Syphilis

Syphilis is a chronic, systemic, sexually transmitted infection caused by the spirochaete Treponema pallidum subsp. pallidum. It is the "great imitator" — its protean clinical features mimic many diseases, and NEET PG loves it for its staging, serology (VDRL vs TPHA vs FTA-ABS), the Jarisch–Herxheimer reaction, congenital stigmata, and benzathine penicillin regimens.

Etiology & basic microbiology

• Organism: Treponema pallidum — a thin, motile, helical spirochaete (6–15 µm long), too slender to be seen on light microscopy with Gram or routine stains.
• Cannot be cultured on artificial media — a recurrent exam fact. Maintained historically in rabbit testes.
• Visualised by: dark-ground (dark-field) microscopy, direct fluorescent antibody (DFA), or silver stains (Warthin–Starry, Levaditi) in tissue.
• Transmission: sexual contact (commonest), transplacental (congenital syphilis — can cross at any time, classically after 16–18 weeks), blood transfusion, and direct contact with infectious lesions.
• Incubation period: average ~21 days (range 9–90 days) for the primary chancre.

High-yield: T. pallidum cannot be grown in vitro and is not visible on Gram stain — diagnosis is by dark-ground microscopy or serology.

Classification / staging

Syphilis is divided into acquired and congenital forms; acquired syphilis is further staged.

Stage	Timing after infection	Hallmark lesion	Infectivity
Primary	3 weeks (9–90 days)	Painless chancre + regional lymphadenopathy	High
Secondary	6 weeks–6 months	Rash (palms/soles), condylomata lata, mucous patches	Highest
Early latent	< 1 year (WHO: < 2 yr)	Asymptomatic, seroreactive	Can relapse, infectious
Late latent	> 1 year	Asymptomatic, seroreactive	Non-infectious (except pregnancy)
Tertiary	1–30 years	Gummas, cardiovascular, neurosyphilis	Non-infectious

High-yield: "Early" syphilis = primary + secondary + early latent (within 1 year). This matters because early syphilis is treated with a single dose of benzathine penicillin, whereas late/late-latent needs three weekly doses.

Primary syphilis

• Chancre = the primary lesion at the site of inoculation. Begins as a papule that ulcerates.
• Classic features: single, painless, indurated (button-like), clean-based ulcer with a rolled margin; non-purulent serous exudate teeming with spirochaetes.
• Sites: glans/coronal sulcus, labia, cervix, anus, lips, oral cavity.
• Bilateral, painless, rubbery, non-tender, non-suppurative regional lymphadenopathy ("bullet nodes").
• Heals spontaneously in 3–6 weeks even without treatment — leading to a false sense of cure.

High-yield: The chancre is painless and indurated — contrast with the painful, soft, non-indurated ulcers of chancroid (Haemophilus ducreyi). "Hard chancre = syphilis; soft chancre = chancroid."

Secondary syphilis

Results from haematogenous and lymphatic dissemination; the most florid, multi-system stage and the most infectious.

• Rash: symmetrical, non-itchy, coppery-red maculopapular eruption involving the palms and soles — a near-pathognomonic exam clue.
• Condylomata lata: moist, flat-topped, broad, wart-like papules in warm intertriginous areas (perianal, vulval) — highly infectious, swarming with treponemes. (Distinguish from condylomata acuminata = HPV genital warts, which are dry and papilliferous.)
• Mucous patches and "snail-track ulcers" on oral/genital mucosa.
• Moth-eaten (patchy) alopecia of the scalp and lateral eyebrows.
• Generalised non-tender lymphadenopathy, low-grade fever, malaise, arthralgia.
• Split papules at angle of mouth; Biette's collarette (peripheral scaling of papules).

High-yield: Rash on palms and soles + condylomata lata + moth-eaten alopecia = secondary syphilis until proven otherwise. Other palm/sole rashes to remember: Rocky Mountain spotted fever, hand-foot-mouth disease, Kawasaki, erythema multiforme.

Latent syphilis

• Asymptomatic period detected only by reactive serology with no clinical signs.
• Early latent (< 1 yr): relapses of secondary lesions may occur; considered infectious.
• Late latent (> 1 yr): non-infectious except vertical transmission in pregnancy.
• A patient with reactive serology and unknown duration is treated as late latent (3 doses).

Tertiary (late) syphilis

Develops in ~⅓ of untreated patients, years to decades later. Three main forms:

1. Gummatous (benign tertiary) syphilis → gumma: a granulomatous, rubbery, painless lesion with central necrosis in skin, bone (sabre tibia, periostitis), liver, etc. Few organisms; represents delayed hypersensitivity.
2. Cardiovascular syphilis → endarteritis of vasa vasorum of the aorta → syphilitic aortitis, ascending thoracic aortic aneurysm, aortic regurgitation, and "tree-bark" intimal wrinkling. Coronary ostial stenosis.
3. Neurosyphilis (can occur at any stage):
   • Asymptomatic (abnormal CSF only)
   • Meningovascular (strokes in young)
   • General paresis of the insane (GPI) — dementia, personality change
   • Tabes dorsalis — degeneration of dorsal columns → lightning pains, sensory ataxia, Argyll Robertson pupil, Charcot joints, loss of proprioception, positive Romberg.

High-yield: Argyll Robertson pupil = "Accommodation Reflex Present, Pupillary (light) reflex Absent" — small, irregular pupils that constrict to near but not to light. Classic of tabes dorsalis/neurosyphilis ("prostitute's pupil — accommodates but does not react").

Congenital syphilis

Transplacental transmission; risk highest with maternal early syphilis. Divided into early (< 2 yr) and late (> 2 yr).

Early congenital (< 2 yr)	Late congenital (> 2 yr) / stigmata
Snuffles (haemorrhagic rhinitis)	Hutchinson's teeth (notched, peg incisors)
Maculopapular rash, condylomata lata	Mulberry/Moon molars
Hepatosplenomegaly, jaundice	Interstitial keratitis
Pseudoparalysis of Parrot	Eighth nerve deafness
Periostitis, Wimberger sign (metaphyseal erosion of tibia)	Saddle nose, frontal bossing (Olympian brow)
Saber shin (rare early)	Saber shin, Higoumenakis sign (clavicle)
	Rhagades (perioral fissures), Clutton's joints

High-yield: Hutchinson's triad = Hutchinson's teeth + interstitial keratitis + eighth-nerve deafness → late congenital syphilis. Wimberger sign (bilateral medial tibial metaphyseal destruction) is a radiological clue in the infant.

Mnemonic for late stigmata: "HUTCHINSON" — Hutchinson teeth, Unilateral/bilateral keratitis, Tibia (saber shin), Clutton's joints, deafness (eighth nerve), nose (saddle), etc.

Diagnosis & investigations

Direct demonstration

• Dark-ground microscopy of exudate from chancre/condylomata lata = investigation of choice for early (primary) syphilis where serology may still be negative. Shows motile corkscrew spirochaetes.
• DFA-TP, PCR for T. pallidum DNA, silver staining of biopsy.

Serology — the NEET PG favourite

Serology divides into non-treponemal (reagin) and treponemal (specific) tests.

Feature	Non-treponemal (VDRL, RPR)	Treponemal (TPHA, FTA-ABS, TP-PA, EIA)
Antigen	Cardiolipin–lecithin–cholesterol	T. pallidum antigens
Use	Screening + monitoring response	Confirmation
Quantitative titres	Yes — falls with treatment	No (stay positive for life)
Becomes negative after Rx	Yes (titres fall ≥ 4-fold)	Usually stays positive lifelong
Sensitivity in primary	Lower (may be negative early)	FTA-ABS = earliest to become positive
Specificity	Lower (biological false positives)	High
Best for neurosyphilis (CSF)	CSF-VDRL = highly specific	FTA-ABS on CSF = sensitive

• FTA-ABS is the first to become reactive in primary syphilis and the most sensitive overall; it stays positive for life ("FTA-ABS = First To Appear").
• TPHA / TP-PA are confirmatory treponemal tests.
• VDRL/RPR are best for screening and monitoring treatment response because they are quantitative — a ≥ 4-fold drop in titre (e.g., 1:32 → 1:8) indicates successful treatment.

High-yield: CSF-VDRL is highly specific (confirmatory) but poorly sensitive for neurosyphilis. A negative CSF-VDRL does NOT exclude neurosyphilis; a positive one confirms it.

Diagnostic flow

Screen with VDRL/RPR → if reactive, confirm with TPHA/FTA-ABS → titre VDRL for baseline → treat → repeat VDRL at 6 & 12 months to confirm ≥4-fold fall.

This is the traditional algorithm. Many labs now use a reverse algorithm: treponemal EIA/CLIA first → then RPR to assess activity → discordant cases confirmed by TPHA.

Biological false-positive VDRL

A reactive VDRL with a negative treponemal test. Causes — mnemonic "VDRL":

• Viral infections (EBV, hepatitis, HIV), Vaccination, Varicella
• Drug abuse (IV), DLE/SLE & antiphospholipid antibody syndrome (very high yield)
• Rheumatic fever, Rheumatoid arthritis
• Leprosy, Lymphoma, Liver disease; also pregnancy, malaria, old age, TB.

High-yield: A false-positive VDRL is a recognised clue to SLE / antiphospholipid syndrome. Treponemal tests (TPHA/FTA-ABS) will be negative in true biological false positives.

Prozone phenomenon

• In secondary syphilis (and congenital), very high antibody titres can cause a falsely negative VDRL due to antigen–antibody lattice failure. Resolved by diluting the serum. A classic trap question.

Management — penicillin is supreme

Drug of choice = benzathine penicillin G (IM). No clinically significant penicillin resistance exists in T. pallidum.

Stage	Regimen
Early syphilis (primary, secondary, early latent)	Benzathine penicillin G 2.4 MU IM single dose
Late latent / latent of unknown duration / tertiary (non-neuro)	Benzathine penicillin G 2.4 MU IM weekly × 3 (total 7.2 MU)
Neurosyphilis	Aqueous crystalline penicillin G 18–24 MU/day IV (3–4 MU q4h) × 10–14 days
Congenital syphilis	Aqueous crystalline/procaine penicillin G IV/IM × 10 days
Pregnancy	Penicillin only — desensitise if allergic; no proven alternative

• Penicillin allergy (non-pregnant, non-neuro): doxycycline 100 mg BD × 14 days (or 28 days for late) or ceftriaxone. Azithromycin is NOT recommended (macrolide resistance reported).
• Pregnant + penicillin-allergic: penicillin desensitisation is mandatory — doxycycline is teratogenic and erythromycin doesn't cross the placenta adequately.

High-yield: Early syphilis = ONE dose benzathine penicillin 2.4 MU IM. Late/latent unknown = THREE weekly doses. Neurosyphilis = IV aqueous penicillin (benzathine does NOT achieve treponemicidal CSF levels).

Jarisch–Herxheimer reaction

• An acute febrile reaction within 2–24 hours of starting treatment (commonest after the first dose), due to release of endotoxin-like substances from dying spirochaetes (cytokine surge — TNF, IL-6).
• Features: fever, chills, myalgia, headache, tachycardia, flare of existing lesions, transient hypotension. Usually self-limiting (resolves in 24 h).
• Most common and most florid in secondary syphilis; dangerous in pregnancy (may precipitate preterm labour/foetal distress) and in cardiovascular/neurosyphilis.
• Management: antipyretics (paracetamol), reassurance; it is NOT an allergy and is not a reason to stop penicillin.

High-yield: Jarisch–Herxheimer = fever + flare of rash within hours of penicillin; it is due to spirochaete lysis, NOT penicillin allergy. Treat with paracetamol; do not withhold therapy.

Follow-up

• Repeat quantitative VDRL/RPR at 6 and 12 months (and 24 months for late/neuro). Success = ≥ 4-fold fall in titre. Failure or rise = re-treat and evaluate CSF + HIV.

Syphilis & HIV

• Genital ulcers (chancre) increase HIV transmission/acquisition several-fold.
• HIV can cause atypical, aggressive syphilis, faster progression to neurosyphilis, and unreliable serology (falsely negative due to prozone, or persistently high titres).
• Always test for HIV in any patient with syphilis and vice versa.

Key differential diagnoses

Disease	Organism	Ulcer character	Lymph node
Syphilis (chancre)	T. pallidum	Single, painless, indurated, clean	Bilateral, painless, non-suppurative
Chancroid	H. ducreyi	Multiple, painful, soft, ragged, dirty	Unilateral, painful, suppurative bubo
LGV	Chlamydia trachomatis L1–L3	Small, transient, painless	Groove sign, painful matted buboes
Granuloma inguinale (Donovanosis)	Klebsiella granulomatis	Beefy-red, painless, "rolled"	Pseudobuboes; Donovan bodies
Genital herpes (HSV)	HSV-1/2	Multiple painful vesicles → ulcers	Tender bilateral

High-yield: Classic ulcer pairing: painless ulcer + painful adenopathy → think LGV; painless ulcer + painless adenopathy → syphilis; painful ulcer + painful suppurative node → chancroid; painless beefy-red ulcer that bleeds → donovanosis.

Complications

• Cardiovascular: aortic aneurysm, aortic regurgitation, coronary ostial stenosis.
• Neurological: tabes dorsalis, GPI, meningovascular stroke, optic atrophy.
• Ocular/otic: interstitial keratitis, uveitis, sensorineural deafness.
• Obstetric: stillbirth, hydrops fetalis, prematurity, congenital syphilis.
• Gummatous destruction of palate/nasal septum (perforation, saddle nose).

Recently asked / exam angle

• Which test becomes positive earliest in primary syphilis? → FTA-ABS (most sensitive in early disease).
• Best test to monitor treatment response? → VDRL/RPR (quantitative; expect ≥4-fold fall).
• Most specific test for neurosyphilis on CSF? → CSF-VDRL (specific, not sensitive).
• Cause of biological false-positive VDRL? → SLE/APLA syndrome, pregnancy, leprosy, viral infections (treponemal tests negative).
• Prozone phenomenon → false-negative VDRL at high titre in secondary syphilis; correct by dilution.
• DOC for syphilis in pregnancy with penicillin allergy? → Desensitise and give penicillin (not doxycycline/azithromycin).
• Jarisch–Herxheimer reaction mechanism (spirochaete lysis, cytokine release) and that it is not allergy.
• Argyll Robertson pupil — accommodates but doesn't react to light; tabes dorsalis.
• Hutchinson's triad of late congenital syphilis.
• Condylomata lata vs acuminata differentiation and which is most infectious.
• Wimberger sign in congenital syphilis radiograph.
• Single vs three-dose benzathine penicillin (early vs late) — frequently tested numerically.

Rapid revision

1. T. pallidum — non-culturable spirochaete; seen on dark-ground microscopy, not Gram stain.
2. Primary lesion = painless, indurated chancre with painless bilateral nodes; incubation ~21 days.
3. Secondary syphilis = rash on palms & soles + condylomata lata + moth-eaten alopecia; most infectious stage.
4. Condylomata lata = syphilis (most infectious); condylomata acuminata = HPV warts.
5. FTA-ABS = first to become positive and most sensitive; stays positive for life.
6. VDRL/RPR = screening + monitoring (quantitative); ≥4-fold titre fall = cure.
7. CSF-VDRL = specific but insensitive for neurosyphilis.
8. Prozone phenomenon = false-negative VDRL at high titre → dilute serum.
9. Biological false-positive VDRL → SLE/APLA, pregnancy, leprosy, viral infections.
10. Early syphilis = single 2.4 MU benzathine penicillin; late = 3 weekly doses; neurosyphilis = IV aqueous penicillin.
11. Jarisch–Herxheimer = fever + lesion flare within hours of penicillin from spirochaete lysis — treat with paracetamol, not steroids/stopping.
12. Hutchinson's triad (notched teeth + interstitial keratitis + eighth-nerve deafness) + Argyll Robertson pupil (accommodates, no light reaction) are the don't-miss eponyms.