination performed after several days on HAART showed severe inflammation of the vitreous body and areas of necrosis (Figs. 1A, B). The patient was thus treated with ceftriaxone 2 g/d, initially in association with methylprednisolone, for 3 weeks. The evolution over the following weeks was characterized by persistent very dense hyalitis (Fig. 1C), associated with left eye blindness and a secondary neovascular glaucoma, which was medically controlled. Blood levels of TPHA and FTA-IgG slightly decreased whereas the VDRL test became negative.
Patient 2 was a 33-year-old man with no significant history who complained of pain in the right eye that had increased over several days in October, 2006. The ophthalmologic examination found signs of right eye acute granulomatous anterior uveitis. The left eye was healthy, with an unremarkable funduscopic examination. Examination of the skin revealed dorsal syphilids. VDRL was found to be positive, as was FTA IgM and TPHA (1/5120). HIV serology was also found to be positive, with a CD4 count of 38/mm3 and an HIV viral load of 4.68 log10 copies/mL. The CSF examination was normal. No other opportunistic infection was discovered. The patient was treated with intravenously ceftriaxone 2 g/d for 3 weeks, and HAART was quickly started. The ophthalmological and general symptoms quickly improved until normalization during the later consultations.
Patient 3 was a 47-year-old man diagnosed HIV-positive in 2007. His clinical examination was normal and no HAART was started since his CD4 lymphocyte count and HIV viral load were 915/mm3 and 3.54 log10 copies/mL, respectively. He soon reported declining acuity in the left eye with mild pain (left visual acuity 2/10 vs. 10/10 in the right). Slit-lamp examination showed slight anterior chamber activity. Funduscopy revealed cells in the vitreous humour and a yellowish placoid lesion in the macula. On angiographic examination, the macular lesion was hypofluorescent and associated with temporal spotty hypofluorescent lesions giving a “leopard skin” aspect. These fundus lesions were compatible with syphilitic acute posterior placoid chorioretinitis (Figs. 2A–D). The patient explained that 3 months earlier he had had an erosive lesion of the glans which could have been a chancre. Blood VDRL, TPHA (1/40,960), and FTA-IgM were highly positive. The CSF examination showed 7 leukocytes, but the test for syphilis was negative. The patient was first treated with benzylpenicillin intravenously 2.106 units 6/d for a week then with ceftriaxone 2 g/d for 2 weeks, with intravenously prednisolone then oral prednisone for 6 days. Clinical examination showed a significant improvement with normalization of the fundus, but with a dirty granite-like aspect, and a residual visual acuity of 5/10. Angiography was also normal (Figs. 2E, F). During the next months TPHA levels regularly decreased (from 1/40,960 to 1/1280) meanwhile VDRL and FTA IgM became negative.
Patient 4 was a 42-year-old man, HIV infected since 1999, with postinjury blindness of the left eye, who experienced an episode of asymptomatic syphilis infection treated with benzylpenicillin in 2003. After being lost to follow-up for more than 2 years, during which time his HAART was stopped for several months, he presented in 2007 with severely diminished visual acuity in the right eye (light perception only). The deterioration had occurred over a few months. Examination of the right eye showed the sequelae of anterior granulomatous uveitis with multiple posterior synechia and a white cataract. No anterior chamber activity was noted. B-scan sonography of the posterior segment was normal. The CD4 count was 64/mm3 (8%), HIV viral load 5.58 log10 copies/mL, and TPHA (1/327,680), VDRL, FTA IgG and IgM were (highly) positive. CSF examination showed 71 leukocytes (100% lymphocytes), a normal glucose level, a high level of proteins (1.35 g/L), and an intrathecal synthesis of immunoglobulin associated with positive syphilis serology. Cefriaxone (2 g/d) for 15 days and HAART were started. There was no subsequent improvement in visual acuity, albeit TPHA continuously decreased, and FTA IgM and VDRL became negative.
Though the overall prevalence of ocular syphilis in our patients (4/509, 0.79%) is close to that reported in other studies (from 0.6% to 1%7,8), the proportion of syphilis cases with ocular involvement (20%) is higher than that usually reported (from 6% to 9%8,9). All were homosexual men, which is consistent with the reported increase in syphilis in this population. The positive diagnosis of syphilis was made on clinical features and biologic results (VDRL, TPHA, FTA).10 Confirmation of ocular syphilis is ideally based on a specific polymerase chain reaction on samples from the vitreous body,11 but it was inconclusive or not performed in our patients. However, the high level of positivity of the different syphilis tests, the decrease in positivity or negativity following antibiotic therapy, the ocular improvement sometimes observed after this treatment, as well as the lack of other aetiology, support the syphilitic origin of the ocular troubles.
Ocular syphilis is polymorphous, and rarely observed in the primary but more frequently in the secondary and tertiary stages of the disease (mainly uveitis, but also scleritis, episcleritis, keratitis, retinitis, papillitis, cystoid macular oedema, vasculitis, optic neuritis).12–14 Patient 3 presented acute syphilitic posterior placoid chorioretinitis, which is an infrequent presentation of syphilitic chorioretinitis.15 Funduscopy revealed an aspect of single or multiple yellowish patches in the posterior pole. Angiography showed a vast zone of early hypofluorescence with small hypofluorescent spots (“leopard spots”) on the periphery of the main damage. Acute syphilitic posterior placoid chorioretinitis16 has been identified among immunosuppressed patients, especially if associated with corticotherapy, which was not the case in our patient.
Thus, given the findings in our patients, immunodepression is not a prerequisite for ocular syphilis. In particular, in patients with CD4 above 50/mm3 with ocular manifestations (uveitis, retinitis), the diagnosis of ocular syphilis has to be considered before that of CMV ocular infection. Since none of our patients were on antiretroviral therapy at the onset of the ocular syphilis, and given that they experienced significant levels of HIV replication, it may be speculated that uncontrolled HIV replication may be a more important prognostic factor of ocular involvement, perhaps via the inflammation associated with HIV replication.
Moreover, 85% of cases of ocular syphilis are associated with neurosyphilis,17 and, 10% of cases of neurosyphilis are associated with ocular involvement.18 However, our cases show that ocular syphilis may occur independently and needs to be screened for even in the absence of neurologic symptoms. Lastly, even though antibiotics are prescribed according current recommendations,19 delayed or late administration may result in significant sequelae (near blindness), as observed in 2 of our cases.
Thus, with the increasing incidence of syphilis infections, related to the absence or relaxation of prevention measures, ocular syphilis is reappearing. This highlights the need for better prevention, but also for early diagnosis and antibiotic treatment. Further studies are needed to identify which syphilitic patients are at risk of ocular involvement and complications, and to determine the impact of antiretroviral therapy.
1. Chao JR, Khurana RN, Fawzi AA, et al. Syphilis: Reemergence of an old adversary. Ophthalmology 2006; 113:2074–2079.
2. Pialoux G, Vimont S, Moulignier A, et al. Effect of HIV infection on the course of syphilis. AIDS Rev 2008; 10:85–92.
3. Villanueva AV, Sahouri MJ, Ormerod LD, et al. Posterior uveitis in patients with positive serology for syphilis. Clin Infect Dis 2000; 30:479–485.
4. Aldave AJ, King JA, Cunningham ET Jr. Ocular syphilis. Curr Opin Ophthalmol 2001; 12:433–441.
5. Deschenes J, Seamone CD, Baines MG. Acquired ocular syphilis: Diagnosis and treatment. Ann Ophthalmol 1992; 24:134–138.
6. Wilhelmus K, Lukehart SA. Syphilis. In: Pepose SJ, Holland GN, Wilhelmus KR, eds. Ocular Infection and Immunity. St. Louis, MO: Mosby-Year Book, 1996:1437–1466.
7. Shalaby IA, Dunn JP, Semba RD, et al. Syphilitic uveitis in human immunodeficiency virus-infected patients. Arch Ophthalmol 1997; 115:469–473.
8. Balba GP, Kumar PN, James AN, et al. Ocular syphilis in HIV-positive patients receiving highly active antiretroviral therapy. Am J Med 2006; 119:448.e21–e25.
9. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: Association with clinical and laboratory features. J Infect Dis 2004; 189:369–376.
10. Lynn WA, Lightman S. Syphilis and HIV: A dangerous combination. Lancet Infect Dis 2004; 4:456–466.
11. Muller M, Ewert I, Hansmann F, et al. Detection of Treponema pallidum in the vitreous by PCR. Br J Ophthalmol 2007; 91:592–595.
12. Kiss S, Damico FM, Young LH. Ocular manifestations and treatment of syphilis. Semin Ophthalmol 2005; 20:161–167.
13. Teasley LA, Foster CS. Syphilis: An ophthalmologic update. Int Ophthalmol Clin 2007; 47:133–144.
14. Pleimes M, Hartschuh W, Kutzner H, et al. Malignant syphilis with ocular involvement and organism-depleted lesions. Clin Infect Dis 2009; 48:83–85.
15. Gass JD, Braunstein RA, Chenoweth RG. Acute syphilitic posterior placoid chorioretinitis. Ophthalmology 1990; 97:1288–1297.
16. Joseph A, Rogers S, Browning A, et al. Syphilitic acute posterior placoid chorioretinitis in nonimmuno-compromised patients. Eye 2007; 21:1114–1119.
17. Levy JH, Liss RA, Maguire AM. Neurosyphilis and ocular syphilis in patients with concurrent human immunodeficiency virus infection. Retina 1989; 9:175–180.
18. Flood JM, Weinstock HS, Guroy ME, et al. Neurosyphilis during the AIDS epidemic, San Francisco, 1985–1992. J Infect Dis 1998; 177:931–940.
19. Gaudio PA. Update on ocular syphilis. Curr Opin Ophthalmol 2006; 17:562–566.