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SYPHILIS - COMPLETE Q&A FOR DERMATOLOGY RESIDENTS

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SECTION 1: BASIC SCIENCE & MICROBIOLOGY

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• Length: 6-15 μm (Andrews: 5-20 μm)
• Number of coils: 8-20 (Rook's); as a practical guide, ~7-8 coils per diameter of a red blood corpuscle
• Coil wavelength: 1.1 μm; amplitude: 0.4 μm
• Actively motile with THREE characteristic movements: rotation around its long axis (appears to quiver and screw backwards and forwards), projection in the direction of the long axis, and bending/twisting from side to side
• The precise uniformity of spiral coils is NOT distorted during movement
• Cannot be cultured on any biochemical medium in vitro
• Only known host: humans
• Rabbit is used in laboratory studies

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• Its genome contains only about one quarter the number of genes of most bacteria
• It lacks significant metabolic capacity
• Very sensitive to temperature - some enzymes work poorly at typical body temperature (this also explains why fever therapy was historically effective)
• These two factors - limited metabolic capacity and temperature sensitivity - contribute to inability to culture in vitro

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1. Rapid dissemination - enters bloodstream within hours of infection; reaches brain within 18 hours of inoculation
2. Very low antigenic mass - number of organisms in each tissue is very low, perhaps below a "critical antigenic mass"
3. Minimal surface antigens - expresses only ~1% as many antigenic targets on its surface as E. coli
4. Outer membrane lacks lipopolysaccharide and contains few, poorly immunogenic transmembrane proteins
5. Rapid outer membrane protein mutation - subpopulations with different surface antigens accumulate during infection
6. Th1→Th2 switch - macrophage suppression caused by prostaglandin E2 down-regulation
7. Hyaluronidase - surface-associated enzyme aids tissue penetration
8. Depressed cell-mediated immunity - lowered CD4+ lymphocyte count in later stages

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• Less than 2% difference in genomes - they are "genetically monomorphic bacteria"
• Yaws first arose in Africa, spread with human migration
• Endemic syphilis evolved from yaws; became endemic in Middle East and Balkans
• Syphilis (T. p. pallidum) may have originated in the New World from T. p. pertenue (yaws), analogous to HIV evolving from SIV in Africa
• A tribe in Guyana had a spirochetal infection with features of BOTH yaws and syphilis - its sequenced genome suggested it was the ancestor of T. p. pallidum, supporting the Columbian theory
• Syphilis became primarily venereally transmitted toward the end of the 15th century

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MCQ SET 1: MICROBIOLOGY

• A) 3-4
• B) 5-6
• C) 7-8 ✓
• D) 10-12

• A) 6 hours
• B) 12 hours
• C) 18 hours ✓
• D) 36 hours

• A) Half
• B) One quarter ✓
• C) One third
• D) Equal number

• A) Rotation on long axis
• B) Projection along long axis
• C) Lateral bending/twisting
• D) Flagellar whip motion ✓

• A) Guinea pig
• B) Mouse
• C) Rabbit ✓
• D) Hamster

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SECTION 2: EPIDEMIOLOGY

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• WHO estimates >1 million people acquire chlamydia, gonorrhoea, syphilis, or trichomoniasis each DAY
• WHO global targets: reduce incidence of syphilis by 90% from 2016 baseline values by 2030
• Additional WHO aim: abolish congenital syphilis cases in over 80% of countries
• In the USA, rates of primary and secondary syphilis are highest in persons 20-29 years old
• Major racial health disparity: Blacks are disproportionately affected - rates >5 times higher than non-Hispanic whites
• MSM (men who have sex with men), ethnic minorities, and young people are disproportionately affected in high-income countries
• STI rates remain high in those living with HIV and those using PrEP

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SECTION 3: PRIMARY SYPHILIS

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• Incubation period: 9-90 days (average 21 days / 3 weeks) after exposure
• Number: Usually single, but may be multiple (especially in HIV)
• Character: Painless, indurated (hard, cartilaginous), well-defined, clean-based ulcer
• Base: Clean, serous discharge
• Edges: Raised, rolled, indurated
• Lymphadenopathy: Unilateral or bilateral, painless, rubbery, non-tender regional lymphadenopathy (usually inguinal)
• Location in men: Coronal sulcus, glans, prepuce, shaft, meatus (extragenital: lips, tongue, fingers, nipple, anus)
• Location in women: Labia majora/minora, fourchette, cervix (cervical chancres may be missed)
• Duration: Heals spontaneously in 3-8 weeks even without treatment
• Treponemes: Abundant in the serous exudate - dark-field microscopy positive BEFORE antibodies appear

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• Other STIs: Genital herpes (painful, vesicular), chancroid (Haemophilus ducreyi - painful, soft ulcer), donovanosis (granuloma inguinale), lymphogranuloma venereum, HPV
• Dermatoses: Erosive balanitis, Behçet disease (painful, recurrent oral+genital ulcers), fixed drug eruption, aphthae
• Neoplasia: Squamous cell carcinoma (especially on penis/vulva in older patients), Bowen disease
• Traumatic ulcers
• Oral chancre DDx: Tonsillitis (painful), oral carcinoma

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SECTION 4: SECONDARY SYPHILIS

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• Appears 6-8 weeks after the chancre (may overlap with primary - chancre may still be present in up to 25% of cases)
• Represents haematogenous dissemination of T. pallidum
• Constitutional symptoms: fever, malaise, headache, myalgia, arthralgia, sore throat, anorexia, weight loss
• Generalized lymphadenopathy (shotty, non-tender, bilateral) - including epitrochlear nodes (classic)
• Hepatitis, uveitis, meningitis, nephropathy (immune complex glomerulonephritis) can all occur
• Duration of untreated secondary syphilis: resolves spontaneously over 2-6 weeks
• Up to 25% of patients with early latent syphilis may relapse into secondary syphilis

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• Macular rash (roseola syphilitica): First cutaneous eruption; faint, pink-red macules on trunk, flexures; transient; easily missed
• Maculopapular rash: Most classic; generalized, symmetrical, copper-red/ham-coloured papules; characteristically involves PALMS AND SOLES (key exam point); non-pruritic; the sine qua non of secondary syphilis
• Papular syphilide: Firm, discrete, red-brown papules; may be follicular
• Psoriasiform syphilide: Hyperkeratotic, scaly papules resembling psoriasis; show psoriasiform hyperplasia of epidermis with spongiosis and interface changes with abundant PLASMA CELLS on histology
• Annular syphilide: More common in dark-skinned individuals; annular, arcuate plaques, especially on face and genitals
• Nodular syphilide: Grouped, indurated nodules
• Lues maligna (malignant syphilis): Rare; pustular, necrotic, ulcerating lesions with rupioid (oyster-shell) crusts; seen in immunocompromised (HIV); constitutional symptoms severe

• Broad, flat, moist, warty papules/plaques
• Sites: perianal, perivulval, penile shaft, groin, axillae, submammary folds
• Highly infectious - teeming with spirochetes
• DDx: condyloma acuminata (HPV - verrucous, filiform, not flat)

• Oval, painless, grey-white erosions/plaques on oral mucosa, tongue, tonsils, genital mucosa
• "Snail-track ulcers" on the tongue/palate
• Split papules at angles of mouth (pathognomonic)
• Highly infectious

• "Moth-eaten" alopecia - patchy, non-scarring hair loss of scalp, beard, eyebrows, eyelashes
• Non-inflammatory; hairs can regrow with treatment
• Also affects eyebrows: "Omnibus sign" or "flag sign" of eyebrow loss

• Hypopigmented macules on posterior neck/upper chest
• More visible in dark-skinned individuals
• Caused by perivascular inflammation affecting melanocytes

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• Psoriasiform hyperplasia of the epidermis
• Spongiosis (intercellular oedema)
• Interface changes (vacuolar/lichenoid)
• Abundant plasma cells in the dermis - this is the HALLMARK feature
• Perivascular infiltrate of lymphocytes and plasma cells
• Endothelial swelling/proliferation (endarteritis obliterans)
• Spirochetes demonstrable by immunohistochemistry (IHC) within the epidermis
• Silver stains (Warthin-Starry, Steiner) can also demonstrate organisms

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• Pityriasis rosea (has herald patch, follows Blaschko lines on trunk, usually pruritic)
• Drug eruption (pruritic, morbilliform, timing with drug)
• Psoriasis (well-demarcated, silvery scale, Auspitz sign)
• Viral exanthem (usually pruritic, prodrome, child/young adult)

• Lichen planus (pruritic, Wickham's striae, wrists/ankles/genitals)
• Scabies (pruritic, burrows, web spaces)
• Infectious mononucleosis (painful lymphadenopathy, pharyngitis, + ampicillin rash)
• Seborrhoeic dermatitis (greasy scale, seborrhoeic distribution)
• Reactive arthritis / circinate balanitis
• Cutaneous T-cell lymphoma
• Lupus erythematosus
• Erythema multiforme

• Condyloma acuminata (HPV): verrucous, filiform, less flat/moist
• Kaposi sarcoma

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MCQ SET 2: PRIMARY & SECONDARY SYPHILIS

• A) 7 days
• B) 14 days
• C) 21 days ✓
• D) 42 days

• A) Pruritic, vesicular rash on the trunk
• B) Non-pruritic maculopapular rash involving palms and soles ✓
• C) Painful ulcers on mucous membranes
• D) Unilateral lymphadenopathy

• A) Verrucous, filiform papules caused by HPV
• B) Broad, flat, moist papules of secondary syphilis ✓
• C) Crusted, hyperkeratotic nodules of tertiary syphilis
• D) Smooth, pearly papules of molluscum contagiosum

• A) Necrotizing granulomas with central caseation
• B) Spongiotic vesiculation with eosinophils
• C) Psoriasiform hyperplasia with abundant plasma cells ✓
• D) Subepidermal bulla formation

• A) Scarring, with follicular destruction
• B) Non-scarring, with potential for regrowth ✓
• C) Associated with positive ANA
• D) Due to direct invasion of hair follicles by treponemes causing permanent damage

• A) Herpes labialis
• B) Angular cheilitis (candidal)
• C) Secondary syphilis ✓
• D) Pemphigus vulgaris

• A) Mediastinal nodes
• B) Epitrochlear nodes ✓
• C) Pre-auricular nodes
• D) Posterior cervical nodes only

• A) Condylomata lata on the neck
• B) Hypopigmented macules on the posterior neck ✓
• C) A string of mucous patches on the cervix
• D) Perioral papules

• A) Tertiary syphilis with gumma formation
• B) Congenital syphilis with pneumonia alba
• C) A malignant variant of secondary syphilis with pustulo-ulcerative necrotic lesions, especially in HIV ✓
• D) Neurosyphilis with tabes dorsalis

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SECTION 5: LATENT SYPHILIS

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• Definition: No clinical stigmata of active disease; disease detectable ONLY by positive serological tests
• Diagnosis of exclusion: active primary, secondary, tertiary, and neurosyphilis must be ruled out; CSF must be normal; chest X-ray must be normal

• Syphilis acquired within the preceding 1 year (CDC/Fitzpatrick definition)
• Criteria for classifying as early latent (any ONE of):
  1. Documented seroconversion OR sustained (>2 weeks) fourfold or greater increase in nontreponemal test titers within the past year
  2. Unequivocal symptoms of primary or secondary syphilis within the past year
  3. Sex partner documented to have primary, secondary, or early latent syphilis within the past year
  4. Reactive nontreponemal + treponemal tests if only possible exposure occurred within previous 12 months
• Vertical transmission can still occur in early latency
• Up to 25% may relapse into secondary syphilis
• Treatment same as primary/secondary syphilis

• Syphilis acquired more than 1 year ago (or unknown duration)
• Sexual transmission very unlikely (no mucocutaneous lesions)
• Requires longer treatment course
• Late manifestations arise in ~25% of those with latent syphilis, often decades later

• No clinical evidence of active disease
• Normal CSF
• Normal chest X-ray (PA + left oblique to view aorta)
• Positive STS confirmed by a second specimen

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SECTION 6: TERTIARY SYPHILIS

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• A gumma is a chronic granulomatous lesion with central necrosis
• Sites: skin, bone, liver, testis, upper respiratory tract, brain
• Skin gummas: Begin as painless, deep-seated nodules → break down → "punched-out" ulcers with a "wash-leather" (chamois-leather) base → heal with tissue-paper scarring
• Bone gummas: Periostitis; nocturnal bone pain (worse at night = classic); destructive osteitis
• Palate/nasal septum: Perforation → "saddle-nose" deformity, oro-nasal fistula; collapse of the nasal bridge
• Testicular gumma: Painless testicular swelling → orchitis
• Excellent response to penicillin (unlike other forms of tertiary syphilis)
• DDx of skin gumma: lupus vulgaris (TB), leishmaniasis, Wegener's granulomatosis, Buruli ulcer, deep fungal infections, sarcoid

• Latent period: 10-30 years
• Mechanism: endarteritis obliterans of vasa vasorum of aorta → medial necrosis → aortic dilatation
• Aortic aneurysm: Most common; usually involves ascending aorta (atherosclerotic aneurysms usually affect descending aorta) - "tree-bark" or "eggshell" calcification of ascending aorta on X-ray
• Aortic regurgitation: "Tambour" quality of aortic diastolic murmur
• Coronary ostial stenosis: Angina
• Chest X-ray: Widening of aortic knuckle; linear calcification in wall of ascending aorta
• Treatment: Does NOT reverse established damage; penicillin + corticosteroids (to prevent Jarisch-Herxheimer reaction)

• Facial: Lupus vulgaris, rosacea, lupus erythematosus
• Truncal: Psoriasis, mycosis fungoides
• Legs: Chronic venous ulcer, Bazin disease

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MCQ SET 3: LATENT & TERTIARY SYPHILIS

• A) 10%
• B) 25%
• C) One-third ✓
• D) Half

• A) Normal skin, no scarring
• B) Hypertrophic scar
• C) Tissue-paper (atrophic) scarring ✓
• D) Keloid formation

• A) Descending thoracic aorta
• B) Abdominal aorta
• C) Ascending aorta ✓
• D) Aortic arch equally

• A) Osteosarcoma
• B) Tertiary syphilis periostitis ✓
• C) Paget disease
• D) Osteoporotic fracture

• A) Atherosclerosis
• B) Marfan syndrome
• C) Syphilitic aortitis ✓
• D) Takayasu arteritis

• A) Congenital cartilage defect
• B) Gummatous destruction of the nasal septum/palate in tertiary syphilis ✓
• C) Secondary syphilis mucous patch on septum
• D) Lues maligna involving the nose

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SECTION 7: NEUROSYPHILIS

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1. Asymptomatic neurosyphilis: CSF abnormalities only (elevated protein, pleocytosis, positive VDRL); no symptoms
2. Syphilitic meningitis: Headache, neck stiffness, cranial nerve palsies (especially CN II, VII, VIII), raised intracranial pressure; may cause hydrocephalus; occurs within 1-2 years of infection
3. Meningovascular syphilis: Endarteritis obliterans of cerebral vessels → stroke-like episodes in a young person; may have prodrome of weeks of headaches, personality change; "syphilitic stroke" in young adults

• Direct parenchymal invasion of the brain
• Mnemonic: PARESIS = Personality change, Affect abnormal, Reflexes hyperactive, Eye changes (Argyll Robertson pupil), Sensorium abnormal (dementia/delusions of grandeur), Intellect impaired, Speech abnormal (slurring)
• Argyll Robertson pupil: accommodates but does NOT react to light ("prostitute's pupil" - accommodates but doesn't react)
• CSF: positive VDRL, elevated protein, lymphocytic pleocytosis

1. Tabes Dorsalis (Locomotor Ataxia):
   • Degeneration of posterior columns and posterior nerve roots
   • Features: Lightning pains (stabbing, brief, lancinating - typically in legs), Romberg positive, wide-based ataxic gait, loss of deep pain sensation, loss of proprioception
   • Argyll Robertson pupil (80%)
   • Charcot joints (neuropathic arthropathy): painless destruction of joints (knees most common) due to loss of pain sensation
   • Visceral crises: gastric crisis (severe epigastric pain + vomiting mimicking surgical abdomen), rectal, vesical crises
   • Bladder dysfunction (atonic bladder)
   • Hypotonia, absent ankle and knee jerks
   • Trophic ulcers on plantar surface of feet ("perforating ulcer")
2. Taboparesis: Combined features of tabes dorsalis + general paresis

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• CSF-VDRL: Highly SPECIFIC but not sensitive (~30-70% sensitivity); a reactive CSF-VDRL is diagnostic of neurosyphilis
• CSF protein: Elevated (>45 mg/dL)
• CSF cell count: Lymphocytic pleocytosis (>5 WBC/mm³)
• CSF-FTA-ABS: More sensitive than VDRL but less specific; a reactive CSF-FTA-ABS does NOT confirm neurosyphilis but a NON-REACTIVE CSF-FTA-ABS essentially rules it out
• TPHA index (CSF TPHA / serum TPHA ratio): Used in some centres

• All HIV-seropositive patients with syphilis
• Neurological or ophthalmological symptoms/signs
• Treatment failure
• High serum RPR titre (>1:32) in late latent syphilis
• Tertiary syphilis (cardiovascular, gummatous)

• First line: Aqueous crystalline benzylpenicillin G: 18-24 million units/day IV given as 3-4 MU every 4 hours for 10-14 days (Fitzpatrick's: 18-24 MU/day IV × 14 days)
• Alternative: Procaine penicillin 2.4 MU IM OD + probenecid 500 mg QDS for 14 days
• Rook's recommends corticosteroids (prednisolone 40-60 mg daily for 3 days, starting 1 day before antibiotics) for cardiovascular and neurosyphilis to prevent Jarisch-Herxheimer reaction

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MCQ SET 4: NEUROSYPHILIS

• A) Dilated pupil that reacts to light but not accommodation
• B) Small, irregular pupil that accommodates but does NOT react to light ✓
• C) Unilateral fixed dilated pupil with ptosis
• D) Miosis with anhidrosis and enophthalmos

• A) General paresis
• B) Tabes dorsalis ✓
• C) Meningovascular syphilis
• D) Syphilitic meningitis

• A) CSF-FTA-ABS
• B) CSF-TPPA
• C) CSF-VDRL ✓
• D) CSF protein elevation

• A) Epilepsy
• B) Eye changes (Argyll Robertson pupil) ✓
• C) Encephalitis
• D) Emotional lability

• A) Hip joints
• B) Ankle joints
• C) Knee joints ✓
• D) Wrist joints

• A) <1 year
• B) 2-7 years ✓
• C) 10-15 years
• D) 20-30 years

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SECTION 8: DIAGNOSIS & SEROLOGY

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NONTREPONEMAL TESTS (Reagin tests):

• Based on: Cardiolipin-cholesterol-lecithin antigen (lipoidal antigen released from host cells damaged by T. pallidum)
• Tests: RPR (Rapid Plasma Reagin) and VDRL (Venereal Disease Research Laboratories)
• RPR: Macroscopic flocculation test; uses charcoal particles; can be done without microscope; used for screening
• VDRL: Microscopic flocculation; used for CSF testing (RPR not validated for CSF)
• Become positive: 5-6 weeks after infection (shortly before chancre heals)
• Strongly positive throughout secondary phase
• Quantitative - expressed as titres (e.g., 1:16, 1:32); used to monitor treatment response
• Treatment success: fourfold (2-dilution) fall in titre within 6-12 months (e.g., 1:32 → 1:8)
• Serofast reaction: Persistent low-titre RPR/VDRL after adequate treatment (does NOT mean treatment failure)
• Become negative after treatment (especially if treated early in first year)
• May become negative spontaneously after decades even without treatment

TREPONEMAL TESTS (Specific tests):

• Detect antibodies against T. pallidum antigens specifically
• Tests: FTA-ABS (Fluorescent Treponemal Antibody Absorption), TPPA (T. pallidum Particle Agglutination), MHA-TP (Microhemagglutination Assay - T. pallidum), EIA/CIA (Enzyme/Chemiluminescence Immunoassay)
• Sensitivity and specificity >95%, even in primary syphilis (newer EIA/TPPA)
• IgM EIA: Becomes detectable 2-3 weeks after infection (at time of chancre appearance); useful in primary syphilis; becomes NEGATIVE after treatment of early syphilis (92% negative at 1 year post-treatment)
• IgG EIA/FTA-ABS/MHA-TP/TPPA: Become positive at 4-5 weeks; remain positive for LIFE in majority even after treatment (13-24% may become negative with treatment)
• Qualitative only - NOT used for monitoring treatment response

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1. Screen with RPR/VDRL (nontreponemal, quantitative)
2. If reactive → confirm with treponemal test (FTA-ABS or TPPA)
3. If treponemal test positive → diagnosis confirmed; treat based on stage
4. Advantage: Quantitative titre for monitoring

1. Screen with EIA or CIA (treponemal) - automated, high throughput
2. If reactive treponemal EIA → test with RPR/VDRL (nontreponemal, quantitative)
3. If RPR reactive → diagnosis confirmed, stage and treat
4. If treponemal EIA reactive but RPR non-reactive → test with a second, DIFFERENT treponemal test (e.g., TPPA if initial EIA used)
   • If second treponemal test positive + RPR negative → possible past treated/untreated syphilis; detailed history needed
   • If second treponemal test negative → likely false positive on initial EIA

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• Principle: Reflects light obliquely off the spirochete; T. pallidum appears as a bright white, corkscrew organism against a dark background
• When positive before serology: In primary syphilis, DFM is positive BEFORE antibodies appear - it is the only way to diagnose very early primary syphilis
• Specimen collection: Cleanse lesion with saline-soaked gauze → abrade with dry gauze → gently squeeze edge → collect serous exudate on coverslip edge → place on slide
• Limitations:
  • Cannot be used for ORAL lesions (commensal oral treponemes are morphologically identical to T. pallidum)
  • For oral lesions, use Direct Fluorescent Antibody (DFA) testing
  • Requires fresh specimen and immediate examination
  • Technically demanding; repeat on consecutive days if initially negative
• Morphology on DFM: Pale white, fine corkscrew organism; close, very regular coils; characteristic motility (rotation on long axis + lateral bending)
• PCR: In developed countries, PCR-based tests are becoming more available for direct detection

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MCQ SET 5: SEROLOGY & DIAGNOSIS

• A) FTA-ABS
• B) TPPA
• C) RPR (nontreponemal, quantitative) ✓
• D) CSF-VDRL

• A) 2-3 weeks
• B) 5-6 weeks ✓
• C) 8-10 weeks
• D) 12-16 weeks

• A) Pregnancy
• B) Malaria
• C) SLE ✓
• D) Infectious mononucleosis

• A) In less than 5% of patients
• B) Only for 1 year
• C) In the majority (87-76%) of patients for life ✓
• D) Only in neurosyphilis

• A) VDRL
• B) FTA-ABS
• C) RPR ✓
• D) TPPA

• A) Penile shaft
• B) Vulva
• C) Oral cavity ✓
• D) Rectum

• A) Becomes detectable 4-5 weeks after infection
• B) Stays positive for life after treatment
• C) Becomes detectable 2-3 weeks after infection and becomes negative after treatment of early syphilis ✓
• D) Is used primarily to diagnose late latent syphilis

• A) 1:32 to 1:16
• B) 1:32 to 1:8 ✓
• C) 1:16 to 1:8
• D) 1:32 to 1:4

• A) Treat empirically
• B) Repeat RPR in 6 months
• C) Perform a second, different treponemal test (e.g., TPPA) ✓
• D) Perform CSF examination

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SECTION 9: TREATMENT

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PENICILLIN - DRUG OF CHOICE AT ALL STAGES

• First line: Benzathine penicillin G 2.4 million units IM single dose
• Alternative (penicillin allergy, non-pregnant): Doxycycline 100 mg BD × 14 days

• First line: Benzathine penicillin G 2.4 MU IM weekly × 3 doses (total 7.2 MU)
• Alternative: Doxycycline 100 mg BD × 28 days

• First line: Aqueous crystalline benzylpenicillin G 18-24 MU/day IV, given as 3-4 MU IV every 4 hours × 10-14 days
• Alternative (Rook's): Procaine penicillin G 1.8-2.4 MU IM OD + probenecid 500 mg QDS × 14 days
• Corticosteroids with neurosyphilis and cardiovascular syphilis: Prednisolone 40-60 mg/day × 3 days, starting 1 day before antibiotics

• Doxycycline (preferred alternative for early syphilis)
• Ceftriaxone 500 mg IM OD × 10 days (if no anaphylaxis to penicillin)
• Azithromycin 500 mg OD × 10 days OR 2 g single dose (CONCERN: emerging azithromycin resistance - macrolides no longer recommended in Rook's 2024)
• Erythromycin (less reliable, not preferred)

• Penicillin desensitisation is MANDATORY in pregnant women allergic to penicillin - no alternative has documented efficacy for preventing congenital syphilis
• Macrolides are NO LONGER a treatment option in pregnancy (Rook's 2024)

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• Acute febrile reaction occurring 2-8 hours after first dose of treatment for syphilis (and other spirochetal infections)
• Mechanism: Massive release of treponemal lipoproteins and cytokines (TNF-α, IL-6, IL-8) upon spirochete lysis
• Features: Fever (temperature rise of 1-2°C), rigors, headache, myalgia, exacerbation of existing skin lesions, hypotension, tachycardia
• Duration: Usually resolves within 12-24 hours
• Most common in secondary syphilis (when spirochetal load is highest)
• Most dangerous in: Pregnancy (can precipitate uterine contractions and preterm labour/fetal distress), cardiovascular syphilis, neurosyphilis
• Treatment:
  • Reassurance; self-limiting
  • Antipyretics (paracetamol/acetaminophen)
  • For neurosyphilis and cardiovascular syphilis: pre-treat with prednisolone 40-60 mg/day × 3 days starting 1 day before antibiotics (Rook's)
  • Do NOT stop penicillin
• Does NOT indicate penicillin allergy

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• Serological monitoring (RPR titres) at: 3, 6, 12 months after treatment
• For late syphilis: also at 24 months
• Treatment success: fourfold (2-dilution) fall in nontreponemal titre within 6-12 months
  • Primary/secondary: RPR should be non-reactive or <1:4 by 12 months
  • Late syphilis: slower decline acceptable
• Treatment failure or re-infection criteria: fourfold rise in titre OR titre fails to fall appropriately AND the patient has symptoms
• In failure cases: CSF examination before re-treatment
• HIV-positive patients: More frequent monitoring (3, 6, 9, 12, 24 months); CSF examination in all seropositive patients with syphilis (Rook's)
• All patients should be offered screening for other STIs and HIV

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MCQ SET 6: TREATMENT

• A) Doxycycline 100 mg BD × 14 days
• B) Benzathine penicillin G 2.4 MU IM single dose ✓
• C) Azithromycin 2 g single dose
• D) Aqueous penicillin G IV for 14 days

• A) Single dose 2.4 MU IM
• B) 2.4 MU IM weekly × 3 doses ✓
• C) 2.4 MU IM daily × 10 days
• D) 4.8 MU IM single dose

• A) With second dose of penicillin, 24-48 hours after first treatment
• B) 2-8 hours after the FIRST dose of treatment for syphilis ✓
• C) Only in penicillin-allergic individuals
• D) Only in secondary syphilis

• A) Doxycycline 100 mg BD × 14 days
• B) Azithromycin 2 g single dose
• C) Erythromycin 500 mg QDS × 14 days
• D) Penicillin desensitisation ✓

• A) Secondary syphilis (exacerbation of rash)
• B) Primary syphilis (inflammation at chancre site)
• C) Neurosyphilis and cardiovascular syphilis, and pregnancy ✓
• D) Gummatous syphilis (enlargement of gumma)

• A) FTA-ABS becoming non-reactive
• B) TPPA titre falling to zero
• C) Fourfold (2-dilution) fall in nontreponemal (RPR/VDRL) titre ✓
• D) Resolution of symptoms alone

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SECTION 10: SYPHILIS IN SPECIAL POPULATIONS

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• Epidemiology: HIV-positive patients have higher rates of syphilis; syphilis increases HIV transmission (early syphilis lesions contain mononuclear cells with enhanced expression of CCR5, the coreceptor for HIV-1)
• Syphilis increases HIV risk: Disruption of mucosal barrier + local inflammation ↑ HIV acquisition and transmission; maternal syphilis increases risk of HIV vertical transmission
• Altered serology: Immune response less predictable; may have false-negative serology OR unusually high titres; prozone phenomenon more common
• Lues maligna: More common in HIV patients
• Accelerated course: More rapid progression to neurosyphilis
• Treatment: Same regimens as HIV-negative EXCEPT:
  • CSF examination recommended in ALL HIV-positive syphilis patients (Rook's)
  • More frequent follow-up: 3, 6, 9, 12, 24 months
  • Some experts recommend 3 doses benzathine penicillin even for early syphilis in HIV
• HIV testing: Recommended in ALL patients with syphilis; repeat HIV test at 3 months if initially negative and presenting with primary syphilis

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• A false-negative nontreponemal test (RPR/VDRL) result in the presence of very HIGH antibody titres
• Mechanism: Excess antibody prevents antigen-antibody lattice formation needed for visible flocculation
• Seen in: Secondary syphilis (highest antibody titre stage), HIV co-infection
• Solution: Dilute the serum before testing
• Clinical Pearl: A patient with a typical rash of secondary syphilis but a NEGATIVE RPR/VDRL = always suspect prozone. Ask the lab to dilute and repeat the test. This is a classic exam and clinical pitfall.

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MCQ SET 7: SPECIAL SITUATIONS

• A) False positive result due to cross-reactivity
• B) False negative nontreponemal test due to excess antibody ✓
• C) Failure of treponemal tests to become positive
• D) Persistent reactivity after treatment

• A) Gumma
• B) Primary chancre ✓
• C) Condylomata lata
• D) Mucous patches

• A) Primary syphilis
• B) Secondary syphilis ✓
• C) Latent syphilis
• D) Tertiary syphilis

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SECTION 11: CONGENITAL SYPHILIS

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• T. pallidum crosses the placenta and infects the fetus
• Can occur at any stage of pregnancy but most commonly in the second trimester (after 16 weeks - when Langhans cell layer of placenta thins)
• Transmission rate: Highest in early maternal syphilis (primary/secondary ~70-100%); lower in late latent syphilis (~30%)
• Results in: stillbirth, miscarriage, hydrops fetalis, prematurity, neonatal death, or live-born infected infant
• Women who have had documented treatment for syphilis in the past do NOT need re-treatment in current/subsequent pregnancies IF no clinical evidence and RPR/VDRL is negative

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• Pemphigus syphiliticus: Vesiculobullous lesions on palms and soles - the most dramatic neonatal presentation; highly infectious
• Maculopapular/papulosquamous rash: Similar to secondary syphilis in adults; involves palms/soles; copper-red papules
• Condylomata lata: In moist areas (perineum, around anus)
• Mucous patches: Oral, nasal
• Rhinitis ("snuffles"): Profuse, serosanguineous nasal discharge (first symptom in many); HIGHLY infectious

• Hepatosplenomegaly (common), often with jaundice
• Anaemia and thrombocytopenia ("blueberry muffin" appearance in severe cases)
• Osteochondritis syphilitica (Wegner's disease): Destruction of cartilage-bone junction (metaphysis); Wimberger sign = bilateral symmetrical destruction of proximal medial metaphyses of tibiae on X-ray; very painful - infant keeps limb immobile (pseudoparalysis of Parrot/syphilitic pseudoparalysis)
• Periostitis (thickening of periosteum on X-ray)
• Lymphadenopathy (epitrochlear nodes = classic)
• Pneumonia alba: White lungs due to interstitial pneumonitis with dense fibrous tissue
• CNS: Meningitis, meningoencephalitis, bulging fontanelle, convulsions → hydrocephalus, severe intellectual impairment
• Choroiditis, chorioretinitis (anterior uveitis rare in ECS)

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1. Hutchinson's Triad:
   • Hutchinson's teeth: Peg-shaped, notched upper central incisors (permanent dentition); barrel-shaped with a central notch; characteristic "screwdriver" or "Hutchinson notch" appearance
   • Interstitial keratitis: Commonest and most serious late lesion; bilateral corneal clouding with ciliary injection; "brush-like" vessels penetrating from sclera into deep cornea; photophobia, pain; NOT improved by antisyphilitic treatment - requires topical/subconjunctival corticosteroids; risk of blindness
   • Sensorineural deafness (VIIIth nerve deafness): Bilateral; progressive; may present in childhood or young adulthood; NOT improved by penicillin
2. Other Stigmata:
   • Moon's (mulberry) molars: First molars with multiple small cusps on a domed occlusal surface instead of normal 4 cusps; pathognomonic
   • Clutton joints: Painless, bilateral, symmetrical synovitis of knees; resolves spontaneously; unaffected by antisyphilitic treatment
   • Saber shins: Anterior bowing of tibiae from periostitis
   • Saddle-nose deformity: Collapse of nasal bridge from gummatous destruction of septum/cartilage
   • Rhagades (Parrot's lines): Linear fissures/scars radiating from angles of mouth, nose, anus, genitals from healed early CS mucous patches
   • Frontal bossing: Prominent forehead (Olympian brow)
   • Hydrocephalus, intellectual impairment
   • Chorioretinitis: "Salt and pepper" fundal appearance
   • Leukoderma syphiliticum at back of neck
   • High-arched (Gothic) palate

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MCQ SET 8: CONGENITAL SYPHILIS

• A) Neurosyphilis affecting the motor cortex
• B) Pain from syphilitic osteochondritis (Wegner's disease) causing the infant to hold the limb immobile ✓
• C) Meningeal irritation
• D) Peripheral neuropathy

• A) Linear periosteal reaction along diaphysis of long bones
• B) Bilateral symmetric destruction of proximal medial metaphyses of tibiae ✓
• C) "Tree bark" calcification of the aorta
• D) Saddle-nose deformity on facial X-ray

• A) Interstitial keratitis + Hutchinson's teeth + sensorineural deafness ✓
• B) Saddle nose + rhagades + Clutton joints
• C) Moon's molars + saber shins + frontal bossing
• D) Chorioretinitis + Clutton joints + saber shins

• A) Hips
• B) Ankles
• C) Knees ✓
• D) Wrists

• A) Interstitial keratitis
• B) Clutton joints
• C) Sensorineural deafness
• D) None of the above - all three are "allergic" phenomena unresponsive to penicillin ✓

• A) A type of rash around the nose
• B) Profuse, serosanguineous nasal discharge (infectious rhinitis) ✓
• C) Choanal atresia
• D) Nasal septal perforation

• A) Peg-shaped, notched permanent incisors
• B) First molars with multiple cusps on a domed surface (mulberry molars) ✓
• C) Delayed eruption of deciduous teeth
• D) Enamel hypoplasia of all molars

• A) Trunk and face
• B) Scalp and neck
• C) Palms and soles ✓
• D) Mucous membranes only

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SECTION 12: CLINICAL CASE SCENARIOS

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CASE 1

1. Dark-field microscopy of the serous exudate from the ulcer (test before antibodies appear)
2. IgM EIA (detectable 2-3 weeks post infection)
3. Specific treponemal test (FTA-ABS/TPPA) - positive earlier than RPR
4. Repeat RPR in 2 weeks

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CASE 2

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CASE 3

• CSF-VDRL (highly specific for neurosyphilis)
• CSF cell count (expect lymphocytic pleocytosis >5 WBC/mm³)
• CSF protein (expect elevated >45 mg/dL)
• CSF glucose

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CASE 4

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CASE 5

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SECTION 13: FINAL HIGH-YIELD CLINICAL PEARLS

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1. "He who knows syphilis knows medicine" (Osler) - syphilis mimics almost every disease in every organ system.
2. Primary syphilis = painless, indurated, clean-based ulcer + non-tender rubbery inguinal nodes. Painless = think syphilis. Painful = think herpes or chancroid.
3. Never rule out primary syphilis with a negative RPR alone. RPR may be negative in very early primary syphilis. Use DFM + treponemal test.
4. Palms and soles involvement in a rash = syphilis until proven otherwise. (Also: Rocky Mountain Spotted Fever, erythema multiforme, hand-foot-mouth disease, drug reaction, RMSF).
5. Non-pruritic rash differentiates secondary syphilis from most of its mimics (pityriasis rosea, drug eruptions, viral exanthems - all usually pruritic).
6. Plasma cells on skin biopsy = always think syphilis.
7. Prozone phenomenon = false negative RPR in secondary syphilis (highest titre stage). If the rash looks like secondary syphilis but RPR is negative, ask for dilution.
8. Epitrochlear lymphadenopathy in secondary syphilis is a classic sign - examine the epitrochlear region in every patient with a suspicious rash.
9. Argyll Robertson pupil = "accommodates but does not react" ("prostitute's pupil"). Small, irregular, bilateral. Pathognomonic of neurosyphilis.
10. Tabes dorsalis = Lightning pains (not constant, stabbing, brief) + wide-based gait + absent DTRs + Romberg positive + AR pupils. A middle-aged patient with "joint pains" and an apparently normal joint may have Charcot arthropathy from tabes.
11. Ascending aortic aneurysm in a middle-aged person without hypertension = think syphilitic aortitis. Atherosclerotic aneurysms prefer the descending/abdominal aorta.
12. Gumma responds beautifully to penicillin - dramatic improvement in 48-72 hours is almost diagnostic of tertiary gummatous syphilis.
13. JHR is NOT allergy - it is a pharmacological reaction to treponemal lipoproteins. Do NOT stop penicillin. Most dangerous in pregnancy and neurosyphilis.
14. In pregnant, penicillin-allergic women: desensitise. No other antibiotic is proven to prevent congenital syphilis. Macrolides are contraindicated (Rook's 2024).
15. Congenital syphilis TRIAD = Hutchinson's teeth + interstitial keratitis + sensorineural deafness. The keratitis and deafness do NOT respond to penicillin (allergic/immune phenomena).
16. Snuffles (nasal discharge) in a neonate = congenital syphilis until proven otherwise. It is highly infectious.
17. Treponemal tests stay positive for life in most patients. You cannot use FTA-ABS/TPPA to monitor treatment. Only RPR/VDRL titres monitor response.
18. RPR for screening; VDRL for CSF. RPR is not validated for CSF testing.
19. Syphilis + HIV = faster progression, higher chance of neurosyphilis, atypical serology. Always test for HIV in syphilis patients and vice versa.
20. "Great Imitator" = syphilis can mimic lichen planus (secondary syphilis papules), psoriasis (psoriasiform syphilide), alopecia areata (moth-eaten alopecia), condyloma acuminata (condylomata lata), pityriasis rosea, and even malignancy (gummas). When in doubt, test for syphilis.
21. For treatment monitoring: RPR should fall fourfold within 6-12 months for early syphilis. If it doesn't fall - suspect treatment failure or reinfection; perform CSF exam and consider re-treatment.
22. Oral chancres cannot be diagnosed by DFM (commensal oral treponemes are identical morphologically). Use DFA (direct fluorescent antibody) test for oral lesions.
23. Wimberger sign on X-ray = early congenital syphilis = bilateral symmetrical tibial metaphyseal destruction.
24. Clutton joints + interstitial keratitis = late congenital syphilis - both are immune-mediated, not infectious; treat with corticosteroids, not just penicillin.
25. Neurosyphilis can occur at ANY stage - T. pallidum reaches the CSF within 18 hours of infection. Asymptomatic neurosyphilis (CSF changes without symptoms) is common in early syphilis.

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QUICK REFERENCE SUMMARY TABLE

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