Conditions such as Neurosyphilis (NS), which is an infection of the nerve, are a result of the Treponema pallidum bacteria. In any of the stages of syphilis, T. pallidum has the ability to invade the central nervous system.

Neurosyphilis is an illness that has worried physicians for centuries, and that seems to reemerge in different forms with some regularity. Pathogenic organisms in the Central Nervous System also show a variety of symptoms, from inflammation to stroke, dementia, meningitis, and asymptomatic carriers. Diagnostic tools are not perfect at all, so one must have a lot of scepticism about the actual diagnosis in order to get the right one. Unfortunately, none of the presented tests can be treated as a good and useful gold standard, and there is no consensus regarding the diagnostics of the disease in question.

Concerning many locations, the proportion of people who acquired syphilis has been growing. Practitioners must know the potential and limitations of the diagnosis in order to properly recognize individuals who develop this fatal complication of untreated syphilis. This is related to diagnostic accuracy through reviews that looked at certain tools. Although polymerase chain reaction (PCR) methods don’t have a good gold standard, a review found that they are less sensitive than cerebrospinal fluid (CSF) serological assays. An additional study discovered that CSF treponemal-specific antibody tests work differently depending on how common Neurosyphilis was before the test.

Statistics data on Neurosyphilis

An estimated, in the year 2020 alone, there were 22.3 million people globally who had a T pallidum illness, with 7.1 million new cases. However, there is no data available at the national level on Neurosyphilis, and there are hardly any surveys that indicate the rate at which the disease is spreading.

Neurosyphilis is still prevalent globally because 1.2% to 1.8% of syphilis patients will develop Neurosyphilis. The estimated annual incidence of Neurosyphilis in Europe is believed to be from 0. 16 to 2.1 per 100,000 adults; in Australia, it was 2.47 cases per 10,000 people from 2007 to 2016; in British Columbia, Canada, it went from 0.03 cases per 10,000 people in 1992 to 0.8 cases per 10,000 people in 2012; and in Guangdong, China, it went from 0.21 cases per 10,000 people in 2009 to 0.31 cases per 10,000 people in 2014.

Essentially, SARS is more prevalent in male populations within the higher-income regions of the globe. The incidence is exceedingly high among individuals in low- and middle-income countries. According to WHO, syphilis was the highest in Africa in 2016. This may be because the continent lacked necessary health education, health resources, health facilities, and infrastructure. According to the researchers, those who are suffering from Neurosyphilis also depict similar trends. Due to the stigma that is associated with Neurosyphilis, in addition to struggling to bear the financial brunt of the illness, patients’ quality of life is severely impacted.

Risk factors for Neurosyphilis in HIV-negative patients

Sex and age

One major factor is that men are affected by syphilis at a higher rate, and especially in China, the United States of America as well as Europe, most MSM (men who have sex with men) engage in sexual activities. For instance, males with syphilis have increased in the US, with the figures standing at 40,299 in 2008 and 121,100 in 2018. Importantly, syphilis does not prevail in high-income or upper-middle-income countries. Affordability can make it easier for MSM to get syphilis by letting them move around more. But it’s easy to find and treat syphilis, which can help stop the disease from spreading. Different factors affect how common syphilis is.

While studies in Sub-Saharan Africa have shown that men are more likely to get syphilis than women, this is likely because women in that area are culturally, economically, and socially pushed to the edges. A related risk factor for Neurosyphilis has been found to be male sex, in addition to its statistical importance. Researchers looking into how sex hormones affect the growth and progression of Neurosyphilis may help us learn more about how the disease works biologically.

An additional risk factor for HIV-negative neurosyphilis cases is being older (45 to 60 years or more). This connection might be because diseases last longer in older people. In this way, getting older is linked to increasing immunosenescence, which makes getting infections more likely. It is interesting that Neurosyphilis has been linked to some neurological diseases, like Alzheimer’s disease (AD). As a result of studying AD pathology, it has been shown that the curly fibres found there are actually individual spirochetes. When they stick together in clusters, they form similar senile plaques.

Serum non-treponemal test titer

Non-treponemal tests, like the rapid plasma reagin (RPR) test and the toluidine red unheated serum test (TRUST), are better at diagnosing Neurosyphilis than treponemal tests, according to previous research. If blood-derived anti-treponemal IgG antibodies can get through the BBB and into the CSF, this could explain why the results are wrong. According to a multivariate analysis, a higher serum RPR titer raises the chance of getting Neurosyphilis but not secondary syphilis. It was eight times more likely for HIV-negative syphilis patients with blood TRUST titers of 1:16 or higher to get Neurosyphilis. Importantly, people whose blood RPR levels drop by four times after treatment are more likely to get asymptomatic Neurosyphilis (ANS), which shows that ANS and treatment failure are linked.

Specific genes carried by the host

Genetic differences in immunity control genes called single-nucleotide polymorphisms (SNPs) may affect how likely someone is to get Neurosyphilis. People who have the IL-10 promoter genotypes −1082 GG and −592 CC, and the TLR1_1805GG, TLR2_2258GA, and TLR6_745CT/TT genes are more likely to get Neurosyphilis. At the moment, most of the risk factors found in studies can’t be changed. This makes it hard to change risk factors to lower disease risk. There is a lack of knowledge about psychosocial and physical activity factors to establish what has to be done in an effort to avoid these factors.

Risk factors for Neurosyphilis in HIV-positive patients

The most recent European guideline on the management of neurosyphilis reports that there is no higher predisposition of neurological involvement for HIV-infected patients with early syphilis. An undifferentiated study, on the other hand, found that people with syphilis who also have HIV are more likely to get Neurosyphilis. For example, this could be because people who are HIV-positive are more likely to get thorough tests at the right time. Although the CNS is a more immunologically privileged site because of the blood-brain barrier (BBB) and the limited movement of immune cells, the CNS’s ability to defend itself against T. pallidum is weakened by the lower number of CD4 T cells and meningeal lesions found in HIV-positive patients.

Beyond being male, being older, and having high antibody levels, HIV-positive people also have a number of other risk factors that make their immune systems less effective. The chance of Neurosyphilis is higher in people who have a lot of viruses and fewer CD4(+) T cells (less than 350 cells/µl) than in the general population, according to many studies. Increased HIV-ribonucleic acid (RNA) virus load can cause T. pallidum to cause programmed cell death of CD4(+) and CD8(+) T cells. Actually, the interaction between HIV and T. pallidum is complicated, and not enough study has been done on it. Numerous experts agree that neurosyphilis symptoms can be mistaken for HIV infections, which are mostly marked by a higher number of karyocytes and a higher protein concentration. Although antiretroviral therapy (ART) may improve this condition, it is still not clear if syphilis patients who have never had ART should have a lumbar puncture. In any case, failing to receive ART or syphilis treatment is most certainly a large risk factor for Neurosyphilis.

Causes of Neurosyphilis

• Infection with Treponema pallidum: Syphilis is predominantly an infection with the bacteria called Treponema pallidum. Neurosyphilis is the form of this bacteria that also attacks the nervous system of an affected individual.

• Late-Stage Syphilis: Neurosyphilis is a manifestation of the third stage of syphilis and can develop years after getting infected, especially if the infection is not treated or if it is treated inappropriately.

• Inadequate Treatment or Untreated Syphilis: If you do not get rid of syphilis or only partially cure it, bacteria can remain in your body and enter the nervous system.

• Immune System Responses: When it comes to the advancement of the disease, microbes are capable of hindering the operation of the body’s defence. In some cases, the body attempts to fight an infection or any disease and, as a result, damages the CNS by making it swollen.

• Blood-Brain Barrier Penetration: Contrary to this, the Treponema pallidum bacteria can infiltrate past the blood-brain barrier. This is a barrier that, under normal circumstances, should exclude many things from entering the brain and spinal cord, especially toxic substances.

• Inflammation: Neurosyphilis signs might worsen or flare up when your body attempts to develop an immune response against the infection. This can cause inflammation, which then is detrimental to nerve tissue.

• Vascular Damage: From the infection, one can develop vasculitis, which ultimately affects blood vessels, causing inflammatory diseases, reducing blood flow to the organs, and even causing brain stroke.

• Direct Tissue Invasion: It can penetrate the brain tissue directly, and the symptoms depend on the areas of the brain in which the bacterium has invaded.

• Individual Susceptibility: People’s reactions to syphilis and the chance of getting Neurosyphilis depend on genetics, general health and more.

• Coinfections or Comorbidities: As their immune systems are already weaker, people who have other illnesses, especially HIV, are more likely to get Neurosyphilis. Other health problems that happen at the same time can make the disease worse by increasing its chances and harshness.

Diagnosis of Neurosyphilis

The diagnosis of Neurosyphilis is claimed to involve a combination of epidemiological data, neurological or neuropsychiatric signs and symptoms, serologic study of the blood and CSF, and imaging, depending on the type. Most major standards say that lumbar puncture is the best way to treat syphilis in people who have neurological symptoms. Still, the brain signs of Neurosyphilis are not very clear.

In the initial stages, Neurosyphilis involves the meninges and HCV; hence, the symptoms are early headache, nausea, vomiting, blurred vision, and stiff neck. Late Neurosyphilis targets the spinal cord and brain parenchyma, and its symptoms are ataxia, memory loss, confusion, depression, hallucinations, mania and others. Neurosyphilis can mimic many neurological and mental disorders, surprisingly. Some of the examples of autoimmune-related disorders include autoimmune encephalitis, acute ischemic stroke, status epilepticus, posterior uveitis and asymptomatic optic perineuritis. According to these traits, T. pallidum could probably penetrate and cause lesions of the CNS in one way or another.

A CSF test is one of the diagnostic requirements. Neurosyphilis susceptibility research informs understanding of how a disease is and how it can be managed. However, there are areas unknown, for example, when patients should get CSF testing to screen for Neurosyphilis. A great deal of concern for neurological signs and symptoms, the stages of syphilis and HIV seropositivity during lumbar puncture is noted.

Regardless of the type of syphilis, all specialists are unanimous, thinking that patients with neurological signs or symptoms should have a CSF study. A routine lumbar puncture cannot be recommended for HIV-positive and HIV-negative patients without neurological symptoms since evidence for this procedure increasing clinical benefit is scarce. It correlates to your question of how likely ANS will transform into Neurosyphilis with symptoms and the risk-benefit assessment of lumbar puncture.

Treatment and antibiotic management of Neurosyphilis

Neurosyphilis treatment must take into account the BBB’s ability to pass through and the drug’s beneficial concentrations in the CSF. Infusion of aqueous crystalline penicillin G through an IV is the suggested way to treat Neurosyphilis (18–24 million units per day, continuously for 10–14 days). Penicillin-allergic people may be able to use doxycycline or ceftriaxone instead, as they can easily cross the blood-brain barrier. If you take doxycycline by mouth, it can help other STDs at the same time. Patients with Neurosyphilis who were treated with procaine G penicillin or doxycycline had similar results. Compared to ceftriaxone, which needs to be given intravenously, its therapeutic benefit seems to be up for debate.

A later study found that ceftriaxone was linked to a 23% failure rate in treating HIV-infected people with ANS. As for another prospective pilot study of HIV-infected patients with ANS, there was no change in the immune system response to treatment with ceftriaxone versus procaine penicillin plus probenecid. Inhibiting Oat3 can lower the secretion from renal tubules and stop the active transport of intracranial penicillin. This makes penicillin G more bioavailable. A stronger quintuple of benzathine penicillin G, ceftriaxone, and doxycycline has a better efficacy than the suggested combination.

Furthermore, linezolid is cheap, safe, and well-accepted when taken by mouth for a short time, and there is enough of it in the cerebrospinal fluid for use. Also, it was found out that before it was used in humans, linezolid may be effective in the treatment of syphilis. Researchers have recently made progress in growing T. pallidum in a lab dish. This has made it easier to find possible treatments for syphilis, as shown by the minimum inhibitory concentration (MIC). Using neurosyphilis-related strains in future studies will give stronger proof for choosing drugs to treat Neurosyphilis.

However, T. pallidum, the bacteria that causes syphilis, has not demonstrated any clinical data of penicillin resistance thus far, even though the researcher has identified increased gene mutations associated with penicillin resistance, and they assert treatment may cease to work in the long run. It is possible to state that there are cases of increasing resistance of T. pallidum to macrolides when reviewing molecular epidemiological investigations. This is happening at the same time as more macrolides are being used because of guidelines. Azithromycin was not even listed as an alternative treatment for syphilis in the 2020 European recommendation. As a way to deal with the problem of drug resistance, subtractive genomics methods have been used to find Salvicine as a possible treatment molecule for T. pallidum.

Prevention of Neurosyphilis

Patients with early-stage Neurosyphilis can get better with penicillin treatment. Still, it’s not easy to identify Neurosyphilis early on, and prevention is especially important for late-stage patients because they don’t have a good outlook. Creating syphilis vaccines is also very important for improving public health because congenital syphilis can be deadly.

Specific to Neurosyphilis, the syphilis vaccine stops the spread of T. pallidum from an infected spot and stops Neurosyphilis from developing. To make a syphilis vaccine, problems like growing T. pallidum in the lab, changing the antigens in TprK, and the low amount and weakness of outer membrane proteins (OMPs) have made it hard to get to clinical trials yet. Researchers have shown positive responses to this quest despite these problems. A different kind of antigen presentation system (noninfectious Borrelia burgdorferi) was created to express T. pallidum antigens in order to test how well a syphilis vaccine worked.

Recent improvements in long-term culture methods (by cocultivation with rabbit epithelial cells in a microaerophilic atmosphere) and drug sensitivity testing in vitro could help with growing T. pallidum. For genetic tests, new enrichment techniques that don’t depend on culture or high-sensitivity methods have also been made available. Using gel microdroplet techniques can make it less likely that the outer membrane will be extracted, and bioinformatics methods can help predict OMPs without the performance problems that come with a fragile outer membrane.

Antigenic variation can also be dealt with by creating strains that make it harder to change TprK. Finding new targets for vaccines has never been easier, but due to the new fields of molecular biology and bioinformatics, several adhesins, including TP0136, TP0751, and TP0954, have been discovered as possible vaccines. This shows how important they are in T. pallidum invasion and spread. Some of the problems with these options right now are that they need to be given in very large amounts, they don’t protect against other diseases, and adjuvants may cause side effects.

Although some scientists have tried making multicomponent vaccines, no one has yet been completely protected from getting sick. There’s no doubt that vaccinations that cause partial protection help stop the spread of the disease and stop it from getting worse to form Neurosyphilis.

The main way that T. pallidum is spread is through skin-to-skin or mucosal touch during sexual encounters. It can also be transmitted from one individual to the other. About three decades prior, individuals primarily mentioned HIV when referring to sexually transmitted diseases. Others have been relegated to the background, such as syphilis. The concept of preexposure prophylaxis for HIV has been well studied for its effectiveness as a way of preventing the spread of the virus. However, PrEP has not as yet been implemented as a way of controlling the spread of syphilis. Surprisingly, more people with syphilis get HIV PrEP in Australia than people who don’t go through the program. There is a thing called “risk compensation” that might explain this link between the two. When the risk of getting HIV goes down, people may think less carefully and act more dangerously.

A study from Germany found that HIV PrEP did not change the rate of syphilis among MSM. This means that worries about risk compensation should not stop men who are behaviorally likely to get HIV from using PrEP. Additional research is needed to find out how HIV PrEP affects the number of cases of syphilis in different areas or countries. Using combination prevention methods or making a syphilis-specific PrEP is very important.

An additional successful way to stop the source of infection is through treatment as prevention (TasP). Being HIV-positive means taking HIV medications to prevent the sexual spread of HIV. Higher than normal numbers of babies born to women with syphilis also have Neurosyphilis. Prenatal treatment with at least 2.4 MU penicillin given at least 28 days before delivery has been shown to greatly lower the chance of congenital syphilis in people who already have syphilis. According to a case-control study, treating Neurosyphilis is still hard, even though penicillin is used to treat most pregnant women with syphilis. This is because sexual partners aren’t treated properly. Unfortunately, Neurosyphilis is still hard to handle and control effectively.

Discussion

Neurosyphilis forms part of the later stage of syphilis and is restricted to people who have syphilis and have an undesirable prognosis involving the central nervous system. Even though Neurosyphilis has been studied for hundreds of years, many things are still unknown. More observational studies need to be done right away, and national or regional monitoring systems should be thought about as well to make up for the lack of epidemiological studies on Neurosyphilis. Recent research, as we have talked about, shows that Neurosyphilis, the immune system, and genetics are all linked. However, these methods need time to be put into practice in clinical settings. Along with studying T. pallidum itself, it is important to also look at how pathogens and hosts interact with each other, especially pathogens that are good at invading neurons and hosts that are easily infected.