Tertiary syphilis: symptoms and complications

Tertiary syphilis is the late, symptomatic phase of Treponema pallidum infection, which develops years or decades after the initial infection if treatment is untreated or inadequate. At this stage, various organs and systems are affected: the skin and soft tissues (gummatous form), the cardiovascular system (cardiovascular form, most often syphilitic aortitis and its sequelae), and the nervous system (late neurosyphilis). Current guidelines emphasize: even if tertiary syphilis is suspected, diagnostic testing and treatment should be initiated without delay. [1]

Epidemiologically, the tertiary stage is now less common than in the pre-antibiotic era; however, against the backdrop of an increase in the overall incidence of syphilis in Europe and globally, clinicians are again seeing late complications more frequently. In 2023, 41,051 confirmed cases of syphilis were registered in the countries of the European Union and the European Economic Area (9.9 per 100,000 population), which is 13% higher than in 2022; this trend increases the pool of patients who potentially reach late stages without treatment. [2]

It is important to distinguish "late latent" syphilis (a serologically active but asymptomatic stage) from "tertiary" syphilis (with organ damage). This determines both the treatment regimen and the need for cerebrospinal fluid testing and additional instrumental methods. According to US guidelines, all patients with tertiary syphilis are recommended to undergo a lumbar puncture before starting treatment, as the treatment strategy changes when neurosyphilis is detected. [3]

Life-threatening complications include syphilitic aortopathy with ascending aortic aneurysm and valve regurgitation, severe forms of late neurosyphilis, and destructive gummas of internal organs. Even at this stage, antibacterial therapy inhibits the pathogen's activity and prevents further tissue destruction, but is not always able to reverse the damage already done. This underscores the value of early diagnosis and long-term follow-up after treatment. [4]

What Happens in Tertiary Syphilis: Pathogenesis and Targets

The pathogenesis of tertiary syphilis involves prolonged persistence of Treponema pallidum with chronic granulomatous inflammation. Gumma is a characteristic focal lesion with a necrotic center and a ridge of granulation tissue; it can occur in the skin, bones, liver, upper respiratory tract, and virtually any organ, gradually destroying and deforming tissue. Gummas are often unifocal, grow slowly, and can mimic a tumor on imaging. [5]

The cardiovascular form predominantly affects the ascending aorta: syphilitic meso-aortitis causes dilation, aneurysm formation, as well as stenosis of the coronary artery orifices and aortic regurgitation. Although this complication has become rare, modern clinical practice describes cases with the threat of aortic rupture and a combination with neurosyphilis—a reminder that the "classic" condition remains relevant if the infection has been untreated for a long time. [6]

Late neurosyphilis is a broad term, encompassing everything from parenchymatous forms (progressive paralysis, tabes dorsalis) to meningovascular lesions, strokes in relatively young patients, and chronic cognitive decline. Neurosyphilis can occur at any stage, but with prolonged untreated progression, the likelihood and severity of damage increases. The clinical spectrum ranges from headaches and visual disturbances to ataxia and dementia. [7]

The immunopathological background of the tertiary stage explains two key clinical facts: firstly, symptoms often progress over years and are disguised as other diseases (vasculitis, tumors, degenerative diseases); secondly, antibacterial therapy stops the activity of treponemes, but does not always reverse existing structural damage (for example, poststenotic changes in the aorta or neuronal loss). This requires multidisciplinary management: infectious disease specialist, cardiologist, vascular surgeon, neurologist. [8]

Clinical forms and leading signs

Three "lines" of tertiary syphilis are gummatous, cardiovascular, and late neurosyphilis. The gummatous form manifests as painless or moderately painful nodules and infiltrates prone to disintegration and the formation of ulcers with dense edges; lesions are often solitary, but can be multiple and involve different organs. Involvement of the upper palate and nasal septum can lead to perforation and deformation. [9]

The cardiovascular form typically presents with signs of aortic regurgitation (shortness of breath, fatigue, pulsatile phenomena), chest pain due to aortic dilation, or ischemia due to coronary stenosis. Instrumental examination reveals aortic root dilation, an ascending aortic aneurysm, and sometimes signs of active inflammation based on positron emission tomography/computed tomography. [10]

In late neurosyphilis, persistent headaches, visual and hearing impairment, ataxia, paresthesia, neuropathic pain, sphincter dysfunction, stroke at a young age, and progressive cognitive and behavioral changes are alarming. In some cases, ocular and ear syphilis "accompany" the neurosyphilis form, requiring the same aggressive treatment regimen as for neurosyphilis. [11]

A separate group of manifestations are "rare gummas" of internal organs (liver, spleen, bone tissue), which mimic tumors or specific infections. In recent years, clinical cases of liver and bone gummas have been described in immunocompromised individuals, highlighting the need for a targeted search for syphilis in the differential diagnosis of "unclear lesions." [12]

Table 1. Tertiary syphilis: forms and key clinical clues

Form	Typical "beacons"	What to look for during an examination
Gummatous	Nodes/infiltrates prone to disintegration; deformities of the nose/palate	Ultrasound/MRI/CT of lesions; biopsy if in doubt
Cardiovascular	Shortness of breath, aortic regurgitation, chest pain	EchoCG, CT angiography of the aorta, PET/CT
Late neurosyphilis	Headaches, ataxia, cognitive decline, stroke	Lumbar puncture, MRI of the brain, ophthalmo-/otorevision

Diagnostics: step-by-step algorithm with an emphasis on foci

The first step is to confirm the syphilitic nature of the process serologically: a combination of treponemal tests and a quantitative non-treponemal test for the initial titer. In the tertiary stage, non-treponemal titers may be low, but their dynamics serve as a guide to the effectiveness of treatment, so a quantitative titer is always necessary. [13]

The second step is to evaluate the nervous system. According to US guidelines, all patients with tertiary syphilis should have their cerebrospinal fluid examined before treatment; if cerebrospinal fluid abnormalities are detected, treatment is administered according to the neurosyphilis regimen. This is crucial: treatment regimens and durations vary, and outcomes are better if neurosyphilis is recognized before an "inappropriate" regimen is prescribed. [14]

The third step is instrumental verification of organ damage. If a cardiovascular form is suspected, echocardiography (assessment of regurgitation and aortic root size) and computed tomography-angiography of the aorta are performed; if indicated, positron emission tomography/computed tomography is performed to detect inflammation of the wall. Gummatous foci are assessed using ultrasound or magnetic resonance imaging; if in doubt, a biopsy is performed. [15]

The fourth step is screening for concomitant infections and risk factors. All patients are tested for human immunodeficiency virus (HIV); if the result is negative and the risk is high, prophylaxis for HIV infection in vulnerable patients is discussed. If indicated, testing for viral hepatitis and other sexually transmitted infections is included. A surveillance plan with serological follow-up points is then developed. [16]

Table 2. Mini-algorithm for diagnosis of tertiary syphilis

Step	Action	For what
1	Dual serology with quantitative titer	Confirm syphilis and obtain a zero point
2	Lumbar puncture	Exclude/confirm neurosyphilis and select a regimen
3	Instrumental verification of organ damage	Plan treatment (cardiac surgery, oncodiagnostics, etc.)
4	Screening for concomitant infections, monitoring plan	Comprehensive safety and outcome management

Differential diagnosis: from "pseudotumor" to vasculitis

Gummatous lesions must be distinguished from malignant neoplasms, tuberculosis, deep mycoses, sarcoidosis, and granulomatous vasculitis. Biopsy (granulomatous inflammation with necrosis), serology for syphilis, and regression of the lesion after etiotropic treatment—a characteristic feature of gummas—can help. [17]

The cardiovascular form is differentiated from degenerative aneurysms, vasculitis (including giant cell arteritis), and hereditary aortopathy. The patient's age, concomitant symptoms of syphilis, and positive serology guide the diagnosis; PET/CT and dynamics during treatment help confirm inflammatory activity. [18]

Late neurosyphilis should be distinguished from neurodegenerative diseases (Alzheimer's disease, frontotemporal degeneration), inflammatory, and vascular lesions. Key factors include cerebrospinal fluid changes, treponemal markers in the cerebrospinal fluid, and the response to penicillin therapy. When in doubt, treatment for neurosyphilis is the preferred approach, as delay increases the risk of irreversible damage. [19]

Finally, the possibility of a combination of forms is always taken into account: syphilitic aortitis and neurosyphilis may coexist in one patient, which dictates a combined plan - etiotropic therapy plus cardio-/neuronal monitoring and, if necessary, aortic surgery. [20]

Table 3. Differential diagnostics by “branches”

Branch	Similar conditions	What is the difference?
Gummas	Tumors, tuberculosis, deep mycoses, sarcoidosis	Biopsy, serology, regression on penicillin
Aorta	Degenerative aneurysms, vasculitis, Marfan syndrome	Aortic root involvement, PET/CT, serology
Nervous system	Neurodegeneration, vasculitis, infections	Cerebrospinal fluid (VDRL/treponemal tests), MRI, response to therapy

Treatment

The basic principle: before treating "as tertiary," ensure that there is no neurosyphilis—this determines the choice of regimen. All patients suspected of having tertiary syphilis undergo a lumbar puncture; if cerebrospinal fluid abnormalities are detected, the regimen is switched to the neurosyphilis regimen. This approach reduces the risk of undertreatment and repeated courses. [21]

If cerebrospinal fluid data are unremarkable and the case is gummatous or cardiovascular without neuronal involvement, the standard treatment in the US is benzathine benzylpenicillin 2.4 million international units intramuscularly once a week for 3 weeks (a total of 7.2 million international units). This is a regimen for late syphilis, used for "non-neural" tertiary forms. With treatment, gummas usually regress within weeks to months. [22]

For neurosyphilis, ocular, or aural syphilis, high-dose water-soluble benzylpenicillin is administered intravenously for 10-14 days (the standard regimen of the Centers for Disease Control and Prevention); then, according to US recommendations, 1-3 weekly injections of benzathine benzylpenicillin 2.4 million international units can be added to "even out" the total duration of therapy. In the UK, alternatives are also allowed in case of intolerance - ceftriaxone 2 grams intramuscularly/intravenously for 10-14 days - at the discretion of a specialist. [23]

The 2024 UK guidelines specifically note the role of corticosteroids in neurosyphilis: prednisolone 40-60 milligrams once daily for 3 days, beginning 24 hours before antibiotics, to reduce the risk of inflammatory worsening. This is especially important for ocular and aural syphilis, where swelling and inflammation can worsen vision or hearing loss. The decision is made by a specialist based on the risk/benefit ratio. [24]

In cases of true penicillin allergy in non-pregnant women and in the absence of neurosyphilis, alternative regimens are being discussed: doxycycline 200 milligrams twice daily for 28 days, or amoxicillin 2 grams three times daily plus probenecid 500 milligrams four times daily for 28 days (UK guidelines). However, the evidence base is weaker than for penicillin; serological monitoring is mandatory. In pregnant women, there are no alternatives; desensitization and treatment with penicillin are indicated. [25]

Cardiovascular tertiary syphilis is managed jointly by cardiologists and vascular surgeons. Antibiotics treat the infection but do not correct the mechanical consequences: aortic dilation, valvular insufficiency, or coronary stenosis. Surgical correction (valve/aortic replacement) is often required after infection clearance or simultaneously, for emergency indications. Some centers prefer penicillin "neuro-scheme" therapy for the cardiovascular form; this is decided on an individual basis. [26]

Gummatous lesions of the skin and organs often significantly improve within the first months of treatment; large defects often require reconstructive surgery or ENT correction (e.g., in cases of nasal septal perforations or palatal defects). Biopsy monitoring is usually not required if clinical and radiological regression is achieved with the correct treatment regimen. [27]

The Jarisch-Herxheimer reaction—an acute deterioration within the first day of therapy (fever, chills, tachycardia, increased pain)—also occurs in later stages. It is usually self-limiting and requires symptomatic support; in the neuro-, ocular-, and aural forms, it is logical to discuss a short course of steroids in advance, as recommended by the British Association. [28]

Serological monitoring after treatment for tertiary syphilis is performed at standard points (usually 6, 12, and 24 months) with an assessment of a fourfold decrease in non-treponemal titer. However, in very late forms, progression may be slower, and some patients remain "serofast." Clinical and instrumental stabilization of lesions and the absence of signs of relapse are more important. If in doubt, re-evaluation of cerebrospinal fluid and retherapy are considered. [29]

Finally, treatment involves more than just antibiotics. Testing for human immunodeficiency virus and other sexually transmitted infections is always included, partners are informed, and a secondary prevention and monitoring plan is developed, especially for cardiovascular lesions (repeat echocardiography/computed tomography-angiography of the aorta according to schedule). This interdisciplinary approach improves the long-term prognosis. [30]

Table 4. Therapy guidelines by form

Clinical situation	Basic scheme	Additionally
Gummatous/cardiovascular (without neurosyphilis)	Benzathine-benzylpenicillin 2.4 million units intramuscularly weekly × 3 (total 7.2 million units)	Serology 6-12-24 months; in case of cardioform - observation by a cardiac surgeon
Neurosyphilis/ocular/ear	Water-soluble benzylpenicillin IV for 10-14 days; then 1-3 weekly intramuscular injections of 2.4 million units.	Consider short course of steroids; MRI/ophthalmo/oto-monitoring
Penicillin intolerance (non-pregnant)	Ceftriaxone 2 g intramuscularly/intravenously for 10-14 days (neuroform) or doxycycline/amoxicillin+probenecid for 28 days (non-neuro)	Strict control of effectiveness; only penicillin for pregnant women

Complications and prognosis: what changes after treatment

Without treatment, tertiary syphilis leads to severe outcomes: ruptured aortic aneurysm, progressive heart failure with aortic regurgitation, strokes and irreversible cognitive impairment, and bone and soft tissue destruction. The World Health Organization clearly states: the tertiary phase can affect the brain, nerves, eyes, liver, heart, blood vessels, bones, and joints, and can even lead to death. [31]

After adequate penicillin therapy, the prognosis depends on the extent of the structural damage already present. Gummas usually regress, scar, and cease progressing; neurological deficits may stabilize or partially improve, but are not always completely reversible; aortopathy requires a separate cardiac surgical solution and lifelong monitoring. [32]

The serological "curve" in late forms declines more slowly than in early forms; the absence of a fourfold decline within a strict timeframe does not equate to failure if there is a clinical and instrumental effect and reinfection has been excluded. In questionable cases, a repeat examination of the cerebrospinal fluid is performed and retherapy is discussed. [33]

At the population level, a reduction in the incidence of tertiary forms is achieved through early diagnosis and the availability of penicillin. The rise in overall incidence in Europe is a signal to strengthen screening and referrals to prevent patients from being lost to follow-up and developing late complications years later. [34]

Prevention and monitoring: how to prevent late forms

Prevention of tertiary syphilis involves early detection and treatment of the early stages. In practice, this means a low threshold for testing for any ulcerative/rash syndromes, regular screening of at-risk groups, outreach to partners, and rapid access to penicillin. These principles are incorporated into international guidelines and remain the best "vaccine" against late complications. [35]

For patients with late forms, a monitoring plan is developed: serology at 6, 12, and 24 months, clinical and instrumental monitoring of foci (echocardiography/computed tomography-angiography for the cardioform; MRI and neurological testing for the neuroform; for gummas, a clinical and radiological assessment of regression). In the absence of dynamics or in case of relapse of symptoms, an unscheduled assessment is carried out. [36]

Medical teams discuss the possibility of a Jarisch-Herxheimer reaction in advance, prescribe symptomatic support, and, in the case of neuro-/ocular/otomorphic syndromes, a prophylactic short course of steroids according to British guidelines. The patient is educated about the signs of deterioration (worsening neurological deficits, new chest pain, chest tightness, decreased vision/hearing), which require immediate medical attention. [37]

Finally, all patients are tested for human immunodeficiency virus (HIV); if the result is negative and there is a significant risk, HIV prophylaxis is discussed, as combination prophylaxis reduces the burden of coinfections and improves long-term outcomes. This is part of comprehensive care for people with sexually transmitted infections. [38]