Multisystem Processes & Disorders

Syphilis: stages, diagnosis, and treatment

Clinical Overview and When to Suspect Syphilis

— A painless genital, anal, or oral ulcer (primary chancre)

— Diffuse maculopapular rash involving palms and soles, often with mucous patches or condylomata lata (secondary)

— Unexplained neurologic, ocular, or otic symptoms in a sexually active adult (neurosyphilis can occur at any stage)

— New positive HIV diagnosis (co-infection rate is very high — screen all)

— Pregnancy at first prenatal visit, with repeat screening at 28 weeks and delivery in high-prevalence areas

— Men who have sex with men (MSM) — every 3–6 months if active

— Persons living with HIV

— Pregnant individuals (per USPSTF, A recommendation)

— Sex workers, incarcerated persons, those with new/multiple partners

— Patients reporting recent partner with syphilis or other STI

— Primary: chancre, ~3 weeks after exposure

— Secondary: 4–10 weeks later, systemic

— Early latent: asymptomatic, infection acquired <1 year

— Late latent / unknown duration: ≥1 year or unknown

— Tertiary: gummas, cardiovascular (aortitis), late neurosyphilis — years later

Syphilis is a systemic infection caused by the spirochete Treponema pallidum, transmitted via sexual contact, vertical transmission, or rarely blood/transplant exposure.

US incidence has risen sharply since 2000, with congenital syphilis cases more than quadrupling in the last decade — making screening and recognition a Step 3 preventive medicine priority.

Suspect syphilis in any patient with:

High-risk populations to screen routinely:

Stages drive both presentation and treatment duration:

Board pearl: "Early syphilis" = primary + secondary + early latent (all <1 year) and is treated with a single dose of benzathine penicillin G 2.4 million units IM. Anything beyond 1 year or unknown duration requires 3 weekly doses.

Untreated syphilis progresses unpredictably; roughly one-third develop tertiary disease, so empiric treatment for high-suspicion exposure is appropriate.

Presentation Patterns and Key History

— Appears ~21 days post-exposure (range 10–90)

— Heals spontaneously in 3–6 weeks even without treatment — patients often don't seek care

— Painless regional lymphadenopathy common

— Diffuse maculopapular rash including palms and soles (classic Step 3 buzzword)

— Constitutional symptoms: fever, malaise, sore throat, myalgia, generalized lymphadenopathy

— Mucous patches (oral, genital) — highly infectious

— Condylomata lata — moist, broad, flat warty plaques in intertriginous areas (not condylomata acuminata, which are HPV)

— Patchy "moth-eaten" alopecia

— Hepatitis, glomerulonephritis, uveitis, or hearing loss possible

— Early latent: documented seroconversion, symptoms, or sexual contact with infected partner within past 12 months

— Late latent / unknown duration: everything else

— Gummas (granulomatous lesions of skin/bone/organs)

— Cardiovascular syphilis: ascending aortitis → aortic regurgitation, aortic aneurysm (vasa vasorum endarteritis)

— Late neurosyphilis: tabes dorsalis, general paresis, Argyll Robertson pupil

— Meningitis, cranial neuropathies (CN VII, VIII), stroke-like syndromes

— Uveitis, optic neuritis, painless vision loss

— Sudden sensorineural hearing loss

Primary syphilis — solitary, painless, indurated chancre with clean base at inoculation site (genital, anal, oral, cervical — often missed in women and receptive partners).

Secondary syphilis — hematogenous dissemination, 4–10 weeks after chancre.

Latent syphilis — seroreactive but asymptomatic.

Tertiary syphilis — years to decades later in ~30% untreated.

Neurosyphilis / ocular / otic syphilis — can occur at any stage.

Key history to elicit: number/gender of partners in past 3–12 months, condom use, HIV status, prior STIs, IV drug use, pregnancy status, last menstrual period, prior syphilis treatment with titers.

Step 3 management: Always ask about ocular and neurologic symptoms in every syphilis patient — their presence mandates lumbar puncture and IV therapy regardless of stage.

Physical Exam Findings

— Inspect external genitalia, perineum, perianal area, and oral cavity in good light

— Chancre: 1–2 cm, round, well-demarcated, indurated edges, clean non-purulent base, painless

— Palpate inguinal nodes: firm, rubbery, non-tender bilateral lymphadenopathy

— Speculum exam in women — cervical chancres frequently missed; rectal exam in MSM

— Skin: symmetric, non-pruritic, copper/pink maculopapular rash; palms and soles involvement is the giveaway

— Mucous membranes: gray-white mucous patches, "snail track" ulcers

— Condylomata lata — moist, flat, smooth plaques in warm folds (perianal, vulvar, axillary)

— Patchy alopecia of scalp, eyebrows ("moth-eaten")

— Generalized lymphadenopathy including epitrochlear nodes (highly suggestive)

— Hepatosplenomegaly possible

— Cardiovascular: early diastolic decrescendo murmur of aortic regurgitation, widened pulse pressure, possibly bounding pulses; pulsatile substernal mass if aortic aneurysm

— Skin/bone gummas: indurated nodules that ulcerate, painless

— Neurologic:

– Argyll Robertson pupil — accommodates but does not react to light ("prostitute's pupil")

– Tabes dorsalis — wide-based ataxic gait, loss of proprioception/vibration, positive Romberg, lancinating pains, Charcot joints

– General paresis — dementia, personality change, dysarthria, tremor

Primary stage exam:

Secondary stage exam (most exam-rich):

Tertiary / late exam findings:

Ocular syphilis: anterior or posterior uveitis, interstitial keratitis, optic neuritis — refer same-day to ophthalmology

Otic syphilis: sensorineural hearing loss, tinnitus, vertigo

Hemodynamic note: In tertiary cardiovascular syphilis, look for wide pulse pressure, head-bobbing (de Musset sign), and signs of decompensated AR.

Board pearl: The triad of palms/soles rash + condylomata lata + generalized lymphadenopathy = secondary syphilis until proven otherwise. Don't be fooled by pityriasis rosea — that spares palms and soles.

Diagnostic Workup — Initial Serology and Direct Detection

— Nontreponemal tests (RPR, VDRL): measure antibodies to cardiolipin; quantitative titers track disease activity and treatment response

— Treponemal tests (FTA-ABS, TP-PA, EIA, CIA): detect antibodies to T. pallidum antigens; usually stay positive for life

— Traditional algorithm: nontreponemal first (RPR/VDRL) → if reactive, confirm with treponemal test

— Reverse-sequence algorithm: treponemal EIA/CIA first → if reactive, reflex to RPR; if discordant, run a second different treponemal test (TP-PA tiebreaker)

— RPR/VDRL titer reported as dilution (e.g., 1:32). A fourfold change = 2 dilutions (1:32 → 1:8 is a fourfold decrease, indicating treatment response)

— Prozone phenomenon: high antibody load (often in secondary syphilis or HIV) → falsely negative RPR; ask lab to dilute the sample if clinical suspicion is high

— False-positive nontreponemal: pregnancy, autoimmune disease (SLE, APS), TB, viral infections, IVDU, age

— Darkfield microscopy of chancre exudate — gold standard for primary syphilis if available

— PCR from lesion swab — increasingly used; not yet FDA-cleared in many US labs

— HIV test — mandatory; repeat in 3 months if negative

— Screen for gonorrhea, chlamydia, trichomonas, hepatitis B and C

— Pregnancy test in patients of childbearing capacity

— CBC, LFTs if secondary syphilis with hepatitis suspicion

Two complementary test categories — both needed because each alone is inadequate:

Two screening algorithms in current US practice:

Interpretation tips:

Direct detection (early lesions when serology may be negative):

Additional baseline labs at diagnosis:

CCS pearl: On a Step 3 CCS case with palms/soles rash, immediate orders should be RPR (quantitative), HIV antibody/antigen, GC/CT NAAT, hepatitis panel — bundle them. Don't forget to order partner notification as a counseling/social action.

Board pearl: A persistently low-positive treponemal test with negative RPR in a previously treated patient = serofast state, not treatment failure.

Diagnostic Workup — Neurosyphilis and Confirmatory Studies

— Neurologic symptoms or signs (cognitive change, cranial nerve deficits, meningitis, stroke)

— Ocular syphilis (uveitis, vision change) — always LP

— Otic syphilis (sudden SNHL, tinnitus) — always LP

— Tertiary syphilis (cardiovascular or gummatous)

— Evidence of treatment failure (titers fail to drop fourfold by 6–12 months)

— Some experts: HIV co-infection with late latent or RPR ≥1:32 and CD4 <350 — practice varies

— CSF-VDRL: highly specific, poorly sensitive — a positive is diagnostic of neurosyphilis

— CSF-FTA-ABS: highly sensitive, poorly specific — a negative effectively rules out neurosyphilis

— CSF pleocytosis (>5 WBC/µL; >20 if HIV+) and elevated protein support diagnosis even if CSF-VDRL negative

— CT/MRI brain if focal deficits or stroke-like syndrome (meningovascular syphilis can mimic CVA)

— CXR or CT chest/aortic imaging in tertiary cardiovascular syphilis to evaluate aortic root and ascending aorta

— Same-day ophthalmology consult with slit-lamp exam for any visual complaint

— Document visual acuity, intraocular pressure, fundus

— Fourfold rise in RPR titer after adequate treatment = reinfection or failure → re-treat AND perform LP

— Persistent positive treponemal with low-stable RPR = serofast, no further treatment needed

— Syphilis is a nationally notifiable disease; report all confirmed and probable cases to public health

Lumbar puncture indications — perform CSF analysis if any of the following:

CSF interpretation:

Imaging:

Ocular evaluation:

Reinfection vs treatment failure:

Reporting:

Key distinction: CSF-VDRL is specific but insensitive — don't rule out neurosyphilis on a negative CSF-VDRL alone. Use the combination of clinical syndrome + CSF cell count/protein + serology.

Board pearl: Ocular or otic syphilis = treat as neurosyphilis even if LP is unremarkable — these are penicillin-IV-requiring scenarios.

Risk Stratification and Treatment Decision Logic

— Primary, secondary, early latent (<1 year) → single-dose IM benzathine PCN G

— Late latent / unknown duration / tertiary (non-neuro) → 3 weekly doses of IM benzathine PCN G

— Neurosyphilis, ocular, otic, congenital → IV aqueous PCN G for 10–14 days

— Neuro/ocular/otic symptoms, tertiary disease, treatment failure

— Pregnant patients with penicillin allergy must be desensitized — no alternative is adequate for the fetus

— Screen all; treatment regimens are the same as HIV-negative patients in current CDC 2021 guidelines, but follow-up titers are checked more frequently (3, 6, 9, 12, 24 months)

— Sexual contacts within preceding 90 days of a patient with primary, secondary, or early latent syphilis → treat presumptively, even if seronegative

— Contacts >90 days prior → treat presumptively if serology unavailable or follow-up uncertain

— Late latent partners → test and treat based on results

— Expedited partner therapy (EPT) legal status varies — check state law

— Mandatory reporting to local health department

— Partner notification (patient-initiated, provider-initiated, or DIS-assisted)

— HIV testing and PrEP counseling for negatives

— Hepatitis B vaccination if non-immune; HAV/HPV per guidelines

First decision: What stage is this? Stage determines drug, route, and duration.

Second decision: Any reason to do an LP? (See chunk 5)

Third decision: Pregnancy?

Fourth decision: HIV status?

Partner management:

Public health actions to bundle on every case:

CCS pearl: On a CCS case, after starting penicillin, order public health notification, partner counseling, HIV test, and follow-up RPR in 6 months — these "soft" orders are scored.

Board pearl: A pregnant patient with penicillin allergy and syphilis at any stage → admit (or arrange supervised outpatient) for desensitization then full PCN therapy. Doxycycline is teratogenic; macrolides have treatment-failure rates and fetal transmission.

Pharmacotherapy — First-Line Penicillin Regimens

— Primary, secondary, or early latent: 2.4 million units IM × 1 dose

— Late latent, latent of unknown duration, or tertiary (non-neuro): 2.4 million units IM weekly × 3 doses (total 7.2 million units)

— Missed dose >9–14 days apart → restart series in late latent

— Aqueous crystalline penicillin G 18–24 million units IV daily (3–4 million units q4h or continuous infusion) × 10–14 days

— Alternative if outpatient compliance assured: procaine penicillin G 2.4 million units IM daily + probenecid 500 mg PO QID × 10–14 days

— Some experts add 2.4 million units IM benzathine PCN weekly × 3 after IV course

— Non-pregnant, non-neurosyphilis: doxycycline 100 mg PO BID × 14 days (early) or × 28 days (late latent)

— Alternative: ceftriaxone 1 g IV/IM daily × 10–14 days (cross-reactivity ~2%; avoid in severe penicillin allergy)

— Azithromycin not recommended — macrolide-resistant strains widespread

— Pregnant or neurosyphilis: penicillin desensitization (oral or IV protocol, inpatient with allergy/ID consult) — no acceptable alternative

— Fever, chills, myalgia, headache, worsening rash, hypotension within 2–8 hours of first dose

— Self-limited (resolves <24 h); supportive care with antipyretics and fluids

— Most common in secondary syphilis (high spirochete burden)

— In pregnancy, can precipitate preterm labor or fetal distress — counsel and monitor fetus

— Do not use Bicillin C-R (benzathine + procaine combo) — inadequate benzathine dosing

— Do not substitute oral penicillin V — inadequate tissue levels

Benzathine penicillin G (Bicillin L-A) — the workhorse of syphilis therapy.

Neurosyphilis, ocular syphilis, otic syphilis:

Penicillin allergy management:

Jarisch-Herxheimer reaction:

Critical "do not" list:

Step 3 management: A patient with secondary syphilis who develops fever, myalgia, and hypotension 4 hours after IM PCN → Jarisch-Herxheimer, supportive care, do not stop or change antibiotic, do not workup sepsis reflexively.

Procedural Considerations and Expanded Pharmacology

— Performed in monitored setting (ED, ICU, or supervised infusion unit)

— Oral protocol: 14 escalating doses of PCN V suspension every 15 minutes over ~4 hours

— IV protocol available for higher-risk cases

— After desensitization, standard therapy must be given without interruption; tolerance is lost within 48 h of last dose

— Skin testing with major (PRE) and minor determinants may stratify risk first

— PICC line typically placed for 10–14 day course

— Outpatient parenteral antibiotic therapy (OPAT) program with home infusion or skilled nursing facility is standard

— Daily nursing assessment, weekly CBC, BMP

— Probenecid blocks renal tubular secretion of penicillin → maintains higher plasma/CSF levels

— Avoid probenecid in significant renal impairment, sulfa allergy, peptic ulcer, gout flare

— Take with full glass of water, avoid lying down 30 min after dose (esophagitis risk)

— Photosensitivity counseling

— Avoid concurrent antacids, calcium, iron, dairy (chelation)

— GI upset common; consider doxycycline monohydrate for better tolerability

— Useful when IM PCN unavailable, in correctional settings, or some PCN-allergic patients

— 1 g IM/IV daily × 10–14 days; longer courses for late latent

— Confirm allergy history (true IgE-mediated vs intolerance)

— Pregnancy test

— HIV test

— Baseline RPR titer documented (essential for monitoring response)

Penicillin desensitization — the only acceptable approach for true PCN-allergic pregnant patients or any patient with neurosyphilis and severe allergy.

IV penicillin logistics for neurosyphilis:

Procaine PCN + probenecid alternative:

Doxycycline practical notes (non-pregnant alt):

Ceftriaxone considerations:

Pre-treatment checklist:

CCS pearl: Order acetaminophen PRN prophylactically with the first benzathine PCN dose — preempts Herxheimer symptoms and improves patient comfort.

Board pearl: If a patient has had anaphylaxis to penicillin and is pregnant with syphilis, the answer is always desensitize, then treat with penicillin — never "use doxycycline" or "use erythromycin."

Special Populations — Elderly, Renal, and Hepatic Impairment

— Rising rates of syphilis in adults >65 due to longer sexual activity, dating after widowhood, and underuse of condoms (no pregnancy concern)

— Screen any older adult presenting with new dementia, gait disturbance, or unexplained stroke — late neurosyphilis can mimic Alzheimer's, normal pressure hydrocephalus, or vascular dementia

— Argyll Robertson pupil and tabes dorsalis are exam clues

— Treat per standard staged regimens; renal dose adjustments for procaine PCN/probenecid

— Benzathine PCN G: no dose adjustment required despite renal clearance (long half-life, IM depot)

— Aqueous crystalline PCN G (IV neurosyphilis): adjust dose for CrCl <30 to avoid penicillin neurotoxicity (myoclonus, seizures); typically reduce frequency

— Procaine PCN: avoid in significant renal impairment (procaine accumulation)

— Probenecid: ineffective if CrCl <30, also potentiates toxicity of other drugs — avoid

— Ceftriaxone: no adjustment until severe combined renal/hepatic failure

— Doxycycline: no renal adjustment; preferred tetracycline in CKD

— Penicillins generally safe in hepatic disease

— Doxycycline: use cautiously in severe liver disease but generally tolerated

— Monitor LFTs in patients with secondary syphilis hepatitis — abnormalities should normalize after treatment

— Probenecid interacts with NSAIDs, methotrexate, loop diuretics, antivirals

— Doxycycline reduces warfarin metabolism → INR monitoring

— Avoid combining doxycycline with isotretinoin (pseudotumor cerebri risk)

— In any older patient with positive RPR/treponemal and MMSE/MoCA decline, perform LP — late neurosyphilis is treatable and partly reversible if caught early

Older adults:

Renal impairment:

Hepatic impairment:

Polypharmacy considerations in elderly:

Cognitive screening:

Step 3 management: A 72-year-old with progressive memory loss, broad-based gait, and incidentally positive RPR → LP for CSF-VDRL and cell count, then IV PCN G ×14 days, not memantine.

Board pearl: Penicillin neurotoxicity in CKD presents with myoclonic jerks and seizures — recognize early and reduce dose.

Special Populations — Pregnancy and Congenital Syphilis

— All pregnant patients at first prenatal visit

— Repeat at 28 weeks and at delivery in high-prevalence communities or high-risk patients

— No infant should leave the hospital without maternal syphilis status documented

— Benzathine PCN G at stage-appropriate regimen — only effective fetal treatment

— For late latent or unknown duration: 3 weekly doses; a dose given >9 days late requires restarting the series (stricter than nonpregnant)

— Penicillin allergy → desensitize and treat with PCN, period

— Doxycycline contraindicated; macrolides do not cross placenta reliably

— Can trigger preterm contractions, fetal heart rate decelerations, fetal distress

— Counsel patient, especially in second/third trimester, to seek care if uterine activity, decreased fetal movement, or fever

— Consider fetal monitoring after first dose if viable gestational age

— Stage-appropriate PCN regimen completed ≥30 days before delivery

— Appropriate clinical and serologic response (fourfold titer decline if applicable)

— No evidence of reinfection

— Compare infant nontreponemal titer to mother's; fourfold higher than maternal = probable congenital infection

— Evaluate: physical exam (hepatosplenomegaly, rash, snuffles, hydrops), CBC, LFTs, long-bone x-rays (metaphyseal lucency, periostitis), LP (CSF VDRL, cell count, protein), ophthalmologic exam

— Treat with aqueous PCN G IV × 10 days or procaine PCN IM × 10 days

Screening in pregnancy (USPSTF Grade A):

Treatment in pregnancy:

Jarisch-Herxheimer in pregnancy:

Adequate maternal treatment for congenital syphilis prevention requires ALL:

Congenital syphilis evaluation of newborn:

Late congenital stigmata: Hutchinson teeth, mulberry molars, saddle nose, saber shins, interstitial keratitis, CN VIII deafness (Hutchinson triad)

Pediatric acquired syphilis — investigate for sexual abuse and report to child protective services

Board pearl: Maternal PCN given <30 days before delivery = infant treated as inadequately treated, regardless of maternal titers.

Step 3 management: Penicillin-allergic pregnant patient → admit for desensitization, complete benzathine PCN, then re-test RPR at delivery and document.

Complications and Adverse Outcomes

— Fever, chills, headache, myalgia, transient hypotension within 2–8 hours of first dose

— Mediated by cytokine release from killed spirochetes

— Resolves <24 hours; treat with antipyretics, fluids, supportive care

— Most common in secondary syphilis; counsel before first dose

— Cardiovascular syphilis (10–25 years post-infection): aortitis of vasa vasorum → ascending aortic aneurysm, aortic regurgitation, coronary ostial stenosis → angina/MI

— Gummatous syphilis (3–10 years): granulomatous lesions of skin, bone, viscera; painless, slowly destructive

— Late neurosyphilis (10–30 years):

– Tabes dorsalis: dorsal column degeneration → ataxia, lancinating pain, Charcot joints, urinary retention

– General paresis: progressive dementia, psychiatric symptoms, dysarthria

– Meningovascular syphilis: stroke in young adults

— Permanent vision loss from optic atrophy, chorioretinitis, uveitis-related glaucoma

— Interstitial keratitis (also congenital stigmata)

— Syphilis lesions facilitate HIV acquisition and transmission (mucosal disruption)

— HIV co-infection: more atypical presentations, higher likelihood of neurosyphilis, higher rates of serologic failure

— Stillbirth (~40% of untreated maternal syphilis)

— Preterm birth, hydrops fetalis, neonatal death

— Congenital syphilis with multisystem involvement

Acute treatment complication — Jarisch-Herxheimer reaction:

Untreated primary/secondary → spontaneous symptom resolution but persistent latent infection in most

Latent → tertiary in ~25–40% if untreated:

Ocular syphilis complications:

Otic syphilis: Irreversible sensorineural hearing loss if not treated promptly

HIV interaction:

Pregnancy/fetal complications:

Reinfection — common in high-risk persons; presents as fourfold RPR rise. Always re-treat and re-counsel.

Treatment failure — defined as failure of RPR to decline fourfold by 6–12 months (early) or 12–24 months (late); evaluate for HIV, neurosyphilis (LP), and reinfection.

Board pearl: A young adult with ischemic stroke and no vascular risk factors → think meningovascular syphilis, vasculitis, paradoxical embolus, or dissection. Order RPR.

When to Escalate — Hospitalization, Consults, and Inpatient Triage

— Primary, secondary, early latent, and late latent syphilis without neurologic, ocular, or otic involvement

— Single-dose or 3-dose IM benzathine PCN in clinic

— Neurosyphilis, ocular syphilis, otic syphilis — IV aqueous PCN G × 10–14 days

— Tertiary cardiovascular syphilis requiring imaging, cardiac surgery evaluation

— Severe Jarisch-Herxheimer in pregnancy with fetal distress

— Penicillin desensitization (any PCN-allergic patient requiring PCN)

— Congenital syphilis evaluation and treatment of neonate

— Infectious disease: complex cases, treatment failure, HIV co-infection, neurosyphilis

— Ophthalmology: same-day for any visual symptom + reactive serology

— ENT/audiology: sudden sensorineural hearing loss + reactive serology

— Neurology: cognitive decline, stroke, cranial neuropathy with positive serology

— Cardiothoracic surgery: ascending aortic aneurysm or severe AR from syphilitic aortitis

— Maternal-fetal medicine: syphilis in pregnancy with high titers, late presentation, fetal anomalies

— Pediatric ID and neonatology: congenital syphilis

— Allergy/immunology: penicillin desensitization

— Hemodynamic compromise from severe Jarisch-Herxheimer

— Aortic dissection or rupture from tertiary aortitis

— Stroke from meningovascular syphilis requiring stroke unit

— Mandatory case reporting to local/state health department within statutory window (often 24 hours for primary/secondary)

— Disease Intervention Specialists (DIS) assist with partner notification and tracing — engage early in difficult cases

— Outbreak investigation if cluster identified

Outpatient management is appropriate for:

Hospitalize or arrange IV therapy for:

Specialist consults to order:

ICU criteria:

Public health escalation:

CCS pearl: A patient with secondary syphilis rash AND new vision blurring → admit, ophthalmology consult, LP, IV PCN G 18–24 million units/day × 14 days. Outpatient IM benzathine PCN is wrong.

Step 3 management: Treatment failure (no fourfold drop at 6–12 months) → LP + HIV test + re-treat with 3-dose benzathine PCN (or IV PCN if CSF positive).

Key Differentials — Other STIs and Mucocutaneous Mimics

— Herpes simplex (HSV): multiple, painful, vesicular ulcers on erythematous base; recurrent; positive PCR or Tzanck. Painful tender lymphadenopathy.

— Chancroid (Haemophilus ducreyi): painful, ragged, purulent soft ulcer; tender suppurative inguinal "buboes"; rare in US

— Lymphogranuloma venereum (Chlamydia L1-L3): small painless papule that resolves, then tender unilateral fluctuant inguinal/femoral lymphadenopathy ("groove sign"); proctitis in MSM

— Granuloma inguinale (Klebsiella granulomatis): beefy red, painless, friable, slowly progressive ulcer; Donovan bodies on biopsy

— Behçet disease: recurrent oral and genital aphthous ulcers, uveitis, pathergy; not infectious

— Fixed drug eruption, traumatic ulcer, malignancy in non-healing solitary lesion

— Pityriasis rosea: herald patch, Christmas-tree distribution on trunk, spares palms/soles, pruritic

— Drug eruption: temporal relation to new medication, often pruritic

— Viral exanthem (measles, mononucleosis-related): prodrome, mucosal signs differ

— HIV seroconversion rash: fever, lymphadenopathy, pharyngitis, mononucleosis-like — order HIV (often co-infected)

— Rocky Mountain spotted fever: petechial, palms/soles, fever, tick exposure, headache — emergent

— Hand-foot-mouth disease: vesicles on palms/soles, oral ulcers, children

— Psoriasis (guttate): scaly plaques, post-streptococcal

— Lichen planus: violaceous polygonal papules, Wickham striae

— Lata: flat, smooth, moist plaques, highly infectious, syphilis

— Acuminata: verrucous, cauliflower-like, HPV

Genital ulcer differentials (vs primary chancre):

Secondary syphilis rash differentials:

Condylomata lata vs condylomata acuminata (HPV):

Key distinction: Painless ulcer = syphilis; painful ulcer = herpes or chancroid. "Painful = pus" mnemonic: chancroid is painful and purulent; chancre is painless and clean.

Board pearl: Palms and soles involvement narrows the differential rapidly — syphilis, RMSF, hand-foot-mouth, erythema multiforme, and Kawasaki are the classic palmoplantar rashes.

Key Differentials — Systemic and Neurologic Mimics

— Acute: viral infections (mono, hepatitis), bacterial infections, immunizations, pregnancy

— Chronic: SLE, antiphospholipid syndrome, rheumatoid arthritis, chronic liver disease, IV drug use, advanced age, HIV, leprosy, malaria

— Usually low titer (≤1:8); treponemal test will be negative

— Alzheimer disease, vascular dementia, frontotemporal dementia — progressive cognitive decline; LP differentiates

— Normal pressure hydrocephalus: gait, urinary incontinence, dementia; imaging shows ventriculomegaly

— Multiple sclerosis: relapsing-remitting neurologic deficits, MRI plaques

— HIV-associated neurocognitive disorder

— Lyme neuroborreliosis: another spirochetal cause of meningoencephalitis and cranial neuropathy

— Cerebrovascular disease: young stroke mimics meningovascular syphilis

— Wernicke encephalopathy: ataxia, confusion, ophthalmoplegia

— Bicuspid aortic valve

— Rheumatic heart disease

— Endocarditis

— Connective tissue disorders (Marfan, Ehlers-Danlos, Loeys-Dietz)

— Takayasu and giant cell aortitis

— Aortic dissection

— Viral: EBV, CMV, HIV, hepatitis

— Bacterial: TB, syphilis, brucellosis

— Malignancy: lymphoma, leukemia

— Autoimmune: SLE, sarcoidosis

— Drug-induced: phenytoin, allopurinol

— TORCH (toxo, others, rubella, CMV, herpes) and Zika — different stigmata patterns

False-positive RPR/VDRL — biologic false positives:

Neurosyphilis mimics (positive serology in unrelated condition):

Aortic regurgitation differential (vs syphilitic aortitis):

Generalized lymphadenopathy differentials:

Hutchinson triad (congenital syphilis) vs other congenital infections:

Key distinction: Treponemal tests do not distinguish between syphilis and other treponematoses — yaws, pinta, bejel (tropical, non-venereal) will also be reactive. Travel history matters.

Board pearl: A patient with low-titer RPR, SLE, and lupus anticoagulant likely has a biologic false-positive — confirm with treponemal test. Don't reflexively treat.

Secondary Prevention and Long-Term Plan

— Abstain from sexual contact until lesions fully healed AND completion of treatment AND at least 7 days after single-dose therapy (or completion of multi-week regimen)

— Notify all sexual partners from preceding 3 months (primary), 6 months (secondary), or 12 months (early latent) — longer for late stages

— Future condom use; consider PrEP if HIV-negative and ongoing risk

— Risk of reinfection — syphilis confers no protective immunity

— Mandatory reporting completed

— Engage DIS for partner tracing if patient declines or unable

— Expedited Partner Therapy (EPT) legal status varies — most states permit for chlamydia/gonorrhea, fewer for syphilis; verify locally

— Annual screening at minimum for ongoing risk

— Every 3–6 months for high-risk: MSM, persons living with HIV, multiple partners, sex work

— HIV testing at diagnosis and again in 3 months; if HIV+, linkage to care

— HIV PrEP (tenofovir-emtricitabine or cabotegravir LA) for HIV-negative patients with ongoing risk

— Doxycycline post-exposure prophylaxis (Doxy-PEP) — 200 mg PO within 72 hours of condomless sex — emerging CDC recommendation for MSM and transgender women with prior STI; reduces syphilis, chlamydia, gonorrhea

— Hepatitis B vaccination if non-immune; Hepatitis A for MSM

— HPV vaccination through age 26 (shared decision-making 27–45)

— Mpox vaccination for eligible high-risk groups

— Reinforce contraception counseling, pregnancy planning

— Substance use screening (alcohol, stimulants associated with higher STI risk)

— Mental health screening — STI diagnosis can trigger anxiety, depression, partner conflict

Counsel every treated patient on:

Public health/legal:

Re-screening after treatment:

Co-management priorities:

Health maintenance:

Step 3 management: Every syphilis follow-up visit should include: repeat RPR titer, sexual history update, HIV re-test (if previously negative), reinforce condom/PrEP/Doxy-PEP, and document partner notification.

Board pearl: Doxy-PEP is a Step 3 prevention pearl — emerging standard of care for high-risk MSM and trans women with prior bacterial STI.

Follow-Up, Monitoring, and Counseling

— Primary, secondary, early latent: RPR at 6 and 12 months

— Late latent / unknown duration: RPR at 6, 12, and 24 months

— Neurosyphilis: CSF analysis every 6 months until normalization of cell count, then RPR follow-up

— Early syphilis: RPR at 3, 6, 9, 12, and 24 months

— Late latent: RPR at 6, 12, 18, and 24 months

— Fourfold decline in RPR titer (e.g., 1:32 → 1:8) by 6–12 months in early syphilis

— By 12–24 months in late latent

— Treponemal tests typically remain positive for life — do not retest these to monitor response

— Recurrent or persistent signs/symptoms, OR

— Fourfold sustained increase in titer, OR

— Failure of fourfold decline within expected window

— Action: HIV re-test, LP, and re-treat (usually 3-dose benzathine PCN unless CSF positive → IV PCN)

— Persistent low-stable titer (e.g., 1:2 or 1:4) after adequate treatment

— Common, especially in late latent and HIV co-infected

— No re-treatment needed if no clinical or serologic evidence of failure

— Continue routine STI screening

— Sexual practices, partner changes, symptom check

— Reinforce condom use, PrEP/Doxy-PEP adherence

— Substance use, mental health

— Pregnancy planning and contraception

— Stage at diagnosis, treatment given (dose, date), partner notification, follow-up titers, HIV status

— Maintain easily retrievable baseline titer — essential for interpreting future tests

Serologic follow-up schedule — non-HIV:

Serologic follow-up schedule — HIV co-infected:

Definition of adequate response:

Definition of treatment failure / reinfection:

Serofast state:

Counseling each visit:

Documentation essentials:

CCS pearl: Always document the baseline RPR titer at diagnosis — without it, you cannot determine fourfold response and may unnecessarily retreat (or miss true failure).

Step 3 management: A patient with RPR 1:32 at diagnosis and 1:8 at 6 months → adequate response, no further treatment; continue surveillance.

Ethical, Legal, and Patient Safety Considerations

— Syphilis (all stages including congenital) is a nationally notifiable disease under state public health law

— Report to local health department within statutory window (often 24 hours for primary/secondary, 7 days for latent)

— Reporting overrides standard confidentiality — protected by public health statute

— Patient-initiated, provider-assisted, or DIS-assisted (anonymous third-party notification)

— Patients cannot legally prevent notification of contacts

— Document the discussion and chosen method

— Minor adolescents: most states allow STI testing/treatment without parental consent (varies — know your state)

— Adolescents have right to confidential care; billing/EHR access settings should protect this

— Disclosure to parents requires patient assent except in specific safety situations

— Any STI in a prepubertal child → presumed sexual abuse until proven otherwise → mandatory report to child protective services

— Acquired syphilis in a child requires forensic evaluation, ID, and social work consultation

— Congenital syphilis itself is not abuse but is reportable as a public health failure

— Penicillin desensitization in pregnancy: discuss risks of desensitization, Herxheimer reaction including preterm labor, and fetal benefit. Document maternal decision; she may not refuse on her infant's behalf without robust counseling and ethics consultation.

— Capacity assessment in patients with late neurosyphilis-related dementia — may require surrogate decision-making

— Patient lost to follow-up after first dose of a 3-dose late-latent regimen → restart series if >9–14 days lapse (>9 days strict in pregnancy)

— Discharge from ED with positive RPR but no follow-up arrangement is a patient safety gap — ensure linkage to clinic or DIS

— Inpatient-to-outpatient handoff: communicate stage, treatment given, baseline titer, follow-up schedule

— Syphilis disparities (Black, Hispanic, Indigenous, LGBTQ+, incarcerated populations) reflect structural barriers — providers should approach with non-judgmental, trauma-informed care

Mandatory reporting:

Partner notification:

Confidentiality limits:

Mandated child abuse reporting:

Informed consent edge cases:

Transition-of-care risks:

Health equity:

Board pearl: A pregnant patient who refuses treatment with desensitization presents an ethical dilemma — engage social work, ethics, and OB; document fetal risk counseling; never coerce, but ensure thorough decision-making support.

Step 3 management: STI in a 5-year-old = report to CPS, hospitalize for full workup, ID/forensics.

High-Yield Associations and Rapid-Fire Facts

Spirochetes: T. pallidum, Borrelia burgdorferi (Lyme), Leptospira. All can cause multisystem disease with neurologic involvement.

Treponematoses (also reactive on treponemal tests): syphilis (venereum), yaws (pertenue), pinta (carateum), bejel (endemicum). Travel history matters.

Painless ulcer mnemonic — "no PAIN": syphilis, lymphogranuloma venereum, granuloma inguinale. Painful ulcers: herpes, chancroid.

Palms-and-soles rash differential: secondary syphilis, Rocky Mountain spotted fever, hand-foot-mouth disease, erythema multiforme, Kawasaki, coxsackievirus, meningococcemia (petechial).

Argyll Robertson pupil: accommodates but doesn't react to light — late neurosyphilis, also seen in diabetes and pinealoma.

Tabes dorsalis triad: lancinating pains, ataxia, urinary incontinence; signs include Romberg+, areflexia, loss of proprioception, Charcot joints.

Hutchinson triad (congenital): notched incisors + interstitial keratitis + CN VIII deafness.

Single-dose vs 3-dose: <1 year = 1 dose; ≥1 year or unknown = 3 doses; neuro/ocular/otic = IV ×14 days.

Prozone phenomenon: high antibody → falsely negative RPR. Dilute the serum.

Serofast state: low persistent RPR after treatment, no re-treatment needed.

Jarisch-Herxheimer: cytokine release, 2–8 h after first PCN dose; supportive care; can trigger preterm labor.

Fourfold change: 2 dilutions (1:16 → 1:4 or vice versa) — the key metric for response and reinfection.

Pregnancy + PCN allergy: desensitize, always.

HIV + syphilis: same treatment regimens, more frequent serologic follow-up (q3 months).

Doxy-PEP: 200 mg within 72 h of condomless sex — emerging prevention for MSM and trans women with prior STI.

USPSTF: screen all pregnant patients (Grade A), screen asymptomatic non-pregnant adolescents/adults at increased risk (Grade A).

Bicillin C-R ≠ Bicillin L-A — never substitute; L-A is the correct formulation.

CSF-VDRL: specific not sensitive; CSF-FTA-ABS: sensitive not specific.

Board pearl: "Painless palms-and-soles rash + condylomata lata + lymphadenopathy" = secondary syphilis. Order RPR + HIV. Treat with single-dose benzathine PCN.

Board Question Stem Patterns

— "25-year-old man with painless penile ulcer for 2 weeks; firm, indurated, clean base; non-tender inguinal lymphadenopathy."

— Best test: darkfield microscopy of lesion exudate (or RPR + treponemal)

— Treatment: single-dose benzathine PCN G 2.4 million units IM

— "28-year-old with diffuse maculopapular rash including palms and soles, mucous patches, generalized lymphadenopathy."

— Next test: RPR and HIV

— Treatment: single-dose benzathine PCN G

— "Asymptomatic pregnant woman with reactive RPR 1:8 confirmed by treponemal test at first prenatal visit; no prior history."

— Stage: latent of unknown duration → late latent regimen

— Treatment: 3 weekly doses of benzathine PCN G

— "Pregnant patient with secondary syphilis and history of anaphylaxis to penicillin."

— Answer: penicillin desensitization then standard PCN therapy

— "55-year-old with progressive memory loss, gait ataxia, and pupil that accommodates but doesn't react to light. RPR reactive 1:64."

— Next: lumbar puncture for CSF-VDRL, cell count, protein

— Treatment: IV aqueous PCN G 18–24 million units/day × 10–14 days

— "Man with new uveitis and reactive RPR." → LP + IV PCN G, ophthalmology consult, treat as neurosyphilis

— "Treated for primary syphilis 9 months ago, baseline RPR 1:32, now 1:128 with new partner."

— Answer: HIV test, LP, re-treat with 3-dose benzathine PCN (or IV PCN if CSF reactive)

— "Fever, chills, myalgia, transient hypotension 4 hours after first PCN dose for secondary syphilis."

— Answer: supportive care, do not stop antibiotic, not anaphylaxis

— "Newborn with hepatosplenomegaly, snuffles, periostitis on long-bone X-ray; mother had untreated syphilis."

— Answer: IV aqueous PCN G × 10 days

— "Pregnant patient with palms/soles rash, RPR reported negative." → request diluted RPR (prozone phenomenon)

Stem 1 — Primary syphilis:

Stem 2 — Secondary syphilis:

Stem 3 — Latent syphilis discovered on screening:

Stem 4 — Penicillin allergy in pregnancy:

Stem 5 — Neurosyphilis:

Stem 6 — Ocular syphilis:

Stem 7 — Treatment failure or reinfection:

Stem 8 — Jarisch-Herxheimer:

Stem 9 — Congenital syphilis:

Stem 10 — Prozone:

Board pearl: The single highest-yield Step 3 trigger phrase is "palms and soles" — almost always secondary syphilis on Step 3 stems.

One-Line Recap

Syphilis is a staged spirochetal infection diagnosed by paired nontreponemal (RPR/VDRL) and treponemal serology, treated with stage-appropriate benzathine penicillin G (single dose for early syphilis <1 year, three weekly doses for late latent, IV aqueous PCN G for neuro/ocular/otic/congenital disease), with mandatory partner notification, public health reporting, HIV co-testing, and fourfold-decline serologic follow-up to confirm cure.

— Primary/secondary/early latent (<1 yr): benzathine PCN G 2.4 MU IM × 1

— Late latent / unknown / tertiary non-neuro: benzathine PCN G 2.4 MU IM weekly × 3

— Neuro / ocular / otic / congenital: aqueous PCN G IV 18–24 MU/day × 10–14 days

— Nontreponemal (RPR/VDRL) for titer & monitoring + treponemal (FTA-ABS/TP-PA) for confirmation

— LP for any neuro/ocular/otic symptom, tertiary disease, or treatment failure

— Watch for prozone (falsely negative RPR at high titer) and serofast state (persistent low titer after treatment, no re-treatment)

— Pregnancy + PCN allergy = desensitize, never substitute doxycycline or macrolide

— STI in prepubertal child → report to CPS

— Mandatory public health reporting at every stage; engage DIS for partner tracing

— Co-test for HIV/GC/CT/hepatitis at diagnosis and 3 months

— Offer HIV PrEP and Doxy-PEP (200 mg within 72 h of condomless sex) for high-risk MSM/trans women

— Re-screen high-risk patients every 3–6 months; fourfold RPR decline by 6–12 months confirms cure

Stage → regimen:

Diagnosis essentials:

Special situations:

Prevention & long-term care:

Board pearl: When in doubt on Step 3, palms-and-soles rash + lymphadenopathy = secondary syphilis; painless chancre = primary syphilis; Argyll Robertson pupil + tabes/dementia = late neurosyphilis → LP + IV PCN G.