What is the epidemiology of Neurosyphilis? 

Since the advent of penicillin, rates of syphilis infection have dropped sharply but have become concentrated among people with lower socioeconomic status and have continued to wax and wane in 10- to 15-year cycles.

While neurosyphilis is not reported to the CDC, rates of primary and secondary syphilis increased from 2.9 to 5.3 per 100,000 between 2005 and 2013, with men being at much higher risk than women. 

What is the pathogenesis?

Syphilis is due to infection with the spirochete Treponema pallidum. 

As in other organs, the pathology of syphilis in the CNS is related to inflammation and fibroblast proliferation in the walls of blood vessels leading to luminal stenosis and ischemia.

Clinical manifestations vary based on the size of affected vessels.

What are the typical symptoms of neurosyphilis? 

Neurosyphilis is typically diagnosed by the combination of clinical presentation, routine CSF studies, and serologic tests, which can be divided into treponemal and nontreponemal.

Neurosyphilis is not synonymous with late or tertiary syphilis, with a variety of forms occurring over the lifespan of infection.

How is it diagnosed?

Common nontreponemal tests are the rapid plasma reagent and Venereal Disease Research Lab (VDRL) tests.

While both become elevated early in the disease course, levels fall in later stages of the disease.

A positive CSF VDRL is a highly specific but insensitive marker for diagnosis, with false positives due to pregnancy and a variety of infectious and autoimmune conditions. 

Treponemal tests include the fluorescent treponemal antibody (FTA) test, and T. pallidum hemagglutination assays (TP-HA) are highly sensitive but less specific.

While the VDRL titer falls following treatment, FTA-ABS and TP-HA remain positive for life. 

Neurosyphilis can follow a variety of clinical syndromes:

1. Syphilitic meningitis:

characterized by headache, meningismus, and possibly cranial nerve involvement. Typically occurs in the first 1 to 2 years of infection.

2. Meningovascular syphilis:

patients present with signs and symptoms of both meningitis and ischemic infarctions resulting in focal neurologic signs such as hemiparesis as well as seizures and altered mental status. Typically occurs in the first 10 years of infection.

3. Parenchymatous neurosyphilis (general paresis of the insane):

subacute to chronic dementing illness with impairment in memory, concentration, and potentially pain and ataxia due to tabes dorsalis. Late complication of untreated syphilis.

4. Tabes dorsalis:

due to involvement of the dorsal columns of the spinal cord and the dorsal root ganglia presenting with sensory ataxia, tabetic gait, positive Romberg’s sign, and lancinating pain. Late complication of untreated syphilis. Patton ME, Su JR, Nelson R, et al.: Primary and secondary syphilis—United States, 2005-2013. MMWR 63(18):402-406, 2014.

5. Gummatous neurosyphilis:

symptoms are related to location of gummatous mass lesion; rarely encountered today. Late complication of untreated syphilis.

6. Asymptomatic:

incidental finding upon lumbar puncture.

What is the differential diagnosis?

  • Syphilitic meningitis: viral or aseptic meningitis, Cryptococcus and TB meningitis should be considered in HIV-positive patients.
  • Meningovascular syphilis: other causes of stroke in the young such as either hypercoagulability or dissection.
  • Parenchymatous neurosyphilis: prion disease, autoimmune encephalitis, Hashimoto’s encephalopathy, paraneoplastic encephalitis, neurodegenerative conditions such as frontotemporal dementia, corticobasal syndrome, Alzheimer’s disease, dementia with Lewy bodies, and progressive supranuclear palsy.
  • Gummatous neurosyphilis: CNS tumors.

What are the expected CSF findings in neurosyphilis by manifestation? 

Regardless of symptomatic disease, the CSF of patients with neurosyphilis will likely show mildly elevated protein and mild lymphocytic pleocytosis. Glucose levels are often normal. 

How is this infection treated?

Treatment of neurosyphilis consists of benzathine penicillin 4 million units intravenously every 4 h for 10 to 14 days.

What are the important complications? 

  • Involvement of CN (cranial nerve) VII and VIII is common,
  • optic neuritis,
  • chorioretinitis,
  • retinal vasculitis,
  • neuroretinitis,
  • anterior or posterior uveitis.
  • Patients with radiculitis may develop bowel and bladder dysfunction as well as lancinating pains.
  • The Jarisch–Herxheimer reaction consists of fever, hypotension, tachycardia, headaches, and myalgias and may occur within 24 h of initiation of treatment due to release of antigens from dead spirochetes.

What is the effect of coinfection with HIV on neurosyphilis? 

HIV infection is widely believed to increase the risk of developing neurosyphilis.

Patients with HIV coinfection may be at increased risk of relapse despite appropriate treatment.


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