eMedicine Specialties > Ophthalmology > Infectious Disease

Ocular Manifestations of Syphilis

Manolette R Roque, MD, MBA, DPBO, FPAO, President and CEO, Chief of Service, Ocular Immunology and Uveitis, Consulting Staff, Cornea and Refractive Surgery, Eye Republic Ophthalmology Clinic; General Manager, Ophthalmic Consultants Philippines Co; Consulting Staff, CME Liaison, Section Chief of Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center
Barbara L Roque, MD, Full Partner, Ophthalmic Consultants Philippines Co, Chief of Service, Pediatric Ophthalmology and Strabismus, Consulting Staff, Orbit and Eye Plastics, EYE REPUBLIC Ophthalmology Clinic; C Stephen Foster, MD, FACS, FACR, FAAO, Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institute

Updated: Dec 26, 2007

Introduction

Background

Syphilis is caused by an infection with a spirochete, Treponema pallidum, a thin, tightly wound, relatively stiff, spiral-shaped parasite measuring 10-13 µm. Schaudinn and Hoffman of Hamburg discovered T pallidum in 1905.

This disease has been a source of social stigma, morbidity, and mortality for centuries, and it was notably notorious in the early 1900s for infectious chorioretinitis. The term "syphilis" came from a poem written in 1530 by the Italian poet Hiero Fracastor. His main character, in the poem, was an infected shepherd named Syphillus. Syphilis was first described at the end of the 15th century by an Italian physician, Nicolaus Leonicenus, at the same time of the return of the first European explorers from the New World. When Charles VIII of France invaded Naples with mercenaries from all over Europe, spread of this disease was noted on both war camps and was termed French Pox and Neopolitan Pox, respectively.

Syphilis can be congenital or acquired. The acquired form usually is sexually transmitted, chronic, and systemic. Although the introduction of penicillin in the 1940s decreased the epidemiology, there has been a resurgence of the disease, over the past two decades, especially among nonwhites, male homosexuals, and intravenous drug users. Bacterial resistance, poor socioeconomic backgrounds, increased high-risk sexual activity, and immunodepressing diseases have contributed to this resurgence.

Syphilis has been given titles, such as "the great imitator, the great mimic, and the great masquerader!" of ocular inflammatory conditions. It lacks pathognomonic signs and often presents similar to other ocular inflammatory conditions.

Syphilis is associated with the following ocular diseases: interstitial keratitis, episcleritis, scleritis, iritis, iris papules, chorioretinitis, papillitis, retinal vasculitis, and exudative retinal detachment.

Pathophysiology

Primary syphilis

The predominant lesion of primary syphilis is a chancre at the inoculation site, which usually is at the genitalia region. Chancres are erythematous papules at the inoculation site that later erode to form painless ulcers. They may occur at multiple sites. Spirochetes fill the serous fluid from these lesions. The lesions appear 4 weeks after the initial infection and heal spontaneously in 1-2 months.

After T pallidum penetrates the skin or mucous membrane, the organism enters the lymphatics and blood stream and disseminates shortly after contact. If left untreated, primary syphilis leads to secondary syphilis.

Secondary syphilis

The systemic treponemal load is largest in secondary syphilis. Generalized maculopapular (or pustular rash), and lymphadenopathy are the characteristic lesions in this stage. These lesions appear 4-10 weeks after the initial manifestation. Lesions usually present at the flexor and volar body surfaces (ie, palms, soles). Resolution occurs without scarring, although hyperpigmentation or hypopigmentation may occur. Papules (condylomata lata) at the mucocutaneous junctions, and in moist areas of the skin, appearing as dull pink or gray hypertrophic lesions, are common.

Constitutional symptoms of fever, malaise, headache, nausea, anorexia, and joint pains often are present. The liver, kidneys, and/or GI tract may or may not be involved. Ocular involvement has been reported in 10% of cases, and cerebrospinal fluid (CSF) pleocytosis has been seen in a few cases.

Latent syphilis

Latent syphilis follows secondary syphilis and is divided into 2 groups, early latent and late latent. These subgroups occur within and beyond 1 year after initial infection, respectively. Most cases have been reported to stay at the latent stage with 30% converting to the next stage.

Tertiary syphilis

Tertiary syphilis is divided into 3 groups (ie, benign tertiary, cardiovascular, neurosyphilis). Benign tertiary syphilis characteristically presents with gummatous lesions that are actually granulomas, histologically, in the skin and the mucous membranes. The lesions may occur in the choroid, ciliary body, and iris. Cardiovascular syphilis presents with involvement of the coronary arteries or the aorta. Neurosyphilis may manifest with tabes dorsalis or general paresis. The CNS is affected via the vascular pathways or via direct involvement of parenchyma.

Quaternary syphilis

Quaternary syphilis has been disregarded for some time now; however, with the advent of AIDS-related syphilis cases, this stage is being reintroduced. Some authors use it to describe an aggressive form of neurosyphilis, where there is necrotizing encephalitis in patients with the acute immunodeficiency syndrome.

Frequency

United States

Occurrence is higher in the southern and southwestern United States. It is higher in large urban populations.

In 1940, prior to the introduction of antibiotics, the incidence of primary and secondary syphilis was about 100,000 cases. In 1956, with antibiotic therapy, incidence declined steadily to 10,000 cases.

In the early 1980s, the incidence of syphilis rose to about 35,000. In 1988, 40,275 new cases of primary and secondary syphilis were reported.

In 1990, as a result of intravenous drug and crack cocaine abuse, as well as illegal prostitution, the incidence went up to more than 45,000 cases.

In 1995, 16,500 cases were reported in the Summary of Notifiable Diseases.

International

In Seville, Spain, a report indicates that enhanced opportunity for spread accounts for clustering of syphilis in some towns.

In Singapore, special political and sociologic factors, including prostitution, reduced prescribing of penicillin for gonorrhea because of the emergence of penicillin-resistant strains of Neisseria gonorrhoeae, and loss of "herd" immunity, resulted in an increase of early infectious syphilis from 1980-1984.

Mortality/Morbidity

Morbidity from primary and secondary syphilis ranges from the irritation brought about by the primary lesion to the more significant symptoms of secondary syphilis.

• Infant deaths resulting from syphilis and new admissions of patients with syphilitic psychoses have fallen 99% in the United States since 1940. The total number of cases of late and latent syphilis has fallen 98% in the United States since 1943.
• Congenital syphilitic cases have decreased by 98% since 1941.

Race

Incidence is greater among nonwhites.

Sex

• Incidence is greater in males than in females.
• Garfinkel and colleagues noted that women are screened less frequently for syphilis among emergency department patients with suspected sexually transmitted diseases (STDs).¹ This raises a flag of concern about the underdiagnosis of women.

Age

• Frequency is greater in young adults during the years of peak sexual activity.
• Most new cases occur in persons of both sexes aged 15-39 years, with the highest infection rates in individuals aged 20-29 years.

Clinical

History

It is essential for the physician to pay close attention to the patient's clinical history. A high index of suspicion, combined with an excellent history, leads to a streamlined list of differentials prior to examination.

• Elicit a sexual history (ie, sexual intercourse, oral sex, anal sex).
  • Transmission of T pallidum is almost exclusively sexual.
  • Transmission through skin requires a break in the skin, but T pallidum can penetrate intact mucous membranes.
• Transplacental transmission from an infected mother to an infant accounts for infantile syphilis.
• Prior to modern donor screening procedures and blood banking, blood transfusions were another route for transmission. Spread by transfusion of fresh blood is still possible.
• Intravenous drug abuse contributes to the rising cases of syphilis.
• Syphilis can be spread by accidental contact with an infected lesion.
• The patient may complain initially of nonspecific symptoms, such as photophobia, eye redness, and blurring of vision.

Physical

Syphilis may be congenital or acquired.

• Congenital syphilis
  • Manifestations of the disease affect approximately 70% of infected newborn infants.
  • Congenital syphilis can present with a variety of ocular findings that include the following:
    • Acute and chronic iritis
    • Characteristic corneal lesion (see Interstitial keratitis)
    • Scleritis
    • Chorioretinitis
    • "Salt and pepper" fundus
    • Pseudo–retinitis pigmentosa (pseudo-RP)
    • Retinal periphlebitis
    • Optic neuritis
    • Optic nerve pallor
    • Secondary cataract
• Anterior uveitis
  • Unilateral in 56% of cases
  • Granulomatous with mutton-fat keratic precipitates on the corneal endothelium in 50% of cases
  • Iris nodules
    • Iritis roseata (small, dilated collections of capillaries in the iris)
    • Iritis papulosa (iritis roseata increasing in size to resemble a papule)
    • Iritis nodosa (iritis papulosa increasing in size forming a yellow-red nodule)
    • Treponemal emboli may cause vascular tortuosity and dilatation, which account for the iris nodules.
• Intermediate uveitis
• Posterior uveitis
  • Posterior uveitis (9-18%)
  • Panuveitis (27-47%)
  • Vitreal cells are typical.
  • Vasculitis with or without vascular occlusion, macular edema, stellate maculopathy, disciform macular detachment, serous macular/retinal detachment (pseudohypopyon), pseudo-RP, retinal detachment, neuroretinitis, papillitis, diffuse chorioretinitis, uveal effusion, central retinal vein occlusion (CRVO), subretinal neovascular membrane (SNVM) formation, and retinal necrosis (big blind spot syndrome)
  • Syphilitic posterior placoid chorioretinitis
    • Present in individuals who are HIV positive
    • Large, flat, dry, yellowish, or gray (with baited centers); macular or juxtapapillary placoid lesions at the retinal pigment epithelium (RPE) layer
    • Leopard spot hypofluorescence on fluorescein angiography
• Conjunctiva
  • Chancre in primary syphilis
  • Nonspecific conjunctivitis in secondary syphilis
  • Gumma in tertiary/late syphilis
• Scleritis/episcleritis
  • Nodular or diffuse
  • Usually present in secondary syphilis
• Interstitial keratitis
  • Nonulcerative and nonsuppurative inflammation of the corneal stroma
  • May form stromal neovascularization if untreated
  • Diffuse or localized
  • Congenital (90%) - Commonly appears between the sixth and twelfth years. Corneal edema and infiltrates are present with lacrimation and photophobia. Vascularization of the corneal stroma is characteristic and may give the cornea a pink salmon-patch appearance. The condition generally begins unilaterally and becomes bilateral in 90% of cases.
  • Acquired (10%) - Active interstitial keratitis shows stromal inflammation, especially in the peripheral cornea. Marginal infiltrates of the anterior stroma may be present, usually in association with anterior uveitis. When the uveal inflammation subsides, corneal scarring appears. Evidence of stromal neovascularization just anterior to the Descemet membrane may be present.
• Neuro-ophthalmic manifestations
  • Papillitis
  • Optic neuritis
  • Optic perineuritis
  • Papilledema
• Lids/eyebrows
  • Chancre rarely occurs in the primary stage.
  • Brow loss at its temporal aspect has been reported in secondary and tertiary syphilis.
  • Tarsitis or lid abscess rarely occurs in the tertiary stage.
  • Pseudoepitheliomatous hyperplasia also has been reported, as a rare occurrence, related to the gumma of tertiary syphilis. These lesions generally are elevated, and they have an uneven surface that is either ulcerated or crusty, which appears similar to squamous cell carcinoma or basal cell carcinoma.
• Others
  • Cataract has been seen in syphilis cases; however, it is not fully known whether the development is caused by T pallidum or from the uveitis associated with the disease.
  • Glaucoma almost always is associated with uveitic inflammation. In congenital syphilis, interstitial keratitis is associated with adult secondary glaucoma in 15-20% of patients. The glaucoma develops an average of 27 years after the initial episode of interstitial keratitis has subsided. Clinical evidence has shown 2 different forms of late glaucoma, a deep-chamber, open-angle type, and a shallow-chamber, narrow-angle type. Both types occur with equal frequency and present with characteristic changes of congenital syphilis, such as corneal scarring with ghost vessels and chorioretinal atrophy.

Causes

Spirochete T pallidum

• The only known natural host is Homo sapiens.
• Its origin is unknown.
• The entire genome of T pallidum has been determined. There are 1.1 million base pairs, containing 1041 open reading frames. The study of these open reading frames and their protein products help scientists study the virulence factors, develop a method of culture, develop a vaccine, and develop specific and sensitive diagnostic tests.

Differential Diagnoses

Other Problems to Be Considered

Iritis
Chorioretinitis
Retinal vasculitis
Papillitis
Iris papules
Neurosyphilis
Genital warts
Condyloma acuminata
Lymphogranuloma venereum
Chancroid
Traumatic superinfected lesions
Carcinoma
Mycotic infection
Granuloma inguinale
Lichen planus
Fungal infection
Venereal chlamydial infections
Drug eruptions
Pityriasis rosea
Viral exanthem

Workup

Laboratory Studies

• Serologic nontreponemal tests include Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR).
  • Nontreponemal tests detect antibodies directed against cardiolipin (lecithin) cholesterol antigens.
  • It is simple and convenient for routine screening at the local level. It is a frequent local requirement for premarital and prenatal serology. The false-positive rate for pregnant women is 1-2%.
  • A minimum of 1-3 weeks must pass from the onset of infection for the test to turn positive. It usually is positive in primary syphilis and invariably positive in secondary syphilis.
  • A high titer (>1:16) usually indicates active disease. Biologic false-positive tests (usually <1:8) occur in intravenous drug users, in many acute infections (eg, infectious mononucleosis, mycoplasmal infection, malaria, leprosy), in a variety of chronic disorders (eg, systemic lupus erythematosus), and possibly pregnancy.
  • Quantification of VDRL always should be performed before onset of treatment.
  • Nontreponemal test titers should decrease by 4-fold within 3 months of adequate treatment of primary or secondary disease, and they should decrease by 8-fold within 6 months following therapy for early latent disease.
  • The cerebrospinal fluid (CSF) titer also should diminish with adequate therapy for neurosyphilis; however, the serum nontreponemal test titer may not change in patients with late latent syphilis.
  • The VDRL titer reflects the systemic activity of the disease. Its major value is in monitoring the response to treatment.
  • A persistent fall in VDRL titers after treatment provides essential evidence of an adequate response to therapy.
  • Reactive and weakly reactive tests should be confirmed with fluorescent treponemal antibody absorption (FTA-ABS).
• Serologic treponemal tests include micro-hemagglutination T pallidum (MHA-TP), FTA-ABS, T pallidum particle agglutination (TPA).
  • Their greatest value is in distinguishing false-positive from true-positive reagin test results and in diagnosing late syphilis when blood and CSF reagin test results may be negative.
  • These are highly sensitive and specific tests.
  • Titers are not correlated with clinical activity.
  • The FTA-ABS test is not useful in monitoring response to therapy because it typically remains positive for life.
  • The FTA-ABS test is 98% sensitive, even in latent syphilis.
  • FTA-ABS test and TPA test are preferred over MHA-TP.

Other Tests

• Dark-field immunofluorescence microscopy (direct technique)
  • Fluorescein-labeled anti-T pallidum antibodies are used in an immunofluorescence analysis of exudate or samples are taken from a lesion suggestive of syphilis.
  • The antibody attaches to syphilitic organisms displaying a motile apple-green, corkscrew-shaped T pallidum.
• Electron microscopy: T pallidum organisms can be seen in interstitial and perivascular spaces.
• Ganzfeld electroretinogram (ERG)
  • Ganzfeld ERG was markedly reduced in a case of acute syphilitic posterior placoid chorioretinitis.
  • Multifocal ERG in the affected area was not recordable.
• Indocyanine green (ICG) angiography
  • ICG angiography may be a valuable tool in the assessment of patients with active ocular syphilis.
  • ICG angiography can help identify retinal and choroidal vascular anomalies that would otherwise go undetected by funduscopy and/or fluorescein angiography.
  • ICG angiography can also be useful in monitoring antitreponemal therapy.
  • The following 2 types of anomalies were observed:
    • Late-phase scattered hyperfluorescent spots
    • Persistent staining of retinal vessels

Procedures

• Lumbar puncture
  • Evaluation for asymptomatic neurosyphilis
  • Patients with positive syphilitic serologic tests should have their CSF examined for VDRL titers, total protein, and cell counts, including a differential count.
  • An elevated WBC count with a predominance of lymphocytes in the CSF or an elevated total protein level, even without a positive CSF VDRL test, is indicative of neurologic involvement, and the patient should be treated accordingly, as for neurosyphilis.
• HIV evaluation
  • Patients with ocular syphilis should be evaluated for HIV and vice versa.
  • Reports indicate that young adult patients who are HIV positive often have ocular syphilis.
  • Patients who have HIV may experience an aggressive course of syphilis, rendering standard therapy for primary and secondary syphilis inadequate.
• Polymerase chain reaction
  • Diagnostic role in unusual or atypical ocular inflammation
  • Aqueous or vitreous specimens

Histologic Findings

The organisms usually are superficial in epithelial lesions. A diffuse or focal lymphocytic infiltration is characteristic, particularly perivascularly. The tissue reaction is notable for stenosing intimal fibroplasia of small arteries and arterioles (eg, onion-skinning, obliterative endarteritis), as well as perivascular plasma infiltrate with some lymphocytes and macrophages. It may be found in the iris, ciliary body, or choroid. Chronic granulomatous inflammation containing epithelioid histiocytes and multinucleated giant cells is present. Overlying epidermal changes in skin can be hyperplastic (eg, condylomata lata) or ulcerating (eg, chancre). In tertiary disease, gummas are present (ie, areas of coagulative necrosis surrounded by lymphocytes, plasma cells, and possibly giant cells), and organisms are more abundant. Warthin-Starry silver stain, a specialized direct staining technique, sometimes is used.

Treatment

Medical Care

Patients with ocular syphilis should be treated the same as patients with neurosyphilis.

• The treatment regimen is the same even without CSF evidence of neurosyphilis. The blood-ocular barrier is similar to the blood-brain barrier in terms of decreasing the penetration of drugs. Patients with syphilitic ocular inflammation may have CNS syphilis without a VDRL-positive CSF.
• According to the Morbidity and Mortality Weekly Report (MMWR) No. RR-14, which is the most recent guideline for the treatment of syphilis, the treatment of neurosyphilis is as follows:
• Administer aqueous crystalline penicillin G, 2-4 million U IV q4h for 10-14 days. Alternatively, give procaine penicillin IM qd plus probenecid, 500 mg PO qid both for 10-14 days.
• In addition to the MMWR treatment guidelines for neurosyphilis, the administration of benzathine penicillin is preferred, 2.4 million U IM for 3 weeks, following either of the regimens to achieve a duration of therapy comparable to that of other forms for late syphilis.

Surgical Care

In cases of interstitial keratitis, rehabilitative interventions include a penetrating keratoplasty.

Consultations

• Collaboration with an infectious disease specialist is ideal in cases of suggestive of syphilis. A lumbar puncture may be performed to exclude the possibility of neurosyphilis.
• An allergologist consult may be warranted in cases of penicillin allergy.

Medication

The goal of pharmacotherapy is to eradicate the infection, to prevent complications, and to reduce morbidity.

Parenteral penicillin is DOC for all stages of syphilis. T pallidum is extremely sensitive to penicillin. Since T pallidum resistance to penicillin has not surfaced, the need for alternative drugs in treating syphilis is reserved for penicillin-allergic cases.

Doxycycline, erythromycin, or tetracycline has been suggested for patients allergic to penicillin. Nonpenicillin regimen has been shown to be less effective in the treatment of neurosyphilis; therefore, attempts at penicillin desensitization may be worthwhile.

Antibiotics

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

Penicillin G aqueous, benzathine (Pfizerpen, Bicillin LA)

Bactericidal against penicillin-susceptible microorganisms during stage of active multiplication. Inhibits biosynthesis of cell wall mucopeptide, rendering the cell wall osmotically unstable. Not active against penicillinase-producing bacteria, which include many staphylococcal strains.

Dosing

Adult

2-4 million U of aqueous crystalline penicillin G IV q4h for 10-14 d, followed by 2.4 million U of benzathine penicillin G IM qwk for 3 wk

Pediatric

Dose depends on age and stage of disease; suggested dosages are as follows:
Syphilis <1 year: 50,000 U/kg IM once; not to exceed 2.4 million U
Syphilis > 1 year: 50,000 U/kg IM qwk for 3 doses; not to exceed 2.4 million U

Interactions

Probenecid can increase penicillin effectiveness by decreasing clearance; coadministration with tetracyclines and other bacteriostatic antibiotics can decrease effectiveness of penicillin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in impaired renal function and patients with history of significant allergies and/or asthma

Doxycycline (Bio-Tab, Doryx, Vibramycin, Doxy)

Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Dosing

Adult

100-200 mg/d PO qd or divided bid

Pediatric

<8 years: Not recommended
>8 years: 2-5 mg/kg/d qd or divided bid; not to exceed 200 mg/d

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Erythromycin (E.E.S., E-Mycin, Ery-Tab)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest. For treatment of staphylococcal and streptococcal infections.
In children, age, weight, and severity of infection determine proper dosage. When bid dosing is desired, half-total daily dose may be taken q12h. For more severe infections, double the dose.

Dosing

Adult

250 mg erythromycin stearate/base (or 400 mg ethylsuccinate) PO q6h, or 500 mg q12h (1 h ac or 2 h pc)
Alternatively, 333 mg PO q8h; increase to 4 g/d depending on severity of infection

Pediatric

30-50 mg/kg/d (15-25 mg/lb/d) PO divided q6-8h; double dose for severe infection

Interactions

Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin, increases risk of rhabdomyolysis

Contraindications

Documented hypersensitivity; hepatic impairment

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common (give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Tetracycline (Sumycin)

Treats gram-positive and gram-negative organisms as well as mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).

Dosing

Adult

250-500 mg PO q6h
Mild-to-moderate infections: 500 mg PO bid or 250 mg PO qid for 7-14 d
Severe infections: 500 mg PO qid for 7-14 d

Pediatric

<8 years: Not recommended
>8 years: 25-50 mg/kg/d (10-20 mg/lb) PO qid

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Uricosuric agents

Used primarily to elevate and prolong plasma levels of penicillin.

Probenecid

The generic name is 4-[(dipropylamine-)sulfonyl)]benzoic acid. Inhibits tubular secretion of penicillin, and usually increases penicillin plasma levels by any route the antibiotic is given. A 2-fold to 4-fold elevation has been demonstrated for various penicillins. Used in treatment of hyperuricemia associated with gout and gouty arthritis. Also used as an adjuvant to therapy with penicillin or ampicillin, methicillin, oxacillin, cloxacillin, or nafcillin, for elevation and prolongation of plasma levels by whichever route the antibiotic is given.

Dosing

Adult

500 mg PO qid 10-14 d

Pediatric

Initial: 25 mg/kg body-weight or 0.7 g/m² body surface
Maintenance: (next 9-13 d) 40 mg/kg body-weight or 1.2 g/m² body surface divided qid

Interactions

Salicylates at high dosages and nitrofurantoin may decrease effects of probenecid; increases levels/toxicity of methotrexate, beta-lactam antibiotics, acyclovir, thiopental, clofibrate, dyphylline, pantothenic acid, ketorolac, benzodiazepines, rifampin, sulfonamide, dapsone, zidovudine, sulfonylureas

Contraindications

Documented hypersensitivity; children <2 years; known blood dyscrasia or uric acid kidney stones; coadministration of ketorolac as levels/toxicity of ketorolac are increased significantly

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Crosses placental barrier; use of any drug in women of childbearing potential requires anticipated benefit be weighed against possible hazards; caution in history of peptic ulcer

Follow-up

Further Inpatient Care

• Following treatment, monitor titers for evidence of response or treatment failure. A 4-fold decrease in antibody titers should be evident. The decline in antibody titers is slower in late latent and neurosyphilis.

Further Outpatient Care

• Repeat serum and CSF VDRL titers to monitor adequacy of treatment.
• Clinical manifestations often improve after effective treatment.
• Seroconversion or stable low titers of nontreponemal tests also indicate effective treatment.
• A 4-fold and 8-fold decrease in nontreponemal titers should occur in 3 and 6 months, respectively.
• Patients with neurosyphilis should be monitored with CSF examination every 6 months for decreasing cell count. If there is no decrease in 6 months, or if the cell count does not return to normal in 2 years, retreatment should be considered.

Inpatient & Outpatient Medications

• After inpatient intravenous treatment, 2.4 million U of benzathine penicillin G IM is administered every week for 3 weeks.

Deterrence/Prevention

• Safe sex practices
• Condom use

Complications

• The Jarisch-Herxheimer reaction is the release of endotoxin when a large number of organisms are killed by antibiotics. The Jarisch-Herxheimer reaction is not a dose-related phenomenon; administering a smaller dose is of no value. This reaction occurs about 8 hours after the first injection, usually consisting of mild fever, malaise, and headache and lasting a few hours.
  • Occurs in 50% of patients with primary syphilis
  • Occurs in about 90% of patients with secondary syphilis
  • Rarely seen in quaternary syphilis as a severe reaction
• Irreversible end-organ damage
• Paroxysmal cold hemoglobinemia (PCH)
  • PCH is a rare type of autoimmune hemolytic anemia, occurring primarily in children. PCH manifests as massive intravascular hemolysis with anemia and hemoglobinuria, usually of abrupt onset in the setting of an infectious disease.
  • Secondary PCH may also occur in association with infections in adults. In the latter half of the 19th century, the most common cause was congenital or tertiary syphilis. A near total disappearance of the recurrent, chronic form of secondary PCH occurred with the ability to treat syphilis with antibiotics.
• See also Pathophysiology.

Prognosis

• Ocular syphilis, if clinically diagnosed and appropriately treated early in its course, usually results in full visual recovery.
  • If syphilitic intraocular inflammation is left untreated, chronic progressive intraocular inflammation may ensue.
  • Inflammation leads to secondary glaucoma, chronic vitritis, retinal necrosis, and optic atrophy.

Patient Education

• Advise patients to practice safe sex.
• Advise patients against sharing needles.
• Encourage patients to consider premarital and perinatal screenings.
• For excellent patient education resources, visit eMedicine's Sexually Transmitted Diseases Center and Eye and Vision Center. Also, see eMedicine's patient education articles Sexually Transmitted Diseases, Syphilis, Anatomy of the Eye, and Iritis.

Miscellaneous

Medicolegal Pitfalls

• Misdiagnosis will lead to nontreatment or treatment with the wrong medication, allowing the disease to progress and result in its potentially blinding sequelae.
• A high index of clinical suspicion is required. Remember that syphilis can mimic almost any intraocular inflammatory condition.

Special Concerns

• Pregnancy
  • The penicillin treatment regimen is appropriate for syphilis with pregnancy. The potential problem arises when a penicillin-allergy exists. The optimal treatment of pregnant patients is controversial. An alternate therapy is erythromycin.
  • Avoid doxycycline because of its potential adverse effects on both the mother and the fetus.
  • Penicillin skin testing, and, if necessary, desensitization are recommended.
  • Both an OB-GYN and a pediatrics infectious disease specialist should be invited into the management team.
• Infants/children
  • Treat infants if the mother has untreated syphilis, if the infant has clinical syphilis, if the VDRL or RPR is 4 times that of the mother, or if there is a reactive CSF VDRL test or positive FTA-ABS immunoglobulin M test.
  • Evaluate infants for congenital syphilis when the mother has been treated for syphilis prior to pregnancy.
  • Perform a nontreponemal serologic test on the infant's sera and a CSF test for cells, protein, and VDRL.
  • Perform an antitreponemal testing on the infant and cord or placenta.
  • Perform long bone radiographs and other tests, as clinically indicated.
  • Suspect child abuse and/or molestation in a pediatric patient exhibiting syphilitic lesions.
• Patients who are infected with HIV
  • Treat syphilis in patients who are infected with HIV aggressively with a course sufficient for neurosyphilis, regardless of the CNS examination.
  • In most patients with HIV infection, serologic tests for syphilis are accurate, although there are reports of false-negative test results and delayed seroconversion.
  • Anecdotal evidence suggests that patients infected with HIV are at an increased risk of developing neurosyphilis and have higher treatment failure rates.
  • Do not standardize the treatment of patients who are infected with HIV.
• Penicillin allergy
  • This is not a contraindication to penicillin. When challenged with penicillin, most individuals with a history of penicillin allergy do not manifest symptoms, or the symptoms are mild and affect the skin.
  • Treatment guidelines recommend provocative testing and desensitization, if necessary. Penicillin is the preferred treatment of all types of syphilis.
• Sexual partners
  • Partners of patients who are infected should be evaluated clinically and serologically, and then treated presumptively, if in sexual contact with primary, secondary, or latent syphilis within the preceding 90 days.
  • One third of the patients exposed will contract syphilis in 10-90 days. If the 90-day period has elapsed and the partner is reliable, then treat according to the clinical and serologic evaluation. Presumptive treatment is warranted if follow-up care is in doubt.

Multimedia

Media file 1: Ocular manifestations of syphilis. Interstitial keratitis in a patient with ocular syphilis.

Media file 2: Ocular manifestations of syphilis. Interstitial keratitis in a patient with ocular syphilis.

Media file 3: Ocular manifestations of syphilis. Syphilis chorioretinitis in a 30-year-old patient who is mentally retarded.

Media file 4: Ocular manifestations of syphilis. A 73-year-old female patient with syphilis. Note the optic atrophy, arteriolar narrowing, pigment loss, and clumping.

Media file 5: Ocular manifestations of syphilis. Retinal vasculitis in a patient with ocular syphilis.

Media file 6: Ocular manifestations of syphilis. Fluorescein angiography of same patient as in Media file 5.

Media file 7: Ocular manifestations of syphilis. Chorioretinitis of ocular syphilis.

Media file 8: Ocular manifestations of syphilis. Retinal vasculitis of ocular syphilis as seen on fluorescein angiography.

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Keywords

ocular syphilis, interstitial keratitis, episcleritis, scleritis, iritis, iris papules, chorioretinitis, papillitis, retinal vasculitis, exudative retinal detachment, primary syphilis, secondary syphilis, latent syphilis, tertiary syphilis, quaternary syphilis, Treponema pallidum, T pallidum, lues, chancre, gumma, sexually transmitted disease, STD, HIV, AIDS

Contributor Information and Disclosures

Author

Manolette R Roque, MD, MBA, DPBO, FPAO, President and CEO, Chief of Service, Ocular Immunology and Uveitis, Consulting Staff, Cornea and Refractive Surgery, Eye Republic Ophthalmology Clinic; General Manager, Ophthalmic Consultants Philippines Co; Consulting Staff, CME Liaison, Section Chief of Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center
Manolette R Roque, MD, MBA, DPBO, FPAO is a member of the following medical societies: American Academy of Ophthalmic Executives, American Society of Cataract and Refractive Surgery, American Society of Ophthalmic Administrators, American Uveitis Society, International Ocular Inflammation Society, Philippine Medical Association, Philippine Ocular Inflammation Society, and Philippine Society of Cataract and Refractive Surgery
Disclosure: Nothing to disclose.

Coauthor(s)

Barbara L Roque, MD, Full Partner, Ophthalmic Consultants Philippines Co, Chief of Service, Pediatric Ophthalmology and Strabismus, Consulting Staff, Orbit and Eye Plastics, EYE REPUBLIC Ophthalmology Clinic
Disclosure: Nothing to disclose.

C Stephen Foster, MD, FACS, FACR, FAAO, Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institute
C Stephen Foster, MD, FACS, FACR, FAAO is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, American Association of Immunologists, American College of Rheumatology, American College of Surgeons, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, American Uveitis Society, Association for Research in Vision and Ophthalmology, Massachusetts Medical Society, Royal Society of Medicine, Sigma Xi, and Washington State Medical Association
Disclosure: Nothing to disclose.

Medical Editor

John D Sheppard, Jr, MD, MMSc, Associate Professor of Ophthalmology, Microbiology and Immunology, Director for Thomas R Lee Center for Ocular Pharmacology, Director, Uveitis Service, Eastern Virginia School of Medicine; Consulting Staff, Virginia Eye Consultants
John D Sheppard, Jr, MD, MMSc is a member of the following medical societies: American Academy of Ophthalmology, American Society for Microbiology, American Uveitis Society, Association for Research in Vision and Ophthalmology, and Contact Lens Association of Ophthalmologists
Disclosure: Nothing to disclose.

Pharmacy Editor

Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles
Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.

Managing Editor

J James Rowsey, MD, Director of Corneal Services, St Luke's Cataract and Laser Institute, Florida
Disclosure: Nothing to disclose.

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

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