While it is clear that a dramatic outbreak of syphilis occurred in Naples at the end of the fifteenth century, making that disease newly visible because of its virulence, paleopathologists have now proved that treponematosis existed in the Old World previous to that famous epidemic. It has therefore become important to re-examine not only documentary sources but also visual ones for evidence of the venereal form of that disease. These sources may help to document the extent of syphilis in Europe, where it seems to have been conflated with other diseases such as leprosy. That said, artistic depictions of physical ailments will almost certainly prompt debate, while similarities among syndromes means that an examination of visual evidence will be confusing, perhaps even impossible, when attempting to differentiate between them.

Nineteenth-century medical books will prove valuable in this endeavour, as they frequently include detailed illustrations meant to help physicians in diagnosis and treatment. The Atlas Of Syphilis (1898) by Franz Mraček, for example, is highly recommended for both its visual and written descriptions of the disease. The photographs in Ernest Grin's study of endemic treponematosis in mid-twentieth-century Bosnia are also invaluable for learning about common symptoms. Typical signs that historians will need to look for include, but are not restricted to: rashes, sores, and lesions on the skin, perhaps especially serpiginous phagedena; collapsed nasal bridge; Hutchinson's incisors and Moon's molars; swollen lips; protruding tongue; scars at the corners of the mouth; eighth nerve deafness; balding with cranial scarring; frontal bossing (protruding forehead); severe headaches, especially at night; bowed tibia; and the eye complaint interstitial keratitis, a symptom of congenital syphilis that causes chronic inflammation of the cornea leading to clouded vision and sometimes blindness.

A manuscript illumination from the fourteenth-century encyclopedia, the Omne Bonum, may serve to illustrate the challenges of interpretation ahead for historians seeking to investigate possible representations of treponematosis in works of art. It shows a barber surgeon extracting a tooth from a patient with large pliers that have morphed into a snake with teeth protruding from its skin. The teeth have notches reminiscent of Hutchinson's incisors, as shown in a modern drawing of the deformity, although that is not definitive. More important is the fact that medieval contemporaries believed tooth pain—and sometimes headaches—to be caused by a worm, as noted in the writings of the physician Gilbertus Anglicus (ca. 1180–ca. 1250).