There are several methods to diagnose meningeal syphilis. One of the most common ways include visualizing the organisms by immunofluorescence and dark field microscopy. Dark field microscopy initially had the finding that the spirochete has a corkscrew appearance and that it is spirillar and gram (-) bacteria. Another method would also be through the screening test and serology. Serology includes two types of antibody test: Nontreponemal antibody test and Treponemal antibody test (specific test). The Nontreponemal antibody test screens with VDRL (Venereal Disease Research Lab) and RPR (Rapid Plasma Reagin). The Treponemal antibody test (specific test) confirms with FTA-ABS (Fluorescent treponemal antibody-absorption). Brain imaging and MRI scans may be used when diagnosing patients; however, they do not prove to be as effective as specific tests. Specific tests for treponemal antibody are typically more expensive because the earliest anitbodies bind to spirochetes. These tests are usually more specific and remain positive in patients with other treponemal diseases.

Dark ground microscopy of serous fluid from a chancre may be used to make an immediate diagnosis. Hospitals do not always have equipment or experienced staff members, and testing must be done within 10 minutes of acquiring the sample. Sensitivity has been reported to be nearly 80%; therefore the test can only be used to confirm a diagnosis, but not to rule one out. Two other tests can be carried out on a sample from the chancre: direct fluorescent antibody testing and nucleic acid amplification tests. Direct fluorescent testing uses antibodies tagged with fluorescein, which attach to specific syphilis proteins, while nucleic acid amplification uses techniques, such as the polymerase chain reaction, to detect the presence of specific syphilis genes. These tests are not as time-sensitive, as they do not require living bacteria to make the diagnosis.

The most popular treatment forms for any type of syphilis uses penicillin, which has been an effective treatment used since the 1940s.

Other forms also include Benzathine penicillin, which is usually used for primary and secondary syphilis (it has no resistance to penicillin however). Benzathine penicillin is used for long acting form, and if conditions worsen, penicillin G is used for late syphilis.

Blood tests are divided into nontreponemal and treponemal tests.

Nontreponemal tests are used initially, and include venereal disease research laboratory (VDRL) and rapid plasma reagin (RPR) tests. False positives on the nontreponemal tests can occur with some viral infections, such as varicella (chickenpox) and measles. False positives can also occur with lymphoma, tuberculosis, malaria, endocarditis, connective tissue disease, and pregnancy.

Because of the possibility of false positives with nontreponemal tests, confirmation is required with a treponemal test, such as treponemal pallidum particle agglutination (TPHA) or fluorescent treponemal antibody absorption test (FTA-Abs). Treponemal antibody tests usually become positive two to five weeks after the initial infection. Neurosyphilis is diagnosed by finding high numbers of leukocytes (predominately lymphocytes) and high protein levels in the cerebrospinal fluid in the setting of a known syphilis infection.

Specific age groups, persons who participate in risky sexual behavior, or those have certain health conditions may require screening. The CDC recommends that sexually active women under the age of 25 and those over 25 at risk should be screened for chlamydia and gonorrhea yearly. Appropriate times for screening are during regular pelvic examinations and preconception evaluations. Nucleic acid amplification tests are the recommended method of diagnosis for gonorrhea and chlamydia. This can be done on either urine in both men and women, vaginal or cervical swabs in women, or urethral swabs in men. Screening can be performed:

- to assess the presence of infection and prevent tubal infertility in women

- during the initial evaluation before infertility treatment

- to identify HIV infection

- for men who have sex with men

- for those who may have been exposed to hepatitis C

- for HCV

In addition to evaluation of any symptoms and signs, various blood tests can be done:

- Venereal Disease Research Laboratory test (VDRL)

- Fluorescent treponemal antibody absorption (FTA-ABS)

- Rapid plasma reagin (RPR)

- Treponema pallidum particle agglutination assay (TPPA)

Also, it is important to test the cerebrospinal fluid for signs of syphilis.

Additional tests to look for problems with the nervous system may include the following:

- Cerebral angiogram

- Head CT scan

- Lumbar puncture ("spinal tap") to acquire a sample for cerebrospinal fluid analysis

- MRI scan of the brain, brainstem, or spinal cord

From bubo pus or ulcer secretions, "H. ducreyi" can be identified. PCR-based identification of organisms is available. Simple, rapid, sensitive and inexpensive antigen detection methods for "H. ducreyi" identification are also popular. Serologic detection of "H. ducreyi" is and uses outer membrane protein and lipooligosaccharide.

Testing may be for a single infection, or consist of a number of tests for a range of STIs, including tests for syphilis, trichomonas, gonorrhea, chlamydia, herpes, hepatitis and HIV. No procedure tests for all infectious agents.

STI tests may be used for a number of reasons:

- as a diagnostic test to determine the cause of symptoms or illness

- as a screening test to detect asymptomatic or presymptomatic infections

- as a check that prospective sexual partners are free of disease before they engage in sex without safer sex precautions (for example, when starting a long term mutually monogamous sexual relationship, in fluid bonding, or for procreation).

- as a check prior to or during pregnancy, to prevent harm to the baby

- as a check after birth, to check that the baby has not caught an STI from the mother

- to prevent the use of infected donated blood or organs

- as part of the process of contact tracing from a known infected individual

- as part of mass epidemiological surveillance

Early identification and treatment results in less chance to spread disease, and for some conditions may improve the outcomes of treatment. There is often a window period after initial infection during which an STI test will be negative. During this period, the infection may be transmissible. The duration of this period varies depending on the infection and the test. Diagnosis may also be delayed by reluctance of the infected person to seek a medical professional. One report indicated that people turn to the Internet rather than to a medical professional for information on STIs to a higher degree than for other sexual problems.

Despite many distinguishing features, the clinical spectrums of following diseases may overlap with chancroid:

- Primary syphilis

- Genital herpes

Practical clinical approach for this STI as Genital Ulcer Disease is to rule out top differential diagnosis of Syphilis and Herpes and consider empirical treatment for Chancroid as testing is not commonly done for the latter.

Penicillin is used to treat neurosyphilis; however, early diagnosis and treatment is critical. Two examples of penicillin therapies include:

- Aqueous penicillin G 3–4 million units every four hours for 10 to 14 days.

- One daily intramuscular injection and oral probenecid four times daily, both for 10 to 14 days.

Follow-up blood tests are generally performed at 3, 6, 12, 24, and 36 months to make sure the infection is gone. Lumbar punctures for CSF fluid analysis are generally performed every 6 months.

Neurosyphilis was almost at the point being unheard of in the United States after penicillin therapy was introduced. However, concurrent infection of "T. pallidum" with human immunodeficiency virus (HIV) has been found to affect the course of syphilis. Syphilis can lie dormant for 10 to 20 years before progressing to neurosyphilis, but HIV may accelerate the rate of the progress. Also, infection with HIV has been found to cause penicillin therapy to fail more often. Therefore, neurosyphilis has once again been prevalent in societies with high HIV rates and limited access to penicillin. Blood testing for syphilis was once required in order to obtain a marriage license in most U.S. states, but that requirement has been discontinued by all 50 states over recent years, also contributing to the spread of the disease.

If a pregnant mother is identified as being infected with syphilis, treatment can effectively prevent congenital syphilis from developing in the fetus, especially if he or she is treated before the sixteenth week of pregnancy. The fetus is at greatest risk of contracting syphilis when the mother is in the early stages of infection, but the disease can be passed at any point during pregnancy, even during delivery (if the child had not already contracted it). A woman in the secondary stage of syphilis decreases her fetus's risk of developing congenital syphilis by 98% if she receives treatment before the last month of pregnancy. An afflicted child can be treated using antibiotics much like an adult; however, any developmental symptoms are likely to be permanent.

Kassowitz’s law is an empirical observation used in context of congenital syphilis stating that the greater the duration between the infection of the mother and conception, the better is the outcome for the infant. Features of a better outcome include less chance of stillbirth and of developing congenital syphilis.

The Centers for Disease Control and Prevention recommends treating symptomatic or babies born to infected mother with unknown treatment status with procaine penicillin G, 50,000 U/kg dose IM a day in a single dose for 10 days. Treatment for these babies can vary on a case by case basis. Treatment cannot reverse any deformities, brain, or permanent tissue damage that has already occurred.

It is treatable with penicillin or other antibiotics, resulting in a complete recovery.

Most often the diagnosis is made clinically. Dark field microscopy of samples taken from early lesions (particularly ulcerative lesions) may show the responsible organism. Blood tests such as VDRL, Rapid Plasma Reagin (RPR) and TPHA will also be positive, but there are no current blood tests which distinguish among the four treponematoses.

A syphilid is any of the cutaneous and mucous membrane lesions characteristic of secondary and tertiary syphilis.

It appears about 10 weeks after infection. Patient may present with prodromal symptoms such as fever, acratia, myalgia athralgia, headache, anorexia. Its eruption pattern is macular, papular, follicular papules, or pustule, symmetrical, generalized and dense, round or oval in shape, and is red copper in color.

Diagnosis is usually clinical, but as with yaws and bejel, serological tests for syphilis, such as rapid plasma reagin (RPR) and TPHA, will be positive, and the spirochetes can be seen on dark field microscopy of samples taken from the early papules.

When physical examination of the newborn shows signs of a vertically transmitted infection, the examiner may test blood, urine, and spinal fluid for evidence of the infections listed above. Diagnosis can be confirmed by culture of one of the specific pathogens or by increased levels of IgM against the pathogen.

lymphadenopathy is a common biopsy finding, and may often be confused with malignant lymphoma. It may be separated into major morphologic patterns, each with its own differential diagnosis with certain types of lymphoma. Most cases of reactive follicular hyperplasia are easy to diagnose, but some cases may be confused with follicular lymphoma. There are seven distinct patterns of benign lymphadenopathy:

- Follicular hyperplasia: This is the most common type of reactive lymphadenopathy.

- Paracortical hyperplasia/Interfollicular hyperplasia: It is seen in viral infections, skin diseases, and nonspecific reactions.

- Sinus histiocytosis: It is seen in lymph nodes draining limbs, inflammatory lesions, and malignancies.

- Nodal extensive necrosis

- Nodal granulomatous inflammation

- Nodal extensive fibrosis (Connective tissue framework)

- Nodal deposition of interstitial substance

These morphological patterns are never pure. Thus, reactive follicular hyperplasia can have a component of paracortical hyperplasia. However, this distinction is important for the differential diagnosis of the cause.

It is currently thought that it may be possible to eradicate yaws although it is not certain that humans are the only reservoir of infection. A single injection of long-acting penicillin or other beta lactam antibiotic cures the disease and is widely available; and the disease is believed to be highly localised.

In April 2012, WHO initiated a new global campaign for the eradication of yaws, which has been on the WHO eradication list since 2011. According to the official roadmap, elimination should be achieved by 2020.

Prior to the most recent WHO campaign, India launched its own national yaws elimination campaign which appears to have been successful.

Certification for disease-free status requires an absence of the disease for at least five years. In India this happened on 19 September 2011. In 1996 there were 3,571 yaws cases in India; in 1997 after a serious elimination effort began the number of cases fell to 735. By 2003 the number of cases was 46. The last clinical case in India was reported in 2003 and the last latent case in 2006. India is a country where yaws is now considered to have been eliminated

In March 2013, WHO convened a new meeting of yaws experts in Geneva to further discuss the strategy of the new eradication campaign. The meeting was significant, and representatives of most countries where yaws is endemic attended and described the epidemiological situation at the national level. The disease is currently known to be present in Indonesia and Timor-Leste in South-East Asia; Papua New Guinea, the Solomon Islands and Vanuatu in the Pacific region; and Benin, Cameroon, Central African Republic, Congo, Côte d'Ivoire, Democratic Republic of Congo, Ghana and Togo in Africa. As reported at the meeting, in several such countries, mapping of the disease is still patchy and will need to be completed before any serious eradication effort could be enforced.

According to present research, PFAPA does not lead to other diseases and spontaneously resolves as the child gets older, with no long term physical effects.

However, PFAPA has been found in adults and may not spontaneously resolve.

Death from congenital syphilis is usually due to bleeding into the lungs.

The formation of gummata is rare in developed countries, but common in areas that lack adequate medical treatment.

Syphilitic gummas are found in most but not all cases of tertiary syphilis, and can occur either singly or in groups. Gummatous lesions are usually associated with long-term syphilitic infection; however, such lesions can also be a symptom of benign late syphilis.

The disease can be treated with penicillin, tetracycline (not to be used in pregnant women), azithromycin or chloramphenicol, and can be prevented through contact tracing by public health officials. A single intramuscular injection of long-acting penicillin is effective against endemic treponematoses including pinta, yaws, and bejel

Although the organism that causes bejel, "Treponema pallidum endemicum", is morphologically and serologically indistinguishable from "Treponema pallidum pallidum", which causes venereal syphilis, transmission of bejel is not venereal in nature, generally resulting from mouth-to-mouth contact or sharing of domestic utensils, and the courses of the two diseases are somewhat different.

Differences between the conditions chancre and chancroid:

- Chancre is a lesion typical of infection with the bacterium that causes syphilis, Treponema pallidum

- Chancroid is a lesion typical of infection with the bacterium Haemophilus ducreyi

- Chancres are typically painless, whereas chancroid are typically painful

- Chancres are typically single, whereas chancroid are typically multiple

- Chancres cause regional bilateral lymph node enlargement, whereas chancroid cause regional unilateral lymph node enlargement

- Chancres typically exude serum, whereas chancroid typically have a grey or yellow purulent exudate

- Chancres have a hard (indurated) base with sloping edges, whereas chancroid have a soft base with undermined edges

- Chancres heal spontaneously within three to six weeks, even in the absence of treatment

- Chancres can occur in the pharynx as well as on the genitals. Not to be confused with condyloma lata, which is seen in secondary syphilis

A chancre ( ) is a painless ulceration (sore) most commonly formed during the primary stage of syphilis. This infectious lesion forms approximately 21 days after the initial exposure to "Treponema pallidum", the gram-negative spirochaete bacterium yielding syphilis. Chancres transmit the sexually transmissible disease of syphilis through direct physical contact. These ulcers usually form on or around the anus, mouth, penis, and vagina. Chancres may diminish between four and eight weeks without the application of medication.

Chancres, as well as being painless ulcerations formed during the primary stage of syphilis, are associated with the African trypanosomiasis sleeping sickness, surrounding the area of the tsetse fly bite.