Syphilis

Syphilis
Classification and external resources
Image of helix-shaped organisms responsible for causing syphilis
ICD-10	A50.-A53.
ICD-9	090-097
MedlinePlus	001327
eMedicine	med/2224 emerg/563 derm/413
MeSH	D013587

Syphilis is a sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum subspecies pallidum. The route of transmission of syphilis is almost always through sexual contact, although there are examples of congenital syphilis via transmission from mother to child in utero or at birth.

The signs and symptoms of syphilis are numerous; before the advent of serological testing, precise diagnosis was very difficult. In fact, the disease was dubbed the "Great Imitator" because it was often confused with other diseases, particularly in its tertiary stage. ^[1]

Syphilis can generally be treated with antibiotics, including penicillin. If left untreated, syphilis can damage the heart, aorta, brain, eyes, and bones. In some cases these effects can be fatal.

Signs and symptoms

Different manifestations occur depending on the stage of the disease.

Primary syphilis

Primary chancre of syphilis on the hand. Unlike some kinds of sexually transmitted infections, syphilis infections are not limited to the genitals, and can be transmitted through non-sexual contact.

Primary syphilis is typically acquired via direct sexual contact with the infectious lesions of a person with syphilis.^[2] Approximately 10–90 days after the initial exposure (average 21 days) a skin lesion appears at the point of contact, which is usually the genitalia, but can be anywhere on the body. This lesion, called a chancre, is a firm, painless skin ulceration localized at the point of initial exposure to the spirochete, often on the penis, vagina or rectum. In rare circumstances, there may be multiple lesions present, although it is typical that only one lesion is seen. The lesion may persist for 4 to 6 weeks and usually heals spontaneously. Local lymph node swelling can occur. During the initial incubation period, individuals are otherwise asymptomatic. As a result, many patients do not seek medical care immediately.

Secondary syphilis

Typical presentation of secondary syphilis rash on the palms of the hands and usually also seen on soles of feet.

Secondary syphilis in 52-year-old man with AIDS; the reddish papules and nodules—some pustular—extend over his face, chest, arms, and back

Intensely pruritic, papulonodular eruption of secondary syphilis in a 23-year-old man, extending over his arms and back.

Secondary syphilis occurs approximately 1–6 months (commonly 6 to 8 weeks) after the primary infection. There are many different manifestations of secondary disease. There may be a symmetrical reddish-pink non-itchy rash on the trunk and extremities.^[3] The rash can involve the palms of the hands and the soles of the feet. In moist areas of the body (usually vulva or scrotum), the rash becomes flat, broad, whitish, wart-like lesions known as condyloma latum. Mucous patches may also appear on the genitals or in the mouth. All of these lesions are infectious and harbor active treponeme organisms. A patient with syphilis is most contagious when he or she has secondary syphilis. Other symptoms common at this stage include fever, sore throat, malaise, weight loss, headache, meningismus and enlarged lymph nodes. Rare manifestations include an acute meningitis that occurs in about 2% of patients, hepatitis, renal disease, hypertrophic gastritis, patchy proctitis, ulcerative colitis, rectosigmoid mass, arthritis, periostitis, optic neuritis, interstitial keratitis, iritis and uveitis.

Latent syphilis

Latent syphilis is defined as having serologic proof of infection without signs or symptoms of disease.^[2] Latent syphilis is further described as either early or late. Early latent syphilis is defined as having syphilis for two years or less from the time of initial infection without signs or symptoms of disease. Late latent syphilis is infection for greater than two years but without clinical evidence of disease. The distinction is important for both therapy and risk for transmission. In the real world, the timing of infection is often not known and should be presumed to be late for the purpose of therapy. Early latent syphilis may be treated with a single intramuscular injection of a long-acting penicillin. Late latent syphilis requires three weekly injections. For infectiousness late latent syphilis is not considered as contagious as early latent syphilis. Fifty percent of those infected with latent syphilis will progress into late stage (tertiary) syphilis, 25% will stay in the latent stage, and 25% will make a full recovery.

Tertiary syphilis

Model of the head of a patient with tertiary syphilis.

Tertiary syphilis usually occurs 1–10 years after the initial infection, however in some cases it can take up to 50 years. This stage is characterized by the formation of gummas, which are soft, tumor-like balls of inflammation known as granulomas. The granulomas are chronic and represent an inability of the immune system to completely clear the organism. They may appear almost anywhere in the body including in the skeleton. The gummas produce a chronic inflammatory state in the body with mass effects upon the local anatomy. Other characteristics of untreated tertiary syphilis include neuropathic joint disease, which is a degeneration of joint surfaces resulting from loss of sensation and fine position sense (proprioception). The more severe manifestations include neurosyphilis and cardiovascular syphilis. In a study of untreated syphilis, 10% of patients developed cardiovascular syphilis, 16% had gumma formation and 7% had neurosyphilis.^[4]

Neurological complications at this stage can be diverse. In some patients manifestations include generalized paresis of the insane, which results in personality changes, changes in emotional affect, hyperactive reflexes and Argyll-Robertson pupil. This is a diagnostic sign in which the small and irregular pupils constrict in response to focusing the eyes, but not to light. Tabes dorsalis, also known as locomotor ataxia, a disorder of the spinal cord, often results in a characteristic shuffling gait. See below for more information about neurosyphilis.

Cardiovascular complications include syphilitic aortitis, aortic aneurysm, aneurysm of sinus of Valsalva and aortic regurgitation. Syphilis infects the ascending aorta causing aortic dilation and aortic regurgitation. This can be heard with a stethoscope as a heart murmur. Contraction of the tunica intima leads to a tree bark appearance that is wrinkly. The aortic valve dilation and subsequent insufficiency leads to diastolic regurgitation and causes massive hypertrophy of the left ventricle. The heart grows so large (over 1,000 grams) that the heart is termed cor bovinum (cow's heart). The course can be insidious and heart failure may be the presenting sign after years of disease. The infection can also occur in the coronary arteries and cause narrowing of the vessels. Syphilitic aortitis can cause de Musset's sign,^[5] a characteristic bobbing of the head in synchrony with the heartbeat. The clinical course of these cardiovascular effects causes mediastinal encroachment and secondary respiratory difficulties (dyspnea), difficulty swallowing (dyphagia) and persistent cough because of pressure on the recurrent laryngeal nerve triggering the cough reflex. Pain can stem from erosion of the ribs or vertebrae. Also, the cor bovinum can lead to coronary ostia obstruction and ischemia. The aneurysm developed during the disease course may also rupture, leading to massive intrathoracic hemorrhage and likely death; although the most likely cause of death is the heart failure resulting from aortic regurgitation.

Neurosyphilis

Neurosyphilis refers to a site of infection involving the central nervous system (CNS). Neurosyphilis may occur at any stage of syphilis. Before the advent of antibiotics, it was typically seen in 25-35% of patients with syphilis.

Neurosyphilis is now most common in patients with HIV infection. Reports of neurosyphilis in HIV-infected persons are similar to cases reported before the HIV pandemic. The precise extent and significance of neurologic involvement in HIV-infected patients with syphilis, reflected by either laboratory or clinical criteria, have not been well characterized. Furthermore, the alteration of host immunosuppression by antiretroviral therapy in recent years has further complicated such characterization.

Approximately 35 to 40% of persons with secondary syphilis have asymptomatic central nervous system (CNS) involvement, as demonstrated by any of these on cerebrospinal fluid (CSF) examination:

• An abnormal leukocyte cell count, protein level, or glucose level
• Demonstrated reactivity to Venereal Disease Research Laboratory (VDRL) antibody test

Commonly called Brain Syphilis, Neurosyphilis dementia is also a psychiatric diagnosis wherein a multitude of atypical anti-psychotic medications are used to help control the patient's irrational behaviors, with limited success. The term is used in traditional classifications of organic disorders of the brain.

There are four clinical types of neurosyphilis:

• Asymptomatic neurosyphilis
• Meningovascular syphilis
• General paresis^[6]
• Tabes dorsalis

The late forms of neurosyphilis (tabes dorsalis and general paresis) are seen much less frequently since the advent of antibiotics. The most common manifestations today are asymptomatic or symptomatic meningitis. Acute syphilitic meningitis usually occurs within the first year of infection; 10% of cases are diagnosed at the time of the secondary rash. Patients present with headache, meningeal irritation, and cranial nerve abnormalities, Argyll Robertson pupil (miotic pupil not reactive to light but reactive to accommodation), especially the optic nerve, facial nerve and the vestibulocochlear nerve. Rarely, it affects the spine instead of the brain, causing focal muscle weakness or sensory loss.

Meningovascular syphilis occurs a few months to 10 years (average, 7 years) after the primary syphilis infection. Meningovascular syphilis can be associated with prodromal symptoms lasting weeks to months before focal deficits are identifiable. Prodromal symptoms include unilateral numbness, paresthesias, upper or lower extremity weakness, headache, vertigo, insomnia, and psychiatric abnormalities such as personality changes. The focal deficits initially are intermittent or progress slowly over a few days. However, it can also present as an infectious arteritis and cause an ischemic stroke, an outcome more commonly seen in younger patients. Angiography may be able to demonstrate areas of narrowing in the blood vessels or total occlusion.

General paresis, otherwise known as general paresis of the insane, is a severe manifestation of neurosyphilis. It is a chronic dementia that ultimately results in death in as little as 2–3 years. In general, patients have progressive personality changes, memory loss and poor judgment. In more rare instances, they can have psychosis, depression or mania. Imaging of the brain usually shows atrophy.

Diagnosis

Poster for treatment of syphilis, showing a man and a woman bowing their heads in shame (ca. 1936).

It is only in the 20th century that effective tests and treatments for syphilis were developed. Microscopy of fluid from the primary or secondary lesion using darkfield illumination can diagnose treponemal disease with high accuracy. As there are other treponemes that may be confused with T. pallidum, care must be taken in evaluating with microscopy to correlate symptoms with the correct disease.

Star Wars themed parade float promoting syphilis testing at a 2005 parade in Seattle, Washington, United States.

Present-day syphilis screening tests, such as the Rapid Plasma Reagin (RPR) and Venereal Disease Research Laboratory (VDRL) tests are cheap and fast but not completely specific, as many other conditions can cause a positive result. These tests are routinely used to screen blood donors. It can be noted that the spirochete that causes syphilis does not survive the conditions used to store blood, and the number of transfusion transmitted cases of syphilis is minuscule; but the test is used to identify donors that might have contracted HIV from high risk sexual activity. The requirement to test for syphilis has been challenged due to the vast improvements in HIV testing. False positives on the rapid tests can be seen in viral infections (Epstein-Barr, hepatitis, varicella, measles), lymphoma, tuberculosis, malaria, Chagas Disease, endocarditis, connective tissue disease, pregnancy, intravenous drug abuse, or contamination.^[2] As a result, these two screening tests should always be followed up by a more specific treponemal test. Tests based on monoclonal antibodies and immunofluorescence, including Treponema pallidum hemagglutination assay (TPHA) and Fluorescent Treponemal Antibody Absorption (FTA-ABS) are more specific and more expensive. Unfortunately, false positives can still occur in related treponomal infections such as yaws and pinta. Tests based on enzyme-linked immunosorbent assays are also used to confirm the results of simpler screening tests for syphilis.

Neurosyphilis is diagnosed by finding high numbers of leukocytes in the CSF or abnormally high protein concentration in the setting of syphilis infection.^[2] In addition, CSF should be tested with the VDRL test although some advocate using the FTA-ABS test to improve sensitivity. There is anecdotal evidence that the incidence of neurosyphilis is higher in HIV patients, and some have recommended that all HIV-positive patients with syphilis should have a lumbar puncture to look for asymptomatic neurosyphilis.^[7]

Other Treponematoses

Treponematoses are diseases caused by species of the spirochete Treponema. In addition to syphilis, this group includes:

• Yaws is a tropical disease characterized by an infection of the skin, bones and joints; it is caused by Treponema pallidum subspecies pertenue.
• Pinta - caused by Treponema pallidum subspecies carateum.
• Bejel - caused by Treponema pallidum subspecies endemicum.

Prevention

Abstinence from any and all types of sexual activity or intimate physical contact with an infected person is very effective at reducing the transmission of syphilis. Many microbes that cause sexually transmitted infections are transmitted only through exposure to body fluids such as semen or blood; by contrast, the bacterium T. pallidum readily crosses both cut or intact mucosa and cut skin, including body parts that cannot be protected by a condom. Proper and consistent use of a latex condom substantially reduces, but does not completely eliminate, the spread of syphilis through sexual contact.^[8]

Syphilis cannot be contracted through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing.^[9]

Individuals sexually exposed to a person with primary, secondary, or early latent syphilis within 90 days preceding the diagnosis should be assumed to be infected and treated for syphilis, even if they are currently seronegative. If the exposure was more than 90 days before the diagnosis, presumptive treatment is recommended if serologic testing is not immediately available or if follow-up is uncertain. Patients with syphilis of unknown duration and nontreponemal serologic titers ≥1:32 may be considered as having early syphilis for purposes of partner notification and presumptive treatment of sex partners. Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically and treated appropriately. All patients with syphilis should be tested for HIV. Patient education is important, as well.

Treatment

Depression-era U.S. poster advocating early syphilis treatment

Application of mercury.

The first-choice treatment for all manifestations of syphilis remains penicillin in the form of penicillin G.^[10] The effect of penicillin on syphilis was widely known before randomized clinical trials were used; as a result, treatment with penicillin is largely based on case series, expert opinion, and years of clinical experience. Parenteral penicillin G is the only therapy with documented effect during pregnancy. For early syphilis, one dose of penicillin is sufficient.

Non-pregnant individuals who have severe allergic reactions to penicillin (e.g., anaphylaxis) may be effectively treated with oral tetracycline or doxycycline; however, data to support this is limited. Ceftriaxone may be considered as an alternative therapy, although the optimal dose is not yet defined. However, cross-reactions in penicillin-allergic patients with cephalosporins such as ceftriaxone are possible. Azithromycin was suggested as an alternative. However, there have been reports of treatment failure due to resistance in some areas.^[11] If compliance and follow-up cannot be ensured, the CDC recommends desensitization with penicillin followed by penicillin treatment. All pregnant women with syphilis should be desensitized and treated with penicillin. Follow-up includes clinical evaluation at 1 to 2 weeks followed by clinical and serologic evaluation at 3, 6, 9, 12, and 24 months after treatment.

Azithromycin has been used to treat syphilis in the past because of easy once-only dosing. However, in one study in San Francisco, azithromycin-resistance rates in syphilis, which were 0% in 2000, were 56% by 2004.^[12]

Late latent and infections of unknown duration

If CSF examination yields no evidence of neurosyphilis, then penicillin G is recommended in weekly doses for 3 weeks. If allergic, then tetracycline or doxycycline may also be used for this stage, but for 28 days instead of the normal 14. As with before, the data to support use of tetracycline and ceftriaxone are limited.

Treatment of neurosyphilis

For patients diagnosed with neurosyphilis including ocular or auditory syphilis with or without positive CSF results, aqueous crystalline penicillin G is the treatment of choice. The recommended regimen is intravenous treatment every 4 hours or continuously for 10–14 days. If intravenous administration is not possible, then procaine penicillin is an alternative (administered daily with probenecid for two weeks). Procaine injections are painful, however, and patient compliance may be difficult to ensure. To approximate the 21-day course of therapy for late latent disease and to address concerns about slowly dividing treponemes, most experts now recommend 3 weekly doses of benzathine penicillin G after the completion of a 14-day course of aqueous crystalline or aqueous procaine penicillin G for neurosyphilis. No oral antibiotic alternatives are recommended for the treatment of neurosyphilis. The only alternative that has been studied and shown to be effective is intramuscular ceftriaxone daily for 14 days.

Alternative regimens

Alternative regimens such as tetracyclines are not well studied in HIV infection and a careful follow-up is recommended. Tetra-cyclines are contraindicated in pregnancy.

HIV-infected patients with early syphilis may have a higher risk of neurological complications and a higher rate of treatment failure with currently recommended regimens. The magnitude of these risks, however, although not precisely defined, is probably small. Skin testing or desensitization is recommended in latent syphilis and neurosyphilis in other patients with HIV infection.

Jarisch-Herxheimer reaction

Before administering any treatment, clinicians should warn all patients about the possibility of a Jarisch-Herxheimer reaction, which occurs most often in secondary syphilis and with penicillin therapy, and may be more common in HIV-infected patients.^[13] This reaction is characterized by fever, fatigue, and transient worsening of any mucocutaneous symptoms, and usually subsides within 24 hours. These symptoms can be alleviated with acetaminophen (paracetamol) and should not be mistaken for drug allergy. In addition, clinicians should inform HIV-infected patients that currently recommended regimens may be less effective for them than for patients without HIV infection and that close serologic follow-up is therefore essential.

Tuskegee syphilis study

One of the best-documented US cases of unethical human medical experimentation in the twentieth century was the Tuskegee syphilis study. The study took place in Tuskegee, Alabama, and was supported by the U.S. Public Health Service (PHS) in partnership with the Tuskegee Institute.^[14] The study began in 1932, when syphilis was a widespread problem, especially in poor communities, and when there was no effective treatment or cure. Study researchers recruited a group of 600 black male sharecroppers in the rural area of Tuskegee, Alabama. Of these 600, 399 of the men had the disease in the latent, asymptomatic stage. 201 men were uninfected control patients. The PHS intended to study the progress of the disease and the effects of current treatments at different stages. Available treatments had such severe side effects that doctors questioned whether treatment provided the best outcome for the patient, or whether a man might do as well with no treatment. Patients were misled about the diagnosis of their disease, and about aspects of treatment, such as a painful lumbar puncture for evaluation. During the crisis of the Great Depression, in a segregated state with underfunded services for blacks, patients were recruited in exchange for physical exams, free health care of minor illnesses, free meals and transportation the day of exams, and a $50 death benefit. The study was designed to measure the progression of untreated syphilis. It also was to determine whether syphilis caused cardiovascular damage more often than neurological damage, as untreated disease led to effects in numerous body systems. Researchers hoped to determine whether the natural course of the disease was different in black men versus white men; historically, researchers had by then accumulated more information on the disease in white men.

By 1947 penicillin had been validated as an effective cure for syphilis and was becoming widely used by doctors and public health centers to treat the disease. PHS study directors continued the study, denying patients treatment by penicillin, and actively discouraging them from having penicillin administered by other sources. The men were never advised that they had syphilis, nor were they offered a treatment including Salvarsan or the other arsenical drugs that were in use at the beginning of the study.

The original study was meant to study patients in phases, with treatment after six to nine months. It continued to follow the original members and their families for 40 years. The study ended in 1972, long after 40 wives and 19 children had been infected, and many men had died of syphilis. During the study, 28 men died directly from syphilis, and 100 from other complications. The study ended because a PHS scientist leaked information about it to the Washington Star.

Survivors and patients' families filed a class-action lawsuit against the federal government for the study. This lawsuit was settled out of court and the living subjects and their descendants were awarded a total of ten million dollars. After the settlement was awarded, the government passed the National Research Act, which required the government to review and approve all medical studies involving human subjects.

Epidemiology

Age-standardized death from syphilis per 100,000 inhabitants in 2004.^[15]

     no data      less than 35      35-70      70-105      105-140      140-175      175-210      210-245      245-280      280-315      315-350      350-500      more than 500

In the developed world, syphilis infections declined throughout the 1980s and 1990s due to widespread use of antibiotics and the effect of the HIV epidemic. Since the year 2000, rates of syphilis have been increasing again in the USA, UK, Australia and Europe. Much of the increase has occurred among men who have sex with men and is attributed to increased rates of unsafe sexual practices.^[16][17][18]

History

Alternative names

Effect of syphilis on the skull.

The name "syphilis" was coined by the Italian physician and poet Girolamo Fracastoro in his epic noted poem, written in Latin, titled Syphilis sive morbus gallicus (Latin for "Syphilis or The French Disease") in 1530. The protagonist of the poem is a shepherd named Syphilus (perhaps a variant spelling of Sipylus, a character in Ovid's Metamorphoses). Syphilus is presented as the first man to contract the disease, sent by the god Apollo as punishment for the defiance that Syphilus and his followers had shown him. From this character Fracastoro derived a new name for the disease, which he also used in his medical text De Contagionibus ("On Contagious Diseases").^[19]

Until that time, as Fracastoro notes, syphilis had been called the "French disease" in Italy, Poland and Germany, and the "Italian disease" in France. In addition, the Dutch called it the "Spanish disease", the Russians called it the "Polish disease", the Turks called it the "Christian disease" or "Frank disease" (frengi) and the Tahitians called it the "British disease". These "national" names are due to the disease often being spread by foreign sailors and soldiers during their frequent sexual contact with local prostitutes.

During the 16th century, it was called "great pox" in order to distinguish it from smallpox. In its early stages, the great pox produced a rash similar to smallpox (also known as variola). However, the name is misleading, as smallpox was a far more deadly disease. The terms "Lues"^[20] (or Lues venerea, Latin for "venereal plague") and "Cupid's disease" have also been used to refer to syphilis. In Scotland, syphilis was referred to as the Grandgore. The ulcers suffered by British soldiers in Portugal were termed "The Black Lion".^[21]

Origins

Three theories on the origin of syphilis have been proposed. It is generally agreed upon by historians and anthropologists that syphilis was present among the indigenous peoples of the Americas before Europeans traveled to and from the New World. However, whether strains of syphilis were present in the entire world for millennia, or if the disease was confined to the Americas in the pre-Columbian era, is debated.

• The "pre-Columbian theory" holds that syphilis was present in Europe before the discovery of the Americas by Europeans. Some scholars during the 18th and 19th centuries believed its symptoms were described by Hippocrates in Classical Greece in its venereal/tertiary form.^[22] There are other suspected syphilis findings for pre-contact Europe, including at a 13–14th century Augustinian friary in the northeastern English port of Kingston upon Hull. This city's maritime history, with its continual arrival of sailors from distant places, is thought to have been a key factor in the transmission of syphilis.^[23] Carbon-dated skeletons of monks who lived in the friary showed bone lesions that supporters say are typical of venereal syphilis, although this is disputed by critics of this theory. Skeletons in pre-Columbus Pompeii and Metaponto in Italy with damage similar to that caused by congenital syphilis have also been found,^[24][25] although the interpretation of this evidence has been disputed.^[26] Douglas Owsley, a physical anthropologist at the Smithsonian Institution, and other supporters of this idea say that many medieval European cases of leprosy, colloquially called lepra, were actually cases of syphilis. Although folklore claimed that syphilis was unknown in Europe until the return of the diseased sailors of the Columbian voyages,

  ... syphilis probably cannot be "blamed"—as it often is—on any geographical area or specific race. The evidence suggests that the disease existed in both hemispheres from prehistoric times. It is only coincidental with the Columbus expeditions that the syphilis previously thought of as "lepra" flared into virulence at the end of the fifteenth century.^[27]

  Lobdell and Owsley wrote that a European writer who recorded an outbreak of "lepra" in 1303 was "clearly describing syphilis."^[27]
• The "Columbian Exchange theory" holds that syphilis was a New World disease brought back by Columbus and Martin Alonso Pinzon. They cite documentary evidence linking crewmen of Columbus's voyages to the Naples syphilis outbreak of 1494.^[28] This theory is supported by genetic studies of venereal syphilis and related bacteria, which found a disease intermediate between yaws and syphilis in Guyana, South America.^[29]<^[30]
• Finally, historian Alfred Crosby suggests both theories are partly correct in a "combination theory". Crosby says that the bacterium that causes syphilis belongs to the same phylogenetic family as the bacteria that cause yaws and several other diseases. Despite the tradition of assigning the homeland of yaws to sub-Saharan Africa, Crosby notes that there is no unequivocal evidence of any related disease having been present in pre-Columbian Europe, Africa, or Asia.

Crosby writes, "It is not impossible that the organisms causing treponematosis arrived from America in the 1490s...and evolved into both venereal and non-venereal syphilis and yaws."^[31] However, Crosby considers it more likely that a highly contagious ancestral species of the bacteria moved with early human ancestors across the land bridge of the Bering Straits many thousands of years ago without dying out in the original source population. He hypothesizes that "the differing ecological conditions produced different types of treponematosis and, in time, closely related but different diseases."^[31]

European outbreak

A medical illustration attributed to Albrecht Dürer (1496) depicting a person with syphilis. Here, the disease is believed to have astrological causes.

The first well-recorded European outbreak of what is now known as syphilis occurred in 1494 when it broke out among French troops besieging Naples.^[32] The French may have caught it via Spanish mercenaries serving King Charles of France in that siege.^[27] From this centre, the disease swept across Europe. As Jared Diamond describes it, "[W]hen syphilis was first definitely recorded in Europe in 1495, its pustules often covered the body from the head to the knees, caused flesh to fall from people's faces, and led to death within a few months." The disease then was much more lethal than it is today. Diamond concludes,"[B]y 1546, the disease had evolved into the disease with the symptoms so well known to us today."^[33]The epidemiology of this first syphilis epidemic shows that the disease was either new or a mutated form of an earlier disease.

Researchers concluded that syphilis was carried from the New World to Europe after Columbus' voyages. The findings suggested Europeans could have carried the nonvenereal tropical bacteria home, where the organisms may have mutated into a more deadly form in the different conditions and low immunity of the population of Europe.^[34] Syphilis was a major killer in Europe during the Renaissance.^[35] In his Serpentine Malady (Seville, 1539) Ruy Diaz de Isla 'guesstimated' that over a million people were infected in Europe.^[36]

History of treatments

There were originally no effective treatments for syphilis. The Spanish priest Francisco Delicado wrote El modo de adoperare el legno de India (Rome, 1525) about the use of Guaiacum in the treatment of syphilis. He himself suffered from syphilis. Nicholas Culpeper recommended the use of heartsease (wild pansy), an herb with antimicrobial activities.^[37] Another common remedy was mercury: the use of which gave rise to the saying "A night in the arms of Venus leads to a lifetime on Mercury".^[38] It was administered multiple ways including by mouth, by rubbing it on the skin and by injection.^[39] One of the more curious methods was fumigation, in which the patient was placed in a closed box with his head sticking out. Mercury was placed in the box and a fire was started under the box that caused the mercury to vaporize. It was a grueling process for the patient and the least effective for delivering mercury to the body. The use of mercury was the earliest known suggested treatment for syphilis. This has been suggested to date back to The Canon of Medicine (1025) by the Persian physician, Ibn Sina (Avicenna).,^[40] although this is only possible if syphilis existed in the Old World prior to Columbus (see Origins section). Giorgio Sommariva of Verona is recorded to have used it for this purpose in 1496.

As the disease became better understood, more effective treatments were found. The first antibiotic to be used for treating disease was the arsenic-containing drug Salvarsan, developed in 1908 by Sahachiro Hata while working in the laboratory of Nobel prize winner Paul Ehrlich. This was later modified into Neosalvarsan. Unfortunately, these drugs were not 100% effective, especially in late disease. It had been observed that some who develop high fevers could be cured of syphilis. Thus, for a brief time malaria was used as treatment for tertiary syphilis because it produced prolonged and high fevers (a form of pyrotherapy). This was considered an acceptable risk because the malaria could later be treated with quinine, which was available at that time. This discovery was championed by Julius Wagner-Jauregg,^[41] who won the 1927 Nobel Prize for Medicine for his work in this area. Malaria as a treatment for syphilis was usually reserved for late disease, especially neurosyphilis, and then followed by either Salvarsan or Neosalvarsan as adjuvant therapy. These treatments were finally rendered obsolete by the discovery of penicillin, and its widespread manufacture after World War II allowed syphilis to be effectively and reliably cured.^[42]

History of diagnosis

Portrait of Gerard de Lairesse by Rembrandt van Rijn, ca. 1665–67, oil on canvas. De Lairesse, himself a painter and art theorist, suffered from congenital syphilis that severely deformed his face and eventually blinded him.^[43]

In 1905, Schaudinn and Hoffmann discovered Treponema pallidum in tissue of patients with syphilis.^[44] One year later, the first effective test for syphilis, the Wassermann test, was developed. Although it had some false positive results, it was a major advance in the prevention of syphilis. By allowing testing before the acute symptoms of the disease had developed, this test allowed the prevention of transmission of syphilis to others, even though it did not provide a cure for those infected. In the 1930s the Hinton test, developed by William Augustus Hinton, and based on flocculation, was shown to have fewer false positive reactions than the Wassermann test. Both of these early tests have been superseded by newer analytical methods.

While working at the Rockefeller University (then called the Rockefeller Institute for Medical Research) in 1913, Hideyo Noguchi, a Japanese scientist, demonstrated the presence of the spirochete Treponema pallidum in the brain of a progressive paralysis patient, proving conclusively that Treponema pallidum was the cause of syphilis.^[45] Prior to Noguchi's discovery, syphilis had been a burden to humanity in many lands. Without its cause being understood, it was sometimes misdiagnosed and often misattributed to damage by political enemies.

Notable syphilis-infected people in history

Many famous historical figures, including Charles VIII of France, Hernán Cortés of Spain, Adolf Hitler, Benito Mussolini, and Ivan the Terrible, were often falsely alleged to have had syphilis. Guy de Maupassant and possibly Friedrich Nietzsche are thought to have been driven insane and ultimately killed by the disease. Al Capone contracted syphilis as a young man. By the time he was incarcerated at Alcatraz, it reached its third stage, neurosyphilis, leaving him confused and disoriented. Syphilis led to the death of artist Édouard Manet and artist Paul Gauguin was also said to have suffered from syphilis. Composers who succumbed to syphilis included Hugo Wolf, Frederick Delius, Scott Joplin, Gaetano Donizetti, and possibly Franz Schubert and Niccolò Paganini.

Mental illness caused by late-stage syphilis was once one of the more common forms of dementia. This was known as the general paresis of the insane. One suspected example of syphilis was the insanity of noted composer Robert Schumann, although the precise cause of his death has been disputed by scholars.

The Russian author Leo Tolstoy suffered from syphilis during his youth, which was treated using contemporary arsenic treatment.^[46] A recent article in the European Journal of Neurology (June 2004) hypothesized that the founder of communism in Russia, Vladimir Ilyich Lenin, died of neurosyphilis.^[47]

Keys: S—suspected case; †—died of syphilis

Society and culture

Art

The artist Kees van Dongen produced a series of illustrations for the anarchist publication L'Assiette au Beurre showing the descent of a young prostitute from poverty to her death from syphilis as a criticism of the social order at the end of the 19th century.

The artist Jan van der Straet, also known as Johannes Stradanus or simply Stradanus, painted a scene of a wealthy man receiving treatment of syphilis with the tropical wood guaiacum sometime around 1580.^[51] The title of the work is "Preparation and Use of Guayaco for Treating Syphilis." That the artist chose to include this image in a series of works celebrating the New World indicates how important a "cure" (however ineffective) for syphilis was to the European elite at that time. The richly colored and detailed work depicts four servants preparing the concoction while a physician looks on, hiding something behind his back while the hapless patient drinks.^[52]

The Norwegian Edvard Munch painted "The sins of the father", a portrayal of a horrified woman with her baby, covered in a rash and with a deformed face, lying on a cloth across her knees. This was to portray congenital syphilis, common at the time.

Classic and antique literature

Delicado featured the effects of syphilis in his Portrait of Lozana: The Lusty Andalusian Woman (1528). There are references to syphilis in William Shakespeare's play Measure for Measure, particularly in a number of early passages spoken by the character Lucio. For example, Lucio says "[...] thy bones are hollow"; this is a reference to the brittleness of bones engendered by the use of mercury, which was then widely used to treat syphilis. In Shakespeare's play Othello, the clown at the beginning of Act III makes jest of Cassio, who is leading a musician troupe for Othello, by asking him if he had just arrived from Naples and playing with his nose. (Alluding to the reputation of Naples of being a likely place to contract syphilis, which eats away at the bridge of the nose.)

It has been suggested that the main character in Edgar Allan Poe's "The Tell-Tale Heart" may have been infected with neurosyphilis, due to his strange obsessions and apparent insanity. Francisco de Quevedo puns in his Buscón^[53] about a nose entre Roma y Francia meaning both "between Rome and France" and "between snub and eaten by the French illness".

Jonathan Swift's poetry mentions syphilis as a condition of prostitution that reaches the highest ranks of society. See, for example, "A Beautiful Young Nymph Going To Bed" and "The Progress of Beauty".

Moll dies of syphillis, Hogarth's A Harlot's Progress.

William Hogarth's works frequently show his subject's infection with syphilis. Two examples are A Harlot's Progress and Marriage à-la-mode. In both instances it is used to indicate the moral profligacy of the infected. Some critics have argued that the character of Edward Rochester's first wife, Bertha, in Charlotte Brontë's novel Jane Eyre, suffers from the advanced stages of syphilitic infection, general paralysis of the insane, and point to corroborative evidence within the text to substantiate this view.^[54]

The novel Candide by Voltaire describes Candide's mentor and teacher, Pangloss, as having contracted syphilis from a maidservant he slept with; the syphilis has ravaged and deformed his body. Pangloss explains to Candide that syphilis is 'necessary in the best of worlds' because the line of infection, which, he explains, leads back to Christopher Columbus. If Columbus had not sailed to America and brought back syphilis, Pangloss states, the Europeans would not have been able to enjoy 'New World wonders' such as chocolate. One of the purposes of the novel was to satirize Leibniz's philosophy in Pangloss's disingenuous rose-tinted viewpoint. Pangloss eventually loses an eye and an ear to the syphilis before he is cured. In William Blake's 1794 poem, London, he alludes to syphilis as "the youthful harlot's curse," writing that it "[b]lasts the new-born infant's tear, / And blights with plagues the marriage-hearse."

In Charles Dickens' novel Tale of Two Cities, references are made that allude to the main character, Sydney Carton, having syphilis. In Sarah Grand's late Victorian novel 'The Heavenly Twins', one of the main female characters, Edith Beale, contracts syphilis from her husband and then passes it on to her child. Edith's once beautiful face is marred by the disease, while she descends into madness and eventual death. Sarah Grand uses this character to show the importance of sex education for women, so that they may protect themselves from marrying men who have been diseased by their own sexual exploits. In Eça de Queiroz's novel written in 1870, 'The Mystery of the Sintra Road', some of the characters have syphilis, and it plays an important role in the plot of a recent movie adaptation.^[55]

Henrik Ibsen's once-controversial play Ghosts has a young man who is suffering from a mysterious disease. Though it is never named, the events of the play make it plain that this is syphilis, an inheritance from his dissolute father. However, the young man's mother remains unaffected - this is because it is possible for a woman to carry syphillis and transmit it to her child in the womb without exhibiting any noticeable symptoms. Dr. Rank in Ibsen's play A Doll's House also has inherited syphilis.

Modern literature

• Sarah Grand's novel The Heavenly Twins - Both twins marry syphilitic husbands.
• Isak Dinesen's memoir Out of Africa noted her being infected with syphilis by her husband Bror von Blixen-Finecke.
• Unnamed American medical students described syphilis in a series of early 20th-century American limericks, using medical terminology in the Journal of the American Medical Association January 1942.^[56]
• Thomas Disch in his novel Camp Concentration describe a fictional strain of syphilis that enhances intelligence but is lethal.
• In Thomas Mann's novel Doktor Faustus, the Faust character, Adrian Leverkühn, acquires his genius for musical composition from the neurological effects of syphilis.
• In Dick Francis' novel, Bonecrack the character Enso Rivera is suffering from megalomania caused by syphilis.
• Neal Stephenson's trilogy The Baroque Cycle has multiple characters and historical figures who have syphilis.
• In Leonard Cohen's second novel Beautiful Losers, the character F. is described as having the terminal stages of syphilis.
• In Christina Garcia's novel Dreaming in Cuban, Felicia contracts syphilis from her unfaithful husband.
• In Ken Follett's novel A Dangerous Fortune, the wealthy Edward Pilaster contracts syphilis from using prostitutes.
• In Diana Gabaldon's Lord John and the Private Matter, one of the two plot-lines is centred around whether a secondary character, Joseph Trevelyan, was infected with syphilis or not.

Film, television and stage

Because it was for so long incurable, syphilis has been used as a plot device in many dramatic films, television shows, and plays. Few, such as the Warner Brothers film Dr. Ehrlich's Magic Bullet (1940), focus on the history of the disease. Most involve characters suffering late-stage syphilis, both because neurological damage provides an excuse for strange behaviors and because the disease came to symbolize evils that might be hidden, or problems with family inheritance (which could also apply to personality or genetic defects.) In recent years, syphilis has been mentioned on Grey's Anatomy, House M.D., Law & Order: SVU, Buffy the Vampire Slayer when Xander Harris contracts it due to Chumash spirits at Thanksgiving , Angel, and other television shows. A few particularly notable portrayals include:

• Miss Evers' Boys (1992) is a stage play written by Dr. David Feldshuh, based on the decades-long Tuskegee syphillis experiment. The play was subsequently adapted into a 1997 HBO TV movie. It was nominated for eleven Emmy Awards and won in four categories, including Outstanding Made for Television Movie.
• In Japanese director Akira Kurosawa's film The Quiet Duel (1949), Toshirô Mifune plays a doctor who contracts syphilis after cutting his finger with a scalpel while operating on an infected soldier.
• In Spanish film Alatriste (2006), the main character finds the love of his life, actress María de Castro, dying in a hospital for syphilitics. It is implied that she caught the disease from an affair with Philip IV of Spain.
• In the Masterpiece Theatre version of Bram Stoker's Dracula, Arthur Holmwood, whose father dies of syphilitic insanity, enlists the services of Count Dracula in hopes of curing his congenital syphilis.
• In The Libertine, a 2004 film with Johnny Depp, the main character John Wilmot, second Earl of Rochester, is portrayed as having died of syphilis.
• Beth Henley's 1979 play The Miss Firecracker Contest features the main character, Carnelle Williams infected with syphilis, and previously transmitting it to another character, Mac Sam.

Gallery

Electron micrograph of Treponema pallidum	Syphilis lesions on a patient's back	Syphilis lesions on a patient's chest	Chancres on the penile shaft due to a primary syphilitic infection
Secondary syphilis manifested perineal condyloma lata lesions, which presented as gray, raised papules that sometimes appear on the vulva or near the anus, or in any other warm intertriginous region.	Gumma of the nose due to long standing tertiary syphilis

See also

• Felix Milgrom, who developed a test for syphilis
• Globalization and disease
• Hideyo Noguchi Africa Prize, named to honor the man who identified the causative agent
• List of cutaneous conditions

References

External links

• "Sex, Sin, and Science: A History of Syphilis in America " by John Parascandola
• "Syphilis fact sheet" from the Center for Disease Control
• UCSF HIV InSite Knowledge Base Chapter: Syphilis and HIV
• "A New Gold Standard For Syphilis?" Poster Presentation for European Academy of Dermatology and Venereology 2004 Spring Symposium
• Kipkeepers, Pox and Gleet Vendors: A Rapid History of Syphilis
• Secrets of the Dead (PBS): The Syphilis Enigma
• Syphilis and AIDS: Lessons from history
• The treatment of dementia paralytica by malaria inoculation (A Nobel Prize lecture, December 13, 1927)
• New study blames Columbus for syphilis spread Reuters January 15, 2008
• History of Syphilis
• Origins of Syphilis NYTimes April 29, 2008