Rates of syphilis are increasing particularly in men who have sex with men (MSM), and it can be predicted that associated complications, including ocular and neurological disease, are likely to rise. Any part of the eye can be affected with no uniquely pathognomonic signs to suggest syphilis as an immediate diagnosis. Although most common in secondary and tertiary syphilis, eye involvement can occur at any stage of infection, including primary. Therefore, syphilis needs to be highlighted as a cause of inflammatory eye disease to increase clinician suspicion, avoid diagnostic delay, and enable partner notification. We present the case of a patient with visual loss from chorioretinitis and optic nerve swelling, as a manifestation of ocular syphilis, and concurrent primary genital ulcer disease. Although cases of eye disease and syphilis abound, even those involving probable eyelid and palpebral conjunctiva chancres,1,2 we believe this to be the first reported manifestation of coexisting PCR-confirmed primary genital and ocular syphilis.
In September 2016, a 24-year-old MSM presented to ophthalmology clinic with a 2-month history of bilateral, progressive, painless visual loss, worse on the left. On examination, his Snellen visual acuity was 20/25 in the right and markedly reduced at 20/160 in the left eye (20/20 is “normal” vision). He had bilaterally reduced color vision measured using Ishihara plates, reading only the control plate out of 17 number plates with the right eye and none with the left. Normal red-green color vision would enable reading of 17 of 17 number test plates. There was mild vitritis in both eyes. Fundus examination revealed bilateral optic nerve head swelling more pronounced on the left, multiple active choroidal inflammatory lesions and evidence of multiple older chorioretinal lesions (Fig. 1A). Swelling of the optic nerve fiber layer at the optic nerve head was confirmed by optical coherence tomography scan (Fig. 1B). Humphrey visual field testing showed temporal visual field-defects in his left eye and a few smaller nasal field-defects in the right eye, with moderate reliability (Fig. 2). The reduced color vision and visual field defects were suggestive of optic nerve dysfunction.
He was referred to the STI clinic for assessment, in particular to exclude human immunodeficiency virus (HIV)/primary HIV infection (PHI) as a possible cause of visual loss3 He was seen at this clinic in October 2016, and examination revealed a tiny (<0.2 cm diameter), penile ulcer of which the patient had been unaware, but no features consistent with either PHI or secondary syphilis.
Tests for HIV, hepatitis B/C, chlamydia/gonorrhea, and herpes simplex virus were negative, however, the penile ulcer swab was PCR positive for Treponema pallidum (TP) and serum rapid plasma reagin (RPR) titer of 1:128 was consistent with primary syphilis. Of note, previous syphilis serology was negative approximately 6 months prior. Lumbar puncture (LP) was performed under radiological guidance 25 days into treatment and cerebrospinal fluid (CSF) revealed clear fluid with 3 white blood cells (WBC; lymphocytes), raised protein at 69 mg/dL (normal, 15 to 45 mg/dL), glucose 50.4 mg/dL (normal, 45–80 mg/dL), Treponema pallidum particle agglutination. (TPPA)-positive at 1:320 and RPR-positive (on undiluted CSF but insufficient for quantitative RPR). The CSF findings were in keeping with syphilitic meningitis and, in conjunction with the clinical findings, were consistent with ocular syphilis. MRI of the orbits and brain prior to LP were reported as normal.
Because of the previous documented anaphylaxis with penicillin he was treated with corticosteroids (prednisolone, 40 mg once daily for 3 days) with initiation of doxycycline, an alternative regimen for treating neurological/optic syphilis, (200 mg, twice daily orally for 28 days) 24-hours after the first dose of oral prednisolone, as per British Association of Sexual Health and HIV (BASHH) guidelines.4 Corticosteroids were used to reduce the risk of sight-threatening sequelae of intraocular Jarisch-Herxheimer reaction.5 Although the evidence for preantibiotic treatment with corticosteroid medication is lacking, and not recommended by the Centers for Disease Control and Prevention, BASHH state that “severe clinical deterioration in early syphilis with optic neuritis and uveitis has been reported following treatment and, as steroids are also used in the management of these conditions unrelated to syphilis, biological plausibility would suggest that they may help.”4
At 1 month follow-up, serum RPR titer had fallen to 1:32 (with complete resolution of the genital lesion), visual acuity in the right eye improved to 20/20 unaided, and the left eye was 20/40 unaided, improving to 20/25 with pinhole. HIV testing remained negative throughout follow-up. At 3 months posttreatment the serum RPR had fallen to 1:8 when he reported significant improvement in his eyesight. Repeat CSF examination was performed as part of the 3-month review, in part because of treatment with a non-penicillin-based regimen, it demonstrated: clear fluid, normal glucose (CSF/plasma/glucose ratio = 0.63 [normal >0.6]), 1 WBC, elevated protein 72 mg/dL, TPPA 1:80, and negative RPR (Table 1). The CSF TPPA was felt to represent passive transfer of antibodies from serum. The CSF cytology and CSF and serum oligoclonal band analysis were also negative. Ophthalmological review reported improvement in vision in both eyes: quiescent anterior segments, no active vasculitis, old but inactive choroidal lesions, and some residual left optic disc swelling but improved from previous visit (Fig. 3). By 6 months, the serum RPR remained at 1:8, representing a 16 times decline compared with peak. At 12 months, a more than 4-fold improvement compared with peak RPR is considered an appropriate serological response4 (Table 1).
The global burden of syphilis is huge6 with resurgence in Western countries in the past decade, affecting all sectors of society, including pregnant women and infants,7 but disproportionately involving MSM.8,9 The incidence of syphilis increased by 14% in the UK MSM population in 2016.10 Optic syphilis is reported to be rare,11 in part due to underreporting,12 and difficult to quantify epidemiologically but is likely to increase with rising incidence of syphilis overall.13,14 In a large UK study (British Ocular Syphilis Study) reported in 201415 rates of confirmed intraocular syphilis were extremely low; it was estimated to translate into an annual incidence of 0.3 per million UK adult population. A 2015 US study found a 3.5% to 8.0% prevalence of complicated syphilis (ocular, oto, and neurological) involvement in patients with confirmed syphilis, greater than the previously reported rate of less than 2.0%.16 This might suggest an increase in neurotropism,17 although data on predominant oculotropic strains of TP are mixed.18 Interestingly, in their series of 573 patients with early infection, Dombrowski et al16 described the most common symptom of complicated syphilis as visual loss (4.8%).
Any part of the eye can be affected at any stage19,20 although most commonly in secondary and tertiary syphilis.21 Uveitis/panuveitis22 are the most common presentations described in recent cohorts13,15 but conjunctivitis, retinal vasculitis, and cranial neuropathies are also possible.21 Visual symptoms in syphilis cases should all be investigated for neurosyphilis; treatment is ideally with parenteral penicillin.4 Steroid cover may be considered to prevent the Jarisch-Herxheimer reaction4,23 which can lead to vision loss. Timely treatment may lead to a full cure although long-term complications of syphilitic uveitis include chorioretinal scarring, glaucoma, cataracts, macular edema and iris bombe.12 The patient in this case was treated with corticosteroids and doxycycline as penicillin desensitization was not immediately available and delay may have led to worse visual outcomes. He was closely followed up for a minimum of 1 year, as per BASHH guidelines.4 Although doxycycline is an alternative to penicillin in UK guidelines4 it is not recommended by the Centers for Disease Control and Prevention or other international guidelines. The evidence for its effectiveness is limited24 and based on sparse data, particularly in the context of neurological involvement.25 The recommended use of doxycycline 200 mg twice a day is largely based on a study of 5 patients with syphilis who had CSF concentrations of drug measured, this was found to have a mean penetration into CSF of 26%; these patients were treated for 21 rather than 28 days.24 Further research is required to establish the efficacy of doxycycline in the treatment of neurosyphilis; its optimum dose and duration, the risk of relapse, and the effects of HIV coinfection particularly because, in many areas of the world, penicillin desensitization is not a realistic proposition, and parenteral penicillin stockouts are commonplace.
The case serves to illustrate the potential for overlap between primary and optic syphilis, and the necessity of a careful, detailed physical examination to detect unrecognized syphilis clinical signs. It is limited by several factors including: a delay in initial CSF examination, lack of initial CSF RPR titer, and molecular syphilis typing as some data suggest specific strains of T. pallidum are more neurotropic than others17,18 and no CSF Venereal Disease Reference Laboratory (not available at the UK reference laboratory) which may be more sensitive than RPR.4,26 Finally, although many questions about optic syphilis remain unanswered,27 given the rise in new cases of early syphilis in the United Kingdom and United States, it is likely that there will be a commensurate rise in optic disease; therefore, a high index of suspicion for syphilis in ophthalmology/optometrist clinics and primary care is required. Ideally, this should be accompanied by public information targeting MSM and other high-risk groups.28,29
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