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Continuing Education Activity

With the advent of antibiotics, neurosyphilis became a rare diagnosis. However, syphilis has recently made a resurgence because untreated neurosyphilis causes potentially irreversible sequela. Interprofessional team members must consider it in their differential diagnosis for a wide variety of presentations. This will allow for proper diagnosis and treatment and thus improve patient outcomes. This activity explains when neurosyphilis should be in the differential diagnosis and describes the epidemiology, disease manifestations, evaluation, and management of neurosyphilis. Further, this activity reviews the role of the interprofessional team in caring for patients with this condition.


  • Review the etiology and of neurosyphilis.
  • Describe the history and physical findings suggestive of neurosyphilis.
  • Explain the importance of proper evaluation and treatment of neurosyphilis.
  • Outline the importance of a well-coordinated, effective interprofessional team approach in caring for patients affected by neurosyphilis.


Syphilis is an infectious disease caused by the spirochete bacteria Treponema pallidum subspecies pallidum (T. pallidum). It has been called the "great imitator" due to the multitude of symptoms it produces. The diagnosis becomes further muddled by periods of active disease and latency. The term neurosyphilis refers to an infection involving the central nervous system (CNS) and, unlike primary, secondary, and tertiary syphilis can occur at any time after infection. Studies on rabbits have shown that within hours of initial infection, treponemes may be present in the cerebral spinal fluid (CSF). Additionally, the belief is that bacterial neuroinvasion occurs in all patients, and it is a failure of clearance, which results in the condition.[1][2] Five types of neurosyphilis exist, which range from the early forms consisting of asymptomatic, meningeal, and meningovascular or the late forms of general paresis and tabes dorsalis. The latter generally occurs years or decades after initial inoculation.


T. pallidum is a bacterial spirochete that spreads systemically within minutes of infection. It results in syphilis, which is predominantly a venereal disease, but vertical transmission can also occur, and more rarely, blood transfusion-associated transmission can be seen. Infection occurs via penetration of the spirochete through mucosal membranes as well as epithelial breaks in the skin. Unprotected sex is a major risk factor for the transmission of infection, especially in men who have sex with men (MSM), accounting for approximately 80% of cases in the United States. The penetration of the CNS is thought to happen in most (if not all) individuals. Therefore, neurosyphilis can potentially occur in any patient.[3][4]


With the advent of penicillin, rates of syphilis reached a nadir at the end of the 20th century but since then have steadily climbed, particularly in the MSM population. Although syphilis is a reportable condition, rates of neurosyphilis in the United States are not known partially due to surveillance definitions requiring data that is often unavailable. Before the advent of antibiotics, neurosyphilis was prevalent and occurred in up to 25 to 35 percent of patients with syphilis. Now, it more generally presents in patients with human immunodeficiency virus (HIV), particularly in those who are either untreated, have low CD4+ counts, or detectable HIV RNA levels. Even so, the early forms of neurosyphilis are more frequent than the late forms. High-risk sexual behavior makes individuals vulnerable to syphilis as well as HIV. Thus neurosyphilis is more prevalent among individuals who are also at high risk for HIV, such as MSM.[2][5][6]

The risk of neurosyphilis is 2-3 times more in whites than in blacks and is 2 times more common in men than in women.

In some parts of Africa, the incidence may be approximately 2300 cases per 100,000 population.[7]


As previously mentioned, CNS infection occurs in the majority if not all of the patients with syphilis; however, spontaneous resolution can occur without an inflammatory response. Alternatively, transient or persistent meningitis can occur; in the latter case, they are deemed to have developed neurosyphilis. Neurosyphilis may be asymptomatic or present in an early symptomatic phase, but eventually, if allowed to go untreated, a late symptomatic disease may ensue that is discussed further under history and physical.[4][8]

Treponema pallidum gains access to the body through tiny abrasions of the skin and mucous membranes. Subsequently, mucopolysacharidase helps with its attachment to the host cells causing obliterative endarteritis and necrotic changes in the terminal arterioles.

History and Physical

This article will focus on the manifestations of neurosyphilis; however, patients will likely have a history of syphilis and its associated symptoms, which is discussed in StatPearls - Syphilis.

Neurosyphilis exists in five forms, which may be further classified as early and late neurosyphilis.

Early Neurosyphilis

Asymptomatic Neurosyphilis (ANS)

  • It is the most common form and occurs before symptomatic syphilis develops.
  • Patients are unaware that they are affected and have no signs of neurological disease.
  • It is defined by the presence of CSF abnormalities in a patient with serological evidence of syphilis but no neurological symptoms.
  • Prior to penicillin, the diagnosis of ANS was significant in predicting the prognosis and outcomes of patients regarding the neurological sequelae of syphilis.


  • This results from diffuse inflammation of the meninges.
  • Typical meningeal symptoms include headache, nausea, vomiting, neck stiffness, photophobia, cranial nerve deficits, and possibly seizures.


  • This is defined as the inflammation of the meninges, as well as endarteritis causing thrombosis and infarction of cerebral tissue.
  • Early symptoms are nonspecific and include headache, nausea, vomiting, and vertigo.
  • It causes cerebral vascular syndrome, and the symptoms depend on the site of thrombosis and the corresponding cerebral functions.
  • Spinal cord vessels may also be affected, resulting in meningomyelitis and spastic weakness (particularly in the lower extremities), sensory loss, and muscular atrophy.

Late Neurosyphilis (Parenchymal)

General Paresis (general paralysis of the insane, paralytic dementia)

  • It is due to chronic meningoencephalitis resulting in cerebral atrophy.
  • Symptoms of paretic neurosyphilis can be further divided into early and late symptoms and can occur insidiously or suddenly.
  • Early symptoms include mood disturbances such as irritability, personality changes, changes in sleep habits, and forgetfulness.
  • Late symptoms include labile mood, memory and judgment impairment, confusion, delusions, and seizures.
  • Psychiatric disease including depression, delirium, mania, and psychosis can also result.
  • Neurologically the clinician may see pupillary abnormalities, dysarthria, and tremors.

Tabes Dorsalis

  • It results from the degeneration of the posterior (dorsal) column and roots of the spinal cord.
  • Classically patients have ataxia, lightning (lancinating) pains, bladder dysfunction, paresthesias, and vision changes
  • Additional neurologic deficits include pupillary abnormalities (Argyll Robertson pupils), ocular palsies, diminished reflexes, vibratory and proprioceptive impairments, ocular palsies, and Charcot joints.[2][9][10]


Suspicion of syphilis infection should be confirmed before or considered in conjunction with the diagnosis of neurosyphilis; syphilis is further discussed in StatPearls - Syphilis.

Diagnosis of neurosyphilis remains a challenge due to no existing standardized testing, but it is rather made on a combination of clinical and CSF analysis findings. The Center for Disease Control (CDC) states that in primary and secondary syphilis, patients often have CSF abnormalities. Thus CSF analysis is not recommended if patients are without neurological symptoms. Patients diagnosed with tertiary syphilis should, however, undergo CSF analysis before treatment and should receive a neurosyphilis regime if abnormal. In most cases, a normal CSF excludes neurosyphilis.[2]

  • CSF VDRL - Highly specific and is generally accepted as the diagnostic test of neurosyphilis. CSF rapid plasma reagin (RPR) is not a recommended test due to lower sensitivity.
  • CSF treponemal tests (FTA-ABS) - Highly sensitive; however, it is nonspecific and thus more useful to rule out neurosyphilis when the pretest probability is moderate to low.
  • CSF pleocytosis (defined as greater than five cells/mL) - The diagnosis of neurosyphilis usually needs a CSF white blood cell (WBC) count of 20 cells/microliter or more. This is sensitive but is nonspecific as both infectious and noninfectious causes can result in increased cell count. Interpretation of pleocytosis is further confounded in patients with HIV who may have pleocytosis regardless of the presence of neurosyphilis, particularly if they are not on antiretroviral therapy.
  • CSF protein - may aid in the diagnosis, but their presence is neither sensitive nor specific in the diagnosis.[2][6]

Neuroimaging can be helpful in the diagnosis and management, but findings are generally nonspecific. The most common findings are frontal and temporoparietal atrophy. Nonspecific white matter lesions are found in patients with tabes dorsalis and changes consistent with infarction are usually encountered in patients with meningovascular disease.[2][5]

Reverse sequence screening is an increasingly used algorithm across US laboratories that use treponemal tests as the initial screening to identify those patients with treated, untreated, or incompletely treated syphilis.[11] Because of a lack of validation of the reverse algorithm, higher rates of false-positive results can be seen, leading to difficulty in interpreting these tests, and the need for second confirmatory treponemal tests.

Novel biomarkers are being studied such as beta-2 microglobulin. Its presence may help in the diagnosis of CNS involvement and may aid in monitoring the response to therapy.

As neurosyphilis is a rare diagnosis in the post-penicillin era, much of the evidence level of diagnosis and treatment pertains to syphilis. In screening tests, T. pallidum enzyme immunoassay (EIA) may be necessary for those that are low risk for ruling out the possibility of syphilis (Evidence level IIb). If EIA is positive before the initiation of therapy, additional and confirmatory serological tests such as VDRL/RPR should be performed (Evidence level IV).[12]

In terms of treatment, guidelines from the CDC recommend parenteral penicillin G for all stages of syphilis as it has long been effective and is also the mainstay treatment of neurosyphilis (Evidence level III).[4] After commencing treatment, tests of cure via VDRL/RPR are recommended in all patients (Evidence level III). This follow-up should be performed monthly for three months, and at 6 and 12 months for early syphilis. For patients with late syphilis, this should take place every six months until negative (Evidence level IV). Due to the strong association with HIV, patients that are HIV-positive should have repeat testing yearly (Evidence level IV). Regarding neurosyphilis, CSF studies should be tested every six months until negative (Evidence level IV).[12]

Treatment / Management

Patients with neurosyphilis should be admitted for the initiation of antibiotics as they would require inpatient treatment.

Treatment of neurosyphilis currently includes two regimens recommended by the CDC.

  • Penicillin G 3 to 4 million units is given intravenously every 4 hours for 10 to 14 days, or Penicillin G 24 million units as a continuous infusion for 10 to 14 days
  • Procaine penicillin G 2.4 million units intramuscularly daily plus probenecid 500mg PO four times a day for 10 to 14 days

Both are options after penicillin desensitization in those with a penicillin allergy.

Ceftriaxone is another therapeutic option with the regimen being 2g IV or IM daily for 10 to 14 days.[2][6]

Patients with a high titer of secondary syphilis can develop Jarisch-Herxheimer reaction, which is an immune-mediated self-limited reaction that occurs within 2 to 24 hours of treatment and is characterized by high fever, headache, myalgias, and rash.

Patients need to be followed post-treatment at 3, 6, 9, 12, and 24 months with serial non-treponemal tests. A 4-fold decline in these tests indicates successful treatment.[13]

The CDC recommends a follow-up CSF exam every six months until the abnormalities resolve; if CSF continues to be abnormal after two years, retreatment should be considered.

Differential Diagnosis

Since it is often called the "great imitator," the differential for neurosyphilis is broad; however, the following are important considerations:[5]

  • Brain tumors/abscess - if gummata are found on neuroimaging
  • Acute basal meningitis - when cranial nerves palsy is present other causes of acute meningitis, such as tubercular, should be considered
  • Subarachnoid hemorrhage
  • Herpes encephalitis
  • Electrolyte disturbances
  • Subacute combined degeneration of cord - tabes dorsalis presents in a similar fashion
  • Drug toxicity
  • Multiple sclerosis
  • Wernicke encephalopathy
  • Acute psychiatric illnesses - when a patient of general paresis presents with delirium, mania, psychosis, personality change, or depression.

Toxicity and Adverse Effect Management

The Jarisch-Herxheimer reaction is the primary side effect of treatment. It is due to the release of endotoxin from the lysing spirochetes and characteristically presents as fevers, chills, myalgias, tachycardia, headache, and vasodilation with resultant flushing and/or mild hypotension. The reaction usually occurs in the first 2 to 6 hours of antibiotic administration and resolves within 12 to 24 hours. Management is symptomatic with acetaminophen as the preferred agent.[5]


According to the Nation Institute of Health, the prognosis of patients presenting with neurosyphilis is mostly dependent on the type of neurosyphilis and early detection of the disease. Patients who present with asymptomatic or meningeal neurosyphilis generally return to normal health if treated adequately. Patients with meningovascular disease, general paresis, or tabes dorsalis may improve but usually do not return to their health or functional baseline. Furthermore, patients who are treated years after initial infection tend to have more poor prognoses.[14]


While neurosyphilis itself is a complication of syphilis, untreated neurosyphilis can result in devastating neurological sequelae, including permanent paralysis, dementia, and death. Treatment should be initiated immediately as some complications may be reversible, and the success of therapy has an inverse relationship to the duration of the untreated infection.[9]


Most patients, in whom the diagnosis of neurosyphilis is made or considered, should receive an infectious disease and neurology consult. These specialties may guide further work-up, management, and monitor response to therapy.

Deterrence and Patient Education

Patients diagnosed with syphilis should receive counsel regarding disease transmission and risk reduction via safe sex practices. Pregnant patients should also have counseling on the possibility of vertical transmission. All patients should receive education on the signs and symptoms of neurosyphilis. Patients under therapy for syphilis should be informed about the need for repeat titers as a test of cure; patients who are treated for syphilis and fail to achieve a four-fold decline in non-treponemal titers within 6 to 12 months may have unrecognized neurosyphilis necessitating further work-up and more aggressive treatment. All patients diagnosed with neurosyphilis should also undergo testing for HIV. Providers should inform patients who are undergoing treatment of the Jarisch-Herxheimer reaction as a potential occurrence.[9]

Pearls and Other Issues

Neurosyphilis is a complication of syphilis that can occur at any time post-exposure with syphilis. With the advent of penicillin, it had reached a nadir until the 2000s when it saw a resurgence, particularly in those with high-risk behavior including the MSM and HIV population. It can be asymptomatic or it may result in a range of diseases which include meningeal, meningovascular, general paresis, and tabes dorsalis. Confirmation is via history and CSF studies. Penicillin is the mainstay of treatment, and confirmatory CSF studies should be performed every six months until resolution. The Jarisch-Herxheimer reaction is an expected response and treatment is supportive with acetaminophen.

Enhancing Healthcare Team Outcomes

In the diagnosis and treatment of neurosyphilis, interprofessional team communication between providers may expedite the treatment process. Communication between the consulting provider, and specialties including infectious disease, and neurology, as well as laboratory technicians and pharmacists, helps guide the management of a patient with suspected or confirmed neurosyphilis. It is critical to arrange appropriate follow-up with patients being treated for syphilis/neurosyphilis to confirm complete resolution, which includes the reversal of symptoms and prevention of permanent disability.

For the best outcomes, neurosyphilis is best addressed via an interprofessional team approach that includes primary care clinicians, infectious disease specialists, a neurologist when appropriate, pharmacists, and nurses, particularly those with specialty training in infection control. [Level 5]

Article Details

Article Author

Tuan Ha

Article Author

Prasanna Tadi

Article Editor:

Laurence Dubensky


2/19/2023 10:50:46 PM



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