Tertiary syphilis: causes, symptoms, diagnostics and treatment

Medically reviewed: 15, February 2024

Tertiary Syphilis: The Late and Severe Stage of Syphilis

Tertiary syphilis, an STD (sexually transmitted disease) caused by the spiral-shaped bacterium known as Treponema pallidum, is a complex infection that advances through four distinct stages: primary, secondary, latent, and tertiary.

1. The initial stage, referred to as primary syphilis, is marked by the presence of a painless sore called a chancre, which develops at the location of the initial infection.
2. The second stage involves a rash that can cover the whole body, along with other symptoms such as fever, sore throat, hair loss, and headache.
3. The third stage, or latent syphilis, is a period of no symptoms, but the infection remains in the body.
4. The fourth and final stage is tertiary syphilis, which occurs in untreated individuals who have had syphilis for 10 to 30 years. Tertiary syphilis is a serious and potentially life-threatening condition that affects various organs and tissues, such as the heart, nervous system, and eyes.

Three takeaways about tertiary syphilis

1. Tertiary syphilis is the final and most severe stage of syphilis, a sexually transmitted disease that is caused by a bacterium called Treponema pallidum. This condition emerges in individuals who have not received any treatment for syphilis and have been infected for a duration ranging from 10 to 30 years.
2. Tertiary syphilis is not contagious, but it can cause serious and potentially fatal damage inner organs, which can cause you heart failure or blindness. It can also be a symptom of COVID-19.
3. Tertiary syphilis is a late stage of the disease that can be identified through various diagnostic techniques, including a thorough assessment of the patient’s medical background, a comprehensive physical examination, and the administration of specific tests like blood tests, cerebrospinal fluid analysis, or imaging tests.

Some of the common forms of tertiary syphilis are:

Gummatous syphilis

This involves the formation of gummas, which are soft, non-cancerous growths that can appear on the skin, bones, or internal organs. Gummas can cause ulcers, deformities, or destruction of the affected tissues.

Gummatous syphilis, which is also referred to as late benign syphilis, is a variant of tertiary syphilis that gives rise to the development of soft and non-malignant growths known as gummas. These gummas have the potential to manifest on various parts of the body, this includes not only the skin, bones, and internal organs such as the liver, but also extends to encompass various other components of the body, lungs, or spleen. Gummas can cause pain, swelling, or deformity of the affected area. They can also interfere with the function of the organ or tissue, such as causing difficulty in breathing, swallowing, or urinating.

Gummas are made up of a solid, dead center surrounded by inflamed tissue, resulting in a shapeless proteinaceous mass. The center may partially harden. These central areas begin to decay due to coagulative necrosis, but they also maintain some of the structural characteristics of normal tissues, making them distinguishable from tuberculosis granulomas where caseous necrosis destroys preexisting structures. Additional features observed in gummas at a histological level involve the presence of a central region composed of epithelioid cells with indistinct boundaries and multinucleated giant cells.

Surrounding this central region is a border zone comprising of fibroblasts and capillaries. Furthermore, the outermost zone exhibits infiltration of lymphocytes and plasma cells. As time progresses, gummas gradually undergo fibrous degeneration, ultimately leading to the formation of an asymmetrical scar or a circular fibrous nodule that remains as a remnant.

The pathogenesis of gummatous syphilis is not fully understood, but it is believed to be a result of a delayed hypersensitivity reaction to the Treponema pallidum antigens. The immune system produces antibodies and inflammatory cells that attack the spirochetes and the surrounding tissues, leading to tissue damage and granuloma formation. The granulomas have the potential to increase in size and merge together, resulting in the development of sizable gummas that have the ability to exert pressure on or even cause damage to the nearby structures.

Cardiovascular syphilis

This affects the heart and blood vessels, especially the aorta, which is the main artery that carries blood from the heart to the rest of the body. Cardiovascular syphilis can cause inflammation, weakening, or dilation of the aorta, which can lead to aneurysms, heart failure, or death.

Neurosyphilis

This affects the brain, spinal cord, and nerves, causing various neurological problems, such as dementia, paralysis, seizures, vision loss, or hearing loss. Neurosyphilis can be divided into early and late forms, depending on the onset and severity of the symptoms. It can cause headache, neck stiffness, fever, confusion, memory loss, personality changes, mood disorders, hallucinations, or psychosis. It can also cause motor, sensory, or autonomic dysfunction, such as paralysis, numbness, tingling, pain, bladder or bowel problems, or sexual dysfunction. It can also affect the cranial nerves, causing vision loss, hearing loss, facial palsy, or vertigo.

Tertiary syphilis can be identified through a comprehensive assessment that includes an evaluation of the patient’s medical history, a thorough physical examination, and various diagnostic tests. These tests commonly involve analyzing blood samples, examining cerebrospinal fluid, or employing imaging techniques such as X-rays, ultrasound, or MRI scans. The accuracy of the diagnosis relies on a careful consideration of the underlying factors contributing to the condition, as well as the extent and intensity of the presenting symptoms, and the response to treatment.

The primary goal of treating tertiary syphilis is to eradicate the infection completely and minimize the risk of developing additional complications associated with the disease. It may include antibiotics, such as penicillin, which is the drug of choice for syphilis. However, antibiotics may not reverse the damage that has already been done by the infection. Therefore, early diagnosis and treatment are crucial to prevent the progression of syphilis to the tertiary stage.

Tertiary syphilis is the third period of syphilis, developing in insufficiently treated patients or patients who have not undergone treatment at all. Manifested by the formation of syphilitic infiltrates (granulomas) in the skin, mucous membranes, bones and internal organs.

Granulomas with tertiary syphilis squeeze and destroy the tissue in which they are located, which can lead to death of the disease.

Diagnosis of tertiary syphilis includes a clinical examination of the patient, setting of serological and immunological reactions, examination of the affected systems and organs. Therapy of tertiary syphilis is carried out by courses of penicillin-bismuth treatment with the additional use of symptomatic and tonic means.

Tertiary syphilis explained: what is it, manifestation and risks

Currently, tertiary syphilis is a rare form of syphilis, since in modern venereology, the identification and treatment of most cases of the disease occurs at the stage of primary or secondary syphilis. Tertiary syphilis can occur in patients who have undergone incomplete treatment or have received drugs in insufficient dosage. In the absence of treatment for syphilis (for example, in connection with undiagnosed latent syphilis), about one third of the patients develop tertiary syphilis.

Predisposing factors for the emergence of tertiary syphilis are concomitant chronic intoxications and diseases, alcoholism, senile and children age.

A patient with tertiary syphilis is practically not contagious, since the few treponemas in his body are located deep inside the granulomas and die during their disintegration.

Symptoms of tertiary syphilis

Earlier in the literature indicated that tertiary syphilis develops after 4-5 years from the moment of infection with pale treponema. However, recent data suggest that this period increased to 8-10 years. Tertiary syphilis is characterized by a long course with large latent periods, sometimes taking several years.

Tertiary syphilis skin lesions – tertiary syphilides – develop over months and even years without signs of inflammation and any subjective sensations. Unlike elements of secondary syphilis, they are located on a limited area of ​​the skin and slowly regress, leaving behind scars. The manifestations of tertiary syphilis are lumpy and gummous syphilide.

Lumpy syphilide

Lumpy syphilide – an infiltrative nodule formed in the dermis, slightly protruding above the skin surface, having a size of 5-7 mm, reddish brown color and dense consistency. Usually, in case of tertiary syphilis, nodular eruptions occur in a wavy and asymmetrical manner in a local area of ​​the skin, while individual elements are in different stages of their development and do not merge with each other. Over time, lumpy syphilide undergoes necrosis with the formation of a rounded ulcer with smooth edges, infiltrated base and a smooth clean bottom.

The healing of the ulcer of tertiary syphilis lasts for weeks and months, after which an atrophy site or scar with hyperpigmentation along the edge remains on the skin. Scars that appear as a result of the resolution of several grouped tubercular syphilides form a picture of a single mosaic scar. Repeated rash of tertiary syphilis never occurs in the area of ​​scars.

Gummous syphilide

Gummous syphilide (syphilitic gum) is more likely to be isolated, less often the formation of several gums in one patient. Gumma is a painless node located in the subcutaneous tissue. The most frequent localization of gummas of tertiary syphilis is the forehead, the anterior surface of the legs and forearms, the area of ​​the knee and elbow joints. Initially, the node is mobile and not soldered to the adjacent tissues.

Gradually, it increases in size and loses mobility due to adhesion with the surrounding tissues. Then, in the middle of the node, a hole appears through which the gelatinous liquid is separated.

Slow enlargement of the aperture leads to the formation of an ulcer with crater-like breaking edges. At the bottom of the ulcer a necrotic rod is seen, after the discharge of which the ulcer heals with the formation of a star-shaped retracted scar. Sometimes with tertiary syphilis, gum is resolved without going into an ulcer. In such cases, there is a decrease in the node and its replacement by dense connective tissue.

In the case of tertiary syphilis, gummous ulcers can capture not only the skin and subcutaneous tissue, but also the underlying cartilage, bone, vascular, muscle tissue, which leads to their destruction. Gummous syphilides can be located on the mucous membranes.

Most often it is the mucous membrane of the nose, tongue, soft palate and pharynx. Tertiary syphilis lesion of the nasal mucosa leads to the development of rhinitis with purulent discharge and a violation of nasal breathing, then the destruction of the nasal cartilage occurs with the formation of a characteristic saddle-shaped deformity, nasal bleeding is possible.

With the defeat of tertiary syphilis of the mucous membrane of the tongue develops glossitis with difficulty speaking and chewing food. Lesions of the soft palate and pharynx lead to nasal voices and food ingestion when chewing on the nose.

Violations on the part of somatic organs and systems caused by tertiary syphilis are observed on average 10–12 years after infection.

In 90% of cases, tertiary syphilis occurs with damage to the cardiovascular system in the form of myocarditis or aortitis. The lesions of the skeletal system in tertiary syphilis can be manifested by osteoporosis or osteomyelitis, liver damage – chronic hepatitis, stomach – gastritis or gastric ulcer.

In rare cases, there are lesions of the kidneys, intestines, lungs, nervous system (neurosyphilis).

Complications of tertiary syphilis

The main and most terrible complications of tertiary syphilis are associated with damage to the cardiovascular system. Thus, syphilitic aortitis can lead to an aortic aneurysm, which can gradually squeeze the surrounding organs or suddenly burst with the development of massive bleeding.

Syphilitic myocarditis may be complicated by heart failure, spasm of the coronary vessels with the development of myocardial infarction.

Against the background of complications of tertiary syphilis, the patient may die, which is observed in about 25% of cases.

Diagnosis of tertiary syphilis

In tertiary syphilis, the diagnosis is based primarily on clinical and laboratory data. In 25-35% of patients with tertiary syphilis, the RPR test gives a negative result; therefore, blood tests using RIF and RIBT, which are positive in most cases of tertiary syphilis (92-100%), are of primary importance.

To determine the extent of damage of somatic systems and organs, according to indications, ECG, heart ultrasound, aortography, x-rays of bones, rhinoscopy and pharyngoscopy, gastroscopy and ultrasound of the liver, liver test, lung x-ray, lumbar puncture with cerebrospinal fluid, etc. may be required.

The patient may need additional consultation of a cardiologist, neurologist, otolaryngologist, gastroenterologist, oculist.

Differential diagnosis of tertiary syphilis is carried out with scrofuloderma, indurative erythema, ulcerative manifestations of skin cancer, miliary tuberculosis, actinomycosis, leprosis, disintegrating lipomas.

The diagnostics of tertiary syphilis depends on the clinical presentation, the medical history, the physical examination, and the laboratory tests. The clinical presentation of tertiary syphilis can vary widely, depending on the form and the organ or tissue that is affected.

The medical history of the patient is important to determine the risk factors, the exposure history, and the previous treatment for syphilis. The patient should be asked about their sexual history, their use of condoms, their number and gender of partners, and their history of STIs. The patient should also be asked about their history of penicillin allergy, pregnancy, or HIV infection. The patient should also be asked about their symptoms, their onset, their duration, their severity, and their triggers.

Any physical examination of the patient should include a thorough inspection of the skin, the mucous membranes, the lymph nodes, the eyes, the ears, the nose, the mouth, the throat, the chest, the abdomen, the genitals, the anus, the rectum, the extremities, and the neurological system. The examination should look for any signs of gummas, cardiovascular syphilis, or neurosyphilis. The examination should also look for any signs of primary or secondary syphilis, such as chancres, rash, condylomata lata, or alopecia.

The laboratory tests for tertiary syphilis include serological tests, cerebrospinal fluid (CSF) analysis, and imaging tests. The serological tests are used to detect the presence of antibodies against Treponema pallidum in the blood. The serological tests can be divided into two types:

• non-treponemal tests
• and treponemal tests.

The non-treponemal tests, such as the rapid plasma reagin (RPR) test or the venereal disease research laboratory (VDRL) test, reactions with cardiolipin, a lipid that is not specific to Treponema pallidum. The non-treponemal tests are useful for screening, monitoring, and evaluating the response to treatment. However, they can also be false-positive or false-negative in some conditions, such as pregnancy, autoimmune diseases, or other infections. The treponemal tests, such as the fluorescent treponemal antibody absorption (FTA-ABS) test or the Treponema pallidum particle agglutination (TPPA) test, reactions with Treponema pallidum antigens. The treponemal tests are useful for confirming the diagnosis and ruling out false-positive results. However, they can also remain positive for life, even after successful treatment.

The CSF analysis is used to detect the presence of Treponema pallidum or its antibodies in the CSF, which is the fluid that surrounds the brain and the spinal cord. The CSF analysis is indicated for patients who have signs or symptoms of neurosyphilis.

The CSF analysis is also indicated for patients who have signs or symptoms of ocular syphilis. Such test is indicated for patients who have HIV infection, as they have a higher risk of developing neurosyphilis. The CSF analysis includes the following tests:

• CSF-VDRL test: This is a non-treponemal test that measures the level of antibodies that react with cardiolipin in the CSF. A positive result shows neurosyphilis, but a negative result does not rule it out.
• CSF-FTA-ABS test: A treponemal test for checking levels of antibodies that react with Treponema pallidum antigens in the CSF. A positive result suggests neurosyphilis, but a negative result does not exclude it.
• CSF cell count and protein: These are tests that measure the number and type of cells and the amount of protein in the CSF. These tests can indicate the presence of inflammation or infection in the central nervous system. A high CSF cell count or protein can be seen in neurosyphilis, but also in other conditions, such as meningitis, encephalitis, or brain tumors.
• CSF glucose: This is a test that measures the level of glucose in the CSF. This test can indicate the presence of bacterial infection in the central nervous system. A low CSF glucose can be seen in neurosyphilis, but also in other conditions, such as bacterial meningitis, tuberculosis, or fungal infections.

Treatment of tertiary syphilis

Therapy of tertiary syphilis begins with a preparatory stage in the form of a 2-week course of erythromycin or tetracycline. Then they break into penicillin therapy with two courses with an interval of 2 weeks. Duration of courses and dosages are selected in accordance with the selected drug, the patient’s condition and localization of gum. Penicillin therapy supplement the introduction of bismuth preparations.

When there are contraindications to bismuth (kidney or liver damage), an additional third course of penicillin therapy is prescribed. During the treatment of tertiary syphilis, monitoring of the main indicators of the functioning of the affected organs is always carried out: clinical analysis of blood and urine, liver biochemical tests, coagulogram, ECG, etc.

According to the indications, general-strengthening remedies and symptomatic treatment are prescribed.

The choice, dose, and duration of antibiotic therapy depend on the patient’s condition, the presence of co-infections, such as HIV, and the patient’s allergy status. The general principles of antibiotic therapy for tertiary syphilis are:

• Penicillin G is the preferred antibiotic for all forms of tertiary syphilis, as it has a high efficacy, a low toxicity, and a low cost. Penicillin G can be given intravenously or intramuscularly, duration of penicillin G therapy vary from 10 to 24 million units per day for 10 to 30 days.
• Doxycycline can be used by those who are allergic to penicillin. Doxycycline can be given orally, at a dose of 100 mg twice daily for 28 to 30 days, for all forms of tertiary syphilis. Doxycycline is contraindicated in pregnant women, children, and patients with liver or kidney impairment.
• Ceftriaxone can be given intravenously or intramuscularly, at a dose of 1 to 2 g daily for 10 to 30 days, for all forms of tertiary syphilis. Ceftriaxone is also contraindicated in patients with a history of anaphylaxis to cephalosporins, or with a severe penicillin allergy.
• Azithromycin is usually given orally, at a single dose of 2 g, for all forms of tertiary syphilis. Azithromycin is also contraindicated in patients with a history of anaphylaxis to macrolides, or with a severe penicillin allergy. Moreover, azithromycin has a high risk of resistance, as some strains of Treponema pallidum have developed mutations that make them resistant to azithromycin.

The antibiotic treatment for tertiary syphilis should be monitored and evaluated by serological tests, such as the RPR or the VDRL test, and by clinical examination. The serological tests should be performed before, during, and after the antibiotic therapy, to assess the response and the cure, and should show a four-fold or greater decline in the antibody titers within 6 to 12 months after the antibiotic therapy, indicating a successful treatment. However, some patients may have a persistent or a rebound increase in the antibody titers, indicating a treatment failure or a reinfection. These patients may require a repeat or a prolonged course of antibiotic therapy, or a change of antibiotic.

The clinical examination should also show an improvement or a resolution of the signs and symptoms of tertiary syphilis, such as the disappearance of the gummas, the stabilization of the aorta, or the recovery of the neurological function. However, some patients may have irreversible damage or complications, such as aneurysm rupture, heart failure, dementia, or blindness, that require additional interventions, such as surgery, cardiac devices, or rehabilitation.

It can cause some adverse effects or reactions, such as:

• Allergic reactions:

Some patients may have an allergic reaction to the antibiotic, such as rash, itching, hives, swelling, or anaphylaxis. These reactions may occur immediately or within hours after the administration of the antibiotic. These reactions require immediate discontinuation of the antibiotic and administration of antihistamines, corticosteroids, or epinephrine, depending on the severity of the reaction.

• Jarisch-Herxheimer reaction:

This is a systemic reaction that occurs within 24 hours after the initiation of the antibiotic therapy, as the bacterium dies and releases its toxins. This reaction causes fever, chills, headache, muscle pain, joint pain, or worsening of the lesions. This reaction is self-limiting and usually resolves within 48 hours. This reaction can be managed by antipyretics, analgesics, or anti-inflammatory drugs, and by hydration and rest. This reaction is more common and severe in patients with early syphilis, but it can also occur in patients with tertiary syphilis, especially neurosyphilis or cardiovascular syphilis.

• Drug interactions:

Some antibiotics may interact with other drugs, such as anticoagulants, oral contraceptives, or antiretroviral drugs, and alter their efficacy or toxicity. These interactions may require dose adjustment or monitoring of the drug levels or the adverse effects. These interactions should be checked and avoided by consulting the drug information or the pharmacist.

The antibiotic therapy for tertiary syphilis should be accompanied by counseling and education of the patient and their sexual partners, to prevent the transmission or the reinfection of syphilis. The patient and their sexual partners should be tested and treated for syphilis and other STIs, such as gonorrhea, chlamydia, or HIV. It’s recommended to abstain from sexual activity until the completion of the antibiotic therapy and the resolution of the lesions. Doctor might advise to use condoms consistently and correctly, to reduce the risk of acquiring or transmitting syphilis and other STIs. The patient should also be advised to avoid alcohol, tobacco, or illicit drugs, to improve their general health and their immune system. The patient should also be advised to follow a balanced diet, to exercise regularly, and to get enough sleep, to enhance their well-being and their recovery.

Special Considerations for Tertiary Syphilis Treatment

The treatment of tertiary syphilis may require some special considerations:

Penicillin allergy in tertiary syphilis treatment

Penicillin is the preferred antibiotic for all forms of syphilis, but some patients may have an allergy to penicillin, which can range from mild to severe. Patients with a mild penicillin allergy, such as rash or itching, may be treated with an alternative antibiotic, such as doxycycline, ceftriaxone, or azithromycin. But keep in mind, that these alternative antibiotics contraindicated in some patients, such as pregnant women, children, or patients with liver or kidney impairment. Patients with a severe penicillin allergy, such as anaphylaxis, may be treated with a desensitization protocol, which involves gradually increasing the dose of penicillin under close observation, until the patient can tolerate the full therapeutic dose.

This protocol can be done in an inpatient or an outpatient setting, depending on the availability of the resources and the expertise. This protocol can reduce the risk of an allergic reaction and allow the patient to receive the optimal treatment for syphilis.

Pregnancy and tertiary syphilis treatment

Syphilis can be transmitted from the mother to the fetus during pregnancy, causing congenital syphilis, which can result in miscarriage, stillbirth, prematurity, low birth weight, or birth defects. Therefore, pregnant women should be screened and treated for syphilis as early as possible, preferably in the first trimester. Pregnant women with tertiary syphilis should be treated with penicillin, as it is the only antibiotic that can cross the placenta and treat the fetus. Pregnant women who are allergic to penicillines should be treated with a desensitization protocol, as the alternative antibiotics are not effective or safe for the fetus. Pregnant women and the newborn should be tested and treated for syphilis, if indicated.

HIV and tertiary syphilis treatment

HIV infection can increase the risk of acquiring or transmitting syphilis, as it can impair the immune system and the mucosal barriers. HIV infection can also affect the clinical presentation, the diagnosis, and the treatment of syphilis, as it can cause atypical or severe manifestations, false-negative or false-positive results, or reduced or delayed response. Therefore, patients with tertiary syphilis should be tested and treated for HIV infection, and vice versa. Patients with tertiary syphilis and HIV infection should be treated with penicillin, as it is the most effective and safe antibiotic for both infections.

Conclusion

Tertiary syphilis, the advanced and severe phase of syphilis, which is a sexually transmitted infection triggered by the bacterium Treponema pallidum, is characterized by being non-contagious. However, it can lead to significant and life-threatening harm to internal organs, and sometimes, it can present itself with symptoms similar to a coronavirus infection.

The management of tertiary syphilis presents numerous obstacles and deficiencies in various areas including diagnosis, treatment, and prevention. But there is potential for significant enhancement through future research endeavors, such as the advancement of innovative and superior diagnostic tools, therapeutic medications, clinical trials, as well as epidemiological and behavioral investigations.

Successfully preventing and treating tertiary syphilis necessitates the implementation of a comprehensive and well-coordinated strategy that encompasses screening, testing, treatment, counseling, education, and surveillance at the individual, community, and population levels.