Differential Diagnosis

The diagnosis of any stage or phase of syphilis can be complicated, especially in the setting of HIV. In primary syphilis, the hallmark symptom is a painless lesion usually on the external genital. The differential diagnosis would include other STDs such as genital herpes, chancroid, or lymphogranuloma venereum (LGV). Most of these diseases create a painful lesion or local lymphandenopathy. The lesions associated with secondary syphilis can be confused with other skin manifestations, such as pityriasis rosea, psoriasis, erythema multiforme, tinea versicolor, viral exanthema, scabies, or even a drug reaction. The simplest test used to diagnosis syphilis at these stages is a dark-field examination and/ or direct fluorescent antibody (DFA) stain on lesion exudates or tissue.2 The spirochetes will be visible on examination.

However, if the initial lesion has healed, a diagnosis can be made using the results of two sets of serological tests. PCR and culture are not helpful in the diagnosis of this disease. First-line testing should include one of the nontreponemal tests. These include the VDRL (Venereal Disease Research Laboratory test) and the RPR (rapid plasma reagin test) performed on serum.1 These tests look for the production of antibodies to car-diolipin, which is elevated initially in the course of infection but is not specific to the spirochete causing disease. A reactive titer is > 1: 32; titers less than 1: 8 are considered false positives in the presence of a negative FTA-ABS (see discussion below).1 The non-treponemal tests correlate well with disease activity and eventually become nonreactive after successful treatment or after an extended period of infection. However, some individuals are classified as "serofast" in that their RPR or VDRL results will remain positive for life. The sensitivity for the VDRL is around 80%, and the specificity is around 98% for detecting primary disease.2 For the RPR, sensitivity is around 86%, and specificity is around 98%.2 Other medical conditions such as autoimmune disease, pregnancy, mono-nucleosis, rickettsial infections, or other spirochete infections can create false-positive results. For this reason and especially in low-prevalence populations, any positive result should be followed by confirmatory tests, the treponemal tests.2 These are the FTA-ABS (fluorescent treponemal antibody absorbed test) and the TP-PA (T. pallidum particle agglutination assay). These assays detect antibodies that are specific to the spir-ochete and once positive, will remain positive for life. The sensitivity and specificity for the FTA-ABS are 84% and 94%, respectively for detecting primary disease.2 Therefore, in an effort to diagnose syphilis, a positive RPR should be followed by an FTA-ABS. If positive, syphilis is confirmed. However, a negative RPR with a reported history of a documented yet distant (especially untreated) exposure should also be followed by an FTA-ABS to rule out latent infection.

The symptoms associated with neurosyphilis can be attributed to a number of other diseases or manifestations. Often, individuals with neurosyphilis will present with delusions or dementia or other major affective disorders, prompting an evaluation by a psychiatrist rather than an infectious disease specialist. In this instance, the patient is not getting the required treatment. So, it is slowly becoming the standard of care that individuals admitted to the hospital with dementia or delusions be screened for syphilis to rule out this etiology. Other infectious agents such as herpes viruses, Epstein-Barr virus, arboviruses, enteroviruses, and even advanced HIV disease can cause symptoms similar to those seen in neurosyphilis.

Neurosyphilis is diagnosed when the serum RPR and/or FTA-ABS are reactive, the patient's CSF profile is abnormal with an elevated white count (>5 cells/mm3) or elevated protein, and a CSF VDRL is positive. Neurological symptoms may or may not be present. There are rare occurrences of neurosyphilis with a normal CSF profile, but this is not common, and all three components are needed for a diagnosis. The CSF VDRL (the preferred test for CSF) is highly specific yet only 30-70% sensitive, and the FTA-ABS on the CSF is less specific but highly sensitive. Either test alone is not comprehensive enough for a diagnosis.

CSF invasion by the bacterium can occur in primary and secondary stages of disease, creating an abnormal CSF profile; therefore, CSF analysis is not recommended as part of the routine evaluation during these stages. The CDC criteria for performing a lumbar puncture are (1) neurological or ocular symptoms, (2) late latent syphilis or unknown duration of infection, (3) active tertiary disease, or (4) evidence of treatment failure. Imaging, such as an MRI, can be helpful in demonstrating low-density lesions in the brain and spinal cord that are characteristic of central nervous system (CNS) infection.

When there is concurrent HIV infection, the diagnosis of syphilis can be difficult as there can be an altered serological response. Often, individuals with HIV have a delayed or weak antibody response, so they may not be positive in the expected timeframe. Or the opposite may be the case; they may produce higher than normal levels of antibody, creating false-negative test results due to a prozone effect.3 The prozone effect occurs when the antibody concentration in the sample is greater than the antigen concentration in the assay, thereby binding all the antigen and preventing the formation of a precipitin, creating what looks like a negative result.3 However, when the serum is diluted and the antigen and antibody are in the appropriate ratios, a reactive result is seen. To complicate matters, CSF abnormalities are commonly present in the early stages of HIV and can therefore interfere with a diagnosis. The CSF profile in HIV disease with concurrent primary or secondary syphilis is unknown. Therefore, some sources recommend a lumbar puncture on all HIV patients regardless of stage of disease or symptomatology.1

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