Ophthalmology – Ocular Syphilis

Basics

Description

Ocular syphilis is ocular involvement by the spirochete Treponema pallidum.

Syphilis is a chronic systemic infection capable of affecting essentially any ocular structure and is known as the:

“Great masquerader”

because it can mimic many inflammatory, infectious, vascular, and neoplastic eye diseases.

Ocular involvement may occur during any stage of syphilis and may present as:

• Anterior uveitis
• Intermediate uveitis
• Posterior uveitis
• Panuveitis
• Retinitis
• Retinal vasculitis
• Chorioretinitis
• Optic neuropathy
• Interstitial keratitis

A key management principle is:

Ocular syphilis should be treated with a neurosyphilis regimen, even when cerebrospinal fluid findings are normal.

Etiology

The causative organism is:

Treponema pallidum

a motile spirochete.

Transmission

Acquired Syphilis

Transmission occurs primarily through direct contact with infectious lesions during:

• Vaginal intercourse
• Anal intercourse
• Oral sex

Congenital Syphilis

Transmission occurs:

Transplacentally from an infected mother to the fetus

Maternal screening and treatment during pregnancy are essential for prevention.

Epidemiology

Ocular syphilis accounts for a small but important proportion of uveitis.

Its frequency varies according to:

• Geographic region
• Syphilis prevalence
• HIV prevalence
• Population studied

Ocular disease may occur in both:

• HIV-negative patients
• People living with HIV

Risk Factors

Important risk factors include:

• Unprotected sexual exposure
• Multiple sexual partners
• Men who have sex with men
• HIV infection
• Other sexually transmitted infections
• Intravenous drug use
• Previous syphilis infection or inadequately treated infection

Systemic Stages of Acquired Syphilis

Primary Syphilis

Classically presents with:

Painless chancre

at the inoculation site.

Regional lymphadenopathy may occur.

Secondary Syphilis

May produce:

• Diffuse maculopapular rash
• Palmar and plantar lesions
• Generalized lymphadenopathy
• Fever
• Malaise
• Condylomata lata

Ocular manifestations are particularly important during secondary disease but can occur at any stage.

Latent Syphilis

Serologic evidence of infection without active clinical manifestations.

It is classified as:

• Early latent
• Late latent
• Unknown duration

Tertiary Syphilis

Potential manifestations include:

• Cardiovascular syphilis
• Gummatous disease
• Neurologic disease

Neurologic and ocular involvement can actually occur much earlier and should not be regarded as exclusively “tertiary.”

Congenital Syphilis

Early Manifestations

May include:

• Hepatosplenomegaly
• Mucocutaneous lesions
• Rhinitis
• Bone abnormalities
• Chorioretinitis

Late Manifestations

Classical findings include:

• Frontal bossing
• Saddle nose
• Saber shins
• Hutchinson teeth
• Sensorineural hearing loss
• Interstitial keratitis

The classic Hutchinson triad consists of:

• Interstitial keratitis
• Hutchinson teeth
• Sensorineural deafness

Pathophysiology

Ocular injury results from:

• Direct spirochetal infection
• Host inflammatory response
• Immune-mediated tissue injury
• Vascular inflammation

This can affect both the anterior and posterior segments.

Clinical Presentation

Patients may report:

• Blurred vision
• Floaters
• Photophobia
• Ocular pain
• Redness
• Scotoma
• Metamorphopsia
• Reduced color vision
• Sudden or progressive visual loss

Disease may be:

• Unilateral
• Bilateral
• Asymmetric

Important Clinical Principle

Syphilis can imitate almost any form of uveitis.

Therefore:

Syphilis testing should be considered in essentially all unexplained uveitis, particularly posterior or panuveitis.

Anterior Segment Manifestations

Possible findings include:

• Granulomatous anterior uveitis
• Non-granulomatous anterior uveitis
• Keratic precipitates
• Iris nodules
• Posterior synechiae
• Elevated IOP
• Scleritis
• Episcleritis

Interstitial Keratitis

Classically associated with congenital syphilis.

Features may include:

• Stromal corneal inflammation
• Corneal vascularization
• Photophobia
• Reduced vision

After inflammation resolves, residual:

Ghost vessels

may remain in the corneal stroma.

Vitreous Involvement

Syphilitic posterior disease commonly produces:

• Vitritis
• Haze
• Inflammatory cells

The amount of vitritis may vary considerably.

Posterior Segment Manifestations

Syphilis may produce:

• Retinitis
• Chorioretinitis
• Retinal vasculitis
• Retinal vascular occlusion
• Neuroretinitis
• Optic neuritis
• Optic disc edema
• Exudative retinal detachment
• Placoid chorioretinitis

Acute Syphilitic Posterior Placoid Chorioretinitis

A particularly characteristic manifestation is:

Acute syphilitic posterior placoid chorioretinitis (ASPPC)

Typical appearance:

• Large
• Yellow-gray
• Placoid lesion
• At or near the macula
• Often involving the outer retina and RPE

ASPPC should strongly raise suspicion for syphilis.

OCT Findings in ASPPC

OCT may show:

• Disruption of the ellipsoid zone
• Outer retinal abnormalities
• RPE irregularity
• Hyperreflective material at the RPE/photoreceptor interface
• Later restoration with successful treatment

Fluorescein Angiography

FA may demonstrate:

• Early hypofluorescence
• Late staining
• Retinal vascular leakage
• Optic disc leakage
• Vasculitis

Indocyanine Green Angiography

ICG may demonstrate areas of:

• Choroidal hypofluorescence
• Choriocapillaris involvement

in selected posterior cases.

Fundus Autofluorescence

May help demonstrate:

• RPE disturbance
• Extent of placoid lesions
• Evolution with treatment

Retinal Vasculitis

Syphilitic vasculitis may involve:

• Arteries
• Veins
• Both

It can lead to:

• Vascular occlusion
• Retinal ischemia
• Neovascular complications

Optic Nerve Manifestations

Possible manifestations include:

• Optic neuritis
• Optic perineuritis
• Neuroretinitis
• Papillitis
• Optic disc edema
• Optic atrophy

MRI may be useful when optic nerve or central neurologic involvement is suspected.

Pupillary Findings

The classic Argyll Robertson pupil:

• Accommodates to near
• Reacts poorly or not at all to light

It is historically associated with neurosyphilis but is uncommon in modern practice.

Cranial Neuropathies

Neurosyphilis may produce:

• Oculomotor nerve palsy
• Trochlear nerve palsy
• Abducens nerve palsy
• Other neurologic deficits

Diagnosis

Diagnosis combines:

• Compatible ocular findings
• Syphilis serology
• Exclusion of important mimics

No single ocular appearance confirms syphilis.

Serologic Testing

Testing generally includes both:

1. Nontreponemal test
2. Treponemal test

Nontreponemal Tests

Examples:

• RPR
• VDRL

These provide a quantitative titer and are useful for monitoring treatment response.

Nontreponemal Titers

A clinically meaningful change is generally:

Fourfold change in titer

For example:

• 1:32 → 1:8 = fourfold decline
• 1:8 → 1:32 = fourfold rise

Titers are therefore useful for:

• Monitoring therapy
• Detecting reinfection
• Detecting treatment failure

False-Positive Nontreponemal Tests

False-positive results may occur with:

• Autoimmune disease
• Pregnancy
• Infection
• Older age
• Other inflammatory states

Therefore, reactive nontreponemal testing requires confirmation with a treponemal assay.

Prozone Phenomenon

Very high antibody concentrations may rarely cause a falsely negative nontreponemal test.

If clinical suspicion is strong despite a negative RPR/VDRL, the laboratory can repeat testing using:

Serial dilution

to exclude a prozone effect.

Treponemal Tests

Examples include:

• TP-PA
• FTA-ABS
• Treponemal enzyme immunoassays
• Chemiluminescent immunoassays

These usually remain positive indefinitely after infection.

Therefore:

Treponemal tests should not be used to monitor treatment response.

Reverse-Sequence Screening

Many laboratories now begin with a:

Treponemal immunoassay

followed by quantitative RPR or VDRL.

Discordant results may require a second treponemal test such as TP-PA.

HIV Testing

All patients diagnosed with ocular syphilis should be offered:

HIV testing

because coinfection is important for:

• Overall management
• STI counseling
• Follow-up

Other STI screening should also be considered.

Lumbar Puncture

Older recommendations favored lumbar puncture in virtually all ocular syphilis.

Modern practice is more selective.

When CSF Examination Is Indicated

Lumbar puncture is particularly appropriate when there are:

• Cranial nerve abnormalities
• Meningeal symptoms
• Cognitive changes
• Motor or sensory deficits
• Other neurologic manifestations

CSF evaluation typically includes:

• Cell count
• Protein
• CSF-VDRL

Isolated Ocular Syphilis

If a patient has:

• Reactive syphilis serology
• Confirmed ocular abnormalities
• No neurologic findings

CSF examination is not required before treatment.

Most importantly:

Treatment should not be delayed for lumbar puncture.

CSF-VDRL

CSF-VDRL is:

• Highly specific
• Relatively insensitive

Therefore, a positive result strongly supports neurosyphilis, but a negative result does not completely exclude it.

Neuroimaging

MRI brain and/or orbits may be useful when there is:

• Optic neuropathy
• Cranial nerve palsy
• Focal neurologic deficit
• Concern for CNS disease

Differential Diagnosis

Because syphilis is a great masquerader, the differential is broad.

Consider:

• Sarcoidosis
• Tuberculosis
• Toxoplasmosis
• Acute retinal necrosis
• CMV retinitis
• Behçet disease
• VKH
• HLA-B27-associated uveitis
• Intermediate uveitis
• APMPPE
• Other white-dot syndromes
• Lyme disease
• Fungal endophthalmitis
• Toxocariasis
• Primary vitreoretinal lymphoma

Treatment

Critical Principle

All ocular syphilis should be treated using a neurosyphilis regimen.

Do not use standard single-dose benzathine penicillin treatment alone for active ocular syphilis.

First-Line Treatment

The preferred regimen is:

Aqueous crystalline penicillin G

Total:

18–24 million units/day IV

administered as:

• 3–4 million units IV every 4 hours

or

• Continuous infusion

for:

10–14 days

Alternative Penicillin Regimen

If reliable adherence can be ensured:

• Procaine penicillin G 2.4 million units IM once daily
• Plus probenecid 500 mg orally four times daily

for:

10–14 days

Additional Benzathine Penicillin

Because neurosyphilis regimens are shorter than those used for late latent syphilis, clinicians may consider:

Benzathine penicillin G 2.4 million units IM weekly for 1–3 weeks

after completion of neurosyphilis therapy in selected patients, particularly when the underlying stage would otherwise require a longer course.

Penicillin Allergy

For nonpregnant patients with penicillin allergy, an alternative that may be considered is:

Ceftriaxone 1–2 g IM or IV daily for 10–14 days

However, evidence is less extensive than for penicillin.

If there is concern about ceftriaxone safety or reliability of alternative therapy:

• Penicillin allergy testing
• Desensitization

should be considered.

Pregnancy

Pregnant patients with syphilis should receive:

Penicillin

because penicillin is the only proven treatment that reliably treats maternal infection and prevents fetal syphilis.

Patients with true penicillin allergy should undergo:

Desensitization followed by penicillin therapy

HIV Coinfection

People with HIV and ocular syphilis are treated with the:

Same neurosyphilis regimen

as patients without HIV.

HIV status does not justify using a less intensive regimen.

Adjunctive Corticosteroids

Corticosteroids may be used to control severe ocular inflammation.

Options include:

• Topical corticosteroids
• Systemic corticosteroids
• Selected periocular therapy

However:

Antibiotic therapy is the essential treatment.

Corticosteroids should not substitute for adequate antimicrobial therapy.

Evidence for Steroids

Systemic corticosteroids are frequently used in severe:

• Posterior uveitis
• Optic neuritis
• Marked inflammatory disease

but controlled evidence proving additional benefit is limited.

If used, they should generally be administered:

With or after initiation of appropriate antibiotic therapy

rather than as isolated immunosuppression.

Cycloplegics

For anterior uveitis, cycloplegics may be used to:

• Relieve ciliary spasm
• Reduce pain
• Prevent posterior synechiae

Examples include:

• Cyclopentolate
• Homatropine
• Atropine in severe inflammation

Intravitreal Therapy

Intravitreal antimicrobial treatment is not routinely necessary when appropriate systemic penicillin therapy is given.

It may be considered only in unusual severe circumstances under specialist care.

Jarisch-Herxheimer Reaction

A Jarisch-Herxheimer reaction may occur within approximately 24 hours after treatment begins.

Features include:

• Fever
• Chills
• Headache
• Myalgia
• Temporary worsening of syphilitic lesions

It results from the inflammatory response to rapid spirochetal killing.

Management is generally:

Supportive

It is not a penicillin allergy.

Ocular Jarisch-Herxheimer Reaction

Rarely, ocular inflammation may transiently worsen after therapy begins.

Close observation is appropriate in patients with severe posterior disease or optic nerve involvement.

Congenital Syphilis

Congenital syphilis treatment depends on:

• Infant age
• Maternal treatment
• Neonatal examination
• Serology
• CSF evaluation

A commonly used regimen for confirmed or highly probable neonatal congenital syphilis is:

Aqueous crystalline penicillin G 50,000 units/kg/dose IV

given:

• Every 12 hours during the first 7 days of life
• Then every 8 hours

for a total of:

10 days

Alternative neonatal regimens are determined by pediatric infectious-disease protocols.

Partner Management

Sex partners require:

• Evaluation
• Serologic testing
• Treatment when indicated

This is essential to prevent:

• Reinfection
• Continued transmission

Public Health Considerations

Syphilis is a reportable infection in many jurisdictions.

Management may involve:

• Public health notification
• Partner services
• STI counseling

Follow-Up

Ophthalmic Follow-Up

Serial examination should assess:

• Visual acuity
• Anterior chamber inflammation
• Vitritis
• Retinitis
• Vasculitis
• Macular involvement
• Optic nerve function

Serologic Follow-Up

Treatment response is monitored with:

Quantitative RPR or VDRL titers

Use the same type of test when possible because RPR and VDRL titers are not directly interchangeable.

Expected Response

A favorable response generally includes:

• Clinical improvement
• Falling nontreponemal titers

A fourfold decline is a commonly used marker of adequate serologic response, although the expected timing varies with syphilis stage.

Serofast State

Some successfully treated patients remain persistently reactive at a low titer.

This is called:

Serofast

and does not automatically indicate treatment failure.

Interpretation depends on:

• Initial stage
• Initial titer
• Clinical response
• Reinfection risk

Treatment Failure or Reinfection

Consider further evaluation when there is:

• Recurrent ocular inflammation
• New syphilitic symptoms
• Sustained fourfold rise in RPR/VDRL titer
• Inadequate expected serologic response
• New exposure

Repeat Lumbar Puncture

Routine repeat CSF examination is generally unnecessary when there is:

• Appropriate clinical improvement
• Appropriate serologic response

unless neurologic or ocular findings fail to improve or recur.

Referral

Management should involve:

• Ophthalmology/uveitis specialist
• Infectious disease or sexual health specialist when appropriate

Neurology consultation may be useful when there are:

• Cranial neuropathies
• Cognitive changes
• Other neurologic manifestations

Patient Education

Patients should understand:

• Syphilis is treatable.
• Ocular syphilis requires intensive systemic therapy.
• Sexual partners may also require testing and treatment.
• Reinfection is possible.
• Follow-up blood testing is essential.
• HIV and other STI testing should be performed.

Prognosis

Visual prognosis depends on:

• Severity at presentation
• Duration before treatment
• Macular involvement
• Optic nerve involvement
• Degree of retinal ischemia
• Promptness of therapy

Early diagnosis and appropriate treatment often produce substantial visual recovery.

Poor Prognostic Features

Potentially unfavorable findings include:

• Severe visual loss at presentation
• Optic neuropathy
• Macular involvement
• Extensive retinitis
• Retinal vascular occlusion
• Delayed treatment
• Permanent retinal or optic nerve atrophy

Complications

Possible ocular complications include:

• Corneal scarring
• Cataract
• Secondary glaucoma
• Posterior synechiae
• Cystoid macular edema
• Retinal vascular occlusion
• Retinal detachment
• Macular atrophy
• Optic atrophy
• Permanent visual loss

Ophthalmology Pearls

• Syphilis is the “great masquerader” and can mimic almost any form of uveitis.
• Ocular syphilis can occur during any stage of systemic infection.
• All ocular syphilis should be treated with a neurosyphilis regimen, regardless of CSF findings.
• The preferred treatment is IV aqueous crystalline penicillin G for 10–14 days.
• A single IM dose of benzathine penicillin appropriate for uncomplicated early syphilis is not adequate treatment for active ocular syphilis.
• Acute syphilitic posterior placoid chorioretinitis is a particularly characteristic posterior manifestation.
• Diagnosis requires both a treponemal test and a quantitative nontreponemal test.
• RPR/VDRL is used for treatment monitoring; treponemal tests generally remain reactive and should not be used to monitor response.
• CSF examination is important when neurologic abnormalities are present, but isolated confirmed ocular disease does not require lumbar puncture before treatment.
• All patients should be tested for HIV and considered for other STI screening.
• Corticosteroids may control inflammation, but adequate antimicrobial treatment is the essential therapy.
• A Jarisch-Herxheimer reaction may temporarily worsen systemic or ocular inflammation after treatment begins.
• Prompt diagnosis is critical because syphilitic ocular disease is often highly treatable before irreversible retinal or optic nerve damage occurs.