Infectious Disease Updates
October 1, 2024
By Carol A. Kemper, MD, FIDSA
Medical Director, Infection Prevention, El Camino Hospital, Palo Alto Medical Foundation
Managing Neurosyphilis
SOURCE: Hamill MM, Ghanem KG, Tuddenham S. State-of-Art Review: Neurosyphilis. Clin Infect Dis 2024;78:e57-e68.
This excellent review of the risks and management of neurosyphilis was a bit challenging to locate on the Oxford University Press website, and the recommendations are summarized here.
Introduction
The resurgence in syphilis during the past 10-15 years, worsened by the COVID pandemic and diminished access to sexually transmitted disease (STD) care, at least in the United States, has resulted in greater challenges for the clinician in the management of syphilis and concerns for possible neurosyphilis. Syphilis is a required public health reportable; neurosyphilis is not, and as such, the true prevalence of neurosyphilis is not known. Even the diagnosis of neurosyphilis may be challenging, given the variable presentations and difficulty interpreting serologic and cerebrospinal fluid (CSF) parameters.
Invasion of the central nervous system (CNS) with Treponema pallidum (TP) likely occurs early and more often than most realize. At least 30% of cases of primary or secondary disease without neurologic symptoms may have early invasion of the CNS, although most of these cases of asymptomatic early neurosyphilis resolve without specific treatment. Perhaps ~6% of these initially asymptomatic cases result in symptomatic syphilis meningitis, generally within 12 months of infection. A recent U.S.-based study of 468 persons with all stages of syphilis found 7.9% with vision or hearing changes and 3.5% had abnormal CSF and/or neurologic symptoms.
A brief review of the various presentations of neurosyphilis:
- Early asymptomatic meningitis may resolve on its own without specific CNS treatment.
- Early symptomatic meningitis generally is basilar, may be associated with cranial nerve findings, and can lead to arteritis, thrombosis, and hydrocephalus (within 12 months of infection).
- Meningovascular disease may be associated with CNS or spine meningovasculitis with acute stroke and/or cord involvement (within five to 12 years of infection, although it may have a more rapid onset in human immunodeficiency virus [HIV] infection).
- Parenchymatous involvement is a chronic progressive meningoencephalitis with slow loss of cognitive function, tremors, seizures, psychiatric symptoms, and dementia (> 15 years following infection).
- Tabes dorsalis is a slowly degenerative process affecting the dorsal column of the spine, predominately affecting proprioception (slapping feet) (20-25 years following infection).
- CNS gummas are rare (< 1%) space-occupying lesions, although in the spinal cord they may result in more frequent symptoms (anywhere from 2-40 years following infection).
- Otic and ocular syphilis may occur at any time following infection; any part of the eye may be affected.
Who Should Get a Lumbar Puncture?
- Any patient with syphilis with neurologic signs or symptoms;
- The exception is: Patients with otic or ocular syphilis do not require a lumbar puncture (LP); these patients receive treatment for neurosyphilis regardless. At least 30% will have an abnormal CSF.
- Any patient with syphilis with suspected cardiovascular syphilitic involvement;
- Any patient with a four-fold increase in serologic rapid plasma reagin (RPR) titer, despite stage-appropriate treatment (but consider the timing of the initial titer and when treatment was initiated);
- The approach to asymptomatic patients with serologic non-response (lacking a four-fold decrease in serologic titer) is more complex: generally the longer the duration of latent infection, the greater the time to serologic response, and I would recommend following titers for ~24 months before making a decision.
- Asymptomatic patients with serologic non-response and a titer > 1:32 should receive an additional three doses of benzathine penicillin G (BPG) and follow clinically; consider an LP; consider the likelihood the patient will be compliant with follow-up.
- Asymptomatic patients with serologic non-response and a titer ≤ 1:32 can be retreated with an additional three doses of BPG and followed clinically.
- If retreatment with an additional three doses of BPG is provided, and the titer remains stable, without symptoms, a third course of treatment is not necessary.
Consideration for Persons with HIV Infection
- Persons with syphilis and neurologic signs or symptoms require an LP.
- Despite a few earlier dramatic case reports, failures of treatment, especially in well-controlled HIV infection, appear similar to those without HIV, and the risks for neuroinvasion and neurosyphilis appear similar. Patients with untreated HIV infection may be at greater risk for neurologic complications.
Interpretation of CSF Findings
- CSF antibodies can be due to passive spillover from blood, and current tests cannot distinguish between low-level passive antibody and true CNS infection; therefore, low-level titers must be interpreted in the context of other CSF parameters; CSF visibly contaminated by blood cannot be interpreted.
- CSF Venereal Disease Research Laboratory (VDRL) test remains the gold standard for diagnosis of neurosyphilis but nonetheless lacks sensitivity (48% to 87%). RPR is even less sensitive in CSF and is not recommended. CSF Treponema pallidum antibody testing has limitations in both sensitivity and specificity, and requires interpretation within the context of other CSF parameters and the clinical presentation, and generally is not recommended.
- TP polymerase chain reaction (PCR) has poor sensitivity in CSF (40% to 70%).
- CSF pleocytosis > 5 cells per microliter is considered sensitive but not specific to neurosyphilis, depends on the presentation, and many cases of neurosyphilis may have no pleocytosis; the presence of pleocytosis is supportive evidence; the absence may not be.
- CSF protein — similar to CSF pleocytosis; the presence of elevated CSF protein is considered supportive evidence, but 50% of neurosyphilis cases may have a normal CSF protein.
Treatment of Neurosyphilis
- The mainstay of treatment remains 10-14 days of high-dose intravenous penicillin G (PCN G). There are no available studies comparing 10 vs. 14 days, and these experts recommend 10 days.
- Some clinicians choose to use a single dose of BPG following 10-14 days of intravenous (IV) PCN G treatment, despite a lack of supporting data, essentially providing a similar duration of treatment as one would do for latent syphilis.
- Ceftriaxone appears to be a reasonable alternative when necessary, and there are limited comparative data demonstrating its noninferiority to IV PCN G.
- Doxycycline is not recommended under any circumstances except perhaps for a patient who flatly refuses IV therapy.
- Steroids are not routinely recommended for neurosyphilis, with the exception of some cases of otic and optic involvement.
Follow-Up and Prevention
- Continue to follow serologic titers to response; I would recommend monitoring for at least 24 months before determining failure (which is rare).
- A repeat LP is not required to determine response to treatment.
- Keep in mind that many signs and symptoms of neurosyphilis do not necessarily improve or resolve with treatment.
- Doxycycline for post-exposure sexual prophylaxis may prevent up to 70% of cases of syphilis.
Combatting the Resurgence of Syphilis
SOURCE: Rubin R. Syphilis has surged for reasons that go beyond the pathogen that causes it. JAMA 2024;332:92-95.
Syphilis has continued its upward trend, reaching the highest number of cases in the United States in 2023 since the 1950s. There was a brief dip in cases during the first few months of social isolation with COVID, but, overall, cases have doubled since 2015. It is obvious the current approach of testing those who present with symptoms or other sexually transmitted infections (STIs) is not sufficient. In August 2023, the U.S. Department of Health and Human Services created a National Syphilis and Congenital Syphilis Syndemic (NSCSS) Federal Task Force to investigate and combat the factors contributing to the syphilis epidemic. The use of the word syndemic was telling, indicating the federal government acknowledges the importance of such social factors as sexual behavior and public health coupled with drug use and mental health, and homelessness. This article explores the problems contributing to the rise in syphilis cases:
- A main factor underlying this explosion in syphilis cases is the gradual reduction in public health dollars, both on the federal level as well as the state level, which has strained and even resulted in the elimination of many public health and mental health programs. This reduction in public health funding began with the recession in 2008 and continued through the Obama and Trump administrations — right up to the COVID pandemic. At present, there are only 300 public health laboratories in the United States. This infrastructure is not just critical to providing STI surveillance and treatment, but it provides treatment for tuberculosis and human immunodeficiency virus (HIV), environmental and water testing, waste-water testing for pathogens, and monitoring for foodborne illnesses. I live in California, one of the wealthiest states in the United States, and only 29 of the 61 health jurisdictions in California have a public health laboratory. I remember a time in the 1990-2000s when our county had 30 public health nurses who provided outreach for tuberculosis (TB), HIV, and STI contact tracing and treatment. The last I heard, there were nine public health nurses — for a county that is 90 miles long with nearly 2 million people.
- The COVID pandemic shocked this already strained system, resulting in a diversion of limited resources away from STI treatment and mental health. Many STI clinics were simply closed during COVID. To date, public health in many areas has not recovered, and many seasoned public health workers have quit or retired from extreme burnout. While COVID may have put a dent in people’s sex lives for a few months in early 2020, evidence suggests that sexual activity rebounded by June to July 2020. This three-month hiatus in sexual activity resulted in a transient dip in STI cases, which then was offset by the lack of access to STI clinics. As reported in Infectious Disease Alert in July 2021, Jenness et al calculated that if social (sexual) distancing lasted only three months and the diminished access to public health services lasted 18 months, an estimated excess 57,500 STI and 870 additional HIV cases would occur in the United States over the next five years.1
- The rise in drug use, especially methamphetamines and fentanyl, has been associated with an increase in STIs and syphilis.
- The lack of availability of benzyl penicillin G (BPG), coupled with the recent shortage in BPG, makes access to effective treatment more difficult. In January 2024, the U.S. Food and Drug Administration allowed benzathine benzylpenicillin to be imported from Italy. Just this week, we attempted to locate treatment for a patient — her primary care physician had already informed her they did not have BPG. We contacted a local urgent care in her area, which said they do not give BPG injections. She is going to have to drive more than two hours every week for three weeks for treatment at our facility.
- Targeted testing for syphilis obviously is failing. Similar to screening for latent TB, the provider’s perception of risk is key. However, studies suggest that even when an electronic record flags a chart for STI screening based on simple criteria (high-risk sexual behavior, a history of STI, and pregnancy), only a minority are screened.
- There is a lack of access to primary care, in part because of insurance issues but also because of a burgeoning shortage of primary care physicians. Many individuals receive their only care through local emergency rooms. Capturing this population when they present for care is critical. In 2019, the University of Chicago began a pilot program to provide universal syphilis screening for all emergency room visits.
- Syphilis surveillance during pregnancy is imperfect. Forty-five states require prenatal screening, but the time testing is required differs between states: 84% require first-trimester screening; 17% require third-trimester screening; a few require first-trimester screening along with late-trimester screening for those at risk; and a few require testing at the time of delivery. But prenatal care is haphazard in this country, especially for women with mental health issues or substance use, and screening is not always done. And there are no penalties for failure to screen. There was an opportunity to screen the woman with syphilis described earlier when she was pregnant 12 years ago (in California), but none was performed.
- Ironically, modern technology has made contact tracing harder. Apps for sexual hook-ups make anonymous sex easier, which makes contact tracing impossible. Outbreaks of syphilis often can be traced to large sex parties, where partner identification may not be possible. The increase in homelessness renders contact tracing difficult. People may not have a fixed address or a publicly available phone number.
- And finally, syphilis serologies can be confusing. There is just too much ambiguity in syphilis serologies: which test is falsely positive, which is falsely negative. I often hear primary care physicians say they no longer feel “comfortable” making a diagnosis or offering treatment for syphilis.
What can be done:
- Expand public health dollars, infrastructure, laboratory support, with integrated modern computer systems and electronic medical records, and beef up the public health workforce.
- Expand availability of STI treatment centers.
- Increase the feet-on-the-ground outreach for healthcare among the homeless.
- Have universal screening for syphilis, similar to HIV, especially when individuals are in contact with emergency rooms, urgent care, and primary care.
- Provide improved prenatal care and universal screening for pregnant women at least once during every pregnancy; consider repeat testing in the third trimester or at the time of delivery.
- Improve access and availability of BPG.
- Expand use of doxycycline for post-exposure prophylaxis, which reduces the risk of syphilis and other STIs; one expert referred to it as the “morning-after pill for STI.”
- Improve education of our primary care providers for interpretation of syphilis serologies, coupled with clearer guidance on treatment. Keep it simple.
- And the big-ticket item: Expand treatment for mental health and substance use disorder.
REFERENCE
- Jenness SM, Le Guillou A, Chandra C, et al. Projected HIV and bacterial sexually transmitted infection incidence following COVID-19-related sexual distancing and clinical service interruption. J Infect Dis 2021;223:1019-1028.
Managing Neurosyphilis; Combatting the Resurgence of Syphilis
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