Syphilitic Uveitis: Diagnosis and Management Guide

What is syphilitic uveitis?

Syphilitic uveitis is an inflammatory condition affecting the uveal tract of the eye caused by the bacterium Treponema pallidum, which is also responsible for the sexually transmitted infection syphilis. The uvea, which consists of the iris, ciliary body, and choroid, is highly vascular and prone to inflammation when the infection spreads. Syphilitic uveitis can occur at any stage of the disease (primary, secondary, latent, or tertiary), but it is most commonly associated with secondary or tertiary syphilis. This condition is known as “the great imitator” in ophthalmology because its clinical presentation can resemble many other types of uveitis and ocular diseases, making diagnosis difficult.

Pathogenesis of Syphilitic Uveitis

Syphilis is a systemic infection that affects several organ systems, including the eyes. Following the initial infection, Treponema pallidum enters the bloodstream and spreads to various tissues, including the uvea. The pathophysiology of syphilitic uveitis includes both bacterial infection of the uveal tissues and an immune-mediated inflammation response. The inflammation is usually granulomatous, which means it causes the formation of granulomas, which are immune cell clusters that form in response to chronic inflammation.

Syphilitic uveitis can affect any part of the uveal tract and may manifest as anterior uveitis, posterior uveitis, panuveitis, or even optic neuritis. The inflammatory process can result in a variety of symptoms and complications, depending on the location and severity of the inflammation. If not diagnosed and treated promptly, the condition can cause vision-threatening complications such as retinal detachment, optic neuropathy, and irreversible vision loss.

Clinical Features of Syphilitic Uveitis

The clinical presentation of syphilitic uveitis is highly variable, adding to its reputation as a difficult diagnosis. Syphilitic uveitis symptoms can be mild or severe, affecting one or both eyes. Patients may report the following symptoms:

1. Blurred Vision: Blurred vision is one of the most common symptoms of syphilitic uveitis, which can develop gradually or suddenly. This blurring could be caused by an accumulation of inflammatory cells in the eye’s anterior chamber (anterior uveitis) or by involvement of the retina or optic nerve in posterior uveitis.
2. Photophobia: Another common symptom is light sensitivity, also known as photophobia. Inflamed uveal tissues can cause discomfort or pain when exposed to bright light, making it difficult for patients to tolerate normal lighting conditions.
3. Eye Pain: Syphilitic uveitis frequently causes eye pain, especially in cases of anterior uveitis. The pain can be mild or severe, with many people describing it as a deep, aching sensation. In some cases, the pain is accompanied by redness in the eye and a feeling of pressure or fullness.
4. Redness of the Eye: Inflammation of the uveal tract can make the eye look red or bloodshot. This redness is usually diffuse and can affect the conjunctiva and episclera as well.
5. Floaters: Patients with syphilitic uveitis may notice small, dark spots or shapes moving across their field of vision. The presence of inflammatory cells and debris in the vitreous humor, the gel-like substance that fills the posterior segment of the eye, causes floaters.
6. Reduced Visual Acuity: Depending on the severity and location of the inflammation, patients may experience a significant loss of vision. This can affect both near and far vision, and it may be especially severe in cases involving the retina or optic nerve.
7. Visual Field Defects: In some cases, syphilitic uveitis can cause visual field defects, which are when parts of the visual field become lost or obscured. These defects, which can vary in size and location, may be the result of retinal or optic nerve inflammation.
8. Optic Neuritis: Optic neuritis, or inflammation of the optic nerve, is a severe complication of syphilitic uveitis that can result in sudden vision loss. Optic neuritis patients may experience pain when moving their eyes, as well as a loss of color vision and a central scotoma.

Types of Syphilitic Uveitis

Syphilitic uveitis can manifest in a variety of ways, depending on which part of the uveal tract is involved. The main types of syphilitic uveitis are:

1. Anterior Uveitis: Anterior uveitis refers to inflammation of the iris and anterior chamber of the eye. Syphilitic anterior uveitis patients frequently report pain, redness, photophobia, and blurred vision. Granulomatous inflammation is defined by the presence of large, yellowish-white nodules on the iris (Busacca nodules) or in the anterior chamber (Koeppe nodules). Syphilitic uveitis commonly presents as anterior uveitis.
2. Posterior Uveitis: Posterior uveitis is an inflammation of the retina, choroid, and optic nerve. This type of syphilitic uveitis can cause symptoms such as floaters, blurred vision, and visual field defects. In syphilis, posterior uveitis can manifest as chorioretinitis, an inflammation of the retina and choroid, or as optic neuritis, which can cause significant visual impairment if not treated promptly.
3. Panuveitis is an inflammation of the entire uveal tract, including the iris, ciliary body, and choroid. Patients with syphilitic panuveitis may have symptoms of both anterior and posterior uveitis. Panuveitis is usually more severe and can lead to complications like retinal detachment or optic neuropathy.
4. Interstitial Keratitis: While not technically a type of uveitis, interstitial keratitis is a corneal manifestation of congenital syphilis. It is characterized by corneal stromal inflammation, which results in corneal opacification and vision loss. Patients with interstitial keratitis may exhibit photophobia, pain, and a distinctive “ground-glass” appearance of the cornea.

Epidemiology and Risk Factors

Syphilitic uveitis is a rare but increasingly recognized cause of uveitis, especially in populations where syphilis is prevalent. Syphilitic uveitis is becoming more common in recent years, coinciding with the resurgence of syphilis as a public health concern. Several factors can cause syphilitic uveitis, including:

1. History of Syphilis: People who have had syphilis before, especially those who had untreated or inadequately treated infections, are more likely to develop syphilitic uveitis. The condition can develop at any stage of syphilis, but it is most commonly linked to secondary or tertiary syphilis.
2. Immunosuppression: Immunocompromised people, including those with HIV/AIDS, are more likely to develop syphilitic uveitis. The co-infection of syphilis and HIV is well known, and the presence of HIV can alter the clinical presentation and progression of syphilitic uveitis.
3. Lack of Access to Healthcare: People who have limited access to healthcare or do not receive timely syphilis diagnosis and treatment are more likely to develop complications, such as syphilitic uveitis.
4. High-Risk Sexual Behaviors: Participating in high-risk sexual behaviors, such as unprotected sex with multiple partners, raises the risk of contracting syphilis and, as a result, developing syphilitic uveitis.

Differential Diagnosis

Syphilitic uveitis’ clinical presentation can be similar to other types of uveitis and inflammatory diseases, necessitating a differential diagnosis. Conditions that may present similarly are:

1. Tuberculous Uveitis: Infection with Mycobacterium tuberculosis causes tuberculous uveitis, which can be characterized by granulomatous inflammation similar to syphilitic uveitis. Both conditions can cause anterior, posterior, or panuveitis, but tuberculous uveitis is more often associated with tuberculosis-related systemic symptoms such as fever, weight loss, and night sweats.
2. Sarcoidosis is a systemic granulomatous disease that can cause uveitis. Sarcoid uveitis can look like syphilitic uveitis, especially in its granulomatous form, which includes mutton-fat keratic precipitates and iris nodules. Sarcoidosis, on the other hand, is frequently associated with systemic manifestations such as hilar lymphadenopathy and pulmonary involvement.
3. Viral Uveitis: Herpesviruses, such as herpes simplex virus (HSV) or varicella-zoster virus (VZV), can cause both anterior and posterior uveitis. Viral uveitis can cause corneal involvement (keratitis) and sectoral iris atrophy, which syphilitic uveitis does not.
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5. Autoimmune Uveitis: Autoimmune uveitis, which includes conditions such as Behçet’s disease and Vogt-Koyanagi-Harada (VKH) syndrome, can cause inflammation of the uveal tract and other ocular symptoms similar to syphilitic uveitis. Behçet’s disease is frequently accompanied by recurrent oral and genital ulcers, as well as skin lesions, whereas VKH syndrome is distinguished by bilateral panuveitis, poliosis (whitening of eyelashes or brows), vitiligo, and neurological symptoms. These systemic characteristics differentiate these autoimmune conditions from syphilitic uveitis.
6. Toxoplasmosis: The protozoan Toxoplasma gondii causes ocular toxoplasmosis, which can present with posterior uveitis and, in some cases, retinochoroiditis. It usually causes a focal retinochoroiditis with a distinct “headlight in the fog” appearance due to an active lesion surrounded by hazy vitreous inflammation. Toxoplasmosis, unlike syphilitic uveitis, rarely causes anterior uveitis and is typically unilateral.
7. Lyme Disease: Borrelia burgdorferi can cause uveitis, which can be anterior, posterior, or panuveitis. Lyme disease’s ocular manifestations are frequently associated with other systemic signs of the disease, such as erythema migrans (a distinctive rash), arthritis, and neurological symptoms, which can help distinguish it from syphilitic uveitis.

Given the variety of uveitis presentations and the overlap in symptoms between different etiologies, an accurate diagnosis of syphilitic uveitis requires a thorough clinical evaluation, as well as appropriate laboratory and imaging tests.

Diagnostic methods

To confirm the presence of Treponema pallidum infection, clinical suspicion, a detailed patient history, and specific laboratory tests are required to diagnose syphilitic uveitis. Because the ocular manifestations of syphilitic uveitis can be similar to those of other inflammatory and infectious diseases, a systematic approach to diagnosis is required to ensure appropriate treatment.

Clinical Examination

1. Ophthalmic Examination: The first step in diagnosing syphilitic uveitis is to conduct a comprehensive ophthalmic examination. This includes visual acuity testing, slit-lamp biomicroscopy, and a dilated fundus exam. During a slit-lamp examination, the ophthalmologist may notice signs of anterior uveitis, such as keratic precipitates, anterior chamber cells, and inflammation. Indirect ophthalmoscopy can detect posterior segment involvement, including chorioretinal lesions, retinal vasculitis, and optic nerve inflammation.
2. Fluorescein Angiography (FA) is an imaging technique that involves injecting fluorescein dye into the bloodstream and then capturing sequential images of the retinal vasculature. In syphilitic uveitis, this technique can reveal areas of retinal vasculitis, choroidal inflammation, or optic disc leakage. FA is especially useful for detecting subtle posterior segment involvement that may not be visible on clinical examination alone.
3. Optical Coherence Tomography (OCT) is a non-invasive imaging technique that generates cross-sectional images of the retina and optic nerve. In patients with syphilitic uveitis, OCT can detect retinal edema, subretinal fluid, and structural changes in the retina and optic nerve. OCT is also useful for monitoring treatment response and detecting complications like macular edema or optic neuropathy.
4. B-Scan Ultrasonography: When media opacities (such as dense cataracts or vitreous hemorrhage) obscure the view of the posterior segment, B-scan ultrasonography can be used to assess the vitreous, retina, and optic nerve. A B-scan can reveal retinal detachment, choroidal thickening, or vitreous debris associated with syphilitic uveitis.

Laboratory Testing

1. Serologic Testing: Serologic testing is necessary to confirm the diagnosis of syphilis in patients with suspected syphilitic uveitis. The diagnosis is usually made using a combination of non-treponemal tests (e.g., Rapid Plasma Reagin [RPR], Venereal Disease Research Laboratory [VDRL] test) and treponemal-specific tests. Non-treponemal tests are used for screening and monitoring treatment response, whereas treponemal-specific tests are more sensitive and can confirm the diagnosis of syphilis.
2. Cerebrospinal Fluid (CSF) Analysis: If neurosyphilis or optic neuritis is suspected, a lumbar puncture may be performed to examine cerebrospinal fluid (CSF). Elevated protein levels, pleocytosis (increased white blood cells), and a positive VDRL test are all signs of neurosyphilis in the CSF. CSF examination is especially important in HIV-positive patients, who have a higher risk of neurosyphilis.
3. Polymerase Chain Reaction (PCR): PCR testing can detect Treponema pallidum DNA in ocular fluids, such as aqueous or vitreous humor, in cases of syphilitic uveitis. PCR is a highly sensitive and specific test that can directly confirm the presence of the bacterium, particularly in unusual cases or when serological tests are inconclusive.

Differential testing for other causes of uveitis

In addition to testing for syphilis, it is critical to rule out other possible causes of uveitis. This may include tests for tuberculosis (e.g., tuberculin skin test, interferon-gamma release assays), sarcoidosis (e.g., chest X-ray, serum angiotensin-converting enzyme [ACE] levels), and viral infections (e.g., herpes simplex virus, varicella-zoster virus serology).

Neuroimaging

If there is a suspicion of neurosyphilis or optic nerve involvement, neuroimaging tests such as magnetic resonance imaging (MRI) of the brain and orbit may be recommended. MRI can detect optic nerve enhancement, meningeal enhancement, or other CNS abnormalities associated with neurosyphilis, providing additional evidence to support the diagnosis of syphilitic uveitis.

Syphilitic Uveitis Management

Managing syphilitic uveitis necessitates a multidisciplinary approach that addresses both the ocular inflammation and the systemic infection caused by Treponema pallidum. The primary goals of treatment are to eliminate the infection, manage the uveitis, avoid complications, and preserve vision. Timely intervention is critical to avoiding permanent visual impairment, especially because syphilitic uveitis can mimic other types of uveitis and be misdiagnosed.

Antibiotic Therapy

The primary treatment for syphilitic uveitis is antibiotic therapy to eliminate the Treponema pallidum bacterium. The preferred treatment regimen is determined by the stage of syphilis and whether the patient exhibits neurosyphilis.

1. Penicillin G is the first-line treatment for syphilitic uveitis. For patients without neurosyphilis, a common regimen consists of intramuscular benzathine penicillin G (2.4 million units) administered once weekly for three weeks. In cases of suspected or confirmed neurosyphilis, aqueous crystalline penicillin G (18-24 million units per day) is given intravenously every 4 hours for 10 to 14 days. This high-dose regimen is required to ensure adequate penetration of the cerebrospinal fluid and ocular tissues.
2. Alternative Antibiotics: If possible, desensitization to penicillin is the preferred approach for penicillin-allergic patients. If desensitization is not possible, other antibiotics, such as doxycycline (100 mg orally twice daily for 28 days) or ceftriaxone (2 g intravenously or intramuscularly daily for 10 to 14 days), may be used. These alternatives are less effective than penicillin and are usually considered only when penicillin is not available.
3. Jarisch-Herxheimer Reaction: It is critical to understand the Jarisch-Herxheimer reaction, which is an acute febrile response that can occur within 24 hours of starting antibiotic treatment for syphilis. Endotoxins released by dying bacteria cause this reaction, which may temporarily worsen uveitis symptoms. Patients should be closely monitored during the first phase of antibiotic therapy, and supportive care, such as antipyretics and anti-inflammatory medications, may be given to alleviate symptoms.

Corticosteroid Treatment

Corticosteroids are used in addition to antibiotic therapy to control the inflammation caused by syphilitic uveitis. Corticosteroid use must be carefully balanced to avoid suppressing the immune response required to fight the infection.

1. Topical Corticosteroids: For patients with anterior uveitis, topical corticosteroids like prednisolone acetate 1% eye drops may be recommended. The frequency of administration is determined by the severity of the inflammation, with the dose gradually tapering off as the uveitis improves. Topical corticosteroids help reduce inflammation, pain, and the formation of synechiae (iris-lens adhesions).
2. Systemic Corticosteroids: In cases of posterior uveitis, panuveitis, or optic neuritis, systemic corticosteroids (such as oral prednisone) may be necessary. Systemic corticosteroids are usually started at a high dose (e.g., 40-60 mg per day) and gradually tapered based on the patient’s response. Systemic corticosteroids are especially useful in preventing complications like optic nerve damage and retinal detachment.
3. Periocular or Intravitreal Steroid Injections: In severe cases where systemic corticosteroids are inadequate or poorly tolerated, periocular (sub-Tenon’s) or intravitreal steroid injections may be considered. These injections deliver high concentrations of corticosteroids directly to the site of inflammation, allowing for more targeted uveitis treatment.

Monitoring and Follow-up

Patients with syphilitic uveitis require close monitoring throughout treatment to assess response and detect complications early. Follow-up visits should include a thorough ophthalmic examination, which should include visual acuity testing, slit-lamp biomicroscopy, and a dilated fundus examination. The number of follow-up visits depends on the severity of the uveitis and the patient’s response to treatment.

1. Response to Antibiotic Therapy: Non-treponemal serologic tests (e.g., RPR, VDRL) are commonly used to assess a decrease in antibody titers. A fourfold decrease in titers over 6 to 12 months is considered an adequate response. Persistent or rising titers can indicate treatment failure or reinfection.
2. Complication Management: Patients should be closely monitored for syphilitic uveitis complications such as cataract formation, glaucoma, retinal detachment, and optic neuropathy. Corticosteroid use may increase the risk of steroid-induced glaucoma, so intraocular pressure should be measured on a regular basis.
3. Screening for Other Sexually Transmitted Infections (STIs): Because syphilis is associated with other STIs, patients with syphilitic uveitis should be tested for co-infections such as HIV, gonorrhea, and chlamydia. This is especially important in high-risk populations, such as men who have sex with other men (MSM) and those who have multiple sexual partners.

Prevention & Education

To prevent syphilitic uveitis, address the underlying risk factors for syphilis and ensure timely diagnosis and treatment of the infection. Public health interventions such as STI education, routine screening in high-risk populations, and safe sexual practices are critical components of prevention.

Patients with syphilitic uveitis should be educated on the importance of following their treatment regimen, attending follow-up appointments, and notifying their sexual partners in order to prevent further syphilis transmission. Counseling and support services may also be helpful for patients dealing with the diagnosis and its consequences.

Trusted Resources and Support

Books

• “Uveitis: Fundamentals and Clinical Practice” by Robert B. Nussenblatt and Scott M. Whitcup: This textbook offers comprehensive coverage of uveitis, including syphilitic uveitis, with detailed information on diagnosis, treatment, and management strategies. It is an essential resource for ophthalmologists and other healthcare professionals involved in the care of patients with uveitis.
• “Clinical Ophthalmology: A Systematic Approach” by Jack J. Kanski and Brad Bowling: Widely regarded as a key reference in ophthalmology, this book provides in-depth information on various ocular conditions, including syphilitic uveitis. It is an invaluable guide for clinicians seeking to enhance their understanding of uveitis and its management.

Organizations

• Centers for Disease Control and Prevention (CDC): The CDC offers extensive resources on sexually transmitted infections, including syphilis and its complications such as syphilitic uveitis. The CDC website provides up-to-date guidelines on the diagnosis, treatment, and prevention of syphilis, as well as educational materials for both healthcare providers and patients.
• American Uveitis Society (AUS): The AUS is a professional organization dedicated to the study and management of uveitis. It provides resources for clinicians, researchers, and patients, including information on syphilitic uveitis, the latest research findings, and access to expert care. The AUS also offers a platform for collaboration and knowledge sharing among uveitis specialists.