Syphilis

Syphilis is caused by infection with the obligate intracellular gram negative spirochaete, Treponema pallidum. Endemic treponemes such as yaws and pinta have been present in Europe and Asia for thousands of years however syphilitic infection has been recognised for only hundreds of years (from approx. the 15th century). The exact origins remain unclear, however, the “Colombian hypothesis” suggests syphilis was brought to the Western world by mariners returning from either Africa or the Americas and has subsequently spread throughout the world [1, 2]. Syphilis has been a disease of great interest since its recognition with a very large published literature. It is often described as “the great mimicker” as its clinical manifestations can imitate so many other diseases in many different organ systems. As Sir William Osler opined: “the physician who knows syphilis, knows medicine”. Ocular involvement has been recognised for many decades and occurs in different stages of syphilis (Fig. 1).

Fig. 1: Natural history of syphilis infection from primary to tertiary stages including early CNS invasion (approx. 40% of cases) and both early and late neurosyphilis.
figure 1

Ocular syphilis, including optic neuritis can occur at any time point along this course. (Permissions from Ghanem, Ram, and Rice 2020, NEJM).

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Syphilis is most commonly transmitted through unprotected sexual contact. The organism enters by crossing intact mucous membranes or via microabrasions in the skin. It may also be transmitted vertically from an infected mother to her unborn foetus, or very rarely by blood transfusion or other direct transmissions [3].

Epidemiology

A peak of syphilis infection was recorded in the USA in the early 1940s when recording of infection rates was instituted. Subsequently there were many years of declining syphilis infection rates due to the availability of penicillin treatment. There was a second, but smaller, spike in infection rates in the 1980s and early 1990s during the HIV/AIDS pandemic. This was followed by another period of declining infection resulting from public health campaigns regarding safe sex habits [4].

However, since 2001, reported syphilis infection rates have increased every year in the USA, Europe, Australia and China [4,5,6,7,Who needs a neurology or neuro-ophthalmology consultation?

Evaluation by a neurologist or neuro-ophthalmologist is important for ocular syphilis patients with neurological symptoms and for those with concurrent HIV infection. Those with hearing loss also need evaluation by an otologist [49]. Neurological evaluation could confirm a diagnosis of neurosyphilis and, more importantly, exclude other neurological disorders which may involve multiple anatomical sites and require alternative management. Ocular syphilis, neurosyphilis and otosyphilis patients all need lumbar puncture and CSF examination as part of their work-up and then careful follow-up to ensure adequate treatment for the best possible outcomes.

Serological investigations

A diagnosis of syphilis relies on positive serology for syphilis and additionally, for a diagnosis of neurosyphilis, on CSF abnormalities including increased protein, pleocytosis and a positive CSF VDRL.

Treponemal and non-treponemal testing

Specific tests react to treponemal antibodies against spirochaetes and include; fluorescent treponemal-antibody absorption (FTA ABS), Treponema pallidum haemagglutination assay (TPHA), Treponema pallidum particle agglutination assay (TPPA), microhaemagglutination assay for antibodies to Treponema pallidum (MHA-TP), and Treponema pallidum enzyme immunoassay (TP-EIA). They remain positive for life following infection and remain positive after successful treatment. A positive result does not inform the recency or activity of infection. False-positive results can occur from other inflammatory diseases such as systemic lupus erythematosus or from other infections especially other spirocheteal infections such as yaws, bejel and pinta.

Rapid plasma reagin (RPR) and VDRL are non-specific tests that detect cardiolipin antibodies produced in response to cardiolipin-cholesterol lecithin antigen in active syphilis infection. These tests are read by dilutional titration, decrease following treatment and increase with active infection. Usually a 4x fold titre decrease/increase is a significant result as a halving or doubling could result from reader interpretational error. With appropriate treatment, titres typically return to non-reactive or occasionally to a long term low titre (Fig. 12).

Fig. 12: Graph depicting serological testing reactivity during the natural history of syphilis infection.
figure 12

Treponemal specific tests react to treponemal antibodies which once positive remain so for life (although there will be no reaction the first few weeks of primary infection). Non-treponemal testing react in response to cardiolipin-cholesterol lecithin antigen in active syphilis infection. With adequate treatment titres will normally return to a non-reactive level. Again, there may be no reactive result in early infection. (Permissions from Ghanem, Ram, and Rice 2020, NEJM).

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False negative results may occur with non-treponemal testing, especially in early primary/acute infection, and patients may need re-testing two weeks after initial presentation. False-positive non-treponemal testing can occur with infections such as tuberculosis, rickettsia and leprosy, in endocarditis and during pregnancy [33, 50, 51].

Availability of specific assays varies and it is critical that clinicians liaise with their local Infectious Disease physicians and laboratories to determine the available tests and their interpretation.

Treatment

As with every aspect of syphilis there are no universally accepted guidelines for treatment. The CDC recommended treatment for isolated anterior uveitis in a patient with primary, secondary, and early latent syphilis is a single intramuscular (IM) injection of 2.4 million units (MU) of benzathine penicillin G. The CDC recommend treating patients with syphilitic posterior uveitis, panuveitis and optic nerve involvement, as neurosyphilis. The CDC recommended treatment for neurosyphilis is aqueous crystalline penicillin G (benzylpenicillin), 18–24 million units daily, given as 3–4 million units IV every 4 h or continuously infused, for 10–15days and most clinicians follow this guidance [52].

Penicillin allergy complicates management. Many patients who think they are penicillin allergic, when carefully questioned, are not. If there is doubt, skin testing can be performed. In selected patients desensitisation could be considered. Severe penicillin allergy necessitates using different antibiotics. Ceftriaxone 1–2 g intramuscularly (IM/IV) daily for 14 days has been documented as effective in treating patients with ocular syphilis. Doxycycline 100 mg twice per day for 28 days has also been used to successfully treat syphilitic uveitis [52, 53].

Topical steroid therapy will control anterior segment inflammation in anterior uveitis. Systemic corticosteroid therapy is essential to limit the inflammatory mediated ocular damage in patients with posterior uveitis, panuveitis, and optic neuritis. A course of oral corticosteroids such as prednisolone beginning at 1 mg per kg and tapering over a minimum of 6-8 weeks is a widely used regimen and is standard practice in our unit. Pulsed intravenous methylprednisolone, peri-ocular or intravitreal corticosteroids have been reported to be effective in selected cases but should be used cautiously as the use of these medications has been correlated with poor outcomes, possibly due to their use in more severe ocular disease [54, 55]. Intravitreal dexamethasone or triamcinolone is effective therapy for treatment resistant macular oedema but consideration should be given to the possibility of activating a co-existing infection especially when there are additional risk factors. A classic example is reactivating CMV retinitis in HIV infected or severely immunocompromised patients following intravitreal triamcinolone (Fig. 13) [56].

Fig. 13: A case of CMV retinitis in the infero-temporal quadrant of an eye, we believe in response to local steroid (sub-tenons triamcinolone) as treatment for post operative (cataract surgery) CMO.
figure 13

Although these are rare complications, caution is required in patient with potential risk factors for such infection, e.g. HIV/immunosuppression.

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Systemic corticosteroid therapy is required to control uveitis or optic neuritis in the setting of syphilis infection. As with other infectious forms of uveitis, paradoxical worsening can occur and cause significant vision threatening uveitis/optic neuritis if systemic corticosteroids are not used as part of the treatment regimen (as demonstrated in the case vignette of Fig. 8). The paradoxical worsening is analogous to that seen in patients with Tubercular uveitis and the immune reconstitution syndrome seen in HIV patients. We recommend starting oral prednisolone concurrently with antimicrobial therapy. Increased doses of corticosteroids (ie. greater than prednisolone 1 mg/kg) may be needed to control paradoxical worsening. We find that the Jarisch-Herxheimer hypersensitivity response that some patients develop secondary to spirochaetes lysed by antibiotic therapy is well controlled by the corticosteroid dose required to control syphilitic uveitis.

There are several important practical management points to emphasise.

  1. 1.

    The Ophthalmologist has a major role in the diagnosis and management of syphilis. Careful clinical assessment with a thorough history and ocular examination combined with a directed review of systems to detect risk factors for infection. If we don’t test for syphilis, we won’t diagnose syphilis. In patients with uveitis and optic neuritis, there is very rarely a good reason not to test for syphilis.

  2. 2.

    Multimodal imaging has greatly increased our diagnostic acuity to recognise ocular syphilis involving the posterior segment and optic nerve. OCT imaging, widefield digital and autofluorescence imaging, and widefield fluorescein angiography have transformed diagnosis and follow up of many uveitis disorders. As an example, in patients with ocular syphilis, placoid fundus lesions are now readily diagnosed with widefield imaging and recognition of these lesions is enhanced with fundus autofluorescence and OCT imaging (Fig. 3). Multimodal imaging in patients with optic neuritis (or a diagnosis of intermediate uveitis) may reveal subtle retinal involvement that is not apparent on routine clinical examination (Fig. 10). Not uncommonly, widefield imaging systems such as Optos (Dunfermline, UK) will obtain good quality fundus images when clinically, we struggle to view the fundus due to media opacity/vitritis, small pupils/posterior synechiae or a severely photophobic patient (Fig. 14).

    Fig. 14: Widefield imaging of a case of ASPPC.
    figure 14

    The placoid lesion is obscured, A, due to mild vitritis and pigment on the anterior capsule from broken synechiae. Widefield FAF, B clearly identifies the despite the media opacity. Images C, D illustrate the placoid lesion, on widefield imaging and FAF respectively, days later after the media opacity had improved. We find SLO widefield imaging (e.g. Optos, Dunfermline. UK) will often identify posterior lesions obscured due to media opacity.

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  3. 3.

    If at all possible, a multidisciplinary management approach is of great benefit to both the patient and the Ophthalmologist managing patients with ocular syphilis. This is standard practice in our unit. Sexual health or Infectious Disease physicians will assess for co-morbidities that might complicate treatment. Where syphilis is a notifiable disease, they will ensure the correct processes are followed and that contact tracing is performed. They will perform a sexual health screen and, critically, test for HIV infection.

  4. 4.

    Routine lumbar puncture is not necessary in patients with ocular syphilis as we treat all patients with posterior uveitis, pan uveitis and associated optic neuropathy as if they have neurosyphilis.

  5. 5.

    Patients with posterior or pan uveitis, or optic neuritis need 14 days of intravenous penicillin therapy which requires some form of central venous access (typically a PICC). In some locations, this will necessitate a 14 day hospital admission. In other centres where “hospital in the home” is available, many patients can be managed as outpatients. The medical team will follow the patient to ensure that syphilis has been effectively eradicated and manage patients with relapses or incomplete treatment responses.

  6. 6.

    In patients who have been adequately treated for ocular syphilis, a new presentation with uveitis could be due to a re-infection with syphilis. This is well recognised in the MSM risk group of patients.

Issues requiring further research consideration

One of the uncertainties that remain for ophthalmologists and neuro-ophthalmologists managing patients with ocular syphilis is understanding the relationship between ocular and neurosyphilis and what the practical implications might be of further research in this area.

While we already know that most patients with syphilis get early spread of treponemes to the central nervous system, it appears that the majority do not develop clinical disease and instead clear the infection. A similar process may well be occurring within the eye, with early sub-clinical invasion and clearance and only a small number of patients having persisting intraocular infection. From a clinical perspective this is more of an academic interest, rather than related to direct patient care at this stage. However, it may give us insight into those who are at increased risk of future ocular and/or neurosyphilis. Understanding the risk factors and biomarkers of this risk, could allow better targeting of more aggressive treatment in the early phases of disease, as well as closer patient monitoring. This leads us back to the question of whether these biomarkers are likely to be found in the CSF, intraocular fluids or peripheral blood. There may also be genetically determined variations in innate immunity that alter susceptibility to ocular and neurosyphilis.

Looking at this question from the other side, there are likely to be patients with optic neuritis or symptomatic neurosyphilis with unrecognised ocular syphilis. Should all patients with optic neuritis to have multimodal imaging to look for retinal involvement, as this may affect longer term visual outcomes, or guide more localised treatment options? Should all neurosyphilis patients with or without visual symptoms have ocular multimodal imaging (widefield imaging including fundus autofluorescence) for the same reasons?

Finally, do we need to consider at what point ocular syphilis becomes neurosyphilis? Isolated anterior uveitis is an uncommon but important ocular manifestation of syphilis that usually occurs early in the natural history of syphilis and is adequately treated with a single dose of intramuscular penicillin. In contradiction, patients typically (but not always) develop posterior uveitis, panuveitis and optic neuritis later in the natural history of untreated syphilis and it is not uncommonly associated with asymptomatic or symptomatic neurosyphilis. For this reason, most centres including our unit treat all such patients with the treatment regimen used for neurosyphilis and follow up the patients for ocular relapse or development of other symptoms.

Conclusion

This review has given an overview of the clinical features, diagnosis and management of ocular syphilis. It is not a detailed comprehensive review as multiple such reviews have been published over the past few years. This manuscript has focused on the practical diagnostic and management issues and addressed the relationship between ocular and neurosyphilis, which remains unclear despite many clinical cases series and reviews.