Syphilis (Treponema pallidum)

Meet the patient

A 26-year-old man comes to the sexual-health clinic with a single, clean, painless ulcer on the glans he first noticed a week ago. On the bench you feel rubbery, non-tender inguinal nodes on both sides. He feels entirely well. His partner is eight weeks pregnant.[1][2]

Three questions run every syphilis encounter, and this man plants all of them: what stage is this? (a painless indurated chancre is primary), is the disease already systemic? (yes — the chancre is a sign of an infection that disseminated hours after acquisition), and who else is at stake? (the partner, the fetus, and his HIV status). Hold those three and the rest of the page slots into place.[1][7]

What syphilis actually is — four stages, one spirochete

Syphilis is a chronic, systemic infection by the spirochete Treponema pallidum that marches through four well-demarcated stages if you do not treat it. Each stage has features so specific they are exam currency, and the stages are separated by silent intervals — which is exactly why the disease gets missed between the chancre that healed and the dementia that arrives two decades later.[1][2]

It is the original "great imitator": the same organism produces, in turn, a painless genital ulcer, a coppery rash on the palms and soles, a stroke in a young person, an ascending aortic aneurysm, a chronic dementing illness, a uveitis, and a stillbirth. No other infection wears so many masks. The examiner is testing three things — recognise each stage, read the two-tier serology, and know that penicillin is first-line for every stage and has never met resistance in 70-plus years.[1][6]

Three facts anchor why this disease still matters. First, it resurged globally after 2000 following near-elimination in the 1990s, led by epidemics in men who have sex with men but now spreading through heterosexual populations. Second, congenital syphilis has come roaring back — over 700,000 syphilis-associated adverse pregnancy outcomes worldwide in 2022, the large majority preventable by one course of antenatal penicillin. Third, syphilis and HIV potentiate each other: the chancre multiplies HIV acquisition and transmission risk several-fold, so every syphilis diagnosis mandates an HIV test, and vice versa.[2][7]

Etymology that earns viva marks. The organism's name is a description of what you see down the microscope: Treponema is Greek trepo (to turn) plus nema (thread) — the turning thread, i.e. the corkscrew — and pallidum means pale, because it is too thin to take up a Gram stain, which is why you need dark-field microscopy, not a Gram film. The disease name comes from Fracastoro's 1530 poem Syphilis sive morbus gallicus, in which the shepherd Syphilus offends Apollo and is cursed with the plague — and the older clinical name lues is simply Latin for plague or pestilence.[2]

The turning thread — why this spirochete wins

Two structural tricks let T. pallidum evade immunity and bore into tissue. It is a thin (0.1 to 0.2 micrometre wide, 6 to 20 micrometres long), tightly coiled spirochete with 6 to 14 spirals, and its biology is the whole story of the disease.[2]

• An outer membrane that is hyposialylated and poor in surface proteins — there is almost nothing for antibody or complement to latch onto, which is the basis of its immune evasion and persistence.
• Endoflagella sitting in the periplasmic space whose rotation drives the corkscrew motility that lets it penetrate intact mucosa and abraded skin and swim through viscous tissue.[1]

It cannot be cultured on artificial media — it lacks the machinery to make many of its own amino acids and fatty acids, and is grown only by intratesticular inoculation of rabbits (the Nichols strain, a research tool). That is why laboratory diagnosis rests on dark-field microscopy of lesion exudate and on serology, never on a culture plate.[2]

The chancre is not a localised early event — it is the cutaneous sign of an infection that has already spread. The organism divides locally roughly every 30 hours, but dissemination begins within hours: it enters the lymphatics, reaches regional nodes, then streams into the bloodstream as spirochetemia well before the chancre appears. This single fact explains why you treat even an isolated-looking chancre with systemic, stage-based penicillin, and why secondary syphilis can blossom even after the chancre has quietly healed.[1][2]

Every syphilitic lesion, from chancre to gumma to aneurysm, shares one histological signature: obliterative endarteritis. A perivascular infiltrate of lymphocytes and plasma cells plus endothelial proliferation narrows and obliterates the vessel lumen; tissue ischaemia and the host response then make the clinical lesion. Tertiary lesions are paucibacillary — the gumma is essentially a hypersensitivity reaction to a handful of surviving organisms — which is why tertiary disease is destructive but barely transmissible.[2]

The stage-by-stage mechanism maps straight onto the clinical stages:[1]

• Primary (chancre). Dense plasma-cell and lymphocytic infiltrate with endarteritis at the inoculation site makes a painless, clean-based, indurated ulcer — the firmness is the infiltrate. It heals spontaneously in 3 to 6 weeks untreated, but the organism disseminated long before.[1]
• Secondary. Immune-complex deposition and widespread vasculitis in skin and mucosa produce the maculopapular rash, mucous patches and condylomata lata; lesions teem with spirochetes. Fever, malaise, lymphadenopathy, hepatitis and immune-complex nephrotic syndrome reflect multi-organ seeding.[2]
• Latent. The cellular and humoral response partly controls the infection; spirochetes persist in low numbers in lymph nodes, CNS and other tissue. The patient is asymptomatic but seropositive — and in pregnancy can still transmit to the fetus.[1]
• Gummatous (tertiary). A type IV (delayed) hypersensitivity granuloma around a few persistent organisms: central gum-like necrosis ringed by epithelioid cells, giant cells, plasma cells and obliterative endarteritis. Destructive, but paucibacillary.[2]
• Cardiovascular syphilis. The organism seeds the vasa vasorum of the ascending aorta and arch, causing obliterative endarteritis of the nutrient vessels, ischaemic medial necrosis and loss of elastic fibres — the artery dilates into an ascending aneurysm with aortic regurgitation and coronary ostial stenosis. The gross appearance is the "tree-bark" intimal wrinkling. The aneurysm involves the ascending aorta and arch and spares the aorta distal to the renal arteries — the single feature that separates it from an atherosclerotic aneurysm. It declares itself 15 to 30 years after infection.[2]

Jarisch-Herxheimer reaction — the mechanism every patient must be warned about. Within 2 to 24 hours of the first penicillin dose, massive lipoprotein release from dying spirochetes fires a cytokine storm (TNF-alpha, IL-6, IL-8): fever, chills, myalgia, headache, exacerbation of rash and transient hypotension. It is self-limiting over 12 to 24 hours and is NOT a drug allergy — penicillin must be continued. It is commonest in early, high-spirochete-load disease (up to 70 percent of secondary syphilis) and matters most in pregnancy (fetal distress, preterm labour, stillbirth — monitor the fetus) and in cardiovascular or neurosyphilis (transient clinical worsening). Antipyretic pretreatment blunts but does not reliably prevent it.[11]

The classification that sets the dose — stage by stage

The stage is the operational framework: it dictates both the clinical picture and the penicillin regimen, so classify before you treat. Syphilis sorts by mode of acquisition and by clinical stage.[1][12]

By acquisition:[1]

• Acquired syphilis — sexual contact (the dominant mode), rarely blood transfusion, needlestick, or direct contact with an infectious lesion.
• Congenital syphilis — transplacental from about 16 weeks' gestation, or at delivery through contact with an infectious genital lesion.[1]

By stage (acquired syphilis):[1]

• Primary — chancre at 9 to 90 days (average 21 days).
• Secondary — the systemic stage, 2 to 12 weeks after the chancre; the two may overlap.
• Latent — asymptomatic with positive serology, split into early latent (within 1 year; CDC) or late latent / unknown duration (beyond). The cut-off decides the dose: early latent gets a single benzathine dose, late latent or unknown duration gets three weekly doses — get this wrong and you under-treat.
• Tertiary — 1 to 30 years after infection, in roughly one-third of untreated patients: gummatous, cardiovascular, neurosyphilis.[1]

Everyone forgets: the European/BASHH guideline uses a 2-year cut-off for early versus late latent, while the CDC uses 1 year — both then treat late latent with three weekly doses. Name the local convention in the viva.[12]

Neurosyphilis is classified on its own because it can appear at any stage, not only tertiary:[3][4]

• Asymptomatic — CSF abnormalities (pleocytosis, raised protein, positive CSF-VDRL) without symptoms.
• Symptomatic — meningeal (acute syphilitic meningitis), meningovascular (endarteritis causing stroke), general paresis (parenchymal encephalitis with dementia), tabes dorsalis (posterior column degeneration), ocular syphilis (uveitis, optic neuritis), otic syphilis (sensorineural hearing loss, vertigo).[1]

Subspecies and the endemic treponematoses — a history trap. T. pallidum subsp. pallidum causes venereal syphilis; pertenue causes yaws; endemicum causes endemic (non-venereal) syphilis (bejel); carateum causes pinta. All four are serologically indistinguishable — they give identical positive RPR/VDRL and treponemal tests — so a positive syphilis serology in someone from a yaws-endemic region (tropical Africa, Asia, Pacific) may not be venereal syphilis at all. The examiner loves this point.[2]

How common, who, and why it came back

Syphilis is worldwide, and it came back. After near-elimination in high-income countries in the 1990s, it has risen since 2000: the WHO estimates about 8 million new adults (15 to 49 years) acquired syphilis in 2022, and congenital syphilis now drives over 700,000 adverse pregnancy outcomes a year — stillbirths, neonatal deaths, congenitally infected infants — most of them preventable.[2][7]

Humans are the only reservoir. The principal route is sexual, through mucosal or abraded skin. Vertical (transplacental) transmission begins from about 16 weeks and the woman remains infectious to her fetus throughout. Rare modes — blood transfusion (now screened out), needlestick, and direct non-sexual contact with a lesion (the classic is a healthcare worker inoculating a finger into an extragenital chancre).[1][2]

Infectivity tracks the stage. Primary and secondary lesions (chancre, mucous patches, condylomata lata) teem with spirochetes and are highly infectious; latent and tertiary disease is essentially non-infectious to sexual partners — yet a woman with latent syphilis can still pass it to her fetus. That asymmetry is the whole rationale for stage-based treatment and the public-health emphasis on early disease.[1]

Who you screen and why:[1]

• Men who have sex with men — the dominant epidemic in high-income countries.
• HIV co-infection — bidirectional synergy; syphilis amplifies HIV transmission and vice versa.
• Multiple partners, condom non-use, commercial sex work, recreational drug use (especially chemsex).
• Adolescents and young adults (peak incidence 15 to 35 years).
• Partners of anyone diagnosed with early syphilis.
• Pregnant women — untreated infection is devastating to the fetus.
• Socioeconomic deprivation and limited healthcare access — these drive the congenital syphilis epidemic through missed antenatal screens.[2]

The syphilis–HIV synergy is a perennial exam point, and it is bidirectional. The chancre and the secondary ulcers disrupt mucosal integrity and recruit HIV-susceptible cells (CD4-positive T-cells, macrophages, dendritic cells), raising HIV acquisition and transmission risk two- to fivefold. In the other direction, HIV co-infection speeds progression, produces atypical or multiple lesions, raises the risk of neurosyphilis, and throws up a prozone false-negative non-treponemal test. Test HIV in every syphilis case, full stop.[1][3]

[1]

The four faces on the ward — one stage at a time

Recognising the stage is the central clinical skill, because the stage sets the picture and the penicillin regimen both. The clinical course is dictated by stage and modified by HIV status, pregnancy and immune competence.[1][2]

Primary — the chancre. At 9 to 90 days (average 21 days) after exposure, a single, painless, clean-based, indurated (firm, cartilaginous) ulcer appears at the inoculation site — most often glans penis, prepuce, shaft, labia, cervix or anal margin, less often lip, tongue, pharynx, finger, nipple or rectum. It has a raised firm border, a smooth clean base with clear serum exudate teeming with spirochetes, and non-tender, rubbery regional nodes (inguinal for a penile chancre). It heals spontaneously in 3 to 6 weeks even untreated, leaving a faint scar. The classic trap: the extragenital chancre (anal, oral) is easily missed, the cervical chancre is invisible and highly infectious, and in HIV co-infection chancres may be multiple or atypical.[1]

Secondary — the systemic stage. At 2 to 12 weeks after the chancre (the two can overlap, so a healing chancre may still be present when the rash erupts). The cardinal features are:[1][2]

• Diffuse, symmetric, non-itchy maculopapular rash (the syphilide), coppery-red, classically on the PALMS and SOLES — the single highest-yield cutaneous clue — also trunk, flexures, face; subtle or florid.
• Condylomata lata — broad, flat, moist, grey-white, highly infectious plaques in warm intertriginous sites (perianal, vulval, scrotal, inframammary, axillary). Not the dry, cauliflower-like viral wart (condyloma acuminata).
• Mucous patches — painless grey-white eroded patches on tongue, buccal mucosa, lips, palate, pharynx; the confluent form is the "snail-track" ulcer. Highly infectious.
• Generalised, non-tender, rubbery lymphadenopathy — epitrochlear, cervical, axillary, inguinal.
• Patchy ("moth-eaten") alopecia of scalp, beard, eyebrows and eyelashes — a specific feature.
• Systemic symptoms — low-grade fever, malaise, headache, sore throat, arthralgia, myalgia, anorexia, weight loss.
• Less common: mild hepatitis, immune-complex membranous nephropathy (nephrotic syndrome), gastritis, iritis or uveitis, periostitis (nocturnal bone pain), split papules at the oral commissures, and meningitis with cranial nerve (VII, VIII) involvement.[2]

The rash, condylomata and mucous patches all teem with spirochetes — secondary syphilis is the most infectious stage of all. The lesions resolve spontaneously over weeks even untreated, but the patient is now seropositive and may slide on to latent and tertiary disease.[1]

Latent — asymptomatic but seropositive. No clinical signs; picked up on serology (antenatally, in STI screening, at blood donation, or on contact tracing). Early latent (within 1 year, CDC; 2 years, BASHH) is infectious to partners and fetus; late latent or unknown duration is non-infectious to partners but still transmissible across the placenta.[1][12]

Tertiary — in roughly one-third of untreated patients, 1 to 30 years on. Three sub-forms that may coexist:[2]

• Gummatous — granulomatous nodules, plaques or ulcers with central gum-like necrosis on skin, mucosa, bone (skull, tibia, palate, nasal septum) and viscera (liver, testis, lung). Cutaneous gummas are punched-out ulcers; palatal and septal gummas perforate into the saddle-nose deformity.
• Cardiovascular — ascending aortic aneurysm (expansile supraclavicular or suprasternal mass, tracheal tug, hoarseness from recurrent laryngeal nerve stretch, dysphagia, risk of fatal rupture), aortic regurgitation (collapsing water-hammer pulse, wide pulse pressure, early diastolic murmur at the left sternal edge, bounding peripheral pulses), coronary ostial stenosis (angina without atherosclerotic coronary disease). Declares itself 15 to 30 years after infection.[2]
• Neurosyphilis — meningeal, meningovascular stroke, general paresis, tabes dorsalis, ocular, otic. Can occur at any stage (see below).[3][4]

Congenital syphilis — clinical face. The fetus infected in utero may present with hydrops fetalis, miscarriage or stillbirth. The liveborn neonate shows early congenital syphilis (under 2 years): hepatosplenomegaly, jaundice, petechiae or purpura from thrombocytopenia, "snuffles" (a blood-stained, highly infectious nasal discharge), maculopapular rash, periostitis and osteochondritis, anaemia, failure to thrive. The late stigmata (over 2 years) are the classic exam features:[7][8]

• Hutchinson triad — the pathognomonic set: (1) Hutchinson teeth (notched, peg-shaped, widely spaced central incisors); (2) interstitial keratitis (corneal scarring, visual impairment); (3) sensorineural deafness (eighth nerve).
• Saddle nose (depressed bridge from gummatous septal destruction), saber shin (anterior tibial bowing from periostitis), mulberry molars (malformed first molars), frontal bossing, rhagades (linear perioral scars), Clutton joints (painless knee synovitis), and neurodevelopmental impairment.[1]

Accommodates but does not react — the pupil and the neurosyphilis syndromes

Neurosyphilis is not a late stage — it is a compartment. T. pallidum invades the CNS early; CSF pleocytosis is detectable in up to 40 percent of early syphilis even without neurological symptoms. Which syndrome you see depends on which compartment dominates, and the syndromes are among the most examinable in infectious diseases.[3][4]

• Meningeal — acute basilar meningitis: headache, meningism, cranial nerve palsies of VII and VIII, seizures.
• Meningovascular — endarteritis of cerebral vessels producing stroke, classically in the middle cerebral artery territory in a young person, 5 to 10 years after infection. Send syphilis serology in every young-adult stroke.
• General paresis — chronic progressive meningo-encephalitis with cortical atrophy (widened sulci, shrunken gyri): progressive dementia, personality change, psychiatric features classically of grandiosity and delusions of grandeur, a tremulous tongue and facial muscles, dysarthria, and the Argyll Robertson pupil. Declares 15 to 20 years after infection.
• Tabes dorsalis — degeneration of the dorsal columns and dorsal nerve roots: lightning (lancinating) neuropathic pains, sensory ataxia with a positive Romberg and a high-stepping stamping gait, loss of vibration and joint position sense, hyporeflexia or areflexia in the legs, Charcot (neuropathic) joints, and visceral crises (gastric, rectal, laryngeal). Declares 15 to 25 years after infection.[4]
• Ocular syphilis — uveitis (anterior, intermediate or posterior), optic neuritis or retinitis, panophthalmitis; can cause permanent visual loss.
• Otic syphilis — sensorineural hearing loss, tinnitus, vertigo.

The Argyll Robertson pupil — the prostitute pupil. A small, irregular pupil that constricts on accommodation (near effort) but does NOT constrict to light — memorably, it accommodates but does not react. Test it at the bedside: ask the patient to look at your finger 15 cm away (it constricts), then shine a bright pen torch (it does not). The lesion is in the dorsal midbrain (pretectal) fibres of the light reflex, sparing the near-reflex pathway to the Edinger-Westphal nucleus. Classic for tabes dorsalis and general paresis — but not pathognomonic: it also occurs in diabetes and other dorsal midbrain lesions.[3][4]

When to image the brain. MRI brain is the modality that earns marks here: mesiotemporal T2 or FLAIR hyperintensity with cortical atrophy in general paresis, cortical and subcortical infarcts with meningeal enhancement and arteritic changes in meningovascular syphilis, and a ring-enhancing gumma mass that can mimic tumour or abscess. CT or MR angiography shows the arteritic vessel; echocardiography and CT or MR aortography nail the ascending aneurysm with the tree-bark aorta.[5]

Why the Argyll Robertson pupil accommodates but does not react (deep mechanism)

The light reflex runs from retina to pretectal nuclei in the dorsal midbrain, then bilaterally to the Edinger-Westphal nuclei. The near reflex (accommodation) reaches the Edinger-Westphal nucleus through a separate, more ventral cortical pathway. A dorsal midbrain (pretectal) lesion therefore abolishes the light response while sparing accommodation — the dissociation that defines the pupil, and the reason it also turns up in other dorsal midbrain (Parinaud) contexts, not only syphilis.[4][14]

The great imitator at the bedside — face off the genital ulcer

Because syphilis imitates everything, each stage has its own differential, and the discriminator is almost always one specific clinical detail plus the serology. The genital-ulcer face-off is the perennial exam table — learn it cold.[1][2]

[1]

One-line discriminator for the ulcer: painless indurated single ulcer with rubbery nodes is syphilis until serology proves otherwise; painful rules out syphilis and points to herpes, chancroid or Behcet; the beefy granulomatous ulcer with Donovan bodies is donovanosis; the bubo with a groove sign is LGV.[1]

Differential of the secondary rash (maculopapular, palms and soles): pityriasis rosea (herald patch, fir-tree trunk, spares palms and soles), drug eruption (eosinophilia, temporal link), measles, rubella, infectious mononucleosis rash (especially after amoxicillin), meningococcaemia, Rocky Mountain spotted fever, guttate psoriasis, tinea corporis, hand-foot-mouth disease, scabies (itchy, burrows). The discriminating cluster: the syphilide is non-itchy, hits the palms and soles, and rides with mucous patches, condylomata lata, lymphadenopathy and positive serology.[1][2]

Condylomata lata vs condyloma acuminata (viral warts, HPV 6/11): lata are flat, moist, grey-white and teeming with spirochetes (highly infectious); acuminata are dry, exophytic and cauliflower-like. The treatment is entirely different — penicillin versus wart destruction — so the distinction is not academic.[1]

Differential of cardiovascular syphilis (aneurysm or aortic regurgitation): atherosclerosis, bicuspid aortic valve, Marfan and other connective-tissue disorders, aortic dissection, ankylosing spondylitis, rheumatic heart disease, Takayasu arteritis. The syphilitic aneurysm classically involves the ascending aorta and arch and spares the aorta distal to the renal arteries, with tree-bark intimal wrinkling — confirmed by positive serology.[2]

Differential of general paresis (young or atypical dementia, new psychiatric illness): Alzheimer disease, frontotemporal dementia, vascular dementia, HIV encephalopathy, Wilson disease, autoimmune encephalitides. Syphilis serology belongs in the reversible-dementia screen of any young or atypical dementia — a positive result here is one of the few dementias you can actually treat.[3][4]

Differential of tabes dorsalis (sensory ataxia, lancinating pains): vitamin B12 deficiency (subacute combined degeneration — also dorsal columns, but with upper motor neuron signs and macrocytosis), vitamin E deficiency, hereditary sensory and autonomic neuropathy, diabetic neuropathy, multiple sclerosis. Tabes is set apart by the Argyll Robertson pupil, lancinating pains, areflexia and a positive Romberg with positive syphilis serology.[4]

Differential of a young-adult stroke: carotid or vertebral dissection, patent foramen ovale (paradoxical embolism), antiphospholipid syndrome, vasculitis, Fabry disease — and meningovascular syphilis. Send syphilis serology as part of every young-stroke work-up.[3]

Differential of stillbirth, hydrops fetalis or neonatal sepsis: parvovirus B19, Rh alloimmunisation, CMV, toxoplasmosis, listeria, GBS — and congenital syphilis. Send maternal syphilis serology and treat empirically if positive.[7][8]

Bedside assessment — the named signs that earn marks

Syphilis is systemic, so the examination is systemic: skin and mucosa, nodes, abdomen, cardiovascular system, nervous system and eyes, plus a full sexual and (in pregnancy) obstetric history. These are the named signs examiners reach for:[1][2]

The structured examination, in order:[1]

• Skin and mucosa — palms, soles, trunk, flexures (condylomata), scalp (alopecia), oral mucosa (mucous patches, snail-track ulcers), genital and perianal area. Wear gloves — moist lesions are infectious.
• Lymph nodes — epitrochlear, cervical, axillary, inguinal (rubbery, non-tender, generalised in secondary).
• Abdomen — hepatosplenomegaly (secondary, congenital).
• Cardiovascular — aortic regurgitation, aneurysm, heart failure.
• Neurological — pupils (Argyll Robertson), higher mental function (dementia, grandiosity), cranial nerves (VII, VIII palsies), gait (sensory ataxia, positive Romberg), reflexes (areflexia in tabes), sensation (vibration and joint position), and a stroke screen.
• Ophthalmic — visual acuity, slit-lamp (uveitis), optic disc (optic neuritis or atrophy), red eye.
• Obstetric (in pregnancy) — fundal height, ultrasound for hydrops, hepatosplenomegaly and growth restriction; fetal monitoring.[1]

History essentials: sexual contacts (number, gender, dates, condom use), last sexual contact, known STIs and HIV status, drug and alcohol use; in pregnancy — gestation, prior antenatal syphilis results, prior treatment, the partner's status; in suspected tertiary disease — onset and progression of dementia, psychiatric change, gait disturbance, pains, visual or hearing change, cardiovascular symptoms.[1]

Two-tier serology — the test that runs the show

Diagnosis rests on two-tier serology plus, in early disease, direct visualisation of the organism from a moist lesion. There is no culture. Neurosyphilis needs CSF; tertiary disease needs imaging.[1][2][10]

Direct visualisation — dark-field microscopy. Exudate from a moist lesion (chancre, mucous patch, condyloma lata) under dark-field illumination shows motile spirochetes — the definitive test for early infectious lesions. Not useful for oral or rectal lesions (commensal spirochetes give false-positives), needs a viable lesion and an experienced eye, and sensitivity falls after topical antibiotics. PCR of a lesion swab is the modern alternative where available.[2]

The two-tier serological strategy — the cornerstone. Serology is always read as a pair of test types:[1]

The number rule that governs the titre: a fourfold change is a two-dilution change, and that is what is significant. A fall from 1:16 to 1:4 after treatment confirms response; a rise from 1:8 to 1:32 means re-infection or treatment failure. TPPA is the most sensitive and specific treponemal test; FTA-ABS is less specific; rapid point-of-care tests help where labs are scarce but miss early primary disease.[10]

The PROZONE phenomenon — the false-negative that loses marks. In florid secondary syphilis, antibody excess interferes with the flocculation reaction and the RPR or VDRL reads falsely negative. Suspect it the moment a clinically typical secondary syphilis comes back with a negative screen, and request dilution of the serum, which unmasks the true high titre. It is commonest in HIV co-infection and pregnancy — both high-spirochete-load states.[1][10]

False-positive RPR or VDRL — confirm with a treponemal test. Split acute (under 6 months — recent vaccination, acute viral infection, malaria, pregnancy) from chronic (over 6 months — SLE, antiphospholipid syndrome, chronic infections, IV drug use, malignancy, ageing). A false-positive non-treponemal test is confirmed by a negative treponemal test.[1][10]

Screening algorithms — traditional vs reverse. The traditional algorithm screens with a non-treponemal test (RPR) first, then confirms positives with a treponemal test. The reverse algorithm screens with a treponemal test (EIA/CIA) first, then reflexes to RPR for activity and a discordant-resolving test. The reverse algorithm catches more late or latent cases (which may have a negative RPR) but generates more false-positives needing clinical adjudication — many labs now run it.[1]

CSF examination — when and what. Tap the CSF for neurological, ocular or otic signs; treatment failure (titre not falling fourfold by 6 to 12 months); tertiary disease; HIV co-infection with late latent syphilis and a high non-treponemal titre (over 1:32); and suspected congenital syphilis. The CSF findings:[3][4]

• CSF-VDRL (or CSF-RPR) — highly specific but insensitive. A positive confirms neurosyphilis; a negative does not exclude it (sensitivity only 30 to 70 percent).
• CSF-FTA or CSF-TPPA — more sensitive but less specific; a negative argues against neurosyphilis.
• CSF cell count — lymphocytic pleocytosis (over 5 cells per microlitre); CSF protein raised (over 0.45 g/L); CSF glucose usually normal (may be low in meningeal disease); CSF IgG index or oligoclonal bands raised, supporting intrathecal synthesis.[1]

Imaging. MRI brain for meningovascular syphilis (cortical and subcortical infarcts, meningeal enhancement), gumma (ring-enhancing mass mimicking tumour or abscess) and general paresis (mesiotemporal T2 or FLAIR hyperintensity with cortical atrophy); CT or MR angiography for stroke and arteritic changes; echocardiography and CT or MR aortography for cardiovascular syphilis (ascending aneurysm, aortic regurgitation, tree-bark aorta); plain radiographs for gummatous bone disease (skull, tibia) and in suspected congenital syphilis (Wimberger sign — destruction of the medial proximal tibial metaphysis — plus periostitis and osteochondritis of the long bones).[5][8]

Other laboratory tests. Full blood count (anaemia in congenital or secondary disease; thrombocytopenia), LFTs (hepatitis in secondary), urinalysis (proteinuria or nephrotic syndrome in secondary), HIV test (mandatory — co-infection changes management), hepatitis B and C serology; in pregnancy, ultrasound for hydrops, hepatosplenomegaly and growth restriction; in suspected congenital syphilis, neonatal examination, long-bone radiographs, CSF, full blood count, LFTs and placental pathology.[1]

Antenatal screening — the STORCH screen. Syphilis is part of the antenatal STORCH screen (Syphilis, Toxoplasma, Rubella, CMV, HSV). Universal screening at booking is standard; in high-prevalence settings repeat at 28 weeks and at delivery. A positive screen must be confirmed and the woman treated the same day with penicillin appropriate to her stage.[13]

There is no single named clinical scoring system for syphilis; the operational framework is the CDC or WHO case definition combined with the stage-based serological titre response — a fourfold fall confirming cure, a fourfold rise indicating re-infection or treatment failure.[1]

Penicillin for every stage — the ladder that never broke

Penicillin is first-line for every stage of syphilis, and it has stayed universally effective for over 70 years — no resistance has ever been documented. The systematic review evidence is clear that penicillin is first-line; the randomised evidence for the non-penicillin alternatives is weaker, which is exactly why you reach for doxycycline or ceftriaxone only when penicillin is impossible. The regimen is set by the stage.[1][6]

[1] [1]

The dose ladder in one breath: early disease (primary, secondary, early latent) is a single 2.4 MU intramuscular dose; late latent, unknown duration and tertiary non-neuro is three weekly doses — and a gap over 14 days means restart the whole course; neurosyphilis and ocular or otic syphilis need intravenous aqueous penicillin 18 to 24 MU per day for 10 to 14 days.[1][6]

Penicillin allergy and desensitisation. In pregnancy and in neurosyphilis, penicillin cannot be substituted — no alternative reliably reaches treponemicidal levels in the fetus and the CSF. Perform skin testing where available and incremental oral or IV desensitisation in a monitored setting (start near 1 unit, doubling every 15 to 30 minutes to reach the full dose over about 4 hours), then treat with penicillin. Desensitisation is temporary — re-sensitise for each subsequent course — and is done even in patients with a history of anaphylaxis, because the risk of untreated syphilis (congenital syphilis, neurosyphilis) exceeds the risk of a managed desensitisation.[1]

Drugs NOT to use. Azithromycin single-dose (high-level resistance via the 23S rRNA A2058G mutation is common); doxycycline or tetracycline in pregnancy (teratogenic, tooth and bone effects); topical treatment alone (inadequate); corticosteroid as monotherapy (no antitreponemal effect — use only adjunctively in ocular syphilis or to limit the Jarisch-Herxheimer reaction in cardiovascular or neurosyphilis); ciprofloxacin; oral penicillin V (insufficient treponemicidal levels).[1][6]

Follow-up and serological response. Repeat RPR or VDRL at 6, 12 and 24 months. Expect a fourfold (two-dilution) fall by 6 to 12 months in primary and secondary syphilis. Treatment failure or re-infection is a titre that does not fall fourfold by 6 to 12 months, or that rises fourfold — re-evaluate (HIV status, CSF, adherence, partner re-exposure) and re-treat. HIV co-infection needs closer follow-up (every 3 months) and a lower threshold for CSF examination.[1][3]

Partner notification and epidemiological treatment. Trace, test and epidemiologically treat every sexual contact of primary, secondary and early latent syphilis — presumptive benzathine penicillin G 2.4 MU IM single dose for partners exposed within the previous 90 days, regardless of their serology, because they may still be in the window. Advise sexual abstinence until lesions have healed and treatment is complete, and re-test HIV at 3 months to cover the seroconversion window. Syphilis is statutorily notifiable in most jurisdictions — report to public health; congenital syphilis is a sentinel event that triggers review of maternal screening and treatment.[1][2]

Pregnancy and the fetus — treat today, before twenty weeks

In pregnancy, penicillin is the only acceptable drug, and the day you find a positive result is the day you treat. Doxycycline and tetracycline are contraindicated (teratogenic, tooth and bone effects), ceftriaxone is not endorsed in pregnancy, and so a penicillin-allergic pregnant woman must be desensitised and treated with penicillin — no substitute is acceptable, and treatment must not wait for confirmatory tests when the suspicion is high.[13]

Screen universally at booking, and in high-prevalence settings repeat at 28 weeks and at delivery. Efficacy falls if treatment is completed less than 30 days before delivery, so timing matters as much as the drug. The vertical transmission risk of untreated primary or secondary maternal syphilis is 70 to 100 percent; with adequate penicillin before 16 to 20 weeks, the residual risk of congenital syphilis is about 2 percent — treat before twenty weeks and you have, for practical purposes, prevented congenital syphilis.[7][13]

Watch the fetus through the Jarisch-Herxheimer reaction. In pregnancy it can precipitate fetal distress, preterm labour and stillbirth, so monitor the fetus after the first dose, give paracetamol 1 g and fluids, and observe. This is one of the few places where a "self-limiting" reaction demands active surveillance.[11]

Congenital syphilis — evaluate and treat the neonate. The neonate of a treated or inadequately treated mother needs a full work-up (examination, full blood count, LFTs, CSF, long-bone radiograph, audiology, ophthalmology). Treat proven or highly probable disease with IV aqueous crystalline penicillin G 50,000 units per kg every 12 hours (first 7 days of life) then every 8 hours for 10 days; if more than one day is missed, restart. For the infant with a normal examination whose mother was inadequately treated, give benzathine penicillin 50,000 units per kg IM single dose if the full evaluation is normal and follow-up is assured.[7][8]

The mechanism of congenital damage. T. pallidum crosses the placenta from about 16 weeks (when trophoblastic involution lowers the barrier). The fetal inflammatory response drives hepatosplenomegaly, anaemia, thrombocytopenia, hydrops fetalis and stillbirth; survivors carry the early picture and the irreversible late stigmata — the developing teeth, bone, cornea and eighth nerve are the targets. Early detection and treatment of the neonate can resolve the acute disease but cannot reverse established stigmata (Hutchinson teeth, saddle nose, deafness, neurodevelopmental damage). Prevention by treating the mother before 16 to 20 weeks is near-total.[7][8]

How syphilis patients come to harm (the preventable list)

Most syphilis harm is preventable, and the failures cluster around the same mistakes. These are the harms an examiner will name back at you:[1]

• Missing the prozone false-negative — a florid secondary syphilis with a negative RPR that you sent home. Dilute the serum.[1][10]
• Misreading a false-positive RPR as syphilis — pregnancy, SLE, antiphospholipid syndrome. Confirm with a treponemal test before you label the patient.[1]
• Treating late latent or unknown-duration syphilis with a single dose instead of three weekly benzathine doses (restart if any gap over 14 days).[1]
• Using doxycycline or tetracycline in pregnancy — contraindicated; desensitise to penicillin.[13]
• Missing congenital syphilis in an asymptomatic neonate of an inadequately treated mother — evaluate fully and treat.[8]
• Not testing HIV in every syphilis case — the bidirectional synergy is non-negotiable.[1]
• Attributing a young person's stroke to vasculitis or dissection without a syphilis test — meningovascular syphilis is on every young-stroke list.[3]
• Missing the aneurysm — attributing an ascending aortic aneurysm to atherosclerosis when it spares the aorta distal to the renal arteries and the serology is positive.[2]
• Stopping penicillin for a Jarisch-Herxheimer reaction mistaken for allergy — it is not allergy, it is self-limiting, and penicillin must continue.[11]
• Deferring treatment in pregnancy to await confirmatory tests — treat the same day when suspicion is high.[13]

The subtypes and scenarios that bite

A quick map from stage to first action — keep this as your bedside lookup.[1]

• Primary — painless chancre plus rubbery nodes; single benzathine dose; warn about the Jarisch-Herxheimer reaction; trace and treat partners; test HIV.[1]
• Secondary — rash on palms and soles, mucous patches, condylomata lata, lymphadenopathy, fever; highly infectious; single benzathine dose; watch for a prozone false-negative RPR and for ocular and neuro involvement.[1]
• Early latent — asymptomatic, within 1 year; single benzathine dose; infectious to partners and fetus.[1]
• Late latent or unknown duration — asymptomatic, beyond 1 year; three weekly benzathine doses (restart if any gap over 14 days); non-infectious to partners but still transmissible in pregnancy; check CSF for neurological signs or HIV with a high titre.[1]
• Gummatous (tertiary) — granulomatous skin, bone or organ lesions; paucibacillary; three weekly benzathine doses; biopsy to exclude malignancy and tuberculosis.[2]
• Cardiovascular syphilis — ascending aneurysm, aortic regurgitation, coronary ostial stenosis; three weekly benzathine doses plus cardiothoracic surgery for the aneurysm and valve; the vasculitis continues despite antibiotics.[2]
• Neurosyphilis (meningeal, meningovascular, general paresis, tabes dorsalis, ocular, otic) — IV aqueous penicillin 18 to 24 MU per day for 10 to 14 days; MRI brain; CSF examination; functional recovery depends on the stage at treatment (early syndromes recover well, chronic parenchymal disease only partially).[3][4]
• Ocular or otic syphilis — uveitis, optic neuritis, sensorineural deafness, vertigo; treat as neurosyphilis (IV penicillin 10 to 14 days) plus a corticosteroid adjunct; urgent ophthalmology or ENT; outcome depends on the speed of treatment.[9]
• Asymptomatic neurosyphilis — CSF abnormalities without symptoms; treat as neurosyphilis if the CSF is abnormal, especially in HIV co-infection.[3]
• Syphilis in pregnancy — penicillin by stage; treat the same day; desensitise if allergic; fetal monitoring for the Jarisch-Herxheimer reaction; re-screen in the third trimester and at delivery in high-risk women.[13]
• Congenital syphilis — early (hepatosplenomegaly, snuffles, rash, periostitis, stillbirth) and late stigmata (Hutchinson triad, saddle nose, saber shin); IV aqueous penicillin for 10 days in the neonate; prevention by maternal screening and treatment before 20 weeks.[7][8]
• Syphilis in HIV co-infection — atypical or multiple lesions, rapid progression, prozone false-negative and false-positive serology, higher neurosyphilis risk; standard penicillin regimens (no increased dose) but closer serological follow-up (every 3 months) and a lower threshold for CSF examination; treat HIV with antiretroviral therapy concurrently.[1][3]

A few more special populations. Paediatric acquired syphilis is rare and usually means sexual abuse or vertical transmission — involve forensic and safeguarding input, and use benzathine penicillin 50,000 units per kg IM (max 2.4 MU) single dose for early disease (avoid doxycycline under 8 years — tooth discoloration). The elderly may surface decades later with cardiovascular syphilis or general paresis; treat by stage, but structural damage is irreversible. MSM are the dominant epidemic in high-income countries — screen every 3 to 6 months, check HIV and hepatitis A, B and C, vaccinate against hepatitis A and B, and offer HIV PrEP. Benzathine penicillin is renally excreted but needs no dose adjustment in renal impairment; in the anticoagulated patient use a small needle and prolonged pressure at the IM site, or consider an IV regimen if the INR is significantly raised.[1]

Prognosis, disposition, and what reverses

With penicillin, primary and secondary syphilis are essentially cured; without it, roughly one-third of patients progress to tertiary disease. The prognosis hinges on how much structural damage has already accrued before you treat.[1][2]

• Primary and secondary — chancre and rash resolve; cure is near-universal with penicillin.[1]
• Latent — disease activity ceases; the titre falls slowly, and the treponemal test usually stays positive for life.[1]
• Gummatous — penicillin halts progression and heals active gummas but does not reverse established structural damage.[2]
• Cardiovascular — penicillin halts the vasculitis but does not reverse an aneurysm or aortic regurgitation; surgery carries the structural burden and the prognosis.[2]
• Neurosyphilis — outcome depends on the stage at treatment: meningeal and meningovascular disease recover well; general paresis and tabes dorsalis (chronic parenchymal destruction) recover only partially, even as the CSF normalises over months.[3][4]
• Ocular or otic — outcome depends on speed of treatment; early IV penicillin can restore vision and hearing, delay risks permanent loss.[9]
• Congenital — early neonatal treatment resolves acute disease but cannot reverse established stigmata; prevention by maternal treatment before 16 to 20 weeks is near-total.[7][8]

Disposition. Most cases are managed as outpatients in sexual health or dermatology with IM penicillin and follow-up serology. Admit for neurosyphilis (IV penicillin for 10 to 14 days), cardiovascular complications, an ocular emergency, severe congenital syphilis, and pregnant women with high-spirochete-load secondary syphilis needing Jarisch-Herxheimer observation. Historically, untreated syphilis cut life expectancy by roughly 15 percent; death came from aneurysm rupture, neurosyphilis or congenital infection. With penicillin, mortality is essentially that of any residual structural damage.[1][2]

Evidence and the names that score marks

Viva name-drops, in order of impact. The CDC 2021 STI Treatment Guidelines (Workowski) is the treatment backbone — benzathine 2.4 MU IM single dose for early disease, weekly for three doses for late, IV aqueous penicillin 18 to 24 MU per day for 10 to 14 days for neurosyphilis, and the fourfold titre follow-up thresholds. The 2020 European Guideline (Janier, BASHH or IUSTI) sets the 2-year early-versus-late latent cut-off versus the CDC's 1 year. The Lancet Seminar (Peeling, 2023) is the contemporary overview and documents the global resurgence and the congenital syphilis emergency.[1][2][12]

On treatment evidence. The JAMA systematic review (Clement, Okeke, Hicks, 2014) confirms penicillin as first-line and is candid that the randomised evidence base is thin, with doxycycline, tetracycline and ceftriaxone supported mainly by observational data — the reason non-penicillin regimens are second-line.[6]

On neurosyphilis. The State-of-the-Art Review (Hamill, Ghanem, Tuddenham, Clin Infect Dis 2024) and Neurosyphilis in 2025 (Sethi and Marks) are the contemporary neurosyphilis references: CSF-VDRL is specific but insensitive, IV aqueous penicillin for 10 to 14 days is the regimen, CSF follow-up at 6 months, and ocular and otic syphilis are treated as neurosyphilis. The Continuum review (Chow, 2021) maps the clinical syndromes, and the J Neuroradiol imaging paper (Correa, 2023) the MRI patterns — mesiotemporal T2 change in general paresis, infarcts and arteritis in meningovascular disease, gumma.[3][4][5][14]

On the tests, the reaction, and the fetus. Park and colleagues (Clin Infect Dis 2020) establish that TPPA is the most sensitive and specific treponemal test. Butler (Am J Trop Med Hyg 2017) sets out the Jarisch-Herxheimer reaction as cytokine-mediated (TNF-alpha, IL-6, IL-8), commonest in early syphilis (up to 70 percent in secondary) and self-limiting over 12 to 24 hours. The congenital syphilis pair — Gilmour and Walls (Clin Microbiol Rev 2023) on global epidemiology and Sankaran and colleagues (Children, 2023) as the illustrative review with the Hutchinson triad, Wimberger sign and neonatal treatment — anchors prevention by maternal treatment before 20 weeks. Furtado and colleagues (Surv Ophthalmol 2022) cover ocular syphilis: uveitis and optic neuritis, treated as neurosyphilis with IV penicillin plus a corticosteroid adjunct. Singh, Wong and Robinson (Curr Opin Obstet Gynecol 2025) reaffirm universal antenatal screening, repeat third-trimester or delivery testing in high-prevalence settings, and same-day treatment.[9][10][11][13]

Regional deltas. All major guidelines agree penicillin is first-line for every stage and that universal antenatal screening is the cornerstone of congenital syphilis prevention, but they differ in detail. The United States (CDC 2021) uses a 1-year cut-off and increasingly a reverse (treponemal-first) screening algorithm, with repeat pregnancy screening at 28 weeks and delivery in high-risk groups. Europe (BASHH or IUSTI 2020) uses a 2-year cut-off and doxycycline for 14 versus 28 days as second-line. The WHO backs point-of-care treponemal testing and syndromic STI management where labs are scarce, plus the triple elimination of mother-to-child transmission of HIV, syphilis and hepatitis B. In India (NACO), syphilis is folded into the National AIDS Control Organisation's syndromic STI management (genital ulcer disease treated syndromically for syphilis and herpes), and maternal screening under RMNCHA-plus uses rapid plasma reagin at the first antenatal visit, with benzathine penicillin the mainstay.[1][12]

The mantra, and the mnemonics

[1]

The mantra: penicillin for every stage, two-tier serology, accommodate-but-don't-react, treat the mother before twenty weeks.[1][6]

Ward-round test — three stems, thirty seconds each

Stem 1 — the painless ulcer with rubbery nodes (answer)

The 26-year-old man from the top of the topic: a single, clean, painless ulcer on the glans with rubbery, non-tender inguinal nodes; he feels well; his partner is eight weeks pregnant. Diagnosis, first investigations, and first treatment step? Model: This is primary syphilis until proven otherwise — the induration and the rubbery non-tender nodes are the giveaway. Send two-tier serology (RPR or VDRL plus TPPA) and, where available, dark-field microscopy of the chancre exudate for motile spirochetes; test HIV, hepatitis B and C, and screen the partner (and her pregnancy). Treat with benzathine penicillin G 2.4 million units intramuscularly as a single dose, warn him about the Jarisch-Herxheimer reaction in the next 24 hours, trace and epidemiologically treat partners exposed within 90 days, and arrange follow-up serology at 6, 12 and 24 months expecting a fourfold titre fall. If the partner is confirmed positive in pregnancy, treat her the same day with penicillin appropriate to her stage.[1][13]

Stem 2 — new-onset dementia with an Argyll Robertson pupil (answer)

A 54-year-old man is brought in by his family for progressive personality change, grandiosity, a tremulous tongue and unsteadiness. His pupils are small and irregular: they constrict when he looks at your near finger but not to a bright pen torch. What is the diagnosis, the confirmatory tests, and the treatment? Model: This is general paresis (neurosyphilis) — the Argyll Robertson pupil (accommodates but does not react) with dementia and grandiosity is the classic constellation. Confirm with serology (RPR or VDRL plus TPPA) and CSF examination — CSF-VDRL is highly specific but insensitive, so a positive confirms and a negative does not exclude; expect a lymphocytic pleocytosis and raised protein. Add an MRI brain (mesiotemporal T2 or FLAIR hyperintensity with cortical atrophy) and an HIV test. Treat with intravenous aqueous crystalline penicillin G 18 to 24 million units per day for 10 to 14 days; meningeal and meningovascular disease recover well, but chronic parenchymal general paresis recovers only partially.[3][4][5]

Stem 3 — the pregnant woman with a positive booking RPR (answer)

A 24-year-old at 14 weeks' gestation has a positive RPR at 1:32 at her booking visit, confirmed by a positive TPPA. She recalls a painless ulcer six months ago that healed on its own. What do you do today, and why does the timing matter? Model: This is secondary or early latent syphilis in pregnancy — treat the same day, because she is well within the window where treatment prevents almost all congenital syphilis. Penicillin is the only acceptable drug in pregnancy: benzathine penicillin G 2.4 million units intramuscularly as a single dose for early disease (or three weekly doses if reclassified as late latent). Doxycycline and tetracycline are contraindicated; if she reports penicillin allergy, desensitise and treat with penicillin. Warn her about the Jarisch-Herxheimer reaction and monitor the fetus for distress or preterm labour in the first 24 hours. Treat the partner, test HIV, and re-screen at 28 weeks and at delivery. Efficacy falls if treatment finishes less than 30 days before delivery; before 16 to 20 weeks, the residual risk of congenital syphilis is about 2 percent.[7][13]

References

1. [1]Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021 MMWR Recomm Rep, 2021.PMID 34292926
2. [2]Peeling RW, Mabey D, Chen XS, et al. Syphilis Lancet, 2023.PMID 37481272
3. [3]Hamill MM, Ghanem KG, Tuddenham S. State-of-the-Art Review: Neurosyphilis Clin Infect Dis, 2024.PMID 37593890
4. [4]Chow F. Neurosyphilis Continuum (Minneap Minn), 2021.PMID 34623102
5. [5]Corrêa DG, de Souza SR, Freddi TAL, et al. Imaging features of neurosyphilis J Neuroradiol, 2023.PMID 36641134
6. [6]Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: a systematic review JAMA, 2014.PMID 25387188
7. [7]Gilmour LS, Walls T. Congenital Syphilis: a Review of Global Epidemiology Clin Microbiol Rev, 2023.PMID 36920205
8. [8]Sankaran D, Partridge E, Lakshminrusimha S. Congenital Syphilis-An Illustrative Review Children (Basel), 2023.PMID 37628309
9. [9]Furtado JM, Simões M, Vasconcelos-Santos D, et al. Ocular syphilis Surv Ophthalmol, 2022.PMID 34147542
10. [10]Park IU, Tran A, Pereira L, et al. Sensitivity and Specificity of Treponemal-specific Tests for the Diagnosis of Syphilis Clin Infect Dis, 2020.PMID 32578866
11. [11]Butler T. The Jarisch-Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis Am J Trop Med Hyg, 2017.PMID 28077740
12. [12]Janier M, Unemo M, Dupin N, et al. 2020 European guideline on the management of syphilis J Eur Acad Dermatol Venereol, 2021.PMID 33094521
13. [13]Singh AE, Wong T, Robinson J. Syphilis screening in pregnancy: no time for complacency Curr Opin Obstet Gynecol, 2025.PMID 40574693
14. [14]Sethi V, Marks M. Neurosyphilis in 2025 Curr Opin Neurol, 2025.PMID 40605685