Syphilis is caused by the bacteria Treponema pallidum which is spread through sexual contact. The T. pallidum enters the blood stream 1-2 months after initial infection, allowing it to invade other organs and the central nervous system (CNS) as well. Failure of the immune system to clear the bacteria from the body can result in neurological damage; however, the neurological and psychiatric symptoms may take 5-25 years to emerge[1] . General paresis is the form of neurosyphilis most associated with psychiatric symptoms. Symptoms can include emotional and cognitive deficits, confusion, and headaches; frontal atrophy is common, with temporal atrophy occurring in some cases[2] . A second, rarer form of neurosyphilis is tabes dorsalis, which occurs from the degeneration of the posterior columns and roots of the spinal cord. Symptoms include ataxia and a loss of peripheral reflexes and proprioception[3] . Diagnosis of syphilis typically uses two sets of serological tests, one for screening and the other for confirmation. The former detects immune activity while the latter detects the presence of treponemes. The primary method of treatment for syphilis is penicillin, and antipsychotics are used to treat any psychotic symptoms associated with general paresis.

1.1 Introduction



1.1a Transmission and infection
T._pallidum.jpg
T. Pallidum. Image source: CDC PHIL, #1977.
Syphilis is caused by the spirochete bacterium Treponema pallidum. This bacterium, or treponeme is usually transmitted through sexual contact via abrasions in the mucosal membrane or the skin. Once T. pallidum enters the body, it establishes infection by adhering to epithelial cells and parts of the extracellular matrix in the skin and mucosa[4] . Once bound to the tissue, it starts replicating at the site of infection. This process induces a local inflammatory response which results in a painless chancre 3-6 weeks after the infection. The chancre disappears after 1-2 months, indicating that the local infection has cleared and T. pallidum has invaded other tissues and organs via the bloodstream (see above [4]).

1.1b Disease course

Disease_course1.jpg
Disease course. Image source: Ho & Lukehart, 2011.
The course of syphilis is divided into four main stages: primary, secondary, latent, and tertiary syphilis. The primary stage of syphilis includes the exposure, infection and initial spread of the bacterium. In most cases, clinical manifestations of this stage are limited to an inflammatory response, which manifests in the form of chancres (see above [4]).
Secondary syphilis occurs after the chancre heals in 1-2 months. This indicates that the bacterium has invaded the bloodstream, and has spread throughout the body. Similar to the primary stage, inflammatory responses are the common clinical symptoms of secondary syphilis. The most common non-CNS symptom is maculopapular rash, and additional symptoms include mucous tissue and ocular inflammation, muscle aches and weight loss (see above [4]). The bacterium can also invade the CNS from the bloodstream and cause neurological damage. Symptoms of secondary syphilis in the CNS include meningitis, cranial neuropathy and meningovascular disease. T. pallidum does not secrete any toxins, and most symptoms and tissue damage observed in primary and secondary syphilis are due to endogenous inflammatory and immune responses (see above [4]). These immune responses may clear out local infections and lesions, but T. pallidum can reside in different tissues without clinical manifestations, comprising the latent stage. The bacterium may enter the bloodstream again from its dormant state, causing secondary inflammation symptoms or advancing to the tertiary phase.
Tertiary syphilis can occur with or without central nervous system (CNS) invasion. If syphilis proceeds from the latent stage without entering the CNS, it can cause cardiovascular lesions such as aortitis (aortic aneurisms) or gummas (inflammatory nodules in the skin, bone or liver)[5] . The former may show symptoms 20-30 years after initial infection, while the latter may manifest itself after 1- 45 years. CNS involvement can include general paresis, a form of dementia often associated with psychotic symptoms, and tabes dorsalis which involves spinal cord lesions and manifests as sensory ataxia and bowel dysfunctions. These symptoms may appear 3-50 years following primary syphilis.

1.2 Diagnosis


Diagnosis of syphilis involves two sets of serological tests for screening and confirmation purposes: nontreponemal tests for screening, and treponemal tests for confirmation of T. pallidum[6] .

1.2a Screening

RPR.jpg
RPR test. Image source: drugster.info
The Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) are two serological tests commonly used for screening purposes[7] . These nontreponemal tests measure both immunoglobulin G (IgG) and IgM activity. These antiphopholipid antibodies form in response to both lipids on the surface of the treponeme, and lipid material released from host cells damaged during early infection (see above [6]). The advantages of these tests are that they are quick and inexpensive to perform. This is in contrast with the follow-up treponemal tests, which are technically challenging and expensive to perform.

1.2b Confirmation

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TP-PA test. Image source: bmb.leeds.ac.uk
If the nontreponemal test is positive, the result is then confirmed using treponemal tests. These assays detect the presence of T. pallidum or its polypeptide components as the antigen (see above [6]). Treponemal tests include the fluorescent treponemal antibody absorption test (FTA-ABS), which is a fluorescent antibody technique; the Treponema pallidum particle agglutination (TP-PA) test, which uses agglutination, or clumping of colored particles sensitized to T. pallidum antigens by the serum antibodies; and Western blot, which allows for the visualization of antibodies through specific banding patterns.

1.3 Forms of neurosyphilis


1.3a General paresis

General paresis is associated with several psychiatric and neurological symptoms, and occurs from neuronal atrophy. Psychiatric symptoms include emotional dysregulation, memory deficits, disorientation, and delusions[8] ; neurological symptoms include dysarthria, muscle tremors, and pupillary abnormalities[9] . Psychiatric symptoms typically present before neurological ones, with dementia occurring first in many cases[10] . Neuronal lesions typically involve frontal and temporal lobes (see above [2]). It is unclear whether the lesions occur directly from spirochetes interacting with neuronal tissue, indirectly via damage to cerebral vasculature, or both[11] . However, autopsies of neurosyphilis patients revealed that spirochetes were mainly found in gray matter. Some were found in endothelial cells and microglia, but none were found in white matter[12] .

1.3b Tabes dorsalis

Tabes dorsalis (TD) results from spinal cord lesions caused by syphilis[13] . These lesions can occur directly from spirochetes interacting with the spinal cord, which result in lesions of the posterior column, or indirectly via damage to the blood vessels or meninges. The latter typically results from meningovascular syphilis, which involves infarctions or thrombosis of arteries in the brain or spinal cord (see above [1]). Symptoms of TD include ataxia, pain, and bladder dysfunctions. The most common diagnostic sign is Argyll Robertson pupils, in which pupils accommodate normally when focusing on close objects, but fail to constrict to bright light (see above [2]). The cause of this symptom is unknown, but some evidence points to the rostral midbrain (Zheng, et al. 2011). Other signs include ocular palsy, and impaired reflexes and proprioception (see above [13]).

1.3c Asymptomatic neurosyphilis

Asymptomatic neurosyphilis is defined by serological evidence of CSF abnormalities without neurological symptoms[14] . This distinction was important in the pre-antibiotic era, as having asymptomatic neurosyphilis greatly increased the probability of developing neurological symptoms later in the disease course[15] . However, in the antibiotic era this is less crucial as syphilis can be treated with penicillin, thus greatly reducing the probability of CNS involvement.

1.4 Treatment


1.4a Treatment of syphilis

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Penecillin. Image source: textbookofbacteriology.net.
Penicillin remains that main mode of treatment for syphilis since its introduction in the 1940s. Although there have been no comparative trials to determine the ideal dose, it has been established that a sustained, high dose is most effective[16] . The goal of penicillin treatment is to stop the infection and attempt to reverse its symptoms[17] . Treatment is typically very effective with patients in the early stage of neurosyphilis. The exception is patients with HIV infections, whose treatment takes longer and may be less effective. Treatment for late syphilis is unlikely to reverse symptoms once neurological damage has occurred. Follow-up serological testing is recommended until CSF abnormalities have subsided.

1.4b Treatment of psychiatric symptoms

Many of the psychiatric symptoms present in general paresis are similar to other psychiatric disorders (e.g. schizophrenia, mood disorders, dementia). Thus, many of the pharmacological treatments available for the analogous disorders are used as treatment for the symptoms of general paresis. For example, antipsychotic medication such as the neuroleptic Haloperidol and atypical antipsychotic risperidone are used to treat psychotic symptoms (see above [10]). Emotional dysregulation is often treated with the mood stabilizer divalproex sodium (see above [10]). While symptoms may not exactly match criteria for the various psychiatric disorders, drug treatment is based on disorders that have the best match for the patient profile. The lowest effective dose is typically prescribed to treat the psychiatric symptoms.


References

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