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  • Updated 03.24.2024
  • Released 02.23.1994
  • Expires For CME 03.24.2027




Neurosyphilis is a “great imitator”, and a clinician must be suspicious about the diagnosis as central nervous system infection may present in multivariate fashions. The abandonment of routine serological screening for syphilis has almost certainly reduced the frequency with which early diagnosis of syphilis is established. Concomitant immunosuppression, as occurs with HIV infection, may alter the clinical expression of syphilis. CSF VDRL cannot be used as the gold standard for diagnosis as it is often negative despite the presence of neurosyphilis. In this article, the author details the manifestations, diagnosis, and management of neurosyphilis.

Key points

• The spectrum of neurologic manifestations of syphilis is broad.

• Neurosyphilis is not synonymous with tertiary syphilis. Neurologic manifestations may occur early in the course of infection.

• The incidence of syphilis in some populations is growing, and the possibility that it is the cause of an underlying neurologic abnormality should not be overlooked.

• Neurosyphilis is a treatable disorder, but its sequelae may be permanent.

Historical note and terminology

Syphilis was first described as a clinical entity at the turn of the 15th century. The origin of syphilis remains shrouded in mystery, but a disease commonly referred to as the "Great Pox" or "Evil Pox" was recognized in Europe shortly after Columbus' crew returned to Spain in 1493. The illness figured heavily in the wars that ravaged Europe at the time and, unlike the current disease, was associated with mortality rates as high as 25% in its early stages. Whether syphilis arose from a spontaneous mutation in an endemic treponeme or whether it was brought back to Europe from the Americas remains uncertain. However, there is a paucity of evidence for a similar disease in pre-Columbian Europe and an abundance of evidence, chiefly syphilitic bone disorders, in the pre-Columbian Americas (32).

Francisco Lopez de Villalobos published the first book on the illness in 1498. Physician and author Hieronymus Fracastor provided the name for the disease in his poem "Syphilis sive Morbus Gallicus," published in 1530. Sexual transmission of the disease was identified shortly after its initial clinical recognition. Transmission of the disease to infants breastfed by affected wet nurses and vertical transmission were also commented on in the early literature. Over the years, syphilis became confused with gonorrhea, a situation rectified in the middle of the 18th century after the mistaken conclusions of experiments performed by John Hunter, who self-inoculated urethral pus containing both Treponema pallidum and Neisseria gonorrhea.

In 1903 Metchnikoff and Roux demonstrated transmission of the disease to chimpanzees. Two years later, Schaudinn and Hoffmann identified the causative agent as an almost transparent, spiral-shaped organism that they labeled Spirochaeta pallida. The introduction of dark-field microscopy by Landsteiner in 1906 greatly assisted studies of the organism, and observations of the pathogen in the meninges and brain were made in 1913. Successful serologic tests for syphilis employing a basic lipoidal antigen were first reported by Wasserman, Neisser, and Bruck in 1906, but it was not until 1949 when a specific treponemal test, the Treponemal pallidum immobilization, was first employed.

Until the 20th century, the treatment of syphilis was generally ineffective and largely consigned to heavy metals, such as mercury, arsenic, and bismuth, and to fever therapy. Ehrlich discovered Salvarsan 606, shown to be effective against syphilis, in 1911, and Wagner-Jauregg received the Nobel Prize for the introduction of malarial therapy in 1917. However, the modern treatment of syphilis began in 1943, with the introduction of penicillin by Mahoney.

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