Syphilis — All Stages

• Spirochetal invasion and dissemination: T. pallidum is a microaerophilic spirochete with a protein-poor outer membrane that enables immune evasion. Following inoculation through intact mucosa or abraded skin, treponemes multiply locally at the site of inoculation and within 3-90 days (average 21 days) produce the characteristic primary chancre—a painless, indurated ulcer with a "punched-out" appearance and clean base. Within days of local replication, the organism disseminates hematogenously and lymphatically throughout the body, despite active humoral and cellular immune responses. The outer membrane proteins are poorly immunogenic and vary among organisms, explaining the ineffective early immune response and the organism's ability to establish disseminated infection before local immune containment occurs.

• Secondary syphilis immune-mediated phenomena: Secondary syphilis (2-8 weeks after chancre appearance, or up to 2 years later) represents widespread dissemination coupled with developing but inadequate specific immunity. The clinical manifestations of secondary syphilis are largely immune-mediated rather than due to direct tissue invasion: circulating immune complexes (antigen-antibody complexes) deposit in blood vessel walls, joints, and other tissues, triggering complement activation and recruiting neutrophils and macrophages. This explains the systemic nature of secondary syphilis symptoms including fever, lymphadenopathy, arthralgias, and the characteristic maculopapular rash (including the pathognomonic palms/soles involvement). The mucous patches (painless ulcers in the oral cavity and genital area, highly infectious) and condyloma lata (flat, wart-like lesions in warm, moist areas) represent areas of high bacterial burden with severe inflammation. Secondary syphilis classically includes hepatitis, nephritis, uveitis, periostitis, and other organ involvement mediated by immune complex deposition.

• Latent syphilis and immune stalemate: After untreated secondary syphilis, most patients enter a latent phase lasting years to decades, during which treponemes persist in tissue niches (particularly the central nervous system, eyes, and vascular tissues) while remaining largely sequestered from the immune system. The host develops increasing treponemal-specific antibody titers and some cellular immunity, but this is insufficient to completely clear the organisms. During latency, patients are asymptomatic and rarely contagious (except pregnant women can transmit to offspring). The early latent phase (≤1 year) carries higher risk of secondary syphilis relapse and contagiousness, while late latent syphilis (>1 year) represents more stable bacterial-host equilibrium. Approximately 30% of untreated patients progress to tertiary syphilis.

• Tertiary syphilis: chronic inflammation and tissue destruction: Tertiary syphilis develops 3-30+ years after primary infection and represents distinct pathophysiologic entities: (1) Neurosyphilis includes general paresis of the insane (GPI—chronic meningoencephalitis causing dementia, personality changes, paresis), tabes dorsalis (selective degeneration of dorsal columns and dorsal roots), and meningitis/meningovascular disease; (2) Gummatous syphilis involves granulomatous inflammation with central necrosis forming destructive lesions in skin, bones, viscera, and cardiovascular tissues—a hypersensitivity reaction to treponeal antigens in tissues with relatively high bacterial load; (3) Cardiovascular syphilis includes aortitis (causing aortic root dilatation, aortic insufficiency, and coronary ostial stenosis) and aortic aneurysms. Tertiary lesions reflect both direct bacterial effects and intense Th1-mediated granulomatous inflammation.

• Congenital syphilis pathophysiology: Vertical transmission occurs when maternal treponemia (untreated or inadequately treated) allows transplacental passage of organisms, particularly during early pregnancy when spirochete concentration in blood is highest (secondary/early latent stages). Fetal infection can cause miscarriage, stillbirth, prematurity, intrauterine growth restriction, or neonatal disease. Congenital manifestations reflect both direct bacterial invasion (producing hepatitis, pneumonitis, osteitis) and immune-mediated inflammation, with variable expression depending on gestational timing and fetal immune response.

• Immune evasion mechanisms: T. pallidum employs multiple strategies to evade immunity: (1) low immunogenicity of outer membrane proteins; (2) coating with fibronectin and other host proteins; (3) production of proteases that degrade complement and antibodies; (4) persistence in immunologically privileged sites (CNS, eyes, testes); (5) antigenic variation. This explains why primary infection doesn't provide solid immunity and reinfection is possible, and why sustained antibody titers persist even after successful treatment.

• Sexual transmission: The primary etiology is sexual contact with someone having infectious syphilis (primary, secondary, or early latent stage). T. pallidum requires moist mucous membranes or abraded skin for transmission and cannot penetrate intact skin. Both receptive and insertive partners can acquire infection through penile-vaginal, penile-anal, or penile-oral contact. MSM constitute the highest-risk population in contemporary epidemiology, with rates of primary and secondary syphilis among MSM being 50-100 times higher than heterosexual populations; within MSM, those with multiple partners, history of HIV infection, or high-risk sexual practices carry elevated risk.

• Vertical (mother-to-child) transmission: Untreated pregnant women with primary, secondary, or early latent syphilis have approximately 70-100% risk of transmission to the fetus. Maternal spirochemia is highest during secondary and early latent stages. Risk is much lower in late latent or tertiary disease due to reduced bacteremia, but transmission remains possible. Maternal serological screening and adequate prenatal treatment prevent congenital syphilis—making this a critical preventive medicine issue.

• Percutaneous exposure and transfusion: Rare transmission can occur through needlestick injury in laboratory settings, transfusion of blood products (though rare in developed nations due to screening), and sharing of injection drug equipment among people who inject drugs (PWID), though this is an uncommon route.

• Risk factors for severe/progressive disease: (1) Untreated status—the greatest risk factor; (2) Immunocompromise, particularly advanced HIV (CD4+ <200 cells/μL) which increases risk of neurosyphilis and accelerates progression; (3) Pregnancy—risk of congenital transmission; (4) Delayed diagnosis—each stage progresses to the next if untreated; (5) Inadequate treatment—incorrect antibiotic selection or dosing.

• Epidemiological risk factors: Young adults (ages 20-39), particularly in urban centers; racial/ethnic disparities (disproportionate burden in Black and Hispanic populations, reflecting systemic inequities in healthcare access); low socioeconomic status; incarceration history; active substance use disorder.

Primary Syphilis

• The chancre (hard chancre, primary ulcer): The hallmark lesion appearing 3-90 days after exposure (mean 21 days) at the inoculation site. Classically described as a painless, indurated ulcer with a "punched-out" appearance, clean granulating base, and smooth raised indurated border. The ulcer is typically solitary but multiple chancres can occur with multiple exposure sites. Location varies with route of exposure: genital penis or labia most common; perianal in receptive anal intercourse; oral/pharyngeal in receptive oral sex. The chancre is highly infectious due to high spirochete concentration in exudate. If untreated, the chancre spontaneously heals in 3-6 weeks even without therapy, sometimes causing patients to forego care (a critical board point—healing doesn't mean cure).

• Regional lymphadenopathy: Painless, indurated, rubbery lymph nodes (called buboes when significantly enlarged, though this term is more classically applied to other infections) develop within days to weeks, typically epitrochlear and inguinal nodes for genital chancres. Lymph node enlargement persists for months.

• Systemic symptoms: Generally minimal or absent in primary syphilis; low-grade fever and malaise may occur.

• Diagnostic clue: A painless ulcer with indurated borders and regional adenopathy should immediately raise suspicion for primary syphilis, especially in sexually active individuals.

Secondary Syphilis

• Rash (most common manifestation): Appears 4-10 weeks after the chancre (or 2-8 weeks after initial exposure) in 75-90% of secondary syphilis cases. The rash is typically maculopapular, non-pruritic, non-blanching, involving trunk and proximal extremities. Characteristic involvement of palms and soles is highly specific for secondary syphilis and appears in ~50% of cases—this classic exam finding is heavily featured on boards. The rash typically spares the face. Discrete lesions are preferred in syphilis (contrasting with other conditions); lesions may be follicular (each hair follicle contains a pustule) or create a "snap-shot" appearance.

• Mucous patches: Painless, shallow ulcers or erosions with white-gray pseudomembrane appearing on oral mucosa, gums, tonsils, pharynx, genital mucosa, and perianal area. These are highly infectious. They may be accompanied by mild pain or difficulty eating. Can resemble oral thrush or other conditions but are truly painless and lack the typical candida appearance.

• Condyloma lata: Flat, broad-based, wart-like lesions in warm, moist areas (perianal, genital, axillae, inframammary, interdigital spaces). These are extremely infectious and distinguish secondary from primary syphilis. Often mistaken for genital warts (condyloma acuminata from HPV) but are flatter and more indurated.

• Generalized lymphadenopathy: Rubbery, non-tender, non-suppurative lymph nodes involving cervical, axillary, inguinal, and epitrochlear nodes; can persist for months.

• Hepatitis: Mild elevation in transaminases and alkaline phosphatase; jaundice is uncommon.

• Constitutional symptoms: Fever, headache, malaise, anorexia, weight loss, arthralgias/arthritis (particularly knees, ankles, wrists—sterile joint inflammation from immune complexes), and myalgias.

• CNS involvement (asymptomatic neurosyphilis): Approximately 25% of secondary syphilis patients have CSF abnormalities (pleocytosis, elevated protein), though most are asymptomatic. Symptomatic manifestations include acute meningitis (fever, headache, nuchal rigidity, CSF pleocytosis), meningovascular disease (stroke-like symptoms from large or small vessel inflammation), and cranial nerve palsies (CN II, VII, VIII most common—especially hearing loss which can be sudden and profound).

• Ocular involvement: Anterior uveitis, posterior uveitis (including retinitis), optic neuritis, and keratitis can cause floaters, photophobia, blurred vision, or uveitic rash.

• Periostitis and bone pain: Particularly affecting long bones; radiographs may show periosteal new bone formation ("saber shins" if tibiae involved, "syphilitic saddle nose" if nasal bones involved, though these are more tertiary).

• Other rarer manifestations: Glomerulonephritis, pneumonitis, hepatic granulomas.

• Important clinical variants: (1) Malignant secondary syphilis—an aggressive form with severe systemic symptoms, high spirochete load, rapid progression, and increased risk of neurosyphilis; more common in immunocompromised hosts (especially advanced HIV). (2) Asymptomatic secondary syphilis—serological evidence of secondary syphilis without clinical symptoms, discovered on routine screening.

Latent Syphilis

• By definition asymptomatic: No clinical signs or symptoms. Diagnosed solely by serology. Divided into early latent (≤1 year from primary infection or documented secondary syphilis) and late latent (>1 year or unknown duration). Early latent patients may occasionally have secondary syphilis manifestations recur, though rare.

Tertiary Syphilis

• Neurosyphilis spectrum (develops in ~8-10% of untreated patients):
• General paresis of the insane (GPI / paretic neurosyphilis): Chronic meningoencephalitis with insidious onset of personality changes, cognitive decline, grandiosity, paranoia, poor judgment, progressive dementia, tremor, dysarthria, hyperreflexia, Argyll Robertson pupils (pupils that accommodate but don't react to light—due to selective damage of light-reflex pathway), and ultimate profound disability. Personality changes often precede cognitive decline and include disinhibition, irritability, and inappropriate behavior. Onset typically 10-20+ years after initial infection.

• Tabes dorsalis: Selective degeneration of dorsal columns and dorsal nerve roots, causing progressive sensory ataxia, loss of proprioception and vibration sense, characteristic "tabetic gait" (high-stepping to compensate for proprioceptive loss), lancinating pains in legs (sudden sharp stabbing pains), Argyll Robertson pupils, hyporeflexia progressing to areflexia, bladder dysfunction (overflow incontinence, frequency), impotence, and trophic changes (painless ulcers, arthropathy from repeated trauma). Romberg sign is typically positive (severe sway or falling with eyes closed due to loss of proprioception). Onset typically 15-30+ years after infection.

• Meningitis and meningovascular syphilis: Acute or chronic meningitis with fever, headache, cranial nerve involvement (CN palsies), and CSF pleocytosis. Meningovascular disease involves large or small vessel inflammation/vasculitis causing stroke-like presentations.

• Gummatous syphilis (~15% of tertiary): Granulomatous lesions that are rare but potentially devastating, appearing in skin (nodules and plaques that ulcerate), bone (causing destructive osteitis), liver (hepatic gummas causing destructive lesions), and other organs. Skin gummas are characterized by copper-colored indurated nodules that break down to form necrotic ulcers with punched-out borders and surrounding inflammation. Characteristic appearance in nasal bones causes "syphilitic saddle nose" deformity (collapse of nasal bridge).

• Cardiovascular syphilis (~10% of tertiary): Aortitis (inflammation of the ascending aorta) develops 10-40+ years after primary infection. Complications include: aortic root dilatation causing aortic regurgitation (presenting as a diastolic decrescendo murmur, wide pulse pressure); coronary artery ostial stenosis; aortic aneurysm (typically thoracic, ascending aorta) potentially causing aortic dissection, rupture, or hemodynamic compromise; and conduction abnormalities from fibrosis of the conduction system. Cardiovascular syphilis accounts for significant morbidity and mortality in untreated disease.

Clinical Suspicion & History

Serological Diagnosis (Gold Standard)

• Treponemal tests

Immediate considerations before dosing

• Stage the disease first: therapy duration is determined entirely by stage and by whether CNS, ocular, or otic disease is present. Per the CDC STI Treatment Guidelines, ocular syphilis, otosyphilis, and symptomatic neurosyphilis are treated urgently as neurosyphilis regardless of CSF findings — do not wait for the lumbar puncture result to start therapy.
• Anaphylaxis readiness: penicillin is given parenterally; epinephrine 0.3 mg IM must be available.

First-line therapy (CDC STI Treatment Guidelines)

• Beta-lactam / long-acting penicillin — benzathine penicillin G IM: 2.4 million units as a single dose for primary, secondary, and early latent syphilis. Treponemes divide slowly, so a sustained low serum level for weeks — not a high peak — is what kills them.
• Late latent, latent of unknown duration, or tertiary gummatous/cardiovascular disease: benzathine penicillin G 2.4 million units IM weekly for three doses.
• Neurosyphilis, ocular syphilis, otosyphilis: aqueous crystalline penicillin G IV for 10–14 days (continuous infusion or divided every 4 hours), because benzathine penicillin does not achieve treponemicidal CSF concentrations. IM procaine penicillin plus oral probenecid is an accepted alternative.
• Congenital syphilis: IV aqueous crystalline or IM procaine penicillin G for 10 days (CDC/AAP Red Book).

Penicillin allergy and escalation

• Tetracyclines — doxycycline for 14 days (early disease) or 28 days (late latent) in non-pregnant, non-neurologic cases; ceftriaxone is an alternative, and true cephalosporin cross-reactivity is only about 1–3%, driven by shared R1 side chains.
• Pregnancy is the absolute exception: only penicillin is adequate, so a penicillin-allergic pregnant patient requires skin testing and desensitization, then benzathine penicillin.

Contraindicated or inadequate

• Doxycycline in pregnancy; azithromycin (documented 23S rRNA macrolide resistance); Bicillin C-R (penicillin G benzathine/procaine combination) substituted for Bicillin L-A; and benzathine penicillin given IV — never do this.

Complications of the disease

• Neurosyphilis (any stage — emergency): treponemes seed the CSF early, so meningitis, meningovascular stroke, cranial neuropathies, general paresis, or tabes dorsalis can occur years apart. Signaled by new headache with stiff neck, stroke in a young patient, Argyll Robertson pupils, or cognitive/personality change. Requires IV penicillin, not IM.
• Ocular syphilis and otosyphilis (emergency): panuveitis, optic neuritis, or sudden sensorineural hearing loss. The signal is acute visual blurring/floaters or abrupt hearing loss in a patient with a positive treponemal test — delay causes irreversible blindness or deafness. Treat as neurosyphilis even if the CSF is normal (CDC).
• Cardiovascular syphilis (emergency when acute): obliterative endarteritis of the vasa vasorum destroys the aortic media, producing tree-bark intima, ascending aortic aneurysm, aortic regurgitation, and coronary ostial stenosis. Signaled by a decrescendo diastolic murmur with wide pulse pressure, or a widened mediastinum; rupture or dissection is immediately life-threatening.
• Congenital syphilis: transplacental infection causes stillbirth, hydrops, snuffles, desquamating palmar/plantar rash, hepatosplenomegaly, and pseudoparalysis of Parrot from osteochondritis; late stigmata are the Hutchinson triad (notched incisors, interstitial keratitis, sensorineural deafness), mulberry molars, saber shins, and saddle nose.
• Enhanced HIV transmission: the breached mucosal barrier of a chancre and local CD4 recruitment raise both acquisition and transmission risk — always co-test for HIV.

Complications of treatment

• Jarisch–Herxheimer reaction: within 24 hours of the first penicillin dose, spirochete lysis releases lipoproteins driving a TNF/IL-6 surge — fever, rigors, myalgia, headache, and transient rash worsening. It is self-limited and managed with antipyretics; it is not a penicillin allergy and does not preclude further dosing. In pregnancy it can precipitate fetal distress, uterine contractions, and preterm labor, so third-trimester patients warrant monitoring.
• **Procaine reaction (Hoigné syndrome)**: inadvertent intravascular procaine penicillin causes acute anxiety, a sense of impending doom, and hallucinations.
• Anaphylaxis to penicillin, particularly after desensitization — an emergency treated with IM epinephrine.
• Serofast state: persistently low nontreponemal titers after adequate therapy; distinguish from treatment failure or reinfection, which show a failure to decline fourfold or a fourfold rise.

• Painless genital ulcer = syphilis; painful ulcer = chancroid: the hard chancre of T. pallidum is indurated, clean-based, and painless with rubbery nodes; Haemophilus ducreyi gives a ragged, painful, purulent ulcer with suppurative nodes. This is the single most repeated ulcer discriminator.
• Rash involving palms and soles: the classic differential is secondary syphilis, Rocky Mountain spotted fever, and coxsackievirus hand-foot-and-mouth disease. Add condyloma lata and mucous patches and the answer is syphilis.
• The one association examiners love: Argyll Robertson pupils — accommodate but do not react to light — point to tertiary neurosyphilis (also seen in tabes dorsalis alongside lancinating pains, sensory ataxia, and a positive Romberg).
• Single best next step with neurologic, ocular, or otic symptoms: lumbar puncture for CSF-VDRL — but start IV aqueous crystalline penicillin G without waiting, and treat ocular/otic disease as neurosyphilis even if CSF is normal (CDC).
• Pregnancy has no alternative to penicillin: a penicillin-allergic pregnant patient gets skin testing and desensitization, then benzathine penicillin. Doxycycline is contraindicated; choosing it is the classic trap.
• Nontreponemal versus treponemal: RPR/VDRL titers fall with cure and are used to monitor response (fourfold decline expected); treponemal tests (FTA-ABS, TP-PA, EIA) stay positive for life and cannot gauge treatment success or reinfection.
• Prozone phenomenon: in secondary syphilis, antibody excess can make an undiluted RPR falsely negative — the fix is to dilute the serum, not to abandon the diagnosis.
• Common distractors to avoid: azithromycin (macrolide resistance), a single IM benzathine dose for neurosyphilis (does not cross into CSF), and calling the post-treatment fever an allergy — that is the Jarisch–Herxheimer reaction, and therapy continues.