Young Stroke Patients: Vdrl Rpr's Importance

Syphilis is a sexually transmitted disease caused by the bacterium Treponema pallidum. It can be transmitted during primary or secondary stages with an efficiency of around 30%.

Neurosyphilis is a result of infection of the central nervous system by Treponema pallidum. It can occur at any time after initial infection, particularly in immunocompromised patients. It may result in focal neurological deficits or global CNS dysfunction. The most common presentation is with neuropsychiatric manifestations. However, syphilis may also cause myelopathy, seizures, strokes, ocular disease and brain stem or cranial nerves abnormalities.

About 10% of patients with neurosyphilis and almost 3% of all syphilis patients present with a stroke. These patients tend to be younger than those with a stroke due to cardioembolism or atherosclerosis. In one study, up to 74% of this category of patients were under the age of 50. Therefore, neurosyphilis should be considered in the evaluation of a young patient with a cryptogenic stroke.

The VDRL test is a screening test for syphilis. It measures substances called antibodies, which the body may produce if infected with the bacteria that cause syphilis. The test is most often done using a blood sample but can also be done using a sample of spinal fluid. The VDRL test is similar to the rapid plasma regain (RPR) test.

The role of syphilis in causing strokes in young people

Syphilis is a sexually transmitted disease caused by the bacterium Treponema pallidum, which infects by penetrating the lining of the mouth or genital area. It can lead to serious complications, including neurosyphilis, which affects the central nervous system and can cause strokes.

Neurosyphilis can occur at any time after the initial infection, particularly in immunocompromised patients. It can result in focal neurological deficits or global central nervous system dysfunction, and may cause myelopathy, seizures, strokes, ocular disease, and brain stem or cranial nerve abnormalities.

About 10% of patients with neurosyphilis and almost 3% of all syphilis patients present with a stroke. These patients tend to be younger than those with a stroke due to cardioembolism or atherosclerosis. In one study, up to 74% of this category of patients were under the age of 50. Therefore, neurosyphilis should be considered in the evaluation of a young patient with a cryptogenic stroke.

The diagnosis of neurosyphilis requires a high degree of clinical suspicion. A lumbar puncture should be performed in suspected cases, and cerebrospinal fluid analysis should be carried out. The diagnosis of neurosyphilis is often associated with a positive fluorescent treponemal antibody absorption (FTAABS) test plus a positive cerebrospinal fluid Venereal Disease Research Laboratory (VDRL) test accompanied by cerebrospinal fluid pleocytosis and elevated cerebrospinal fluid protein levels.

The VDRL test is a screening test for syphilis that measures substances called antibodies, which the body may produce if infected with Treponema pallidum. The test is most often done using a blood sample but can also be done using a sample of spinal fluid. A negative test is normal, indicating no antibodies to syphilis have been detected in the blood sample. The VDRL test's ability to detect syphilis depends on the stage of the disease. It is most sensitive during the secondary and latent stages, and less sensitive during the early and late stages.

In summary, syphilis, caused by the bacterium Treponema pallidum, can lead to neurosyphilis, which affects the central nervous system and can cause strokes, particularly in young people. The VDRL test is a screening tool for syphilis that is often used in conjunction with other tests to confirm a diagnosis.

The diagnostic challenges of syphilis

Syphilis is a bacterial infection caused by the spirochete Treponema pallidum. It has four stages: primary, secondary, latent, and tertiary. The natural course of syphilis includes primary and secondary stages, which are the most infectious. The primary stage is characterised by painless genital chancres, which often resolve spontaneously, making it difficult to diagnose. The secondary stage is marked by a rash on the shoulders, arms, chest, or back, and a condyloma lata in the perianal area. The latent stage can last for many years, and if left untreated, syphilis can progress to the tertiary stage, causing severe and permanent damage to the nervous and cardiovascular systems.

• Atypical Presentations: Syphilis is often referred to as the "Great Imitator" due to its frequent atypical and nonspecific presentations, which can be indistinguishable from other diseases. Neurosyphilis, for example, can present with stroke-like symptoms and neuropsychiatric manifestations, making it challenging to differentiate from other neurological disorders.
• Diagnostic Tests Sensitivity and Specificity: The available diagnostic tests for syphilis have limitations in terms of sensitivity and specificity, especially in the early stages of the disease. For instance, non-treponemal tests (e.g., Venereal Disease Research Laboratory (VDRL) and Rapid Plasma Reagin (RPR) tests) have reduced sensitivity in primary and late latent syphilis, and may not accurately reflect treatment efficacy as the titres can decrease over time, even without treatment. On the other hand, treponemal tests (e.g., Fluorescent Treponemal Antibody Absorption (FTA-ABS) and Treponema Pallidum Particle Agglutination (TPPA)) cannot distinguish between active and past infections as treponemal antibodies can persist for life.
• Prozone Phenomenon: This phenomenon occurs when there is a very high concentration of antibodies in the patient's specimen, leading to false-negative results in non-treponemal tests. It is important to consider this phenomenon when interpreting test results, especially in patients with very high antibody titres.
• Biological False Positives: Non-treponemal tests can yield false-positive results due to various factors such as pregnancy, autoimmune diseases, and other infections like malaria and hepatitis C. This underscores the importance of careful clinical interpretation of test results and considering other diagnostic evidence.
• Challenges in Direct Detection: Direct detection methods such as dark-field microscopy and nucleic acid amplification tests (e.g., polymerase chain reaction, PCR) are useful for diagnosing early primary syphilis when antibodies are not yet detectable. However, these methods depend on the availability of suitable clinical samples, such as moist syphilis ulcers, which may not always be present. Additionally, they require specialised equipment and highly trained personnel, making them less accessible in certain settings.
• Neurosyphilis Diagnosis: Diagnosing neurosyphilis remains a challenge due to its diverse clinical presentations and the limitations of available tests. While a positive VDRL or RPR test in the cerebrospinal fluid (CSF) is considered diagnostic, these tests have limited sensitivity, and negative results do not rule out neurosyphilis. Other CSF parameters, such as pleocytosis and elevated protein levels, are also used in conjunction with serological tests to support the diagnosis.
• Lack of Ideal Cure Test: There is currently no ideal test to confirm cure or eradication of syphilis following treatment. Serological tests may remain positive for extended periods, and the rate of decline in titres is a better indicator of therapeutic response.
• Limited Point-of-Care Tests: While rapid point-of-care tests for syphilis exist, they are primarily used for screening and treponemal antibody detection. There is a need for more accurate and accessible point-of-care tests that can distinguish between active and past infections, especially in high-risk populations like pregnant women and men who have sex with men (MSM).

The treatment of syphilis

Syphilis is a sexually transmitted disease caused by the bacteria Treponema pallidum. It can be transmitted during the primary or secondary stages with an efficiency of around 30%. The disease has been divided into stages based on clinical findings, which guide treatment and follow-up. These stages are:

• Primary syphilis: classically presents as a single painless ulcer or chancre at the site of infection but can also present with multiple, atypical, or painful lesions.
• Secondary syphilis: may include skin rash, mucocutaneous lesions, and lymphadenopathy.
• Tertiary syphilis: can present with cardiac involvement, gummatous lesions, tabes dorsalis, and general paresis.
• Latent syphilis: infections lacking clinical manifestations that are detected by serological testing. Latent syphilis acquired within the previous year is referred to as early latent syphilis, while infections lasting longer are classified as late latent syphilis or latent syphilis of unknown duration.
• Early syphilis (primary, secondary, and early latent syphilis): the World Health Organization (WHO) recommends benzathine penicillin G 2.4 million units administered intramuscularly as a single dose. If benzathine penicillin is unavailable or unsuitable, doxycycline, ceftriaxone, or azithromycin may be used.
• Late syphilis (infections lasting more than two years): WHO recommends benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks. If penicillin is unsuitable or unavailable, doxycycline is suggested as an alternative.
• Neurosyphilis: this complication arises from infection of the central nervous system by T. pallidum and can occur at any stage of syphilis, particularly in immunocompromised patients. Treatment for neurosyphilis often involves intravenous administration of benzylpenicillin.

It is important to note that syphilis can have a wide variety of clinical presentations, and prompt diagnosis and treatment are essential to lower transmission rates and avoid complications in later stages. Additionally, syphilis screening should be considered in the diagnostic work-up of young patients with cryptogenic stroke, as syphilis can cause vasculitis and increase the risk of stroke, particularly in young and male patients.

The epidemiology of syphilis

Syphilis is a bacterial sexually transmitted infection (STI) caused by the bacterium Treponema pallidum. It is easily identifiable, preventable, treatable, and curable. However, if untreated, it can cause serious health issues and last for many years.

The World Health Organization (WHO) estimates that 8 million adults between 15 and 49 years old acquired syphilis in 2022. The infection is transmitted through sexual contact with infectious lesions, blood transfusion, or from a pregnant woman to her fetus. Mother-to-child transmission is usually devastating to the fetus, resulting in stillbirth, neonatal death, prematurity, low birth weight, and congenitally infected infants.

Syphilis has several stages. The first stage, primary syphilis, usually lasts around 21 days, during which a round, painless, hard sore (chancre) appears on the genitals, anus, or elsewhere. Chancre may go unnoticed and heal within 3-10 days, progressing to the second stage if untreated. The second stage includes a non-itchy rash, usually on the palms and soles of the feet, and white or grey lesions in warm and moist areas, such as the labia or anus. Symptoms will disappear without treatment, and the infection often has no symptoms, progressing to the third and final stage (tertiary syphilis) after years if untreated. Tertiary syphilis can lead to brain and cardiovascular diseases, among other conditions.

In Western Europe, the USA, and China, there has been a large increase in syphilis among key populations like men who have sex with men (MSM). In low- and middle-income countries, syphilis remains endemic, with higher burdens and lower treatment rates. The proportion of LMICs with over 100 syphilis cases per 100,000 births is higher than in high-income countries, attributed to failures in testing and treating pregnant women. However, MSM, transgender women, and sex workers are disproportionately affected in all regions.

Syphilis is usually sexually acquired by direct skin-to-skin contact with someone with active primary or secondary lesions. It can also be transmitted congenitally when spirochetes traverse the placenta of an infected woman and infect the fetus, or through blood transfusion. While blood-borne transmission risk is almost non-existent in high-income countries, it persists in low- and middle-income countries.

The prevalence of syphilis has decreased in many countries with endemic syphilis due to the introduction of syndromic management for STIs, behavioral changes, and the effect of AIDS mortality disrupting sexual networks. However, since the introduction of antiretroviral therapy (ART), syphilis rates have increased, especially among MSM, due to the reconstruction of sexual networks and increased sexual contact.

Overall, the distribution of syphilis differs between low- and middle-income countries and high-income countries. Many low- and middle-income countries have poor rates of syphilis testing among women at their first antenatal care visit, with fewer than 25% of women being tested. These countries generally have higher burdens of syphilis and lower treatment rates. While high-income countries have concentrated epidemics in specific populations, low- and middle-income countries still have endemic rates among their general populations.

Continued vigilance and investment are needed to address syphilis worldwide.

The pathophysiology of syphilis

Syphilis is a bacterial infection caused by the spirochete Treponema pallidum. It is transmitted through sexual contact with infectious lesions, from mother to fetus in utero, via blood product transfusion, and occasionally through breaks in the skin that come into contact with infectious lesions. If untreated, syphilis progresses through four stages: primary, secondary, latent, and tertiary.

The central nervous system (CNS) is invaded early in the infection. During the secondary stage, examinations demonstrate that more than 30% of patients have abnormal findings in the cerebrospinal fluid (CSF). During the first 5-10 years after the onset of untreated primary infection, the disease principally involves the meninges and blood vessels, resulting in meningovascular neurosyphilis. Later, the parenchyma of the brain and spinal cord are damaged, resulting in parenchymatous neurosyphilis.

The syphilitic infiltrate reflects a delayed-type hypersensitivity response to T pallidum, and in certain individuals with tertiary syphilis, this response by sensitized T lymphocytes and macrophages results in gummatous ulcerations and necrosis. Antigens of T pallidum induce host production of treponemal antibodies and nonspecific reagin antibodies. Immunity to syphilis is incomplete.

Primary syphilis is characterised by the development of a painless chancre at the site of transmission after an incubation period of 3-6 weeks. The lesion has a punched-out base and rolled edges and is highly infectious.

Secondary syphilis develops about 4-10 weeks after the appearance of the primary lesion. During this stage, the spirochetes multiply and spread throughout the body. Secondary syphilis lesions are quite variable in their manifestations. Systemic manifestations include malaise, fever, myalgias, arthralgias, lymphadenopathy, and rash.

Latent syphilis is a stage at which the features of secondary syphilis have resolved, though patients remain seroreactive. Some patients experience recurrence of the infectious skin lesions of secondary syphilis during this period. About one-third of untreated latent syphilis patients go on to develop tertiary syphilis, whereas the rest remain asymptomatic.

Tertiary syphilis is a late symptomatic disease that can manifest months, years, or even decades after the initial infection as cardiovascular syphilis, late neurosyphilis, or gummatous syphilis.

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