Calculators, Algorithms, Drug Interaction CheckersTools
Back To Search Results

Neurosyphilis

Author: Tuan Ha Author: Prasanna Tadi Author: Stephen W. Leslie Editor: Laurence Dubensky Updated: 4/21/2024 5:42:56 PM

Introduction

Syphilis is an infectious disease caused by the spirochete bacteria Treponema 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). Unlike primary, secondary, and tertiary syphilis, neurosyphilis can occur at any time after infection. Studies have shown that T pallidum may be present in the cerebral spinal fluid (CSF) within hours of initial infection. Bacterial neuroinvasion occurs early in all infected patients, and a failure of clearance results in the clinical manifestations of neurosyphilis.[1][2] 

Five types of neurosyphilis exist, which range from the early forms—consisting of asymptomatic and meningeal (presenting <1 year from infection)—to meningovascular (presenting at 5 to 12 years)—to the late or tertiary forms—general syphilitic paresis and tabes dorsalis (presenting at >10 years from infection). The latter can occur decades after the initial inoculation. Ocular and auditory symptoms may also occur at any stage of infection and are considered forms of neurosyphilis.

Etiology

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Etiology

T pallidum is a gram-negative bacterial spirochete that spreads systemically within minutes of the initial infection. It results in syphilis, which is predominantly a venereal disease, but vertical transmission through pregnancy can also occur, and more rarely, blood transfusion-associated infections can be seen.

Infection occurs via penetration of the spirochete through mucosal membranes and 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) and those infected with HIV.[3][4][5][6][7][8] The penetration of the CNS by T pallidum happens in most (if not all) individuals very quickly, and while it can develop in any infected patient, most will never develop clinical or symptomatic neurosyphilis.[9][10][11] Natural eradication of T pallidum from the CSF is most likely due to enhanced macrophage and helper T cells type 1 cellular immunity activity.[12]

Early treponemal invasion of the CSF has been documented in up to 40% of all patients diagnosed with primary syphilis, 23% with secondary syphilis, and 20% with latent disease.[13][14][15][16][17][18] Prior to the introduction of antibiotics, asymptomatic neurosyphilis was present in 25% to 35% of all patients with early syphilis and in 13.5% of those with tertiary (late) disease.[13] 

Epidemiology

Worldwide, the global incidence of syphilis increased by 60% from 1990 to 2019, according to the Global Burden of Disease Study, with a worldwide incidence of about 50 million infected individuals in 2019.[19] With the advent of penicillin, rates of syphilis reached a historic nadir at the end of the 20th century, but since then, rates have steadily climbed, particularly in the MSM and HIV-positive population. The rate of syphilis among MSM individuals is 15 to 20 times greater than the general male population.[20] MSM represent over 80% of all the new diagnoses of syphilis reported in men in the US. According to the Centers for Disease Control (CDC), almost 50% of MSM individuals with known primary or secondary syphilis are also HIV positive.[3] Although syphilis is a reportable condition, rates of neurosyphilis in the United States are not known partially due to data that is often unavailable.

Before the advent of antibiotics, neurosyphilis was found in about a third of all patients with syphilis. Now, it generally presents in patients with HIV, particularly in those who are either untreated, have low CD4+ counts, or carry detectable HIV RNA levels.[21][22][23][24] Even so, the early forms of neurosyphilis are more common than the late manifestations. High-risk sexual behavior makes individuals vulnerable to HIV as well as syphilis. Thus, neurosyphilis is more prevalent among individuals who are also at high risk for HIV.[2][14][21][25] Those syphilis patients who are initially negative for HIV are more likely to become HIV positive going forward as the behavioral risk factors for the 2 infections are the same.[3] 

The risk of neurosyphilis is about 2 to 3 times higher in Whites than Blacks, even though Blacks have a 5-fold greater incidence of other forms of syphilis. Neurosyphilis is twice as common in men than in women. It is estimated that neurological, ocular, or auditory complications will develop in 3% to 5% of all individuals infected with syphilis in the US.[13]

Pathophysiology

CNS infection with T pallidum occurs in the majority, if not all, of the patients with syphilis; however, spontaneous resolution often occurs without an inflammatory response or clinical symptoms. 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 untreated, a late symptomatic disease may ensue.[11][26]

T pallidum gains access to the body through tiny abrasions of the skin and mucous membranes. Subsequently, mucopolysaccharidase helps it attach to the host cells, causing obliterative endarteritis and necrotic changes in the terminal arterioles. The general neuropathological process involves the development of an inflammatory infiltrate composed primarily of lymphocytes and plasma cells that ultimately cause nerve cell damage and even neuronal death.[27] Demyelination may also occur, as in tabes dorsalis, where this process involves the dorsal roots and posterior spinal columns.[28]

Histopathology

Gross pathology shows atrophy of the frontal and temporal lobes with sparing of the sensorimotor and occipital cortexes, and the lateral ventricles become dilated. Chronic meningitis is most pronounced over the atrophic areas. Microscopically, spirochetes are found in the grey matter, endothelial cells, and microglial cells. White matter is free of spirochetes.[2]

Microscopically, perivascular infiltration of plasma cells and lymphocytes with nerve loss is seen. In the presence of vasculitis, endothelial swelling progressing to endarteritis obliterans can be visualized. Tabes dorsalis will show dorsal root and posterior spinal column demyelination.[13]

History and Physical

This review will focus on the manifestations of neurosyphilis; however, patients will likely have a history of syphilis and its associated symptoms. See StatPearls' companion reference, "Syphilis," for more information.[29]

Symptoms of neurosyphilis in decreasing order of frequency include the following: personality changes, dementia, cognitive decline, or behavioral defects (33%); ataxia with gait disturbances, loss of coordination and balance (28%); stroke (23%); visual abnormalities (17%); urinary symptoms such as incontinence (17%); stabbing or lancinating pains (10%); headache (10%); dizziness or vertigo (10%); hearing loss (10%); and seizures (7%). Possible signs of neurosyphilis include hyporeflexia (50%), impaired sensorium with decreased proprioception (48%), optic changes such as Argyll Robertson pupils (43%), central or cranial neuropathy (36%), dementia or paranoia (35%), positive Romberg test (24%), Charcot joint (13%), hypotonia (10%), and optic atrophy (7%).

Neurosyphilis is a destructive, progressive disease affecting the CNS in many ways, including neuropsychiatric disorders.[30][31][32][33][34][35] In fact, psychological changes are often the initial identifiable symptom of neurosyphilis.[30][31][32][33][34][35] These can develop at any stage of syphilis infection but are typically described as 1 of 5 forms broadly classified as early or late neurosyphilis. Recently, atypical, ocular, and auditory syphilis have been added as neurosyphilis categories.

Among all patients with untreated syphilis before the introduction of antibiotics who developed neurosyphilis, about one-third would be asymptomatic, another third would have tabes dorsalis, and about 10% would demonstrate either syphilitic paresis (general paresis of the insane) or meningovascular neurosyphilis. Tertiary neurosyphilis (tabes dorsalis, syphilitic paresis, and Charcot spine disease) is now quite rare, especially in developed nations, which is thought to be at least partly due to widespread and extensive antibiotic use for unrelated infections.[36][37]

Asymptomatic Neurosyphilis (Early Stage)

Asymptomatic neurosyphilis is the most common type of the disorder and may occur before any other symptoms of syphilis become apparent. It can be found in a third of all neurosyphilis patients.[2] Even though asymptomatic, treatment for neurosyphilis is indicated to prevent progression and the possible development of future neurological symptoms. The key diagnostic points of early asymptomatic neurosyphilis are the lack of neurological symptoms and the CSF examination demonstrating a positive nontreponemal VDRL test serology. Patients may or may not show evidence of primary or secondary syphilis. 

In general, for patients without HIV, a CSF with between 5 and 100 WBCs/microL or a protein level between 45 and 100 mg/dL is most consistent with a diagnosis of neurosyphilis.[13][38][39] The greater the degree of CSF abnormalities, the more likely the development of symptomatic neurosyphilis later. Care should be taken to avoid a traumatic spinal tap, as serologic contamination may occur and give a false-positive result. An FTA-ABS test on the CSF would be sensitive but not specific for asymptomatic neurosyphilis, but a negative assay would be strong evidence against a diagnosis of neurosyphilis.[40]

While the CDC does not recommend a CSF examination before neurological symptoms develop, this would preclude diagnosing most asymptomatic patients with early neurosyphilis, so some exceptions have been suggested. (See Indications to Perform a Lumbar Punction below under the Evaluation section.) 

Meningeal Neurosyphilis (Early Stage)

Early neurosyphilis typically affects the vasculature and meninges. The CSF is almost always positive for the nontreponemal Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR) testing, as well as treponemal antibody assays in early neurosyphilis.[41] Meningeal neurosyphilis usually manifests within a year of the initial infection, although it may not become apparent for several years. Cranial nerves may be affected, most often VII, followed by VIII, VI, and II. The spinal cord is not commonly affected, but when involved, symptoms include sensory loss, back pain, muscle hypotonia, weakness of the lower extremities, and incontinence.[13]

Typical symptoms include headache, confusion, nausea, vomiting, neck stiffness, photophobia, cranial nerve deficits, seizures, and possibly hydrocephalus.[13] Syphilitic gummas may also be present and would appear as localized areas or masses of intense inflammation associated with the meninges.[42] Meningeal neurosyphilis may also appear as acute meningitis with hydrocephalus. Symptoms may be self-limiting, but if untreated, the condition may relapse into a more severe form of neurosyphilis.

Imaging will tend to show diffuse or localized enhancement with contrast enhancement in the leptomeninges from inflammation.[43] Other findings may include inflammatory exudates and perivascular lymphocytic infiltrates in and around the meninges, with possible cranial nerve enhancement.[43][44][45][46][47][48]

CSF abnormalities are more significant than asymptomatic neurosyphilis (CSF usually shows 200-400 WBCs/microL or protein 100-200 mg/dL), and the CSF VDRL is almost always positive.

Meningovascular Neurosyphilis (Intermediate Stage)

Meningovascular syphilis is defined as meningeal inflammation with endarteritis that predisposes the patient to early strokes and cerebrovascular pathology. It typically presents between 5 and 12 years (average 7 years) after the initial infection and accounts for 10% to 15% of all neurosyphilis cases.[13][43][49] Any vessel in the subarachnoid space can be affected. The pathophysiology is perivascular inflammation resulting in intimal thickening from increased fibroblast activity, adventitial fibrosis, inflammatory changes, and infiltration of the affected vasculature with plasma cells and lymphocytes. The net result is the narrowing of the vascular lumen, predisposing the patient to ischemia, thrombosis, and infarctions. Symptoms depend on the site and severity of the vascular compromise and the cerebral areas affected.[49] Obstructive hydrocephalus can also cause neurologic symptoms and mental status changes.[50]

The most common presenting symptom is a stroke in a younger adult, with the middle cerebral artery being the most likely vessel affected.[51][52][53] As such, any younger patient with an unexplained stroke should be tested for neurosyphilis.[51][52][53][54][55][56] Associated symptoms that may precede the stroke include headaches, dizziness, vertigo, insomnia, and psychological changes (eg, mood swings, memory issues, subtle personality changes). These prodromal symptoms are most likely due to associated meningeal inflammation. Spinal cord vessels may also be affected, which would cause meningomyelitis and spastic weakness (particularly in the lower extremities), along with sensory loss and muscular atrophy. 

CSF abnormalities are intermediate (between asymptomatic and meningeal neurosyphilis) at 10 to 100 WBCs/microL and protein levels of 100 to 200 mg/dL. The CSF VDRL is usually positive.

Meningeal enhancement described as patchy or thin may be seen on MRI along with evidence of infarcts and arterial irregularities (basilar and anterior, middle, or posterior cerebral arteries).[57][58][59] Angiographic imaging will demonstrate arterial narrowing of the affected vessels or even total occlusion with areas of cerebral infarction. Concentric vessel wall thickening may be visible on intracranial MRI with gadolinium contrast enhancement.[43] 

Parenchymal Neurosyphilis (Late Stage)

Syphilitic paresis (general paralysis of the insane, paralytic dementia, general paresis)

Syphilitic paresis is now a rare presentation of neurosyphilis. It typically presents initially as a slowly progressive dementia with memory issues, unexplained personality changes, or a similar psychiatric disorder that appears most often 15 to 20 years after the initial infection but may occur even later.[13] It is actually a progressive, chronic meningoencephalitis affecting the frontotemporal lobes. The chronic inflammation results in meningeal fibrosis, small cerebral parenchymal plaques in the frontal and parietal cortices, and cortical atrophy with loss of cerebral function. The cumulative effect of strokes can also contribute to dementia.[60][61][50]

Patients should be appropriately screened for syphilis and neurosyphilis when neuropsychiatric symptoms occur, including progressive dementia, personality changes, forgetfulness, hallucinations, depression, confusion, mania, delirium, psychosis, delusions, or amnesia.[62][63][50][64][65][66] 

Syphilitic paresis is more likely to be associated with agitation and cognitive impairment and less likely to present as delusions and hallucinations.[65] Associated findings may include hypotonia of the face and extremities, abnormal reflexes, and tremors. Late manifestations include tremors, dysarthria, hyperreflexia, myoclonic jerking, significant muscular deterioration, and seizures. In the terminal stage, the patient is typically bedridden, severely disoriented, cachectic, and status epilepticus may be present. Syphilitic paresis is most commonly found in men living in underdeveloped regions where syphilis is prevalent. It will eventually affect about 7% of all untreated individuals worldwide infected with syphilis.[63]

Paresis from causes other than late neurosyphilis generally will not have positive serologic and CSF tests for syphilis and will not demonstrate Argyll Robertson pupils.[62][63][50][64][65][67] Argyll Robertson pupils are characteristic of tertiary or late-stage syphilis and describe small bilateral pupils that constrict when focusing on a close object but sluggishly or not at all when exposed to bright light.[67] See StatPearls' companion reference, "Argyll Robertson Pupil," for more information.[67]

Compared to other psychiatric patients, individuals with syphilitic paresis are more likely to develop psychiatric symptoms at an older age, have no family history of mental health disorders, participate in high-risk sexual behavior, have 1 or more sexual partners who tested positive for STIs, and have a history of drug and alcohol abuse.[65] Abnormal serologic testing and neurologic deficits are key characteristics of syphilitic paresis, differentiating it from primary psychiatric disorders.[32][65] 

The lack of clinical awareness of neurosyphilis as a possible cause of psychiatric disorders frequently results in a delayed diagnosis and late initiation of proper treatment, which is unfortunate as many of these psychological illnesses can be reversed with appropriate antibiotic therapy.[32] It has been suggested that all psychiatric patients with risk factors be screened serologically for T pallidum and, if they test positive, then examined more closely for neurosyphilis.[63][65][68] Studies of patients initially diagnosed with general paresis due to psychiatric illnesses have found that around 38% actually had syphilitic paresis when properly evaluated.[65][69] 

MRI neuroimaging may show cerebral atrophy, ventricular enlargement, and amygdala, frontotemporal lobe, hippocampus, or periventricular region T2 hyperintensity.[13][43][59][70] Imaging may also demonstrate decreased T2 signal intensity in the thalamus, caudate head, putamen, and globus pallidus.[13][43][59][70]

CSF abnormalities typically include between 25 and 75 WBCs/L and protein levels between 50 and 100 mg/dL. The CSF VDRL is almost always positive.

Early cases of syphilitic paresis may recover with antibiotics, but recurrences are possible. Prior to the antibiotic era, syphilitic paresis was responsible for approximately 10% to 25% of all psychiatric hospital admissions and was terminal within 2.5 years.

Tabes Dorsalis (Syphilitic Myelitis)

Tabes dorsalis or syphilitic myelitis results from the functional destruction of the posterior dorsal columns and dorsal nerve roots. The pathology develops from the localized cellular response to the inflammatory infiltrate produced due to the T pallidum infection, resulting from cytokine release, reactive oxidative agents, and neuronal damage from direct bacterial nerve invasion.[71][72] The damage is most severe to the sensory nerves of the posterior spinal columns and dorsal nerve roots.

Typical symptoms will develop 20 to 25 years after treponemal inoculation and include an uncoordinated, unbalanced (ataxic) or stomping gait, sharp (lancinating or stabbing) pain, paresthesias, reduced reflexes, visceral crises (intermittent attacks of severe epigastric pain accompanied by nausea and vomiting), and loss of vibration and proprioception.[13][71][73][74][75] As it manifests in late neurosyphilis, the patient may also exhibit Argyll Robertson pupils and Charcot joints. Pupillary abnormalities are more commonly seen in tabes dorsalis than syphilitic paresis.

The Romberg test will typically be positive, indicating a loss of proprioception. The Romberg test is performed with the patient standing upright and their feet together. The room is darkened, or the patient is blindfolded. Removing visual cues and having the patient stand still leaves only proprioceptive sensation to maintain their balance. Patients with proprioceptive defects will demonstrate instability and a significant loss of balance, which would be a positive test.

MRI spinal imaging is often normal, but it may show evidence of spinal cord atrophy or demonstrate a typical "flip-flop sign" or candle-guttering.[76][77][78][79] Spinal cord atrophy demonstrated on imaging is suggestive of a worse prognosis.[79][80] Affected areas in the posterior columns may demonstrate increased signal intensity. 

Examination of the CSF may be normal in up to 25% of patients, and the CSF VDRL tests may be falsely negative. Only slightly elevated protein or WBC counts in the CSF may be found, typically up to 50 WBCs/microL and protein levels of 45 to 75 mg/dL. The CSF VDRL will be positive in at least 75% of patients with tabes dorsalis. Tibial nerve sensory evoked potentials may be slowed with the involvement of the dorsal roots, but nerve conduction studies are usually normal as motor function is usually not affected.[81]

See StatPearls' respective companion references regarding the "Romberg Test" and "Tabes Dorsalis" for more information.[71][82]

Charcot spine is a rare but severe spinal neuroarthropathy that develops in some patients with tabes dorsalis.[71] The condition is the pathological result of the loss of proprioception and deep sensation over time from dorsal spinal columnar damage caused by the syphilitic infection.[83] This results in a failure of the usual autonomous compensatory muscular activity that normally protects the spine, resulting in localized inflammation with effusions, inflammatory damage to spinal cartilage, discs, and ligaments, and vertebral microtrauma with microfractures.[83][84][85][86]

Over time, this causes progressive damage to the vertebra, spinal discs, ligaments, and associated ligaments, resulting in kyphosis, spinal deformities, loss of deep tendon reflexes, pain, paresthesias, sensory deprivation, spasticity, bladder and autonomic dysfunction, nerve root compression, and vertebral destruction.[83][84][85][86][87][88][89][90][91]

Diagnosing Charcot spine is difficult as the condition is quite rare, the presentation is very late, and the symptoms are nonspecific. Gas inside the disc space on CT imaging is a subtle but highly suggestive finding.[92] The condition has high morbidity, is quite severe, and is extremely debilitating.[83][91][93] 

Atypical neurosyphilis has also been described. This term refers to neurosyphilis cases that do not fit easily into the above standard classifications. The incidence of atypical neurosyphilis is unknown. Some neurosyphilis patients may develop symptoms suggestive of autoimmune, limbic, or herpetic encephalitis.[94][95][96][97] As a group, these patients are more likely to have seizures and tend to have acute changes in cognitive function. They may also present with a slow progression of symptoms. This "atypical" group likely represents an overlap of the standard classes of neurosyphilis. Diagnosis and treatment are the same as for other types of neurosyphilis.

Ocular syphilis is becoming an even more common finding as rates are increasing, especially in HIV-positive patients.[98][99][100][101][102][103][104][105] Any structure in the eye can be affected, but it is most often seen as a uveitis (anterior, posterior, or panuveitis) and may or may not be granulomatous.[98][103] It may also present as interstitial keratitis, retinal vasculitis, posterior placoid chorioretinitis, or optic neuropathy.[98][106] Edema or enlargement of the optic nerve sheath may be seen in some patients with ocular syphilis. A fixed pupil may sometimes be seen due to adhesions forming between the iris and the anterior lens, which should not be confused with an Argyll Robertson pupil.

Symptoms tend to be nonspecific but may include loss of visual acuity, eye pain, increased floaters, flashing lights, and photophobia.[13][98] Any unexplained uveitis should be considered suspicious for ocular syphilis and undergo a CSF examination if the diagnosis is confirmed, as 60% will be expected to show evidence of neurosyphilis.[106][107] The diagnosis is based on clinical findings and serological testing. The CDC suggests that patients with positive serum serology for syphilis who have only isolated visual symptoms with confirmed abnormal ocular pathology on examination may not need CSF testing as they should be treated for neurosyphilis regardless.

Patients mistakenly treated with steroids (either topically or systemically) may suffer an exacerbation of their ocular symptoms.[108] Ocular syphilis may also be associated with other types of neurosyphilis, typically syphilitic meningitis, and can present at any stage of the disease.[13][98]

Untreated, ocular syphilis can lead to blindness and should be treated as an emergency because the loss of vision can be rapidly progressive, especially if there is retinal involvement.[98][109] Ocular syphilis, as well as neurosyphilis in general, is more commonly seen in HIV-positive patients.[105] 

Treatment is with antibiotics (penicillin) using the more aggressive neurosyphilis dosing guidelines. See StatPearls' companion reference, "Syphilis Ocular Manifestations," for more information.[98] 

Otosyphilis (auditory syphilis) typically presents with sensorineural hearing loss, vertigo, dizziness, gait issues, loss of balance, and tinnitus.[13][15][110][111] The hearing loss may be unilateral or bilateral (50%) and can be rapidly progressive.[13][112] Hearing loss can be permanent in some patients, even with treatment. Like ocular syphilis, otosyphilis may present with syphilitic meningitis at any stage or phase of the infection.[110][112] The hearing loss in otosyphilis is usually sensorineural, although conductive hearing loss is also possible.[13]

The underlying etiology of the symptoms is often missed, and the condition is frequently misdiagnosed, leading to unacceptable delays in therapy.[113] Physicians should be suspicious of otosyphilis when patients in high-risk groups for syphilis present with unexplained auditory symptoms so appropriate and timely blood serological testing can be performed.[113] In over 90% of cases, the CSF will not show any evidence of neurosyphilis, so a lumbar puncture for examination of the cerebrospinal fluid is not recommended for isolated otosyphilis without additional symptoms of possible CNS involvement.[111] Older age at diagnosis and higher CSF WBCs indicate a worse prognosis and reduced likelihood of recovery from hearing loss in otosyphilis.[114] Treatment is with penicillin, according to the neurosyphilis dosing schedule.[112][113][115]

Neurosyphilis Classification Summary:

Early/Intermediate Neurosyphilis

  • Asymptomatic Neurosyphilis
    • The most common form of neurosyphilis.
    • Defined as suggestive CSF abnormalities in a patient with serological evidence of syphilis but no neurological symptoms.
    • Occurs before symptomatic syphilis or neurological signs develop.
    • Patients are unaware they are affected and have no signs or symptoms of neurological disease or defects.
  • Meningeal Neurosyphilis (presents <1 year)
    • Results from diffuse inflammation of the meninges.
    • Typical meningeal symptoms include headache, nausea, vomiting, neck stiffness, photophobia, cranial nerve deficits, and seizures.
    • Imaging may show enhancement of the meninges or select cranial nerves.
  • Meningovascular Neurosyphilis (presents at 5-12 years)
    • Defined as 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.
    • 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) (presents >10 years, sometimes decades after infection)

  • Syphilitic Paresis (general paralysis of the insane, paralytic dementia, general paresis)
    • Caused by chronic meningoencephalitis resulting in cerebral atrophy.
    • Symptoms can occur insidiously or suddenly and can be further divided into early and late.
    • Early symptoms include mood disturbances such as irritability, personality changes, alterations in sleep habits, and forgetfulness.
    • Late symptoms include labile mood, memory and judgment impairment, confusion, depression, agitation, psychosis, delusions, and seizures.
    • Neurologically, the clinician may see ophthalmic abnormalities, dysarthria, and tremors.
  • Tabes Dorsalis
    • Results from the degeneration of the posterior (dorsal) column and roots of the spinal cord.
    • Classically, patients have an unsteady gait, balance issues, lancinating or stabbing pains, bladder dysfunction, paresthesias, loss of proprioception, visceral crises, and visual changes.
    • Romberg test is positive.
    • Additional neurologic deficits include Argyll Robertson pupils, ocular palsies, diminished reflexes, vibratory and proprioceptive impairment, and Charcot joints.

Evaluation

Suspicion of a general syphilis infection should be confirmed before or considered in conjunction with the diagnosis of neurosyphilis. Generally, a positive treponemal and nontreponemal test is required for a serological diagnosis of syphilis, but nontreponemal tests tend to normalize over time and may be negative in late neurosyphilis.[29]

The diagnosis of neurosyphilis remains a challenge due to the lack of any existing definitive standardized testing. It is, therefore, based on a combination of clinical findings, symptoms, history, imaging, serological testing, and CSF analysis results.[106][115][116][117] Neurosyphilis patients with dementia and seizures will often respond favorably to antibiotic therapy, so early diagnosis and treatment are critical.

Neurosyphilis cannot be definitively diagnosed without a CSF examination, but it has been argued that this may not always be necessary if it will not affect treatment. For example, patients who refuse a lumbar puncture or where a CSF sample cannot be obtained should be considered for full neurosyphilis treatment regardless, arguing that it is better to overtreat some patients than inadequately treat others.

Early neurosyphilis will almost always demonstrate positive treponemal and nontreponemal tests in serum or CSF fluid.[118][119] Treponema testing includes fluorescent treponemal antibody absorption (FTA-ABS), T pallidum particle agglutination assay (TPPA), T pallidum hemagglutination assay (TPHA), and enzymatic immunoassays (EIAs). These tend to be highly sensitive but relatively nonspecific in the CSF (due to spillover from blood markers) and are usually positive for life, so they cannot be used for monitoring disease. They are unlikely to be negative in cases of neurosyphilis and can be used to rule it out.

Nontreponemal testing includes the Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests, which tend to decline over time; therefore, these can be used to track disease progression and response to therapy.[118][119] The CSF VDRL assay is considered the most suggestive single test for neurosyphilis if positive, with a reported sensitivity from 67% to 72%.[118][119][120][121]

The CDC states that in primary and secondary syphilis, patients often have CSF abnormalities. Thus, CSF analysis is not recommended by the CDC if patients are without neurological, visual, or auditory symptoms. However, some experts have questioned this statement and conclusion, arguing that just because no outcomes research has been published proving a benefit does not necessarily mean such a benefit does not exist.

Polymerase chain reaction (PCR) testing is very sensitive in detecting T pallidum from primary chancres and moist secondary lesions, but it is less reliable in testing the CSF for syphilis and is therefore not approved by the FDA for CSF testing.[39][106][122]

Indications to perform a lumbar puncture for CSF analysis in patients with syphilis include the following: 

  • Untreated syphilis of uncertain duration
  • Untreated or latent syphilis with a duration of 1 year or more
  • Patients with syphilis and neurological symptoms
  • Ocular syphilis (still recommended, although this requirement has recently been called into question)
  • Demonstrated complications of late or tertiary syphilis with or without neurological symptoms
  • Before starting treatment for tertiary syphilis, especially cardiovascular or gummatous
  • Lack of serological response to therapy (treatment failures) as indicated by not exhibiting a 75% decline in nontreponemal assays (VDRL, RPR) after 1 year (or 2 years if HIV positive)
  • A serum RPR level of 1:32 or more has been suggested as a reasonable threshold to use to suggest a lumbar puncture, especially if HIV positive, even in asymptomatic patients
  • A serum RPR level of 1:32 or more after treatment
  • Concomitant HIV infection. Some experts and European guidelines recommend a lumbar puncture for all patients with concomitant HIV infections, especially if they have any of the following:

Patients diagnosed with tertiary syphilis should undergo a CSF analysis before treatment and receive a neurosyphilis regime if abnormal. In most cases, a normal CSF examination excludes neurosyphilis.[2][118] However, HIV can also cause an increase in CSF protein levels and WBC counts, making the diagnosis of neurosyphilis more difficult.

The purpose of CSF testing is to differentiate intrathecally-produced antibodies from those that diffused into the CSF from the bloodstream.[13] Abnormalities may be found on CSF testing as follows:

  • CSF with positive VDRL: Highly specific and generally accepted as the most reliable single diagnostic test of neurosyphilis but not very sensitive.[127] The overall sensitivity of the CSF VDRL for neurosyphilis is only up to 72%.[120] CSF RPR testing is not recommended due to its lower sensitivity unless the VDRL test is unavailable.[118][119][127] A negative CSF-VDRL test does not rule out neurosyphilis, especially if a serum treponemal test is positive and there is clinical suspicion.[129] 
  • CSF with positive treponemal tests: Highly sensitive; however, they are nonspecific and tend to be positive for life.[129] Thus, they are more useful to rule out neurosyphilis when the pretest probability is low to moderate or the VDRL is negative.[40][129] These are the FTA-ABS, TPPA, TPHA, and EIA tests.
    • However, a TPPA titer cutoff of >1:640 in the CSF has been suggested as a realistic threshold level for diagnosing neurosyphilis in highly suspicious patients who are VDRL-negative, especially if a serum treponemal test is positive.[120][129][130]     
    • Due to passive blood-brain diffusion, it can give a false positive reading, which is why treponemal testing of the CSF is not FDA-approved for the diagnosis of neurosyphilis.[40][131]
  • CSF FTA-ABS: This has shown good sensitivity for neurosyphilis (90% to 100% of cases) and is often used off-label as a way to exclude neurosyphilis if the results are negative.[129][132][131][133][134][135][136]
    • Due to passive blood-brain diffusion, it can give a false positive reading, which is why treponemal testing of the CSF is not FDA-approved for the diagnosis of neurosyphilis.[40][131]
  • CSF with increased WBC count (normal ≤5 WBC cells/μL): The diagnosis of neurosyphilis is suggested by a CSF WBC count of 20 cells/μL or more. (Note: 1 μL= 1 mm³) [13][126]
    • This finding is sensitive but nonspecific, as both infectious and noninfectious causes can result in increased cell counts.
    • Interpretation of pleocytosis is further confounded in patients with HIV who may have elevated CSF WBCs regardless of the presence of neurosyphilis, particularly if they are not on antiretroviral therapy. 
    • A negative or normal CSF WBC count (≤5 or fewer WBC/μL) would be suggestive evidence against a diagnosis of neurosyphilis.
  • CSF with increased protein: Increased protein in the CSF (>50 mg/dL) may aid in the diagnosis, but it is neither sensitive nor specific for neurosyphilis.[2][13][14] 

In his textbook on "Modern Clinical Syphilology," Stokes wrote, "The frequency of neurosyphilis in general medical practice depends to a large extent on the thoroughness of the search for signs of neuraxis involvement and the frequency with which the spinal fluid examination is employed." This remains as true today as when it was first written in 1944. 

Neuroimaging can be helpful in the diagnosis and management of neurosyphilis, but findings are generally nonspecific, and there are no pathognomonic signs. MRI is the most sensitive neurological imaging modality, with the most common findings being frontal and temporoparietal atrophy.[30][43] 

Meningeal syphilis will show leptomeningeal and possibly cranial nerve enhancement with contrast.[43] Meningovascular neurosyphilis is likely to demonstrate brain infarcts on MRI, and tabes dorsalis can have nonspecific white matter lesions and myelopathic involvement, as demonstrated by T2-weighted hyperintense dorsal spinal column abnormalities.[2][25][43][59][137] Syphilitic paresis may demonstrate increased intensity on T2-weighted MRI images in several areas, including the hippocampus, frontotemporal lobes, and periventricular region.[13][43][59] Gumma will appear near the meninges as a lump or mass with good diffusion characteristics without hyperperfusion.[43][138][139][140]

Susceptibility-weighted imaging (SWI) of the brain on MRI may show cortical hypointensity.[43] Single-photon emission computerized tomography (SPECT) scanning might indicate patchy cortical distribution of multifocal areas of hypoperfusion.[43] White matter hyperintensities may be seen on T2-weighted MRI images without any mass effect.[43] Parenchymal involvement of the brain, as is seen in patients with neuropsychiatric symptoms, may be demonstrated as cerebral atrophy, infarcts, and possible ventricular dilatation.[43][59][121] Imaging is not required for the routine diagnosis of neurosyphilis. It is only recommended when there is a question of possible increased intracranial pressure or suspicion of some other underlying neurological pathology.[13]

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.[141] Because of a lack of validation of the reverse algorithm, higher rates of false-positive results can be seen, leading to difficulty in interpretation and the need for additional confirmatory treponemal tests.[110][142] In ambiguous or equivocal situations, a biopsy sample can be used for T pallidum 16S ribosomal deoxyribonucleic acid sequencing.[75][143][144]

As neurosyphilis is a rare diagnosis in the post-penicillin era, much of the evidence regarding its diagnosis, progression, and treatment is from older studies and reviews. Novel biomarkers are being studied, such as beta-2 microglobulin. Its presence may help in the diagnosis of CNS involvement and in monitoring the therapeutic response.[145] Another possible biomarker of neurosyphilis includes CSF CXCL13 at a cutoff threshold level of 10 pg/mL or higher, where it has shown sensitivity of 90% but specificity of only 37%.[135][146][147] Other potential CSF biomarkers include various neurofilament levels, interferon, polymerase chain reaction treponema testing, IL-10, IL-17, and IL-26.[13][122][147][148][149][150][151][152][153][154]

In screening tests, T pallidum enzyme immunoassay (EIA) testing may be necessary for those who are at low risk for ruling out the possibility of syphilis. If the EIA is positive before initiating therapy, additional and confirmatory serological tests, such as VDRL/RPR, should be performed for monitoring purposes.[155]

Evaluation and treatment of neurosyphilis in neonates and infants are reviewed in StatPearls' companion reference, "Congenital Syphilis."[156] 

Treatment / Management

Guidelines from the CDC recommend parenteral aqueous penicillin G for all stages of neurosyphilis as it has long been effective and is also the mainstay treatment for this disease.[11][110][115] Compared to syphilis without neurologic involvement, the treatment is longer and more intense. Penicillin has reasonable penetration into the CSF, especially when used at higher dosages.[157] Aqueous penicillin G can reach higher CSF concentrations than other forms of the antibiotic, such as benzathine penicillin, so it is preferred for treating neurosyphilis.[13][158][159][160][161] It is detectable in the CFS for at least 12 hours after administration.[161] The bactericidal concentration of penicillin for treponema is roughly 0.02 mg/L (or 0.018 mg/L) per the WHO.(B3)

Penicillin permanently blocks the critical enzyme necessary for peptidoglycan cross-linking in the bacterial cell wall, essentially stopping its growth, weakening it, and allowing the existing cell wall to break down.[162][163][164][165][166][167][168][169] Without the ability to grow or repair their cell walls, the bacteria cannot reproduce and die as excessive amounts of water quickly enter through osmotic pressure, causing explosive cellular lysis.[162][163][164][165][166][167][168][169] Penicillin may also cause oxidative damage to the bacterial cell.[163][170]

Like most bactericidal antibiotics, penicillin is most effective when the bacteria rapidly multiply. T pallidum has a slow metabolism and reproduces at the very leisurely rate of once every 30 hours. Hence, treatment of neurosyphilis needs to be relatively prolonged and maintained for at least 7 days, although clinical trials have not definitively determined the optimal duration (10 vs 14 days).[29][162] As treponemal reproduction is slower in late tertiary syphilis, a longer course is recommended. Patients with neurosyphilis should be admitted for the initiation of antibiotics in most cases. Steroids are not recommended in the treatment of neurosyphilis.

Treatment of neurosyphilis includes selecting 1 of the 2 protocols currently recommended by the CDC. All forms of neurosyphilis, including ocular syphilis and otosyphilis, should be treated with 1 of the following therapeutic regimens: [110][115]

  • Aqueous crystalline penicillin G 3 to 4 million units, given intravenously every 4 hours for 10 to 14 days, or aqueous crystalline penicillin G 24 million units daily administered as a continuous IV infusion for 10 to 14 days
  • Procaine penicillin G 2.4 million units intramuscularly daily plus probenecid 500 mg PO 4 times a day for 10 to 14 days. This is suggested for highly compliant patients only and may not be available due to the manufacturer's discontinuation in the US. 

Additional treatment with benzathine penicillin G after completion of 1 of the above treatment regimens is considered optional by the CDC for the treatment of neurosyphilis based on having a total duration of therapy equivalent to late latent syphilis.[110][115] While up to 3 weekly doses can be used, pharmacodynamically, a single dose is sufficient to cover a time period equivalent to the duration recommended for late latent syphilis.[13][171]

Patients with a penicillin allergy should undergo penicillin desensitization, if possible.[29][172] Most (>90%) patients who supposedly have a penicillin allergy will not have it confirmed on careful reevaluation and testing.[173][174][175][176][177] This is reasonable for a disease like neurosyphilis, where penicillin is by far the preferred therapy.(A1)

  • Skin testing to confirm the penicillin allergy should be considered except in patients with a known history of anaphylaxis or unusually severe allergic reactions to penicillin, such as Stevens-Johnson syndrome.[29]
  • If the skin testing is negative, an oral challenge with amoxicillin can be done.[29]
  • If the skin testing is positive, a consultation with an allergist for penicillin desensitization should be considered.[29] See StatPearls' companion reference, "Penicillin Allergy," for more information.[172]

If penicillin desensitization is not possible or reasonable, ceftriaxone is recommended as an alternative therapy, as it penetrates the blood-brain barrier well and is bactericidal for T pallidum at low concentrations.[29][178][179][180][181][182][183][184][185] Allergic cross-reactivity with penicillin is very low, and ceftriaxone skin testing can be done for confirmation of safety in extremely allergic, high-risk individuals.[186] (B2)

A number of recent studies suggest that ceftriaxone is at least equal to and may be even more effective than the standard IV aqueous penicillin G regimen in normalizing CSF abnormalities and clinical symptomatic improvement in neurosyphilis.[181][185][187][188][189][190][191][192][193][194][195][196] According to the CDC, the suggested dosage for ceftriaxone would be 2 g IV or IM daily for 10 to 14 days.[2][14][110][115](A1)

Doxycycline (100 mg oral, twice a day) or tetracycline (400 mg orally, twice a day) for 4 weeks may be considered in selected penicillin-allergic individuals, such as in HIV-negative early syphilis patients, except in pregnancy.[197] This treatment regimen has been used effectively previously. It is accepted as an alternative regimen in the UK but is specifically not recommended currently by either the CDC or European guidelines.[110][115][127][198][199][200][201](B2)

Azithromycin is no longer generally recommended due to increasing resistance being reported, although it might be considered in the rare event that no other antibiotics can be used.[202][203][204] (B2)

Neonatal neurosyphilis is assumed in up to 60% of symptomatic newborns with congenital syphilis.[205] Typical symptoms of neurosyphilis in neonates may include seizures, cranial nerve palsy, and cerebral infarcts.[205][206] The passive transmission of maternal antibodies complicates CSF testing in neonates. VDRL testing of the CSF in neonates has a reported specificity of 90% but only 50% sensitivity.[205][206]

Psychiatric and psychological symptoms associated with neurosyphilis can be challenging to treat as there are no established treatment guidelines. However, olanzapine, valproate, and quetiapine have been used and shown efficacy.[207][208][209] Gabapentin has been used effectively for visceral crises (intermittent, severe abdominal discomfort) and pain management.[210](B3)

Follow-up for treatment efficacy is generally determined and tracked with sequential VDRL or RPR serum assays, which are recommended in all neurosyphilis patients. This should be done at 3, 6, 9, 12, 18, and 24 months post-therapy. A 4-fold or greater decline in these test titers indicates successful treatment.[211] (A1)

Benzathine penicillin has relatively minimal penetration into the CSF.[158][159][160] It has, therefore, been suggested that patients with secondary or latent syphilis whose neurosyphilis was treated with this form of penicillin should have a follow-up CSF examination to identify those inadequately treated. The CDC has long recommended a follow-up CSF exam every 6 months until any abnormalities resolve, as normalization of the CSF (WBC count, protein, and VDRL assay) is expected with successful therapy.[155] If the CSF continues to be abnormal after 2 years, retreatment should be considered. Normalization of the CSF will take longer in HIV-positive patients.[212](B3)

Several recent studies have shown that in immunocompetent patients and HIV-positive individuals who are being effectively treated for the HIV virus, a nonreactive RPR titer can reliably predict normalization of their CSF after treatment.[213][214] Therefore, the CDC no longer recommends repeat CSF examinations in such individuals who demonstrate a nonreactive RPR assay and a good clinical response to treatment.[110][115] In other words, a normal serum RPR would indicate successful treatment of the patient's neurosyphilis without the need for additional CSF examination for all patients except those with active HIV infections.[110][115][213][214]

Therapeutic failures requiring retreatment would be identified after completing therapy by any of the following:

  • Patients who have recurrent or persistent symptoms of neurosyphilis
  • Nontreponemal serology titer (VDRL, RPR) indicates a 400% or greater increase
  • Nontreponemal serology titer (VDRL, RPR) fails to decrease by at least 75% or more after 1 year
  • RPR titer of greater than 1:32. Monitoring is recommended for RPR titers of 1:32 or less [115][126]
    • (B2)

Neurosyphilis and HIV have a strong and close association with each other. CSF abnormalities in HIV-positive neurosyphilis patients tend to be more pronounced with higher protein levels and increased WBCs. Neurosyphilis patients who are HIV positive have a reduced or slower response to treatment although there is evidence suggesting that aggressive antiviral therapy for HIV in these patients may diminish their neurological symptoms.[23][215][216][217] Due to the strong association with HIV and their higher rate of reported relapses, HIV-positive neurosyphilis patients should have repeat serology testing for syphilis yearly. (B2)

Treatment of Charcot spine often requires a complicated spinal fusion to stabilize the spine and adequate symptomatic treatment for bothersome specific morbidities in addition to antibiotic therapy as described above.[71][83][93][218][219] However, most surgical patients (75%) will require at least 1 surgical revision. Patients who cannot undergo surgery typically require bed rest and orthopedic braces.[83] The use of implantable stabilizing rods has recently been reported as an alternative, less morbid surgical option.[220] (B2)

Differential Diagnosis

Since it is often called the "great imitator," the differential for neurosyphilis is exceptionally broad; however, the  important considerations are as follows:

  • Acute basal meningitis: when cranial nerve palsy is present, other causes of acute meningitis, as well as tuberculosis, should be considered                       
  • Acute psychiatric illnesses: when a patient of general paresis presents with delirium, mania, psychosis, personality change, dementia, or depression
  • Brain tumors/abscess: if gumma is found on neuroimaging                                                                            
  • Drug toxicity                                                                                                                                                 
  • Electrolyte disturbances                                                                                                                                     
  • Herpes encephalitis                                                                                                                                          
  • Multiple sclerosis                                                                                                                                              
  • Subacute combined degeneration of the spinal cord: usually secondary to vitamin B12 deficiency, it also causes degeneration of the spinal posterior columns and similar symptoms to tabes dorsalis                                                                         
  • Subarachnoid hemorrhage                                                                                                                        
  • Wernicke encephalopathy [25][32][221]

Toxicity and Adverse Effect Management

The Jarisch-Herxheimer reaction is the primary immediate adverse effect of treatment, particularly in neurosyphilis patients with high titers on serologic testing.[222] It is due to the sudden release of endotoxins from the lysing spirochetes and characteristically presents as fever, chills, myalgias, tachycardia, headache, and vasodilation with resultant flushing or mild hypotension.[222] The Jarisch-Herxheimer reaction may be seen more often when treating syphilitic paresis compared to other forms of neurosyphilis.[223][224]

The reaction usually starts in the first 2 to 6 hours of antibiotic administration and resolves within 12 to 24 hours.[222] Management is symptomatic with acetaminophen as the preferred agent.[25] This reaction is self-limiting, and patients should be informed of this possibility when antibiotic treatment is started to avoid confusion with a possible penicillin allergy, as this is not an allergic reaction.[222] See StatPearls' companion reference, "Jarisch-Herxheimer Reaction," for more information.[222]

Prognosis

According to the National Institute of Health, the prognosis of patients presenting with neurosyphilis is primarily dependent on the specific type of neurosyphilis, the neurological areas affected, the severity of any damage, and the early detection of the disease. Patients who present with asymptomatic or meningeal neurosyphilis generally return to normal health if treated correctly and adequately. Patients with meningovascular disease, general paresis, or Charcot spine may improve but usually do not return to their previous level of health or functional baseline. Patients who are treated years after the initial infection tend to have much poorer prognoses.[225]

Complications

While neurosyphilis itself is a complication of syphilis, untreated neurosyphilis can result in devastating neurological sequelae, including permanent paralysis, dementia, spinal degeneration, and death. Treatment with antibiotics should be initiated immediately as some symptoms and complications may be reversible. The success of therapy in reversing neurological symptoms has an inverse relationship to the duration of the untreated treponemal infection.[226]

Consultations

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

Deterrence and Patient Education

Patients diagnosed with syphilis should receive counseling regarding disease transmission and risk reduction via safe sex practices. Pregnant patients should be counseled on the possibility of vertical transmission. All patients should receive education on the signs and symptoms of neurosyphilis and tabes dorsalis. Patients undergoing treatment for syphilis should be informed about the need for repeat titers for tracking their response to therapy and as a test of cure. Providers should inform patients starting antibiotic treatment of the Jarisch-Herxheimer reaction as a potential occurrence and reassure them that it does not indicate a penicillin allergy.[226]

Patients who are treated for syphilis and fail to achieve at least a 4-fold decline in nontreponemal titers within 6 to 12 months may have unrecognized neurosyphilis, necessitating further work-up and more aggressive or repeat therapy. All patients diagnosed with neurosyphilis should also undergo testing for HIV.

Pearls and Other Issues

Neurosyphilis is a complication of syphilis that can occur at any time after an initial exposure to 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-positive populations. 

  • Neurosyphilis can be asymptomatic, or it may result in a range of clinical symptoms, which include meningeal, meningovascular, general or syphilitic paresis, tabes dorsalis, and Charcot spine.
  • Confirmation of the diagnosis is via the history, serum serology, and CSF studies. The most reliable and significant laboratory would be a positive CSF-VDRL, but even this test may be negative in some cases. Consider using CSF FTA-ABS as a negative reading excludes neurosyphilis and CNS involvement.[131]
  • In cases where the data is conflicting and the diagnosis is still uncertain, consider 16S ribosomal deoxyribonucleic acid sequencing for T pallidum.[75][143][144]
  • Penicillin remains the mainstay of treatment. Penicillin-allergic patients should be considered for confirmatory skin testing as most will be proven not to have a true allergy.
  • Benzathine penicillin G is recommended for most types of syphilis, but neurosyphilis should be treated with aqueous crystalline penicillin G according to the CDC guidelines.
  • Ceftriaxone is an acceptable alternative for penicillin-allergic patients who are unable or unwilling to undergo desensitization. Cross-reactivity is very low, penetration into the CSF is good, and the bacteria are sensitive even at low minimum inhibitory concentration (MIC) levels.[29][178][179][180][181][182][183]
  • After treatment, confirmatory CSF nontreponemal studies (VDRL) should be performed every 6 months to track disease until resolution. Retreatment should be considered if the CSF remains positive after 2 years.
  • The Jarisch-Herxheimer reaction is an expected response in patients with high antibody titers. Treatment is supportive as the condition is self-limiting.[222]
  • All psychiatric patients, especially those with an unusual presentation, rapidly progressive dementia, or history of high-risk sexual behavior, should have a serological screening test for syphilis and, if positive, a possible CSF examination.[32]
  •  Ocular and otic symptoms may occur at any stage of infection and are considered forms of neurosyphilis.

Since there is no definitive guideline, validated model, or authoritative single diagnostic test for neurosyphilis, there is a need for better diagnostic methodologies.[14][116] A computer model for use in HIV-negative patients includes only neurological symptoms, CSF VDRL or RPR, CSF WBC count, and CSF protein levels, which means it can be easily implemented on a worldwide basis, even in areas with limited healthcare resources.[227] Preliminary results indicated good performance across variable clinical settings and greatly simplified the diagnosis of neurosyphilis, but the number of patients tested was limited. Confirmation and validation by others are still necessary before they can be recommended for greater worldwide use. Only time will tell if this or some other model will be validated and clinically useful.

Enhancing Healthcare Team Outcomes

In the diagnosis and treatment of neurosyphilis, interprofessional team communications between physicians, advanced care practitioners, nurses, and other healthcare professional will help optimize and expedite the treatment process. Communication between the consulting clinician and specialists, including infectious disease and neurology, as well as laboratory technicians and pharmacists, helps guide the management of a patient with suspected or confirmed neurosyphilis, allowing seamless information exchange and collaborative decision-making among the team members.

It is critical to arrange appropriate follow-up with patients being treated for syphilis, and especially neurosyphilis, to confirm complete resolution. This includes reversing symptoms and preventing permanent patient disability. Therapeutic failures should be retreated. Care coordination is pivotal in ensuring the patient's journey from diagnosis to treatment and follow-up is well-managed, minimizing errors and enhancing patient safety.  

For the best outcomes, neurosyphilis is optimally addressed via an interprofessional team approach that includes public health officials, primary care clinicians, infectious disease specialists, radiologists, neurologists, orthopedic surgeons, otolaryngology and ophthalmology when appropriate, pharmacists, health educators, and nurses, particularly those with specialty training in infection control.

Ethical considerations must guide decision-making, ensuring informed consent and respecting patient autonomy in treatment choices. Each healthcare professional must be aware of their responsibilities and contribute their unique expertise to the patient's care plan, fostering a multidisciplinary approach. By embracing these principles of skill, strategy, ethics, responsibilities, interprofessional communication, and care coordination, healthcare professionals can deliver patient-centered care, ultimately improving patient outcomes and enhancing team performance in the management of neurosyphilis.

References

[1]

Collart P, Franceschini P, Durel P. Experimental rabbit syphilis. The British journal of venereal diseases. 1971 Dec:47(6):389-400     [PubMed PMID: 5160160]

Level 3 (low-level) evidence

[2]

Ghanem KG. REVIEW: Neurosyphilis: A historical perspective and review. CNS neuroscience & therapeutics. 2010 Oct:16(5):e157-68. doi: 10.1111/j.1755-5949.2010.00183.x. Epub 2010 Jul 8     [PubMed PMID: 20626434]

Level 3 (low-level) evidence

[3]

Refugio ON, Klausner JD. Syphilis incidence in men who have sex with men with human immunodeficiency virus comorbidity and the importance of integrating sexually transmitted infection prevention into HIV care. Expert review of anti-infective therapy. 2018 Apr:16(4):321-331. doi: 10.1080/14787210.2018.1446828. Epub 2018 Mar 5     [PubMed PMID: 29489420]

[4]

Solomon MM, Mayer KH. Evolution of the syphilis epidemic among men who have sex with men. Sexual health. 2015 Apr:12(2):96-102. doi: 10.1071/SH14173. Epub     [PubMed PMID: 25514173]

[5]

Mashingaidze R, Moodie Z, Allen M, Bekker LG, Grove D, Grunenberg N, Huang Y, Janes HE, Lazarus EM, Malahleha M, Nchabeleng M, Laher F. Sexually transmitted infections amongst men who have sex with men (MSM) in South Africa. PLOS global public health. 2023:3(4):e0001782. doi: 10.1371/journal.pgph.0001782. Epub 2023 Apr 5     [PubMed PMID: 37018240]

[6]

Hung P, Osias E, Konda KA, Calvo GM, Reyes-Díaz EM, Vargas SK, Goldbeck C, Caceres CF, Klausner JD. High Lifetime Prevalence of Syphilis in Men Who Have Sex With Men and Transgender Women Versus Low Lifetime Prevalence in Female Sex Workers in Lima, Peru. Sexually transmitted diseases. 2020 Aug:47(8):549-555. doi: 10.1097/OLQ.0000000000001200. Epub     [PubMed PMID: 32541611]

[7]

Vergara-Ortega DN, Tapia-Maltos A, Herrera-Ortíz A, García-Cisneros S, Olamendi-Portugal M, Sánchez-Alemán MÁ. High Prevalence of Syphilis and Syphilis/HIV Coinfection among Men Who Have Sex with Men Who Attend Meeting Places in Mexico. Pathogens (Basel, Switzerland). 2023 Feb 21:12(3):. doi: 10.3390/pathogens12030356. Epub 2023 Feb 21     [PubMed PMID: 36986278]

[8]

Zhao T, Chen G, Sun C, Gong X, Li H, Fu G. The epidemic of HIV and syphilis and the correlation with substance abuse among men who have sex with men in China: A systematic review and meta-analysis. Frontiers in public health. 2023:11():1082637. doi: 10.3389/fpubh.2023.1082637. Epub 2023 Feb 17     [PubMed PMID: 36875380]

Level 1 (high-level) evidence

[9]

Castro R, Águas MJ, Batista T, Araújo C, Mansinho K, Pereira Fda L. Detection of Treponema pallidum Sp. Pallidum DNA in Cerebrospinal Fluid (CSF) by Two PCR Techniques. Journal of clinical laboratory analysis. 2016 Sep:30(5):628-32. doi: 10.1002/jcla.21913. Epub 2016 Feb 18     [PubMed PMID: 26892231]

[10]

Patton ME, Su JR, Nelson R, Weinstock H, Centers for Disease Control and Prevention (CDC). Primary and secondary syphilis--United States, 2005-2013. MMWR. Morbidity and mortality weekly report. 2014 May 9:63(18):402-6     [PubMed PMID: 24807239]

[11]

Brown DL, Frank JE. Diagnosis and management of syphilis. American family physician. 2003 Jul 15:68(2):283-90     [PubMed PMID: 12892348]

[12]

Marra CM, Castro CD, Kuller L, Dukes AC, Centurion-Lara A, Morton WR, Lukehart SA. Mechanisms of clearance of Treponema pallidum from the CSF in a nonhuman primate model. Neurology. 1998 Oct:51(4):957-61     [PubMed PMID: 9781512]

Level 3 (low-level) evidence

[13]

Hamill MM, Ghanem KG, Tuddenham S. State-of-the-Art Review: Neurosyphilis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2024 May 15:78(5):e57-e68. doi: 10.1093/cid/ciad437. Epub     [PubMed PMID: 37593890]

[14]

Tuddenham S, Ghanem KG. Neurosyphilis: Knowledge Gaps and Controversies. Sexually transmitted diseases. 2018 Mar:45(3):147-151. doi: 10.1097/OLQ.0000000000000723. Epub     [PubMed PMID: 29420441]

[15]

Ghanem KG, Ram S, Rice PA. The Modern Epidemic of Syphilis. The New England journal of medicine. 2020 Feb 27:382(9):845-854. doi: 10.1056/NEJMra1901593. Epub     [PubMed PMID: 32101666]

[16]

Lukehart SA, Hook EW 3rd, Baker-Zander SA, Collier AC, Critchlow CW, Handsfield HH. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Annals of internal medicine. 1988 Dec 1:109(11):855-62     [PubMed PMID: 3056164]

Level 3 (low-level) evidence

[17]

Perdrup A, Jørgensen BB, Pedersen NS. The profile of neurosyphilis in Denmark A clinical and serological study of all patients in Denmark with neurosyphilis disclosed in the years 1971-1979 incl. by Wassermann reaction (CWRM) in the cerebrospinal fluid. Acta dermato-venereologica. Supplementum. 1981:96():1-14     [PubMed PMID: 6953720]

Level 3 (low-level) evidence

[18]

Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun MH, Chiu M, Bolan G, Johnson SC, French P, Steen E, Radolf JD, Larsen S. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group. The New England journal of medicine. 1997 Jul 31:337(5):307-14     [PubMed PMID: 9235493]

Level 1 (high-level) evidence

[19]

Chen T, Wan B, Wang M, Lin S, Wu Y, Huang J. Evaluating the global, regional, and national impact of syphilis: results from the global burden of disease study 2019. Scientific reports. 2023 Jul 14:13(1):11386. doi: 10.1038/s41598-023-38294-4. Epub 2023 Jul 14     [PubMed PMID: 37452074]

[20]

Cáceres CF, Konda KA, Klausner JD. Syphilis in men who have sex with men: advancing research and human rights. The Lancet. Global health. 2021 Aug:9(8):e1039-e1040. doi: 10.1016/S2214-109X(21)00269-2. Epub 2021 Jul 8     [PubMed PMID: 34246333]

[21]

Taylor MM, Aynalem G, Olea LM, He P, Smith LV, Kerndt PR. A consequence of the syphilis epidemic among men who have sex with men (MSM): neurosyphilis in Los Angeles, 2001-2004. Sexually transmitted diseases. 2008 May:35(5):430-4. doi: 10.1097/OLQ.0b013e3181644b5e. Epub     [PubMed PMID: 18446083]

[22]

Poliseli R, Vidal JE, Penalva De Oliveira AC, Hernandez AV. Neurosyphilis in HIV-infected patients: clinical manifestations, serum venereal disease research laboratory titers, and associated factors to symptomatic neurosyphilis. Sexually transmitted diseases. 2008 May:35(5):425-9. doi: 10.1097/OLQ.0b013e3181623853. Epub     [PubMed PMID: 18446082]

Level 2 (mid-level) evidence

[23]

Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS (London, England). 2008 Jun 19:22(10):1145-51. doi: 10.1097/QAD.0b013e32830184df. Epub     [PubMed PMID: 18525260]

Level 2 (mid-level) evidence

[24]

Dumaresq J, Langevin S, Gagnon S, Serhir B, Deligne B, Tremblay C, Tsang RS, Fortin C, Coutlée F, Roger M. Clinical prediction and diagnosis of neurosyphilis in HIV-infected patients with early Syphilis. Journal of clinical microbiology. 2013 Dec:51(12):4060-6. doi: 10.1128/JCM.01989-13. Epub 2013 Oct 2     [PubMed PMID: 24088852]

Level 2 (mid-level) evidence

[25]

Hobbs E, Vera JH, Marks M, Barritt AW, Ridha BH, Lawrence D. Neurosyphilis in patients with HIV. Practical neurology. 2018 Jun:18(3):211-218. doi: 10.1136/practneurol-2017-001754. Epub 2018 Feb 24     [PubMed PMID: 29478035]

[26]

Marra CM. Neurosyphilis. Continuum (Minneapolis, Minn.). 2015 Dec:21(6 Neuroinfectious Disease):1714-28. doi: 10.1212/CON.0000000000000250. Epub     [PubMed PMID: 26633785]

[27]

Gager WE, Israel CW, Smith JL. Presence of spirochaetes in paresis despite penicillin therapy. The British journal of venereal diseases. 1968 Dec:44(4):277-82     [PubMed PMID: 4884721]

[28]

Carlson JA, Dabiri G, Cribier B, Sell S. The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity. The American Journal of dermatopathology. 2011 Jul:33(5):433-60. doi: 10.1097/DAD.0b013e3181e8b587. Epub     [PubMed PMID: 21694502]

Level 3 (low-level) evidence

[29]

Tudor ME, Al Aboud AM, Leslie SW, Gossman W. Syphilis. StatPearls. 2024 Jan:():     [PubMed PMID: 30521201]

[30]

Jancar N, Simões M, Gonçalves F, Duro J, Aguiar P. Neurosyphilis: The Great Imitator. Cureus. 2022 Dec:14(12):e32747. doi: 10.7759/cureus.32747. Epub 2022 Dec 20     [PubMed PMID: 36686118]

[31]

Taki El-Din Z, Iqbal H, Sharma A. Neurosyphilis-Induced Psychosis: A Unique Presentation of Syphilis With a Primary Psychiatric Manifestation. Cureus. 2023 Mar:15(3):e36080. doi: 10.7759/cureus.36080. Epub 2023 Mar 13     [PubMed PMID: 37056519]

[32]

Kaur B, Khanna D. A Narrative Review of the Many Psychiatric Manifestations of Neurosyphilis: The Great Imitator. Cureus. 2023 Sep:15(9):e44866. doi: 10.7759/cureus.44866. Epub 2023 Sep 7     [PubMed PMID: 37814742]

Level 3 (low-level) evidence

[33]

Yazigi A, Yazigi M, Zainah H. A Rare Case of Neurosyphilis Manifesting as Psychosis in an HIV-Negative Patient. Cureus. 2023 Jun:15(6):e40064. doi: 10.7759/cureus.40064. Epub 2023 Jun 6     [PubMed PMID: 37425525]

Level 3 (low-level) evidence

[34]

Friedrich F, Geusau A, Greisenegger S, Ossege M, Aigner M. Manifest psychosis in neurosyphilis. General hospital psychiatry. 2009 Jul-Aug:31(4):379-81. doi: 10.1016/j.genhosppsych.2008.09.010. Epub 2008 Oct 9     [PubMed PMID: 19555800]

Level 3 (low-level) evidence

[35]

Singh SM, Sharma R, Batra N, Sethi S. Neurosyphilis: An underdiagnosed entity. Asian journal of psychiatry. 2017 Dec:30():47-48. doi: 10.1016/j.ajp.2017.07.015. Epub 2017 Jul 13     [PubMed PMID: 28738261]

[36]

Wolters EC. Neurosyphilis: a changing diagnostic problem? European neurology. 1987:26(1):23-8     [PubMed PMID: 3545845]

Level 2 (mid-level) evidence

[37]

Conde-Sendín MA, Amela-Peris R, Aladro-Benito Y, Maroto AA. Current clinical spectrum of neurosyphilis in immunocompetent patients. European neurology. 2004:52(1):29-35     [PubMed PMID: 15237250]

Level 2 (mid-level) evidence

[38]

Frater JL. The Usefulness of Cerebrospinal Fluid White Blood Cell Count in Neurosyphilis. European neurology. 2023:86(6):404-406. doi: 10.1159/000534724. Epub 2023 Oct 23     [PubMed PMID: 37871580]

[39]

Ding D, Gao J, Zhang W, Xu D. The Diagnostic Performance of Laboratory Tests of Neurosyphilis: A Systematic Review and Network Meta-Analysis. European neurology. 2023:86(6):418-429. doi: 10.1159/000531341. Epub 2023 Aug 7     [PubMed PMID: 37549649]

Level 1 (high-level) evidence

[40]

Harding AS, Ghanem KG. The performance of cerebrospinal fluid treponemal-specific antibody tests in neurosyphilis: a systematic review. Sexually transmitted diseases. 2012 Apr:39(4):291-7. doi: 10.1097/OLQ.0b013e31824c0e62. Epub     [PubMed PMID: 22421696]

Level 1 (high-level) evidence

[41]

Nayak S, Acharjya B. VDRL test and its interpretation. Indian journal of dermatology. 2012 Jan:57(1):3-8. doi: 10.4103/0019-5154.92666. Epub     [PubMed PMID: 22470199]

[42]

Fargen KM, Alvernia JE, Lin CS, Melgar M. Cerebral syphilitic gummata: a case presentation and analysis of 156 reported cases. Neurosurgery. 2009 Mar:64(3):568-75; discussioin 575-6. doi: 10.1227/01.NEU.0000337079.12137.89. Epub     [PubMed PMID: 19240620]

Level 3 (low-level) evidence

[43]

Corrêa DG, de Souza SR, Freddi TAL, Fonseca APA, Dos Santos RQ, Hygino da Cruz LC Jr. Imaging features of neurosyphilis. Journal of neuroradiology = Journal de neuroradiologie. 2023 Mar:50(2):241-252. doi: 10.1016/j.neurad.2023.01.003. Epub 2023 Jan 11     [PubMed PMID: 36641134]

[44]

Jum'ah A, Aboul Nour H, Alkhoujah M, Zoghoul S, Eltous L, Miller D. Neurosyphilis in disguise. Neuroradiology. 2022 Mar:64(3):433-441. doi: 10.1007/s00234-021-02827-3. Epub 2021 Oct 19     [PubMed PMID: 34665270]

[45]

Akgoz A, Mukundan S, Lee TC. Imaging of rickettsial, spirochetal, and parasitic infections. Neuroimaging clinics of North America. 2012 Nov:22(4):633-57. doi: 10.1016/j.nic.2012.05.015. Epub 2012 Sep 29     [PubMed PMID: 23122260]

[46]

Smith MM, Anderson JC. Neurosyphilis as a cause of facial and vestibulocochlear nerve dysfunction: MR imaging features. AJNR. American journal of neuroradiology. 2000 Oct:21(9):1673-5     [PubMed PMID: 11039349]

Level 3 (low-level) evidence

[47]

Skalnaya A, Fominykh V, Ivashchenko R, Averchenkov D, Grazhdantseva L, Frigo N, Negasheva E, Dolya O, Brylev L, Guekht A. Neurosyphilis in the modern era: Literature review and case series. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2019 Nov:69():67-73. doi: 10.1016/j.jocn.2019.08.033. Epub 2019 Aug 16     [PubMed PMID: 31427238]

Level 2 (mid-level) evidence

[48]

Piura Y, Mina Y, Aizenstein O, Gadoth A. Neurosyphilis presenting as cranial nerve palsy, an entity which is easy to miss. BMJ case reports. 2019 Feb 21:12(2):. doi: 10.1136/bcr-2018-226509. Epub 2019 Feb 21     [PubMed PMID: 30796075]

Level 3 (low-level) evidence

[49]

Holmes MD, Brant-Zawadzki MM, Simon RP. Clinical features of meningovascular syphilis. Neurology. 1984 Apr:34(4):553-6     [PubMed PMID: 6538318]

Level 3 (low-level) evidence

[50]

Mukku S, Safal SS, Pritam R, Nashi S, Nagarathna C, Pt S, Netravathi M. Neurosyphilis presenting as rapidly progressive psychosis & dementia - A forgotten entity. Asian journal of psychiatry. 2019 Feb:40():103-106. doi: 10.1016/j.ajp.2019.02.010. Epub 2019 Feb 13     [PubMed PMID: 30785032]

[51]

Ragusa A, Kapustka A, Ganti L, Gue S. Meningovascular Syphilis: A Case of a Young Man Presenting With Acute Stroke and Pulmonary Emboli. Cureus. 2023 Sep:15(9):e44568. doi: 10.7759/cureus.44568. Epub 2023 Sep 2     [PubMed PMID: 37790000]

Level 3 (low-level) evidence

[52]

King CJ, Ngo TH, Constante M. Meningovascular Neurosyphilis Presenting as Multiple Ischemic Infarcts in a Young Adult. Cureus. 2023 Mar:15(3):e36405. doi: 10.7759/cureus.36405. Epub 2023 Mar 20     [PubMed PMID: 37090294]

[53]

Batinić D, Antulov R, Klupka-Sarić I, Ivanković A, Jurina R, Karlović Vidaković M, Talić Drlje I, Arapović J. Cerebral infarction as initial manifestation of meningovascular neurosyphilis in an immunocompetent patient - A case report with long term follow-up. Clinical case reports. 2023 Mar:11(3):e7021. doi: 10.1002/ccr3.7021. Epub 2023 Mar 15     [PubMed PMID: 36937633]

Level 3 (low-level) evidence

[54]

Vaitkus A, Krasauskaite E, Urbonaviciūte I. Meningovascular neurosyphilis: a report of stroke in a young adult. Medicina (Kaunas, Lithuania). 2010:46(4):282-5     [PubMed PMID: 20571297]

[55]

Bhai S, Lyons JL. Neurosyphilis Update: Atypical is the New Typical. Current infectious disease reports. 2015 May:17(5):481. doi: 10.1007/s11908-015-0481-x. Epub     [PubMed PMID: 25896752]

[56]

Ahbeddou N, El Alaoui Taoussi K, Ibrahimi A, Ait Ben Haddou EH, Regragui W, Benomar A, Yahyaoui M. Stroke and syphilis: A retrospective study of 53 patients. Revue neurologique. 2018 May:174(5):313-318. doi: 10.1016/j.neurol.2017.07.014. Epub 2018 Apr 7     [PubMed PMID: 29631855]

Level 2 (mid-level) evidence

[57]

Offiah CE, Turnbull IW. The imaging appearances of intracranial CNS infections in adult HIV and AIDS patients. Clinical radiology. 2006 May:61(5):393-401     [PubMed PMID: 16679111]

[58]

Gállego J, Soriano G, Zubieta JL, Delgado G, Villanueva JA. Magnetic resonance angiography in meningovascular syphilis. Neuroradiology. 1994 Apr:36(3):208-9     [PubMed PMID: 8041441]

Level 3 (low-level) evidence

[59]

Nagappa M, Sinha S, Taly AB, Rao SL, Nagarathna S, Bindu PS, Bharath RD, Murthy P. Neurosyphilis: MRI features and their phenotypic correlation in a cohort of 35 patients from a tertiary care university hospital. Neuroradiology. 2013 Mar:55(4):379-88. doi: 10.1007/s00234-012-1017-9. Epub 2012 Dec 30     [PubMed PMID: 23274762]

[60]

Cintron R, Pachner AR. Spirochetal diseases of the nervous system. Current opinion in neurology. 1994 Jun:7(3):217-22     [PubMed PMID: 8081515]

Level 3 (low-level) evidence

[61]

Obi K, Tsuchiya K, Anno M, Ohta S, Nakamura R, Akiyama H. [Autopsy case of meningovascular neurosyphilis associated with Fischer's plaques]. Brain and nerve = Shinkei kenkyu no shinpo. 2007 Jul:59(7):797-803     [PubMed PMID: 17663152]

Level 3 (low-level) evidence

[62]

Ha T, Tadi P, Leslie SW, Dubensky L. Neurosyphilis. StatPearls. 2024 Jan:():     [PubMed PMID: 31082023]

[63]

Sharma SR, Hussain M, Roy D. General paresis of insane: A forgotten entity. Neurology India. 2020 Mar-Apr:68(2):487-488. doi: 10.4103/0028-3886.284383. Epub     [PubMed PMID: 32415032]

[64]

Stefani A, Riello M, Rossini F, Mariotto S, Fenzi F, Gambina G, Zanusso G, Monaco S. Neurosyphilis manifesting with rapidly progressive dementia: report of three cases. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2013 Nov:34(11):2027-30. doi: 10.1007/s10072-013-1531-5. Epub 2013 Sep 6     [PubMed PMID: 24062212]

Level 3 (low-level) evidence

[65]

Yanhua W, Haishan S, Le H, Xiaomei Z, Xinru C, Ling L, Zhangying W, Dong Z, Yuefen Z, Yan T, Xinni L, Sha L, Yuping N. Clinical and neuropsychological characteristics of general paresis misdiagnosed as primary psychiatric disease. BMC psychiatry. 2016 Jul 11:16():230. doi: 10.1186/s12888-016-0925-3. Epub 2016 Jul 11     [PubMed PMID: 27400713]

[66]

Gao JH, Ding DY, Qi YY, Huang YM, Zhang JL, Zhang W. Neuropsychological Features in Patients with General Paresis of the Insane at an Early Stage. Medical science monitor : international medical journal of experimental and clinical research. 2022 Dec 9:28():e938316. doi: 10.12659/MSM.938316. Epub 2022 Dec 9     [PubMed PMID: 36482803]

Level 2 (mid-level) evidence

[67]

Dichter SL, Khan Suheb MZ, Shubert GS. Argyll Robertson Pupil. StatPearls. 2024 Jan:():     [PubMed PMID: 30725864]

[68]

Calonge N, U.S. Preventive Services Task Force. Screening for syphilis infection: recommendation statement. Annals of family medicine. 2004 Jul-Aug:2(4):362-5     [PubMed PMID: 15335137]

Level 1 (high-level) evidence

[69]

Zheng D, Zhou D, Zhao Z, Liu Z, Xiao S, Xing Y, Suo WZ, Liu J. The clinical presentation and imaging manifestation of psychosis and dementia in general paresis: a retrospective study of 116 cases. The Journal of neuropsychiatry and clinical neurosciences. 2011 Summer:23(3):300-7     [PubMed PMID: 21948891]

Level 2 (mid-level) evidence

[70]

Zifko U, Wimberger D, Lindner K, Zier G, Grisold W, Schindler E. MRI in patients with general paresis. Neuroradiology. 1996 Feb:38(2):120-3     [PubMed PMID: 8692419]

Level 3 (low-level) evidence

[71]

Bhandari J, Thada PK, Leslie SW, Ratzan RM. Tabes Dorsalis. StatPearls. 2024 Jan:():     [PubMed PMID: 32491814]

[72]

Jolivet-Gougeon A, Bonnaure-Mallet M. Treponema, Iron and Neurodegeneration. Current Alzheimer research. 2018:15(8):716-722. doi: 10.2174/1567205013666161122093404. Epub     [PubMed PMID: 27875949]

[73]

Strom T, Schneck SA. Syphilitic meningomyelitis. Neurology. 1991 Feb:41(2 ( Pt 1)):325-6     [PubMed PMID: 1812840]

Level 3 (low-level) evidence

[74]

Huang YH, Shi QX, Xu MM, Chen CZ, Yang ML, Li JJ, Chen YF, Lin ZQ, Lin YY. Spinal Cord Syphilitic Gumma Presenting with Brown-Séquard Syndrome: A Case Report and Literature Review. Annals of clinical and laboratory science. 2019 Mar:49(2):265-270     [PubMed PMID: 31028074]

Level 3 (low-level) evidence

[75]

Centurion-Lara A, Castro C, Shaffer JM, Van Voorhis WC, Marra CM, Lukehart SA. Detection of Treponema pallidum by a sensitive reverse transcriptase PCR. Journal of clinical microbiology. 1997 Jun:35(6):1348-52     [PubMed PMID: 9163442]

[76]

Creech KT, Patel KM, Chaudhry U. Tabes Dorsalis in a Patient Presenting With Right Lower Extremity Paresthesia and Cervical Spine Pain. Cureus. 2021 Mar 20:13(3):e14011. doi: 10.7759/cureus.14011. Epub 2021 Mar 20     [PubMed PMID: 33884252]

[77]

Sun L, Zheng N, Yang Y, Zhang HN. Syphilitic meningomyelitis presenting with visceral crisis: A case report. Medicine. 2018 Jul:97(30):e11661. doi: 10.1097/MD.0000000000011661. Epub     [PubMed PMID: 30045319]

Level 3 (low-level) evidence

[78]

Kikuchi S, Shinpo K, Niino M, Tashiro K. Subacute syphilitic meningomyelitis with characteristic spinal MRI findings. Journal of neurology. 2003 Jan:250(1):106-7     [PubMed PMID: 12528004]

Level 3 (low-level) evidence

[79]

Pandey S. Magnetic resonance imaging of the spinal cord in a man with tabes dorsalis. The journal of spinal cord medicine. 2011 Nov:34(6):609-11. doi: 10.1179/2045772311Y.0000000041. Epub     [PubMed PMID: 22330117]

Level 3 (low-level) evidence

[80]

Goh C, Desmond PM, Phal PM. MRI in transverse myelitis. Journal of magnetic resonance imaging : JMRI. 2014 Dec:40(6):1267-79. doi: 10.1002/jmri.24563. Epub 2014 Feb 6     [PubMed PMID: 24752988]

[81]

Mochizuki H, Kamakura K, Kanzaki M, Nishii T, Matsuo H, Motoyoshi K. Somatosensory evoked potential in neurosyphilis. Journal of neurology. 2002 Sep:249(9):1220-2     [PubMed PMID: 12242542]

Level 2 (mid-level) evidence

[82]

Forbes J, Munakomi S, Cronovich H. Romberg Test. StatPearls. 2024 Jan:():     [PubMed PMID: 33085334]

[83]

Urits I, Amgalan A, Israel J, Dugay C, Zhao A, Berger AA, Kassem H, Paladini A, Varrassi G, Kaye AD, Miriyala S, Viswanath O. A comprehensive review of the treatment and management of Charcot spine. Therapeutic advances in musculoskeletal disease. 2020:12():1759720X20979497. doi: 10.1177/1759720X20979497. Epub 2020 Dec 17     [PubMed PMID: 33414850]

Level 3 (low-level) evidence

[84]

Ledbetter LN, Salzman KL, Sanders RK, Shah LM. Spinal Neuroarthropathy: Pathophysiology, Clinical and Imaging Features, and Differential Diagnosis. Radiographics : a review publication of the Radiological Society of North America, Inc. 2016 May-Jun:36(3):783-99. doi: 10.1148/rg.2016150121. Epub 2016 Apr 8     [PubMed PMID: 27058729]

[85]

Barrey C, Massourides H, Cotton F, Perrin G, Rode G. Charcot spine: two new case reports and a systematic review of 109 clinical cases from the literature. Annals of physical and rehabilitation medicine. 2010 Apr:53(3):200-20. doi: 10.1016/j.rehab.2009.11.008. Epub 2009 Dec 31     [PubMed PMID: 20338837]

Level 3 (low-level) evidence

[86]

Lee D, Dahdaleh NS. Charcot spinal arthropathy. Journal of craniovertebral junction & spine. 2018 Jan-Mar:9(1):9-19. doi: 10.4103/jcvjs.JCVJS_130_17. Epub     [PubMed PMID: 29755231]

[87]

Solinsky R, Donovan JM, Kirshblum SC. Charcot Spine following chronic spinal cord injury: an analysis of 201 published cases. Spinal cord. 2019 Feb:57(2):85-90. doi: 10.1038/s41393-018-0216-6. Epub 2018 Nov 9     [PubMed PMID: 30413802]

Level 3 (low-level) evidence

[88]

Morita M, Miyauchi A, Okuda S, Oda T, Yamamoto T, Iwasaki M. Charcot spinal disease after spinal cord injury. Journal of neurosurgery. Spine. 2008 Nov:9(5):419-26. doi: 10.3171/SPI.2008.9.11.419. Epub     [PubMed PMID: 18976172]

Level 2 (mid-level) evidence

[89]

Hoyt D, Urits I, Orhurhu V, Orhurhu MS, Callan J, Powell J, Manchikanti L, Kaye AD, Kaye RJ, Viswanath O. Current Concepts in the Management of Vertebral Compression Fractures. Current pain and headache reports. 2020 Mar 20:24(5):16. doi: 10.1007/s11916-020-00849-9. Epub 2020 Mar 20     [PubMed PMID: 32198571]

[90]

Selmi F, Frankel HL, Kumaraguru AP, Apostopoulos V. Charcot joint of the spine, a cause of autonomic dysreflexia in spinal cord injured patients. Spinal cord. 2002 Sep:40(9):481-3     [PubMed PMID: 12185610]

Level 3 (low-level) evidence

[91]

Jacobs WB, Bransford RJ, Bellabarba C, Chapman JR. Surgical management of Charcot spinal arthropathy: a single-center retrospective series highlighting the evolution of management. Journal of neurosurgery. Spine. 2012 Nov:17(5):422-31. doi: 10.3171/2012.7.SPINE111039. Epub 2012 Aug 31     [PubMed PMID: 22938550]

Level 2 (mid-level) evidence

[92]

Beers GJ, Carter AP, Leiter B, Shapiro JH. CT detection of retroperitoneal gas associated with gas in intervertebral disks. Journal of computer assisted tomography. 1984 Apr:8(2):232-6     [PubMed PMID: 6707271]

Level 3 (low-level) evidence

[93]

Aebli N, Pötzel T, Krebs J. Characteristics and surgical management of neuropathic (Charcot) spinal arthropathy after spinal cord injury. The spine journal : official journal of the North American Spine Society. 2014 Jun 1:14(6):884-91. doi: 10.1016/j.spinee.2013.07.441. Epub 2013 Sep 26     [PubMed PMID: 24076443]

Level 2 (mid-level) evidence

[94]

Karsan N, Barker R, O'Dwyer JP. Clinical reasoning: the "great imitator". Neurology. 2014 Nov 25:83(22):e188-96. doi: 10.1212/WNL.0000000000001033. Epub     [PubMed PMID: 25422404]

Level 3 (low-level) evidence

[95]

Budhram A, Silverman M, Burneo JG. Neurosyphilis mimicking autoimmune encephalitis in a 52-year-old man. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2017 Jul 24:189(29):E962-E965. doi: 10.1503/cmaj.170190. Epub     [PubMed PMID: 28739848]

[96]

Marešová E, Šutovský S, Štefucová H, Koščálová A, Sabaka P. Neurosyphilis Presenting as Syndrome of Limbic Encephalitis Mimicking Herpes Simplex Virus Neuro-Infection Diagnosed Using CXCL13 Point-of-Care Assay-Case Report. Brain sciences. 2023 Mar 16:13(3):. doi: 10.3390/brainsci13030503. Epub 2023 Mar 16     [PubMed PMID: 36979313]

Level 3 (low-level) evidence

[97]

Mizoguchi T, Hara M, Nakajima H. Neurosyphilis presenting as autoimmune limbic encephalitis: A case report and literature review. Medicine. 2022 Aug 19:101(33):e30062. doi: 10.1097/MD.0000000000030062. Epub     [PubMed PMID: 35984192]

Level 3 (low-level) evidence

[98]

Koundanya VV, Tripathy K. Syphilis Ocular Manifestations. StatPearls. 2024 Jan:():     [PubMed PMID: 32644383]

[99]

Balba GP, Kumar PN, James AN, Malani A, Palestine AG, Welch JN, Timpone JG. Ocular syphilis in HIV-positive patients receiving highly active antiretroviral therapy. The American journal of medicine. 2006 May:119(5):448.e21-5     [PubMed PMID: 16651059]

Level 2 (mid-level) evidence

[100]

Westeneng AC, Rothova A, de Boer JH, de Groot-Mijnes JD. Infectious uveitis in immunocompromised patients and the diagnostic value of polymerase chain reaction and Goldmann-Witmer coefficient in aqueous analysis. American journal of ophthalmology. 2007 Nov:144(5):781-5     [PubMed PMID: 17707328]

Level 3 (low-level) evidence

[101]

Oliver SE, Aubin M, Atwell L, Matthias J, Cope A, Mobley V, Goode A, Minnerly S, Stoltey J, Bauer HM, Hennessy RR, DiOrio D, Fanfair RN, Peterman TA, Markowitz L. Ocular Syphilis - Eight Jurisdictions, United States, 2014-2015. MMWR. Morbidity and mortality weekly report. 2016 Nov 4:65(43):1185-1188. doi: 10.15585/mmwr.mm6543a2. Epub 2016 Nov 4     [PubMed PMID: 27811837]

[102]

Durnian JM, Naylor G, Saeed AM. Ocular syphilis: the return of an old acquaintance. Eye (London, England). 2004 Apr:18(4):440-2     [PubMed PMID: 15069449]

Level 3 (low-level) evidence

[103]

Prokosch V, Thanos S, Busse H, Stupp T. [Ophthalmological symptoms as key findings in neurosyphilis--diagnosis and therapy]. Klinische Monatsblatter fur Augenheilkunde. 2009 Mar:226(3):184-8. doi: 10.1055/s-2008-1027867. Epub 2009 Mar 17     [PubMed PMID: 19294590]

Level 3 (low-level) evidence

[104]

Doris JP, Saha K, Jones NP, Sukthankar A. Ocular syphilis: the new epidemic. Eye (London, England). 2006 Jun:20(6):703-5     [PubMed PMID: 15933744]

Level 3 (low-level) evidence

[105]

Mathew D, Smit D. Clinical and laboratory characteristics of ocular syphilis and neurosyphilis among individuals with and without HIV infection. The British journal of ophthalmology. 2021 Jan:105(1):70-74. doi: 10.1136/bjophthalmol-2019-315699. Epub 2020 Mar 27     [PubMed PMID: 32220852]

[106]

Matsumoto H, Suzuki S, Nagata M, Senoo T, Watanabe M, Kawashima H. Clinical Features of Syphilis Patients with Ocular Symptoms as the Initial Manifestation. Clinical ophthalmology (Auckland, N.Z.). 2023:17():2901-2907. doi: 10.2147/OPTH.S425821. Epub 2023 Oct 3     [PubMed PMID: 37808000]

[107]

Balaskas K, Sergentanis TN, Giulieri S, Guex-Crosier Y. Analysis of significant factors influencing visual acuity in ocular syphilis. The British journal of ophthalmology. 2011 Nov:95(11):1568-72. doi: 10.1136/bjo.2010.194498. Epub 2011 Mar 11     [PubMed PMID: 21398411]

Level 2 (mid-level) evidence

[108]

Rescigno RJ, Glatman M, Patel SN. A complicated case of sarcoidosis. Neurosyphilis. JAMA ophthalmology. 2014 May:132(5):649-50. doi: 10.1001/jamaophthalmol.2014.179. Epub     [PubMed PMID: 24810695]

Level 3 (low-level) evidence

[109]

Gu X, Gao Y, Yan Y, Marks M, Zhu L, Lu H, Guan Z, Shi M, Ni L, Peng R, Zhao W, Wu J, Qi T, Lu S, Qian Y, Gong W, Zhou P. The importance of proper and prompt treatment of ocular syphilis: a lesson from permanent vision loss in 52 eyes. Journal of the European Academy of Dermatology and Venereology : JEADV. 2020 Jul:34(7):1569-1578. doi: 10.1111/jdv.16347. Epub 2020 Jun 25     [PubMed PMID: 32163642]

Level 2 (mid-level) evidence

[110]

Workowski KA, Bachmann LH, Chan PA, Johnston CM, Muzny CA, Park I, Reno H, Zenilman JM, Bolan GA. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2021 Jul 23:70(4):1-187. doi: 10.15585/mmwr.rr7004a1. Epub 2021 Jul 23     [PubMed PMID: 34292926]

[111]

Yimtae K, Srirompotong S, Lertsukprasert K. Otosyphilis: a review of 85 cases. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2007 Jan:136(1):67-71     [PubMed PMID: 17210336]

Level 2 (mid-level) evidence

[112]

Witt LS, Wendy Fujita A, Ho J, Shin YM, Kobaidze K, Workowski K. Otosyphilis. Open forum infectious diseases. 2023 Feb:10(2):ofac685. doi: 10.1093/ofid/ofac685. Epub 2022 Dec 21     [PubMed PMID: 36776779]

[113]

Bradshaw D, Pallawela S, Nelson M, Scott C, Day S. Otosyphilis: missed opportunities for early treatment? Sexually transmitted infections. 2012 Dec:88(8):573. doi: 10.1136/sextrans-2012-050792. Epub 2012 Sep 21     [PubMed PMID: 23002194]

Level 3 (low-level) evidence

[114]

Marra CM, Maxwell CL, Ramchandani M, Tantalo LC, Sahi SK, Dunaway SB, Litvack JR. Hearing loss in individuals at risk for neurosyphilis. International journal of STD & AIDS. 2020 Oct:31(12):1178-1185. doi: 10.1177/0956462420947584. Epub 2020 Sep 14     [PubMed PMID: 32928054]

[115]

Workowski KA, Bachmann LH. Centers for Disease Control and Prevention's Sexually Transmitted Diseases Infection Guidelines. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2022 Apr 13:74(74 Suppl 2):S89-S94. doi: 10.1093/cid/ciab1055. Epub     [PubMed PMID: 35416966]

[116]

Tuddenham S, Katz SS, Ghanem KG. Syphilis Laboratory Guidelines: Performance Characteristics of Nontreponemal Antibody Tests. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020 Jun 24:71(Suppl 1):S21-S42. doi: 10.1093/cid/ciaa306. Epub     [PubMed PMID: 32578862]

[117]

Ito H. Enhancing Neurosyphilis Diagnosis: Evaluating Serum Biomarkers as Non-Invasive Alternatives to Lumbar Puncture. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2023 Oct 6:():. pii: ciad620. doi: 10.1093/cid/ciad620. Epub 2023 Oct 6     [PubMed PMID: 37802911]

[118]

Xie JW, Wang M, Zheng YW, Lin Y, He Y, Lin LR. Performance of the nontreponemal tests and treponemal tests on cerebrospinal fluid for the diagnosis of neurosyphilis: A meta-analysis. Frontiers in public health. 2023:11():1105847. doi: 10.3389/fpubh.2023.1105847. Epub 2023 Feb 2     [PubMed PMID: 36817920]

Level 1 (high-level) evidence

[119]

Castro R, Prieto ES, da Luz Martins Pereira F. Nontreponemal tests in the diagnosis of neurosyphilis: an evaluation of the Venereal Disease Research Laboratory (VDRL) and the Rapid Plasma Reagin (RPR) tests. Journal of clinical laboratory analysis. 2008:22(4):257-61. doi: 10.1002/jcla.20254. Epub     [PubMed PMID: 18623120]

[120]

Marra CM, Maxwell CL, Dunaway SB, Sahi SK, Tantalo LC. Cerebrospinal Fluid Treponema pallidum Particle Agglutination Assay for Neurosyphilis Diagnosis. Journal of clinical microbiology. 2017 Jun:55(6):1865-1870. doi: 10.1128/JCM.00310-17. Epub 2017 Apr 5     [PubMed PMID: 28381602]

[121]

Marra CM, Tantalo LC, Maxwell CL, Ho EL, Sahi SK, Jones T. The rapid plasma reagin test cannot replace the venereal disease research laboratory test for neurosyphilis diagnosis. Sexually transmitted diseases. 2012 Jun:39(6):453-7. doi: 10.1097/OLQ.0b013e31824b1cde. Epub     [PubMed PMID: 22592831]

[122]

Marks M, Lawrence D, Kositz C, Mabey D. Diagnostic performance of PCR assays for the diagnosis of neurosyphilis: a systematic review. Sexually transmitted infections. 2018 Dec:94(8):585-588. doi: 10.1136/sextrans-2018-053666. Epub 2018 Jul 30     [PubMed PMID: 30061192]

Level 1 (high-level) evidence

[123]

Tuddenham S, Ghanem KG. Management of Adult Syphilis: Key Questions to Inform the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2022 Apr 13:74(Suppl_2):S127-S133. doi: 10.1093/cid/ciac060. Epub     [PubMed PMID: 35416969]

[124]

Libois A, De Wit S, Poll B, Garcia F, Florence E, Del Rio A, Sanchez P, Negredo E, Vandenbruaene M, Gatell JM, Clumeck N. HIV and syphilis: when to perform a lumbar puncture. Sexually transmitted diseases. 2007 Mar:34(3):141-4     [PubMed PMID: 16865051]

[125]

Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA. Lumbar puncture in HIV-infected patients with syphilis and no neurologic symptoms. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009 Mar 15:48(6):816-21. doi: 10.1086/597096. Epub     [PubMed PMID: 19187028]

Level 2 (mid-level) evidence

[126]

Cui W, Yan J, Weng W, Gao Y, Zhu W. Factors Associated With Neurosyphilis in Patients With Syphilis Treatment Failure: A Retrospective Study of 165 HIV-Negative Patients. Frontiers in medicine. 2022:9():757354. doi: 10.3389/fmed.2022.757354. Epub 2022 May 20     [PubMed PMID: 35669916]

Level 2 (mid-level) evidence

[127]

Janier M, Hegyi V, Dupin N, Unemo M, Tiplica GS, Potočnik M, French P, Patel R. 2014 European guideline on the management of syphilis. Journal of the European Academy of Dermatology and Venereology : JEADV. 2014 Dec:28(12):1581-93. doi: 10.1111/jdv.12734. Epub 2014 Oct 27     [PubMed PMID: 25348878]

[128]

Wang YJ, Chi CY, Chou CH, Ho CM, Lin PC, Liao CH, Ho MW, Wang JH. Syphilis and neurosyphilis in human immunodeficiency virus-infected patients: a retrospective study at a teaching hospital in Taiwan. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi. 2012 Oct:45(5):337-42. doi: 10.1016/j.jmii.2011.12.011. Epub 2012 Jun 13     [PubMed PMID: 22698630]

Level 2 (mid-level) evidence

[129]

Guarner J, Jost H, Pillay A, Sun Y, Cox D, Notenboom R, Workowski K. Evaluation of treponemal serum tests performed on cerebrospinal fluid for diagnosis of neurosyphilis. American journal of clinical pathology. 2015 Apr:143(4):479-84. doi: 10.1309/AJCPWSL3G8RXMCQR. Epub     [PubMed PMID: 25779998]

Level 2 (mid-level) evidence

[130]

Castro R, Prieto ES, Aguas MJ, Manata MJ, Botas J, Araújo C, Borges F, Aldir I, Exposto Fda L. Evaluation of the Treponema pallidum particle agglutination technique (TP.PA) in the diagnosis of neurosyphilis. Journal of clinical laboratory analysis. 2006:20(6):233-8     [PubMed PMID: 17115423]

Level 2 (mid-level) evidence

[131]

Papp JR, Park IU, Fakile Y, Pereira L, Pillay A, Bolan GA. CDC Laboratory Recommendations for Syphilis Testing, United States, 2024. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2024 Feb 8:73(1):1-32. doi: 10.15585/mmwr.rr7301a1. Epub 2024 Feb 8     [PubMed PMID: 38319847]

[132]

Hooshmand H, Escobar MR, Kopf SW. Neurosyphilis. A study of 241 patients. JAMA. 1972 Feb:219(6):726-9     [PubMed PMID: 5066697]

[133]

Birry A, Kasatiya S. Evaluation of microhaemagglutination assay to determine treponemal antibodies in CSF. The British journal of venereal diseases. 1979 Aug:55(4):239-44     [PubMed PMID: 385012]

[134]

Marra CM, Critchlow CW, Hook EW 3rd, Collier AC, Lukehart SA. Cerebrospinal fluid treponemal antibodies in untreated early syphilis. Archives of neurology. 1995 Jan:52(1):68-72     [PubMed PMID: 7826278]

[135]

Marra CM, Tantalo LC, Maxwell CL, Dougherty K, Wood B. Alternative cerebrospinal fluid tests to diagnose neurosyphilis in HIV-infected individuals. Neurology. 2004 Jul 13:63(1):85-8     [PubMed PMID: 15249615]

Level 3 (low-level) evidence

[136]

Luger A, Schmidt BL, Steyrer K, Schonwald E. Diagnosis of neurosyphilis by examination of the cerebrospinal fluid. The British journal of venereal diseases. 1981 Aug:57(4):232-7     [PubMed PMID: 7023601]

[137]

Khamaysi Z, Bergman R, Telman G, Goldsher D. Clinical and imaging findings in patients with neurosyphilis: a study of a cohort and review of the literature. International journal of dermatology. 2014 Jul:53(7):812-9. doi: 10.1111/ijd.12095. Epub 2013 Nov 21     [PubMed PMID: 24261864]

Level 3 (low-level) evidence

[138]

Neuberger I, Garcia J, Meyers ML, Feygin T, Bulas DI, Mirsky DM. Imaging of congenital central nervous system infections. Pediatric radiology. 2018 Apr:48(4):513-523. doi: 10.1007/s00247-018-4092-1. Epub 2018 Mar 17     [PubMed PMID: 29550865]

[139]

Domingues CSB, Duarte G, Passos MRL, Sztajnbok DCDN, Menezes MLB. Brazilian Protocol for Sexually Transmitted Infections, 2020: congenital syphilis and child exposed to syphilis. Revista da Sociedade Brasileira de Medicina Tropical. 2021:54(suppl 1):e2020597. doi: 10.1590/0037-8682-597-2020. Epub 2021 May 17     [PubMed PMID: 34008719]

[140]

Gonçalves FG, Caschera L, Teixeira SR, Viaene AN, Pinelli L, Mankad K, Alves CAPF, Ortiz-Gonzalez XR, Andronikou S, Vossough A. Intracranial calcifications in childhood: Part 1. Pediatric radiology. 2020 Sep:50(10):1424-1447. doi: 10.1007/s00247-020-04721-1. Epub 2020 Jul 30     [PubMed PMID: 32734340]

[141]

Cohen SE, Klausner JD, Engelman J, Philip S. Syphilis in the modern era: an update for physicians. Infectious disease clinics of North America. 2013 Dec:27(4):705-22. doi: 10.1016/j.idc.2013.08.005. Epub     [PubMed PMID: 24275265]

[142]

Morshed MG, Singh AE. Recent trends in the serologic diagnosis of syphilis. Clinical and vaccine immunology : CVI. 2015 Feb:22(2):137-47. doi: 10.1128/CVI.00681-14. Epub 2014 Nov 26     [PubMed PMID: 25428245]

[143]

Koh PX, Neo SX, Chiew HJ, Singh DR, Saini M, Chen Z. Syphilitic Spinal Disease: An Old Nemesis Revisited. A Case Series and Review of Literature. Sexually transmitted diseases. 2021 Sep 1:48(9):e126-e131. doi: 10.1097/OLQ.0000000000001391. Epub     [PubMed PMID: 33512899]

Level 2 (mid-level) evidence

[144]

Centurion-Lara A, Castro C, van Voorhis WC, Lukehart SA. Two 16S-23S ribosomal DNA intergenic regions in different Treponema pallidum subspecies contain tRNA genes. FEMS microbiology letters. 1996 Oct 1:143(2-3):235-40     [PubMed PMID: 8837477]

Level 3 (low-level) evidence

[145]

Tagarro A, García-Alix A, Alarcón A, Hernanz A, Quero J. Congenital syphilis: beta2-microglobulin in cerebrospinal fluid and diagnosis of neurosyphilis in an affected newborn. Journal of perinatal medicine. 2005:33(1):79-82     [PubMed PMID: 15841621]

Level 3 (low-level) evidence

[146]

Marra CM, Tantalo LC, Sahi SK, Maxwell CL, Lukehart SA. CXCL13 as a cerebrospinal fluid marker for neurosyphilis in HIV-infected patients with syphilis. Sexually transmitted diseases. 2010 May:37(5):283-7. doi: 10.1097/OLQ.0b013e3181d877a1. Epub     [PubMed PMID: 20393380]

Level 2 (mid-level) evidence

[147]

Yang L, Fu Y, Li S, Liu C, Liu D. Analysis of Treponema pallidum DNA and CXCL13 in Cerebrospinal Fluid in HIV-Negative Syphilis Patients. Infection and drug resistance. 2022:15():7791-7798. doi: 10.2147/IDR.S394581. Epub 2022 Dec 29     [PubMed PMID: 36600952]

[148]

Lorenz ZW, Nijhar S, Caufield-Noll C, Ghanem KG, Hamill MM. The Utility of Biomarkers in the Clinical Management of Syphilis: A Systematic Review. Sexually transmitted diseases. 2023 Aug 1:50(8):472-478. doi: 10.1097/OLQ.0000000000001813. Epub 2023 Apr 1     [PubMed PMID: 37010823]

Level 1 (high-level) evidence

[149]

Pastuszczak M, Jakiela B, Wielowieyska-Szybinska D, Jaworek AK, Zeman J, Wojas-Pelc A. Elevated cerebrospinal fluid interleukin-17A and interferon-γ levels in early asymptomatic neurosyphilis. Sexually transmitted diseases. 2013 Oct:40(10):808-12. doi: 10.1097/OLQ.0000000000000024. Epub     [PubMed PMID: 24275734]

[150]

Liu L, Xu D, Chen F, Cai S, Wei J, Deng J, Zheng J, Jin Q, Lun W. Identification of potential biomarkers for diagnosis of syphilis from the cerebrospinal fluid based on untargeted metabolomic analysis. Molecular omics. 2023 Jul 10:19(6):484-491. doi: 10.1039/d3mo00026e. Epub 2023 Jul 10     [PubMed PMID: 37185577]

[151]

Xie L, Li W, Ye WM, Xiao Y, Ke WJ, Niu JJ, Yang TC. Serum Ubiquitin C-Terminal Hydrolase-L1, Glial Fibrillary Acidic Protein, and Neurofilament Light Chain Are Good Entry Points and Biomarker Candidates for Neurosyphilis Diagnosis Among Patients Without Human Immunodeficiency Virus to Avoid Lumbar Puncture. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2023 Aug 14:77(3):472-479. doi: 10.1093/cid/ciad158. Epub     [PubMed PMID: 36929815]

[152]

Chen R, Lin LR, Xiao Y, Ke WJ, Yang TC. Evaluation of cerebrospinal fluid ubiquitin C-terminal hydrolase-L1, glial fibrillary acidic protein, and neurofilament light protein as novel markers for the diagnosis of neurosyphilis among HIV-negative patients. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2023 Feb:127():36-44. doi: 10.1016/j.ijid.2022.11.013. Epub 2022 Nov 15     [PubMed PMID: 36400375]

[153]

Marra CM, Sahi SK, Tantalo LC, Zetterberg H. Serum Neurofilament Light in Neurosyphilis: A Pilot Study. Sexually transmitted diseases. 2023 Jan 1:50(1):42-44. doi: 10.1097/OLQ.0000000000001717. Epub 2022 Sep 30     [PubMed PMID: 36194828]

Level 3 (low-level) evidence

[154]

Shen Y, Dong X, Liu J, Lv H, Ge Y. Serum Interleukin-26 is a Potential Biomarker for the Differential Diagnosis of Neurosyphilis and Syphilis at Other Stages. Infection and drug resistance. 2022:15():3693-3702. doi: 10.2147/IDR.S366308. Epub 2022 Jul 14     [PubMed PMID: 35859909]

[155]

Lewis DA, Young H. Syphilis. Sexually transmitted infections. 2006 Dec:82 Suppl 4(Suppl 4):iv13-5     [PubMed PMID: 17151044]

[156]

Hussain SA, Vaidya R. Congenital Syphilis. StatPearls. 2024 Jan:():     [PubMed PMID: 30725772]

[157]

Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clinical microbiology reviews. 2010 Oct:23(4):858-83. doi: 10.1128/CMR.00007-10. Epub     [PubMed PMID: 20930076]

[158]

Ducas J, Robson HG. Cerebrospinal fluid penicillin levels during therapy for latent syphilis. JAMA. 1981 Dec 4:246(22):2583-4     [PubMed PMID: 7299984]

[159]

Greene BM, Miller NR, Bynum TE. Failure of penicillin G benzathine in the treatment of neurosyphilis. Archives of internal medicine. 1980 Aug:140(8):1117-8     [PubMed PMID: 7396623]

Level 3 (low-level) evidence

[160]

Zenker PN, Rolfs RT. Treatment of syphilis, 1989. Reviews of infectious diseases. 1990 Jul-Aug:12 Suppl 6():S590-609     [PubMed PMID: 2201075]

Level 3 (low-level) evidence

[161]

Sullins AK, Abdel-Rahman SM. Pharmacokinetics of antibacterial agents in the CSF of children and adolescents. Paediatric drugs. 2013 Apr:15(2):93-117. doi: 10.1007/s40272-013-0017-5. Epub     [PubMed PMID: 23529866]

[162]

Yip DW, Gerriets V. Penicillin. StatPearls. 2024 Jan:():     [PubMed PMID: 32119447]

[163]

Fisher JF, Mobashery S. Constructing and deconstructing the bacterial cell wall. Protein science : a publication of the Protein Society. 2020 Mar:29(3):629-646. doi: 10.1002/pro.3737. Epub 2019 Nov 20     [PubMed PMID: 31747090]

[164]

Tomasz A. The mechanism of the irreversible antimicrobial effects of penicillins: how the beta-lactam antibiotics kill and lyse bacteria. Annual review of microbiology. 1979:33():113-37     [PubMed PMID: 40528]

[165]

Park JT, Uehara T. How bacteria consume their own exoskeletons (turnover and recycling of cell wall peptidoglycan). Microbiology and molecular biology reviews : MMBR. 2008 Jun:72(2):211-27, table of contents. doi: 10.1128/MMBR.00027-07. Epub     [PubMed PMID: 18535144]

[166]

Wise EM Jr, Park JT. Penicillin: its basic site of action as an inhibitor of a peptide cross-linking reaction in cell wall mucopeptide synthesis. Proceedings of the National Academy of Sciences of the United States of America. 1965 Jul:54(1):75-81     [PubMed PMID: 5216369]

[167]

Tipper DJ, Strominger JL. Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine. Proceedings of the National Academy of Sciences of the United States of America. 1965 Oct:54(4):1133-41     [PubMed PMID: 5219821]

[168]

Josephine HR, Kumar I, Pratt RF. The perfect penicillin? Inhibition of a bacterial DD-peptidase by peptidoglycan-mimetic beta-lactams. Journal of the American Chemical Society. 2004 Jul 7:126(26):8122-3     [PubMed PMID: 15225046]

[169]

Kohanski MA, Dwyer DJ, Collins JJ. How antibiotics kill bacteria: from targets to networks. Nature reviews. Microbiology. 2010 Jun:8(6):423-35. doi: 10.1038/nrmicro2333. Epub 2010 May 4     [PubMed PMID: 20440275]

[170]

Kawai Y, Kawai M, Mackenzie ES, Dashti Y, Kepplinger B, Waldron KJ, Errington J. On the mechanisms of lysis triggered by perturbations of bacterial cell wall biosynthesis. Nature communications. 2023 Jul 11:14(1):4123. doi: 10.1038/s41467-023-39723-8. Epub 2023 Jul 11     [PubMed PMID: 37433811]

[171]

Collart P, Poitevin M, Milovanovic A, Herlin A, Durel J. Kinetic study of serum penicillin concentrations after single doses of benzathine and benethamine penicillins in young and old people. The British journal of venereal diseases. 1980 Dec:56(6):355-62     [PubMed PMID: 7448577]

[172]

Patterson RA, Stankewicz HA. Penicillin Allergy. StatPearls. 2024 Jan:():     [PubMed PMID: 29083777]

[173]

Chen JR, Tarver SA, Alvarez KS, Tran T, Khan DA. A Proactive Approach to Penicillin Allergy Testing in Hospitalized Patients. The journal of allergy and clinical immunology. In practice. 2017 May-Jun:5(3):686-693. doi: 10.1016/j.jaip.2016.09.045. Epub 2016 Nov 23     [PubMed PMID: 27888034]

[174]

Sunagawa SW, Bergman SJ, Kreikemeier E, Watkins AB, Alexander BT, Miller MM, Schroeder D, Stohs EJ, Van Schooneveld TC, May SM. Use of a beta-lactam graded challenge process for inpatients with self-reported penicillin allergies at an academic medical center. Frontiers in allergy. 2023:4():1161683. doi: 10.3389/falgy.2023.1161683. Epub 2023 Jul 31     [PubMed PMID: 37588449]

[175]

Powell N, Stephens J, Kohl D, Owens R, Ahmed S, Musicha C, Upton M, Kent B, Tonkin-Crine S, Sandoe J. The effectiveness of interventions that support penicillin allergy assessment and delabeling of adult and pediatric patients by nonallergy specialists: a systematic review and meta-analysis. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2023 Apr:129():152-161. doi: 10.1016/j.ijid.2022.11.026. Epub 2022 Nov 28     [PubMed PMID: 36450321]

Level 1 (high-level) evidence

[176]

Ham Y, Sukerman ES, Lewis JS 2nd, Tucker KJ, Yu DL, Joshi SR. Safety and efficacy of direct two-step penicillin challenges with an inpatient pharmacist-driven allergy evaluation. Allergy and asthma proceedings. 2021 Mar 1:42(2):153-159. doi: 10.2500/aap.2021.42.200128. Epub     [PubMed PMID: 33685561]

[177]

Ramsey A, Staicu ML. Use of a Penicillin Allergy Screening Algorithm and Penicillin Skin Testing for Transitioning Hospitalized Patients to First-Line Antibiotic Therapy. The journal of allergy and clinical immunology. In practice. 2018 Jul-Aug:6(4):1349-1355. doi: 10.1016/j.jaip.2017.11.012. Epub 2017 Dec 11     [PubMed PMID: 29242142]

[178]

Shann S, Wilson J. Treatment of neurosyphilis with ceftriaxone. Sexually transmitted infections. 2003 Oct:79(5):415-6     [PubMed PMID: 14573840]

Level 3 (low-level) evidence

[179]

Shuja SH, Naeem U, Eqbal F, Shuja MH. Ceftriaxone - A plausible intervention for treating neurosyphilis? Annals of medicine and surgery (2012). 2022 Oct:82():104662. doi: 10.1016/j.amsu.2022.104662. Epub 2022 Sep 15     [PubMed PMID: 36268347]

[180]

Coyle M, Depcinski S, Thirumoorthi M. Prevention of congenital syphilis using ceftriaxone in a woman with Stevens-Johnson syndrome reaction to penicillin: A case report. Case reports in women's health. 2022 Oct:36():e00446. doi: 10.1016/j.crwh.2022.e00446. Epub 2022 Aug 20     [PubMed PMID: 36072694]

Level 3 (low-level) evidence

[181]

Bettuzzi T, Jourdes A, Robineau O, Alcaraz I, Manda V, Molina JM, Mehlen M, Cazanave C, Tattevin P, Mensi S, Terrier B, Régent A, Ghosn J, Charlier C, Martin-Blondel G, Dupin N. Ceftriaxone compared with benzylpenicillin in the treatment of neurosyphilis in France: a retrospective multicentre study. The Lancet. Infectious diseases. 2021 Oct:21(10):1441-1447. doi: 10.1016/S1473-3099(20)30857-4. Epub 2021 May 26     [PubMed PMID: 34051142]

Level 2 (mid-level) evidence

[182]

Cao Y, Su X, Wang Q, Xue H, Zhu X, Zhang C, Jiang J, Qi S, Gong X, Zhu X, Pan M, Ren H, Hu W, Wei Z, Tian M, Liu W. A Multicenter Study Evaluating Ceftriaxone and Benzathine Penicillin G as Treatment Agents for Early Syphilis in Jiangsu, China. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017 Oct 30:65(10):1683-1688. doi: 10.1093/cid/cix611. Epub     [PubMed PMID: 29020150]

Level 2 (mid-level) evidence

[183]

Hook EW 3rd, Baker-Zander SA, Moskovitz BL, Lukehart SA, Handsfield HH. Ceftriaxone therapy for asymptomatic neurosyphilis. Case report and Western blot analysis of serum and cerebrospinal fluid IgG response to therapy. Sexually transmitted diseases. 1986 Jul-Sep:13(3 Suppl):185-8     [PubMed PMID: 3764632]

Level 3 (low-level) evidence

[184]

Ahmed KA, Fox SJ, Frigas E, Park MA. Clinical outcome in the use of cephalosporins in pediatric patients with a history of penicillin allergy. International archives of allergy and immunology. 2012:158(4):405-10. doi: 10.1159/000333553. Epub 2012 Apr 5     [PubMed PMID: 22487723]

Level 2 (mid-level) evidence

[185]

Marra CM, Boutin P, McArthur JC, Hurwitz S, Simpson PA, Haslett JA, van der Horst C, Nevin T, Hook EW 3rd. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2000 Mar:30(3):540-4     [PubMed PMID: 10722441]

Level 3 (low-level) evidence

[186]

Novalbos A, Sastre J, Cuesta J, De Las Heras M, Lluch-Bernal M, Bombín C, Quirce S. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2001 Mar:31(3):438-43     [PubMed PMID: 11260156]

[187]

Cortés-Penfield NW, Musher DM. Give penicillin or ceftriaxone: neurosyphilis does not deal in absolutes. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2023 Oct 17:():. pii: ciad629. doi: 10.1093/cid/ciad629. Epub 2023 Oct 17     [PubMed PMID: 37847217]

[188]

Wang S, Gu W, Cao Y, Zheng H, Zhang L, Guo X, Chen W, Luo X. Comparison of the clinical efficacy of penicillin and ceftriaxone sodium in the treatment of neurosyphilis with psychiatric symptoms. World journal of psychiatry and mental health research. 2022 Jan 1:5(1):. pii: 1030. Epub 2021 Nov 30     [PubMed PMID: 35005746]

[189]

Ozturk-Engin D, Erdem H, Hasbun R, Wang SH, Tireli H, Tattevin P, Argemi X, Ouamara-Digue E, Gombos A, Lakatos B, Sırmatel F, Cag Y, Pekok AU, Senbayrak S, Balkan II, Gheno M, Uzun N, Kaya S, Cicek-Senturk G, Şengöz G, Tekin R, Çelen MK, Nayman-Alpat S, Ergen P, Şener A, Agalar C, Köse S, Inkaya AÇ, Kaptan F, Al-Majid F, Savasci U, Vahaboglu H. Predictors of unfavorable outcome in neurosyphilis: Multicenter ID-IRI Study. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2019 Jan:38(1):125-134. doi: 10.1007/s10096-018-3403-7. Epub 2018 Oct 27     [PubMed PMID: 30368740]

[190]

Xu N, Yuan JG, Dai QJ, Yuan C, He Y, Jiang TS, Zhu J. Syphilitic uveitis in HIV-positive patients: report of a case series, treatment outcomes, and comprehensive review of the literature. International journal of ophthalmology. 2023:16(8):1250-1259. doi: 10.18240/ijo.2023.08.10. Epub 2023 Aug 18     [PubMed PMID: 37602346]

Level 2 (mid-level) evidence

[191]

Du FZ, Wu MZ, Zhang X, Zhang RL, Wang QQ. Ceftriaxone compared with penicillin G for the treatment of neurosyphilis: study protocol for a multicenter randomized controlled trial. Trials. 2022 Oct 1:23(1):835. doi: 10.1186/s13063-022-06769-w. Epub 2022 Oct 1     [PubMed PMID: 36183101]

Level 1 (high-level) evidence

[192]

Spornraft-Ragaller P, Abraham S, Lueck C, Meurer M. Response of HIV-infected patients with syphilis to therapy with penicillin or intravenous ceftriaxone. European journal of medical research. 2011 Feb 24:16(2):47-51     [PubMed PMID: 21463980]

Level 2 (mid-level) evidence

[193]

Ke W, Fu L, Wang B, Leng X, Zou H. Is ceftriaxone similarly effective to benzylpenicillin in neurosyphilis? The Lancet. Infectious diseases. 2021 Sep:21(9):1207. doi: 10.1016/S1473-3099(21)00463-1. Epub     [PubMed PMID: 34450067]

[194]

Tantalo LC, Lieberman NAP, Pérez-Mañá C, Suñer C, Vall Mayans M, Ubals M, González-Beiras C, Rodríguez-Gascón A, Canut A, González-Candelas F, Mueller J, Tapia K, Greninger AL, Giacani L, Mitjà O. Antimicrobial susceptibility of Treponema pallidum subspecies pallidum: an in-vitro study. The Lancet. Microbe. 2023 Dec:4(12):e994-e1004. doi: 10.1016/S2666-5247(23)00219-7. Epub 2023 Oct 9     [PubMed PMID: 37827185]

[195]

Hartmane I, Ivdra I, Mikazans I, Princevs A, Teterina I, Bondare-Ansberga V, Reinberga L. Use of ceftriaxone as an alternative treatment method in pregnant women diagnosed with syphilis - a single centre experience. International journal of STD & AIDS. 2024 Feb:35(2):130-135. doi: 10.1177/09564624231206845. Epub 2023 Oct 23     [PubMed PMID: 37870192]

[196]

Gomes E Silva A, Alcântara Pedroso L, Veiga Costa F, de Moraes Perlingeiro R, Peixoto de Castro Oliveira P, Biancardi Barreto AL, Luiz Land Curi A. Intravenous Ceftriaxone on an Outpatient Basis in the Treatment of Ocular Syphilis. Ocular immunology and inflammation. 2023 Aug 15:():1-3. doi: 10.1080/09273948.2023.2232443. Epub 2023 Aug 15     [PubMed PMID: 37582224]

[197]

Yim CW, Flynn NM, Fitzgerald FT. Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent or neurosyphilis. Antimicrobial agents and chemotherapy. 1985 Aug:28(2):347-8     [PubMed PMID: 3834836]

[198]

Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2015 Jun 5:64(RR-03):1-137     [PubMed PMID: 26042815]

[199]

Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2006 Mar 15:42(6):e45-9     [PubMed PMID: 16477545]

Level 2 (mid-level) evidence

[200]

Wong T, Singh AE, De P. Primary syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin. The American journal of medicine. 2008 Oct:121(10):903-8. doi: 10.1016/j.amjmed.2008.04.042. Epub     [PubMed PMID: 18823862]

Level 2 (mid-level) evidence

[201]

Kingston M, French P, Higgins S, McQuillan O, Sukthankar A, Stott C, McBrien B, Tipple C, Turner A, Sullivan AK, Members of the Syphilis guidelines revision group 2015, Radcliffe K, Cousins D, FitzGerald M, Fisher M, Grover D, Higgins S, Kingston M, Rayment M, Sullivan A. UK national guidelines on the management of syphilis 2015. International journal of STD & AIDS. 2016 May:27(6):421-46. doi: 10.1177/0956462415624059. Epub 2015 Dec 31     [PubMed PMID: 26721608]

[202]

Lukehart SA, Godornes C, Molini BJ, Sonnett P, Hopkins S, Mulcahy F, Engelman J, Mitchell SJ, Rompalo AM, Marra CM, Klausner JD. Macrolide resistance in Treponema pallidum in the United States and Ireland. The New England journal of medicine. 2004 Jul 8:351(2):154-8     [PubMed PMID: 15247355]

Level 3 (low-level) evidence

[203]

Mitchell SJ, Engelman J, Kent CK, Lukehart SA, Godornes C, Klausner JD. Azithromycin-resistant syphilis infection: San Francisco, California, 2000-2004. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2006 Feb 1:42(3):337-45     [PubMed PMID: 16392078]

Level 2 (mid-level) evidence

[204]

A2058G Prevalence Workgroup. Prevalence of the 23S rRNA A2058G point mutation and molecular subtypes in Treponema pallidum in the United States, 2007 to 2009. Sexually transmitted diseases. 2012 Oct:39(10):794-8     [PubMed PMID: 23001267]

[205]

Stafford IA, Workowski KA, Bachmann LH. Syphilis Complicating Pregnancy and Congenital Syphilis. The New England journal of medicine. 2024 Jan 18:390(3):242-253. doi: 10.1056/NEJMra2202762. Epub     [PubMed PMID: 38231625]

[206]

Ropper AH. Neurosyphilis. The New England journal of medicine. 2019 Oct 3:381(14):1358-1363. doi: 10.1056/NEJMra1906228. Epub     [PubMed PMID: 31577877]

[207]

Turan S, Emul M, Duran A, Mert A, Ugur M. Effectiveness of olanzapine in neurosyphilis related organic psychosis: a case report. Journal of psychopharmacology (Oxford, England). 2007 Jul:21(5):556-8     [PubMed PMID: 17092977]

Level 3 (low-level) evidence

[208]

Tibrewal P, Kumar I, Zutshi A, Math SB. Valproate for treatment of agitation in neurosyphilis: a case report. Primary care companion to the Journal of clinical psychiatry. 2008:10(2):163     [PubMed PMID: 18458725]

Level 3 (low-level) evidence

[209]

Taycan O, Ugur M, Ozmen M. Quetiapine vs. risperidone in treating psychosis in neurosyphilis: a case report. General hospital psychiatry. 2006 Jul-Aug:28(4):359-61     [PubMed PMID: 16814638]

Level 3 (low-level) evidence

[210]

Oshita K, Saeki N, Niinai H, Hamada H, Kawamoto M. Successful treatment of tabetic lightning pain and visceral crisis with gabapentin. Journal of anesthesia. 2011 Dec:25(6):952. doi: 10.1007/s00540-011-1219-z. Epub 2011 Sep 29     [PubMed PMID: 21956795]

Level 3 (low-level) evidence

[211]

Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014 Nov 12:312(18):1905-17. doi: 10.1001/jama.2014.13259. Epub     [PubMed PMID: 25387188]

Level 1 (high-level) evidence

[212]

Marra CM, Maxwell CL, Tantalo L, Eaton M, Rompalo AM, Raines C, Stoner BP, Corbett JJ, Augenbraun M, Zajackowski M, Kee R, Lukehart SA. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2004 Apr 1:38(7):1001-6     [PubMed PMID: 15034833]

[213]

Marra CM, Maxwell CL, Tantalo LC, Sahi SK, Lukehart SA. Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clinical abnormalities after treatment of neurosyphilis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2008 Oct 1:47(7):893-9. doi: 10.1086/591534. Epub     [PubMed PMID: 18715154]

[214]

Xiao Y, Tong ML, Lin LR, Liu LL, Gao K, Chen MJ, Zhang HL, Zheng WH, Li SL, Lin HL, Lin ZF, Yang TC, Niu JJ. Serological Response Predicts Normalization of Cerebrospinal Fluid Abnormalities at Six Months after Treatment in HIV-Negative Neurosyphilis Patients. Scientific reports. 2017 Aug 30:7(1):9911. doi: 10.1038/s41598-017-10387-x. Epub 2017 Aug 30     [PubMed PMID: 28855625]

[215]

Cohen CE, Winston A, Asboe D, Boag F, Mandalia S, Azadian B, Hawkins DA. Increasing detection of asymptomatic syphilis in HIV patients. Sexually transmitted infections. 2005 Jun:81(3):217-9     [PubMed PMID: 15923288]

Level 2 (mid-level) evidence

[216]

Zetola NM, Klausner JD. Syphilis and HIV infection: an update. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2007 May 1:44(9):1222-8     [PubMed PMID: 17407043]

[217]

Katz DA, Berger JR, Duncan RC. Neurosyphilis. A comparative study of the effects of infection with human immunodeficiency virus. Archives of neurology. 1993 Mar:50(3):243-9     [PubMed PMID: 8442701]

Level 2 (mid-level) evidence

[218]

Cassidy RC, Shaffer WO. Charcot arthropathy because of congenital insensitivity to pain in an adult. The spine journal : official journal of the North American Spine Society. 2008 Jul-Aug:8(4):691-5     [PubMed PMID: 17602884]

Level 3 (low-level) evidence

[219]

Devlin VJ, Ogilvie JW, Transfeldt EE, Boachie-Adjei O, Bradford DS. Surgical treatment of neuropathic spinal arthropathy. Journal of spinal disorders. 1991 Sep:4(3):319-28     [PubMed PMID: 1802163]

[220]

Fiechter M, Bratelj D, Jaszczuk P, Capone C, Dragalina C, Pötzel T. Multi-rod fixation in spinal neuroarthropathy: a novel surgical technique. Journal of spine surgery (Hong Kong). 2023 Jun 30:9(2):176-185. doi: 10.21037/jss-22-103. Epub 2023 Mar 24     [PubMed PMID: 37435331]

[221]

Friedrich F, Aigner M, Fearns N, Friedrich ME, Frey R, Geusau A. Psychosis in neurosyphilis -- clinical aspects and implications. Psychopathology. 2014:47(1):3-9. doi: 10.1159/000350059. Epub 2013 May 22     [PubMed PMID: 23711816]

[222]

Dhakal A, Sbar E. Jarisch-Herxheimer Reaction. StatPearls. 2024 Jan:():     [PubMed PMID: 32491752]

[223]

Punia V, Rayi A, Sivaraju A. Stroke after Initiating IV Penicillin for Neurosyphilis: A Possible Jarisch-Herxheimer Reaction. Case reports in neurological medicine. 2014:2014():548179. doi: 10.1155/2014/548179. Epub 2014 Nov 5     [PubMed PMID: 25431710]

Level 3 (low-level) evidence

[224]

Davis LE, Oyer R, Beckham JD, Tyler KL. Elevated CSF cytokines in the Jarisch-Herxheimer reaction of general paresis. JAMA neurology. 2013 Aug:70(8):1060-4. doi: 10.1001/jamaneurol.2013.2120. Epub     [PubMed PMID: 23732875]

Level 3 (low-level) evidence

[225]

Wu Y, Wu W. Neurosyphilis presenting with myelitis-case series and literature review. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2020 Feb:26(2):296-299. doi: 10.1016/j.jiac.2019.09.007. Epub 2019 Dec 16     [PubMed PMID: 31859039]

Level 2 (mid-level) evidence

[226]

Berger JR, Dean D. Neurosyphilis. Handbook of clinical neurology. 2014:121():1461-72. doi: 10.1016/B978-0-7020-4088-7.00098-5. Epub     [PubMed PMID: 24365430]

[227]

Zou H, Lu Z, Weng W, Yang L, Yang L, Leng X, Wang J, Lin YF, Wu J, Fu L, Zhang X, Li Y, Wang L, Wu X, Zhou X, Tian T, Huang L, Marra CM, Yang B, Yang TC, Ke W. Diagnosis of neurosyphilis in HIV-negative patients with syphilis: development, validation, and clinical utility of a suite of machine learning models. EClinicalMedicine. 2023 Aug:62():102080. doi: 10.1016/j.eclinm.2023.102080. Epub 2023 Jul 19     [PubMed PMID: 37533423]

Level 1 (high-level) evidence