Introduction

Sir William Osler, the famous Canadian physician, once remarked that the physician who knows syphilis knows medicine. It is because of the myriad symptoms associated with the disease. The disease is nicknamed the great mimicker and imitator or impostor. It is a sexually transmitted bacterial infection caused by the organism Treponema pallidum. It causes manifestation in many organs of the body. It should be considered a probable diagnosis in high-risk patients with systemic diseases. The disease progresses through various stages with the infection lasting for years.

Girolamo Fracastoro, an Italian physician and poet, wrote that the disease came as a curse from the Greek God Apollo in response to an offence by the shepherd called Syphilis. The disease peaked in the 1940s and reduced after the discovery of the penicillin antibiotic. It remains a major public health concern due to limitations in screening and treatment in underserved populations. 

What causes syphilis?

Treponema pallidum is the causative organism for syphilis.¹ It belongs to the group of bacteria called spirochaetes. It is the only member of that group that causes venereal disease. Humans are the only host and the disease is transmitted from humans to humans.² The predominant mode of transmission is through sexual contact via the mouth, anus, or vagina. Other modes of transmission include: 

• Transfusion of infected blood
• Sharing of sharp instruments or through breaks in the skin
• From an infected mother to the baby through the placenta(congenital syphilis)

Statistics from the World Health Organization(WHO) show that 8 million adults between 15 and 49 years old contracted syphilis in 2022.

Overview of syphilis stages

The organism is transmitted through intact mucous membranes or breaks in the skin, enters the lymphatic system, and then spreads to the blood.³

Untreated syphilis progresses through four(4) stages.

These include:

• Early(primary syphilis)
• Secondary syphilis 
• Latent syphilis
• Late(tertiary syphilis)

Primary syphilis

Symptoms

The primary disease presents as a painless ulcer(wound) at the inoculation (infection) site. It is called chancre. The chancre starts as a papule(a raised growth) on the genitals. The lesions may lie hidden in the cervix and vagina. This becomes ulcerated over time to form a punched-out wound with raised borders. It is usually solitary but may be multiple in Human Immunodeficiency Virus(HIV) infected patients.² The lesion is highly infectious. The chancre may also be present in other sites like the tonsils, nipples, and the inner lining of the mouth.

Other manifestations

Swollen lymph nodes near the infection site may be painful.

Timeline

The chancre usually resolves within 3 -12 weeks, irrespective of the treatment.¹ The healing is usually associated with scarring.

During this phase, the bacteria quickly spread to other body parts, including the cerebrospinal fluid(CSF), though symptoms may not be present. 

Secondary syphilis

Secondary syphilis manifests in about 4-10 weeks after primary syphilis.³ It develops in about a quarter of patients with untreated syphilis. The symptoms result from the multiplication and spread of the organism in the body through the blood.

Symptoms

Widespread skin rashes (typically on the palms and soles) are usually flat, discrete, reddish, and are contagious. They are not itchy. The involvement of the palms and soles is a distinguishing feature and helps in diagnosis.

Lesions may also appear on the mucous membranes(lining) of the mouth and genitals.

Other symptoms

Flu-like symptoms:

• Fever 
• Headache
• Sore throat 
• Fatigue(weakness)
• Muscle pain 
• Joint pains

Widespread swollen lymph nodes which are rubbery, firm, and painful.⁴

Enlargement of the spleen and liver.

Patchy hair loss on the scalp, face, and eyebrows (alopecia) gives the patient a ‘moth-eaten’ appearance.

Condylomata lata: highly contagious grey-white, wart-like lesions in the moist areas of the body) They are usually seen in the skin folds and around the genitals and anus in about 50% of patients with secondary syphilis. They can be painful. They are highly contagious. 

The symptoms of secondary syphilis can resolve without treatment.¹

In HIV-positive patients, a rare form of secondary syphilis may develop. It is known as malignant syphilis or lues maligna. The lesions are more persistent and severe.² It is also associated with more systemic(generalised) manifestations occasionally seen in patients with healthy immune systems. Patients with diabetes, psoriasis, and substance abuse are more at risk.

The diagnosis of syphilis at this stage is through evidence of the disease in the blood, on microscopy(viewing under the microscope), or in a biopsy specimen (analysing a part of the tissue in the lab) 

Blood tests include non-specific tests like Venereal Disease Research Laboratory(VDRL) or Treponema-specific tests. 

Timeline

The skin manifestation of secondary syphilis typically lasts a few weeks. If untreated, they may reoccur within 12 months in about a quarter of the patients.²

Without treatment, the disease enters the latent phase.

Latent syphilis

Characteristics

There is usually no symptom during this phase, though the evidence of the disease is still present in the blood.³

Potential manifestations

Occasionally, some patients may experience a resurgence of some of the skin rashes of secondary syphilis.

If untreated, the majority of the patients will remain without symptoms, and about one-third will develop tertiary syphilis. 

Tertiary or late syphilis

Tertiary syphilis is very rare in contemporary times due to the availability of antibiotic treatment. It develops in 20-40% of patients with untreated syphilis.

It arises due to gradual damage to the tissues. It results from inflammation that develops over months, years, or even decades.^2,5

Tertiary syphilis predominantly affects the cardiovascular(heart and blood vessels) system. In 10-15% of cases, it also affects the central nervous system, which includes the brain and spinal cord. 

Characteristics

The three major categories of tertiary syphilis are:

• Gummatous syphilis
• Cardiovascular syphilis
• Neurosyphilis

Gummatous syphilis 

It is a rare form of tertiary syphilis linked to the presence of gumma. The gumma is nodules that have a necrotic centre and rubbery texture. They look like granulomas and may be mistaken for diseases like sarcoidosis and tuberculosis that cause granulomas.

They are found in the testis, bone, heart, brain, and liver but may also affect other organs.

Gummas on the skin become fibrotic (form fibrous scar tissues) and can break down to form flat wounds. Treponema pallidum is detected in the lesion only rarely.

Cardiovascular syphilis

It develops after around ten years of the original illness. The damage to the organs usually develops slowly. It commonly manifests as:

• Aneurysm (bulge in the wall) of the great vessels supplying blood to the brain (ascending aorta). This results from inflammation.
• Aortitis (the inflammation of the aorta)
• Aortic valve dysfunction 
• Heart failure

Neurosyphilis

Approximately 30% of untreated syphilis patients will have evidence of the disease in their cerebrospinal fluid. Since the development of effective antibiotics, neurosyphilis is now rare in the general population, seen in patients with HIV who are not on treatment. Men are twice as likely to develop neurosyphilis than women.⁵

Neurosyphilis is of three types:

• Early
• Intermediate
• Late

Early neurosyphilis

Early syphilis is of two types:

• Asymptomatic
• Meningeal neurosyphilis

Asymptomatic

At this stage, patients are asymptomatic. However, there is evidence of the disease in the cerebrospinal fluid.

Meningeal neurosyphilis

It manifests as early as within a year after the primary infection. It results from the inflammation of the meninges (the coverings of the brain and spinal cord). The symptoms may resolve on their own. If untreated it progresses into more severe forms of the disease.⁵

The symptoms include:

• Headache
• Nausea
• Vomiting
• Stiffness of the neck
• Light sensitivity
• Seizures
• Deficits of the nerves supplying the brain and face

The diagnosis is made by the presence of the symptoms, brain imaging abnormalities, increased white blood cells in the CSF, and positive(VDRL).

Intermediate stage

Meningovascular neurosyphilis

It develops five(5) to 12 years after the initial infection. Inflammation of the brain and spinal cord coverings occurs. In addition, inflammation of the terminal arteries supplying the brain(endarteritis) leads to clot formation and blocked arteries. It leads to the death of the part of the brain supplied by the arteries.

The initial symptoms are non-specific. They include:

• Headache
• Nausea
• Vomiting
• Loss of balance 

The specific symptoms depend on the part of the brain that is affected. The most common manifestation is stroke in younger adults. Affectation of the spinal cord leads to:

• Weakness of the legs
• Loss of muscle bulk
• Loss of sensation 

The diagnosis is as per meningeal syphilis with the addition of imaging of the blood vessels(angiography)

Late neurosyphilis

Usually, this manifests more than 10 years following the original illness. It is also called parenchymal neurosyphilis.

It can be of two types:

• Syphilitic Paresis (General paralysis of the insane)
• Tabes Dorsalis

Syphilitic paresis (General paralysis of the insane)

It results from chronic inflammation of the meninges (coverings of the brain and spinal cord) and brain matter(encephalitis).

The symptoms could be: 

• Early
• Late

Early symptoms include mood disturbances like:

• Irritability
• Change in sleep patterns
• Forgetfulness
• Changes in personality

Late symptoms include:

• Unstable mood
• Confusion
• Depression
• Delusions
• Seizures

Eye abnormalities (Argyll Robertson pupils) are characteristic of patients with late-stage disease. 

Because of the manifestations of the disease, screening for syphilis is necessary in any patient with psychiatric manifestations.

The diagnosis is made by: 

• Presence of the symptoms, 
• Positive blood and CSF VDRL test
• Evidence of raised white blood cells in the CSF
• Magnetic Resonance Imaging(MRI) abnormalities

Tabes dorsalis

It arises from the destruction of some sections of the spinal cord by the disease. The destruction results from inflammation. The symptoms often appear 20-25 years after the primary disease.

Symptoms include:

• Unsteady gait
• Problems with balance
• Stabbing pains 
• Bladder dysfunction
• Abnormal body sensation in the extremities
• Lack of awareness of the position and movement of the body(proprioception)
• Visual and hearing problems 

The patients may also develop a Charcot spine. It is a rare condition that results from progressive damage to the spine from the lack of proprioception.⁶

Romberg's test and diagnosis confirm the disease. The Romberg’s test confirms a lack of proprioception. In 25% of cases, CSF, VDRL, and MRI of the spinal cord may also be normal. 

Congenital syphilis

It results from the transfer of bacteria from the mother to the baby during pregnancy. It does not progress through the different stages as it is acquired. It may result in abortion or stillbirths. Where the babies survive the pregnancy, they may be born with cataracts(blindness) or deafness.⁷ If untreated, they may also develop symptoms that are similar to secondary syphilis in the first two(2) years of life.

Late manifestations include bone, teeth, and joint abnormalities. Sings of meningitis, seizures, and developmental delays can also be seen in these babies.¹ They may also present with features of late neurosyphilis like tabes dorsalis and general paresis.

Summary

Syphilis, caused by the bacterium Treponema pallidum, is a sexually transmitted infection. Syphilis is known for its varied symptoms and ability to mimic other diseases. It progresses through four stages- primary, secondary, latent, and tertiary. These stages have their respective manifestations. Understanding the different stages and their manifestations enables proper diagnosis and treatment.