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.

Syndromes

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

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

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

Syndromes Table adapted from LP Rowland. Spirochete Infections: Neurosyphilis. In: LP Rowland (ed), Merritt’s Textbook of Neurology. Baltimore: Williams & Wilkins, 1995;200–212. Treatment Table adapted from LP Rowland. Spirochete Infections: Neurosyphilis. In: LP Rowland (ed), Merritt’s Textbook of Neurology. Baltimore: Williams & Wilkins, 1995;200–212; EW Hook. Syphilis. In WM Scheld, RJ Whitley, DT Durack (eds), Infections of the Central Nervous System. Philadelphia: Lippincott–Raven, 1997;669–684.
Adapted from: Goldstein MA and Harden CL. Infectious states. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;83-133. With permission from Elsevier (www.elsevier.com).
Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

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