MRCP PACES Syphilis and Neurosyphilis
  • Caused by infection with Treponema pallidum
  • Cannot be grown in culture media, however there are other serological tests
    • Non-treponemal tests for screening
      • IgG and IgM against phospholipids formed by host in response to lipoidal material released by host cells in early infection
      • Rapid, simple, inexpensive
      • Used to monitor response to treatment and detect re-infection
        • Quantitative VDRL / RPR can be used to establish baseline titre
        • Monitor titre to gauge treatment effectiveness
      • Not entirely sensitive or specific due to cross-reactivity (especially in primary and late latent)
      • Venereal Disease Research Laboratory (VDRL) test
        • Microscopic flocculation test read under a microscope
        • Can be used in CSF samples
        • Antigen suspension must be prepared fresh daily
      • Rapid plasma regain (RPR)
        • Macroscopic flocculation test that does not require a microscope
        • Simplified version of VDRL test
        • Uses stabilized suspension of VDRL antigen
    • Treponemal tests for confirmation of non-treponemal results
      • May remain active for years without treatment; titres correlate poorly with disease activity
      • In populations with low syphilis prevalence, treponemal tests may be used for screening
      • pallidum particle agglutination (TPPA)
        • Used for detection of antibodies to T. pallidum in serum
        • Based on agglutination of coloured carriers sensitized with T. pallidum antigen
        • Positive TPPA with positive VDRL/RPR indicates current infection with syphilis
      • Enzyme immunoassay (EIA)
        • Detects IgM and IgG to T. pallidum
        • EIA against IgM especially useful for detection of early syphilis
        • Better than TPPA in HIV co-infected individuals
  • Stages of infection
    • Primary syphilis
      • Chancre, a painless ulcer which develops on the point of inoculation
      • Usually on the penis, vulva, cervix, within the anus or within the oral cavity
      • May take 9 – 90 days to appear (median 21 – 30 days)
      • May be associated with local lymphadenopathy
      • May have multiple chancres
      • May be painful if superinfected with skin flora / herpes simplex virus
      • Chancre usually heals without scarring spontaneously within 2 – 6 weeks
      • Diagnostic tests at this stage
        • Dark field microscopy from chancre exudate to identify spirochaete
        • Chancre swab for T. pallidum PCR
        • Direct immunofluorescence of chancre smear (direct fluorescent Ab to T. pallidum)
        • pallidum PCR from the blood (20% positive within a few days of inoculation)
        • Syphilis serology negative in 10% of primary syphilis
    • Secondary syphilis
      • Develops 2 weeks – 5 months following appearance of chancre
      • Due to bacteraemic phase of illness
      • Untreated secondary syphilis may recur up to two years after infection, with 90% of recurrences within the first year
      • Macular, maculopapular or pustular rash involving palms, soles
      • Condyloma lata – large, raised, grey-white lesions on mucosal surfaces
      • Patients may have patchy, non-scarring alopecia
      • Also associated with arthralgia, diffuse lymphadenopathy, hepatitis (especially with raised alkaline phosphatase)
      • Brisk immune reaction – immune complex deposition may cause nephrotic syndrome
      • 5% of patients have aseptic meningitis
        • Usually lymphocytic (>5 cells/mm3)
        • Often with transient cranial nerve deficient, most commonly VII, VIII (most common), VI and II
      • Diagnostic tests
        • Swab of mucosal lesions for T. pallidum PCR
        • Serological tests nearly 100% sensitive
        • In patients with previous syphilis, 4x increase in titre is diagnostic
        • CSF for VDRL if aseptic meningitis suspected
    • Latent syphilis
      • Patient is infected with T. pallidum, but has no symptoms of infection
      • Early latent
        • Infection within the last 12 months
        • No signs of primary or secondary syphilis
        • Positive syphilis serology
        • Preceded by negative serology within the last two years, or recent contact with infected case
        • Transmission still possible
      • Late latent
        • No signs of active syphilis
        • Positive syphilis serology
        • Transmission unlikely to occur in this stage
  • Tertiary syphilis
    • May occur anywhere between one and >25 years after initial infection
    • Multi-system disorder affecting CNS, CVS, skin and subcutaneous tissue
    • Occurs in 10 – 40% of patients infected with syphilis
    • Neurosyphilis
      • Meningovascular neurosyphilis
        • Typically 5 – 12 years after infection
        • May cause stroke-like syndrome, especially in territory of middle cerebral artery
        • Mechanisms is infarction secondary to endarteritis
        • Any artery, including spinal cord arteries, may be affected
      • Taboparesis (dementia paralytica, parenchymatous neurosyphilis)
        • Typically 10 – 25 years after infection
        • Irritability, memory loss, personality change, insomnia
        • Progresses to depression, psychosis and dementia
        • Cortical degeneration may cause UMN signs (not seen in tabes dorsalis)
        • Neurological signs
          • May have Argyll-Robertson pupil (reacts to accommodation but not light)
          • Facial tremors
          • Expressionless facies
          • Ataxia and dysarthria
          • Hyperreflexia
          • Extensor plantar reflexes
        • Causes death within months to years
        • MRI shows frontotemporal atrophy and subcortical gliosis
      • Tabes dorsalis (parenchymatous syphilis within the spinal cord)
        • Usually 15 – 30 years after infection
        • Caused by degeneration of the dorsal columns and dorsal roots
        • Typically heralded by shooting pains in the legs and abdomen
        • >90% of patients have Argyll-Robertson pupils
        • Loss of proprioception and vibration sense
        • Rhomberg’s positive with ataxic gait
        • May have wasting, hypotonia and arreflexia (LMN signs)
        • Longstanding dorsal column degeneration causes Charcot’s joints, perforating ulcers
        • Bladder and bowel dysfunction is very common
        • May have cranial nerve palsies
        • May be mistaken for Miller-Fisher syndrome due to ataxia, ophthalmoplegia and arreflexia
    • Cardiovascular syphilis
      • Usually seen 15 – 30 years after infection
      • Most commonly affects ascending thoracic aorta
      • Causes aortic dilation (proximal aortic aneurysm) and aortic regurgitation
      • Risk of aortic dissection is low as they are associated with vascular wall thickening
    • Gummas (late benign syphilis)
      • Proliferative granulomatous lesions
      • Thought to be an inflammatory response to small numbers of treponemal organisms
      • May occur cutaneously or within visceral organs / bone
  • Management
    • Early (primary, secondary early latent) syphilis
      • Benzathine penicillin G 2.4 million units IM once
      • Penicillin allergy:
        • Doxycycline 100mg BD for 14 days
        • Azithromycin 2g PO once
    • Late latent syphilis
      • Benzathine penicillin G 2.4 million units IM once weekly for three weeks
      • Penicillin allergy: doxycycline 100mg BD for 28 days
    • Neurosyphilis
      • Crystalline penicillin G 18 – 24 million units / day for 14 days
      • Monitoring
        • Stabilization or resolution of symptoms
        • Resolution of CSF abnormalities
      • Penicillin allergic
        • Penicillin desensitization is optimal for management of neurosyphilis
        • Otherwise, consider ceftriaxone 2g BD for 14 days
    • Cardiovascular syphilis
      • Benzathine penicillin G 2.4 million units IM once weekly for three weeks, or
      • Crystalline penicillin G 18 – 24 million units / day for 14 days
    • Gummatous syphilis
      • Benzathine penicillin G 2.4 million units IM once weekly for three weeks
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