Syphilis is caused by the spirochete Treponema pallidum. The primary and secondary stages affect skin and mucous membranes. If left untreated, the pathogen invades the CNS, resulting in neurosyphilis. 1 Neurosyphilis can develop at any stage following the initial infection and is usually the result of untreated or inadequately treated syphilis. Although early neuroinvasion by T. pallidum is common, clinical symptoms appear only when spirochetes persist in the CNS.2 Neurosyphilis comprises a spectrum of clinical presentations, ranging from asymptomatic cases to life-threatening conditions, and warrants early recognition and treatment to avoid permanent neurological damage. 3

Between 1990 and 2019, the number of people infected with syphilis increased by 60% worldwide, leading to approximately 50 million infections in 2019.4 According to the World Health Organization (WHO), there were roughly 7.1 million new cases of syphilis worldwide in 2020. 5 Syphilis rates have decreased with the advent of penicillin, but both positive and negative trends have been observed in recent decades, especially among men who have sex with men (MSM) and HIV-positive populations. 1 MSM suffer syphilis rates 15 to 20 times greater than other men, and about half of them are HIV co-infected. Approximately one-third of patients with syphilis develop neurosyphilis before antibiotic use. 6 It is now more common in people with HIV, especially in those with low CD4+ counts or a detectable viral load. 7 Three to five percent of syphilis cases in the United States develop neurological, ocular, or auditory complications, and the estimated rate of neurosyphilis is 0.47 to 2.1 per 100,000 individuals. 8 HIV is a major co-founder that tremendously increases the risk of developing neurosyphilis. Neurosyphilis is two times more common in men than in women and 2-3 times more common in Whites than Blacks, despite higher absolute rates of syphilis in blacks. 7, 9 The United States has seen an increase in primary and secondary syphilis since 2000, consistent with global trends. Whereas in Nagaland, India, syphilis prevalence among female sex workers was found to be 21.1%, with 11.7% of them also testing positive for HIV. 10

Although years may pass before neurological symptoms can be observed, Treponema pallidum enters the central nervous system (CNS) very early in syphilis. Pathogenesis directly affects the invasiveness of bacteria and the host immune response. 11 Although the majority of people can clear bacteria without any symptoms, for some, a chronic infection can persist and result in neurosyphilis, causing inflammation and neurological damage. 12 Neurosyphilis may present either early or late. Early neurosyphilis affects the meninges and blood vessels, causing diseases such as meningitis and stroke-like symptoms. In contrast, late neurosyphilis is typically characterized by inflammation associated with neuroinflammation and neurodegeneration in both the brain and the spinal cord. 3 Treponema pallidum enters the body from small abrasions in either the skin or other mucosal surfaces and can result in blood vessel damage and inflammation. 11, 13 Early invasion of the CNS has been shown by research, and T. pallidum has been identified in the CSF of approximately 30% of patients with early syphilis. Others can clear the bacteria without any symptoms, but if unable to do so, they may develop neurosyphilis. 14

Diagnosing neurosyphilis is complex because of its varied presentations and the limitations of available tests. A comprehensive evaluation considers the medical features, symptoms, patient history, imaging studies, serological tests, and cerebrospinal fluid (CSF) analysis.

Central nervous system (CNS) involvement can occur at any stage of syphilis. CSF abnormalities are often detected early in syphilis, even in the absence of clinical neurological symptoms. If neurological issues such as cognitive dysfunction, deficits, or signs of meningitis are present, CSF examination should be performed before starting treatment. 2, 3

The prognosis for neurosyphilis depends on the timing of diagnosis and treatment. Early detection and effective treatment can prevent major neurological damage and often result in a full recovery. However, in late-stage neurosyphilis, especially in cases involving general paresis or Tabes dorsalis, some neurological damage may be irreversible. 28

Neurosyphilis poses considerable challenges in diagnosis and treatment, owing to its diverse clinical presentations and complications from HIV co-infection. Overlapping symptoms with other CNS disorders can result in misdiagnosis or delayed diagnosis, thereby increasing the risk of lasting neurological damage.3, 29 The increasing rate of syphilis, especially among men who have sex with men (MSM) and individuals living with HIV (PLWH), highlights the importance of focused screening. If left untreated, neurosyphilis can cause serious complications, with increasing cases noted in younger patients with ischemic stroke. However, care must be taken to prevent stigmatization, which can deter individuals from seeking treatment. 30 Although managing neurosyphilis is more challenging with HIV coinfection, patient outcomes are typically comparable to those without HIV infection. Treating neurosyphilis is challenging because of the absence of in vitro cultures for Treponema pallidum, frequent false negatives and positives in diagnostic tests, and limited options for patients allergic to penicillin or ceftriaxone. 31 The serofast phenomenon complicates follow-up and lumbar punctures carry inherent risks. Delays in treatment are common because many patients are unaware of early syphilis symptoms. 1 Effective management involves balancing public education, partner notification, and screening efforts while reducing stigma. Although prophylactic treatment for partners is not recommended, serological testing is essential to assess the transmission risk. 32 Future research should focus on improving the diagnostic tools, identifying specific biomarkers for early neurosyphilis, and developing tailored treatment standards and prevention strategies for MSM and PLWH. 33

Neurosyphilis poses major challenges, especially among men who have sex with men (MSM) and those living with HIV (PLWH). Key issues include misdiagnosis and treatment delays, underscoring the importance of targeted screening and public health efforts to raise awareness and reduce stigma. Accurate diagnosis of neurosyphilis relies on thorough clinical evaluation and cerebrospinal fluid analysis, with penicillin as the standard treatment. However, challenges such as penicillin allergies and the serofast phenomenon necessitate alternative approaches and careful follow-ups. Future research should focus on the development of more sensitive diagnostic tools and innovative treatment methods tailored to at-risk populations. A comprehensive approach could improve the outcomes for individuals affected by this re-emerging disease.