Natural history

Primary syphilis occurs within days of infection via direct inoculation of Treponema pallidum at cutaneous or mucous membrane sites. It is manifested by a syphilitic ulcer, the chancre. Without treatment, the chancre heals over 3 to 6 weeks.

Most patients then progress to the secondary stage, in which systemic spirochetemia is marked primarily by flulike symptoms. Untreated, secondary syphilis also resolves over weeks to months.

After a clinically silent latency period ranging from months to years in length, about one-third of patients with untreated latent syphilis go on to develop tertiary disease, which can present as neurosyphilis, cardiovascular syphilis, gummatous syphilis, or a combination of these.


Neurosyphilis can be subdivided into several syndromes occurring at different points in the natural history of untreated syphilis:


CNS Syphilitic Stage Pathology Manifestations Peak Incidence Neuroimaging
Asymptomatic CNS involvement
  Abnormal CSF (­ protein, WBC >5, VDRL) Asymptomatic Any time ± Meningeal enhancement
Syphilitic meningitis (luetic meningitis)
  Aseptic meningitis (CSF profile as above) Intracranial pressure, cranial nerve palsies, seizures 1–2 yrs postinfection Meningeal enhancement
Meningovascular syphilis
Cerebrovascular Endarteritis, ± infarcts Sudden-onset focal-cerebral symptoms, seizures 5–7 yrs postinfection Infarcts (cortical, subcortical)
Spinal Endarteritis, meningeal inflammation, myelomalacia Paresthesias, weakness, atrophy,sensory loss 5–7 yrs postinfection N/A
Parenchymatous neurosyphilis
Paretic Meningoencephalitis Neuropsychiatric symptoms; seizures 10–20 yrs postinfection Optic atrophy
Tabetic Leptomeningitis; degeneration of posterior roots, dorsal funiculi, brain stem Pain, paresthesias, ataxia, Argyll-Robertson pupil, − deep tendon reflexes, − proprioception 10–20 yrs postinfection N/A
Gummatous neurosyphilis
  Gummata formation Signs secondary to gummata mass effects, seizures Any time Mass lesions
CNS = central nervous system; CSF = cerebrospinal fluid; WBC = white blood cells; N/A = not available; ­ + = increased; − = decreased; ± = with or without


As shown, seizures can occur in all clinically expressed stages of neurosyphilis. In syphilitic meningitis, given the nonfocal stimulus of diffuse meningeal inflammation, seizures tend to be generalized. General paresis (dementia paralytica) also tends to be a nonlocalizing syndrome, and complicating seizures tend to be generalized. In contrast, gummatous neurosyphilis presents with signs and symptoms secondary to mass lesions at gummata sites, so partial seizures with localizing quality are often seen.


Diagnosis of CNS syphilitic involvement involves consideration of a constellation of lab tests within the context of a careful history and physical examination. Well-known serologic screening tests include VDRL and rapid plasma reagent; fluorescent treponemal antibody absorption enhances diagnostic specificity after positive screening test results (although fluorescent treponemal antibody absorption has low specificity of disease activity, remaining positive long after successful treatment). Diagnosis of neurosyphilis requires positive serology and reactive CSF–VDRL.

CSF pleocytosis is the best measure of disease activity. In an untreated patient, there should be 5 or more WBC/mm3. CSF protein is usually elevated, and CSF glucose can be mildly decreased. Also, nonspecifically, CSF gamma globulin can be increased, and oligoclonal bands can be present.


Treatment in all stages is of course directed at the underlying spirochete:


Stage Treatment
Primary, secondary, or early latent PCN G 2–4 million U i.m.
(PCN-allergic: doxycycline, tetracycline)
Late latent or unknown duration PCN G 2–4 million U i.m. q.wk. x 3wks
(PCN-allergic: doxycycline, tetracycline)
Tertiary disease, except neurosyphilis PCN G 2–4 million U i.m. q.wk. x 3wks
(PCN-allergic: doxycycline, tetracycline)
Neurosyphilis PCN G 2–4 million U i.v. q4h. x 14 days
PCN G 2–4 million U i.m. q.d. probenecid
500 mg q.i.d. x 14 days
(PCN-allergic: no alternative)
PCN = penicillin



There is no role for seizure prophylaxis in syphilis. Anticonvulsant treatment should be initiated only after seizure expression. When antiepileptic drugs are needed, the routine principles apply.

Seizure-producing gummas responding too slowly to penicillin can be treated with steroids.23

Reviewed By: 
Steven C. Schachter, MD
Sunday, February 29, 2004