EM@3AM: Neurosyphilis

  • Nov 2nd, 2024
  • Jarvis Garner
  • categories:
    em@3am

Authors: Jarvis Garner, MD (EM Resident Physician, UT Southwestern – Dallas, TX); Emmanuel Ohuabunwa, MD, MBA (Assistant Professor of EM/Attending Physician, UT Southwestern – Dallas, TX) // Reviewed by: Sophia Görgens, MD (EM Physician, BIDMC, MA); Cassandra Mackey, MD (Assistant Professor of Emergency Medicine, UMass Chan Medical School); Alex Koyfman, MD (@EMHighAK)

Welcome to EM@3AM, an emDOCs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.

A 51-year-old male with a history of AIDS presents to the ED accompanied by his partner with complaints of cognitive decline and confusion over one month. Per the patient’s partner, he has not experienced any fevers, chills, cough, congestion, or recent illness and was not complaining of headaches or vision changes. The partner does not know of any other medical history.

Vital signs reveal a temperature of 98.8F, a BP of 115/98, an HR of 72, and RR 16 with an O2 saturation of 98% on room air. On exam, the patient is alert but not oriented to person, place, or time. Hyporeflexia is noted on patellar DTRs. On ocular examination, constriction of the pupils is noted when the eyes are focused on a nearby object but not when the pupils are illuminated. A broad workup is initiated for altered mental status, including an STD panel, which shows a reactive Venereal Disease Research Laboratory (VDRL) and a negative CT head. Cerebrospinal fluid (CSF) studies are obtained in the recumbent position for opening pressures. The CSF studies return positive for CSF VDRL as well as for CSFfluorescent treponemal antibody-absorption test (FTA-ABS), with 75 WBCs/microL and a CSF protein of 60 mg/dL and elevated opening pressures. Neurology is consulted, treatment is started, and the patient is admitted to the hospital for further management.

Question: What is the most likely diagnosis?

Answer: Neurosyphilis

 

Introduction

  • Neurosyphilis is a clinical manifestation of syphilis, a rapidly disseminating sexually transmitted infection caused by the spirochete Treponema pallidum, and humans are the only known host [1]
  • Neuroinvasion by the treponeme may occur in the days following primary infection and is often asymptomatic.
  • Ocular and auditory manifestations of syphilis are considered a form of neurosyphilis and are generally seen in 3% to 5% of all individuals infected with syphilis in the US [3,4]
  • Syphilis is traditionally classified into three stages: primary, secondary, and tertiary [1]. However, neurosyphilis can occur at any stage after infection, and those with co-existing HIV infection may manifest neurological symptoms earlier than those without [2]
  • The following is a brief description of the stages of syphilis [1]
  • Primary syphilis: T. pallidum enters the body, causing a painless, firm, round ulcer known as a chancre typically forms at the site of infection.
  • Secondary syphilis: T. pallidum disseminates throughout the bloodstream, causing symptoms such as a rash, fever, swollen lymph nodes, and genital sores. While these symptoms typically resolve within weeks, they can persist for up to a year.
  • Tertiary syphilis: This stage typically emerges months to decades after the initial infection and can present with cardiovascular issues, neurological disorders, and tumors in the skin, bones, or liver. This stage can result in permanent disability or be life-threatening.

 

There are three forms of neurosyphilis with five stages (refer to the table below) [2,3,4]

Early forms

  • Asymptomatic
  • Meningeal
  • Diffuse inflammation of the meninges

Early or late forms

  • Meningovascular
    • Inflammation of the meninges and endarteritis causing thrombosis and infarction of cerebral tissue

Late forms

  • General syphilitic paresis (muscle weakness)
    • Chronic meningoencephalitis leading to brain atrophy
  • Tabes dorsalis
    • Destruction of the posterior (dorsal) column and roots of the spinal cord

 

Epidemiology

  • Syphilis has been a reportable disease in the United States since 1941, but surveillance of neurosyphilis is inconsistent, and population-based data are scarce [3,5].
  • During the decade of the 1990s, trends showed a year-to-year decline that reached a nadir in the year 2000. Since then, rates of syphilis have been on the rise [2,5].
  • The rate of syphilis is highest among men who have sex with men (MSM) and is estimated to be 15 to 20 times greater than the general male population [6].
  • Neurosyphilis is more prevalent in people who are also at risk for HIV and generally manifests in people with untreated HIV [7].
  • Recent trends have shown an alarming surge of syphilis among women and of congenital syphilis (i.e., vertical transmission) [8].

 

Pathophysiology

  • The bacterium T. pallidum gains access through small abrasions in the skin and mucous membranes. The treponeme rapidly disseminates to areas distant from the portal of entry [3].
  • CNS infection occurs in almost all people with syphilis, but often, natural eradication from the CSF occurs without any clinical symptoms [3,9].
  • The development of an inflammatory process is largely due to the infiltration of lymphocytes and plasma cells which ultimately result in nerve damage (e.g., demyelination as in tabes dorsalis) and subsequent death [10].

 

ED Evaluation

Neurosyphilis is known as a “great imitator” due to the extensive variability of nonspecific symptoms [11].

Diagnosing neurosyphilis is challenging and requires a combination of a high index of suspicion, history, clinical findings, serologies of blood and CSF, and imaging studies [3].

 

History and Physical [12]

Clinical recognition necessitates epidemiological information and a high index of suspicion. Thus, a complete history including a social and sexual history are essential.

The following is a list of some of the most common signs and symptoms in order of frequency.

 

Symptoms:

  • Personality change (i.e., cognitive and behavioral impairment) – 33%
  • Ataxia – 28%
  • Stroke – 23%
  • Ophthalmic symptoms (e.g., blurred vision, photophobia) – 17%
  • Urinary symptoms (e.g., bladder incontinence) – 17%
  • Headache – 10%
  • Lighting pains – 10%
    • Often described as sudden, rapidly spreading and disappearing [13]
  • Dizziness – 10%
  • Hearing loss – 10%
  • Seizures – 7%

 

Signs:

  • Hyporeflexia – 50%
  • Sensory impairment (e.g., decreased proprioception, loss of vibration sense, vertigo) – 48%
  • Pupillary changes (e.g., anisocoria, Argyll Robertson pupils) – 43%
    • Argyll Robertson pupils – constriction of the pupils when the eyes are focused on a nearby objection but not when the pupil is illuminated [2]
  • Cranial neuropathy – 36%
  • Dementia, mania, or paranoia – 35%
  • Romberg sign – 24%
  • Charcot joint – 13%
  • Hypotonia – 10%
  • Optic atrophy – 7%

 

Stages of neurosyphilis [2,3,4]

Laboratory

  • Diagnosing neurosyphilis is challenging due to the lack of definitive tests [3]
  • It requires a combination of clinical findings, patient history, imaging, serology, and CSF analysis [3]
  • In early neurosyphilis, treponemal and nontreponemal tests are usually positive in both the serum and cerebrospinal fluid (CSF), making these tests key indicators for diagnosis during the initial stages [3]
  • Treponemal tests are highly sensitive but non-specific (due to spillover from blood markers), they can be used to rule out the disease
    • Treponema tests include fluorescent treponemal antibody absorption (FTA-ABS), T pallidum particle agglutination assay (TPPA), T pallidum hemagglutination assay (TPHA), and enzymatic immunoassays (EIAs).
  • Non-treponemal tests tend to decline over time; these tests can be used to track disease progression and response to therapy. However, the CSF VDRL assay is considered the most suggestive single test for neurosyphilis if positive, with a reported sensitivity from 67% to 72%
    • Non-treponemal tests include the Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR)
  • Patients with syphilis and neurological signs and symptoms should have a lumbar puncture with CSF testing [4]

 

CSF testing

CSF antibodies [16]

  • These antibodies may represent transudation from blood into CSF or intrathecal production, and available testing cannot reliably distinguish between the two.
  • IgG Predominant with low IgM and absent IgA
  • CSF VDRL is the gold standard test and the only non-treponemal test recommended by the CDC [4]
    • The test lacks sensitivity (27-98.3%); the specificity is somewhere between 74-100% [17]
    • Visibly blood-stained CSF should not be used for assessment. This is because assays are unable to determine is the antibodies are from blood or CSF in origin [18,19]
    • A positive CSF-VDRL establishes the diagnosis of neurosyphilis, but a nonreactive test does not exclude the diagnosis [20]
  • CSF FTA (fluorescent treponemal antibody) test and CSF TPPA (Treponema pallidum particle agglutination) assay are the only treponemal tests included in the CDC guidelines [4,21]
    • CSF FTA is sensitive but lacks specificity
  • CSF pleocytosis [22]
    • Considered to be >5 WBC/microL, but neurosyphilis can occur with a CSF WBC <5 microL
  • CSF protein is the least discriminating CSF parameter a typical cutoff value is >0.45 g/L but this varies between laboratories [23]
  • CSF PCR for T. pallidum [4]
    • Highly sensitive for primary and most secondary lesions but does not have correspondingly high sensitivity on CSF and has not been cleared by the US FDA

 

Imaging

  • Not required as part of the neurosyphilis work up unless another pathology is suspected or clinical evidence of increased intracranial pressure is present [4]
  • MRI maybe more sensitive than CT in detecting brain infarcts in meningovascular neurosyphilis [24]
    • Neurosyphilis shows an extensive variation of MRI patterns [25]

 

Treatment [4,26]

Recommended therapies for neurosyphilis (CDC practice guideline)

  • The CDC does not recommend the routine use of steroids for neurosyphilis
  • The CDC does not recommend the use of doxycycline for neurosyphilis
  • Patients allergic to penicillin should be desensitized and treated with IV penicillin
  • Some experts recommend an additional dose of penicillin G benzathine (2.4 M units IM once) after completing IV therapy
  • Jarisch Herxheimer Reaction [27]
    • Occurs within 24 hours after starting antibiotic treatment and is transient
      • Mechanism is unclear but thought to be from breakdown of spirochetes causing the release of toxins and cytokines
    • Typical symptoms: fever, chills, nausea, vomiting, headache, tachycardia, hypotension, hyperventilation, flushing, myalgia and skin lesions
    • Mild reactions are self-limiting and spontaneously resolve
    • Treatments have been directed at controlling the manifestations and have included: antipyretics, crystalloid infusion, corticosteroids, vasopressors, inotropic support, and transient dialysis

 

Disposition [3, 12]

  • Admission to the hospital is necessary for antibiotic continuation as the recommended treatment should be administered every 4 hours for 10-14 days.
  • Consultation with an infectious disease and neurology specialist can be considered to guide treatment and proper disposition.

 

Pearls

  • Neurosyphilis can be asymptomatic, or it may result in a range of clinical symptoms, which include meningeal, meningovascular, general syphilitic paresis, and tabes dorsalis.
  • Diagnosis of neurosyphilis is confirmed through patient history, serum serology, and cerebrospinal fluid analysis.
  • Ocular and otic symptoms may occur at any stage of infection and are considered forms of neurosyphilis.
  • The most reliable laboratory test is a positive CSF-VDRL, although it may yield negative results in some cases.
  • The CSF FTA-ABS test plays a crucial role in diagnosing neurosyphilis, as a negative result reliably excludes both neurosyphilis and CNS involvement.
  • Penicillin remains the mainstay of treatment. Neurosyphilis should be treated with aqueous crystalline penicillin G according to the CDC guidelines
  • The Jarisch-Herxheimer reaction is expected in patients with high antibody titers. Treatment is supportive.

Which of the following is most consistent with a diagnosis of neurosyphilis?

A) Reactive fluorescent treponemal antibody absorption test and rash on soles of feet

B) Reactive rapid plasma reagin titer and diminished visual acuity

C) Reactive Treponema pallidum particle agglutination assay and genital chancre

D) Reactive venereal disease research laboratory test and palpable epitrochlear node

 

 

 

 

 

Answer: B

Syphilis has varying manifestations depending on the stage of the disease. After infectious exposure, primary and secondary syphilis develop within a few weeks to a few months. Although these early-stage symptoms typically resolve spontaneously even in the absence of treatment, up to 40% of untreated individuals can subsequently develop tertiary syphilis. In addition, both secondary and late-stage (tertiary) syphilis can result in neurosyphilis.

The early manifestations of neurosyphilis occur during the secondary stage and include headache, meningitis, stroke, hearing loss, and ocular findings. Eye involvement has been increasing in recent years, is most commonly secondary to posterior uveitis, and presents with diminished visual acuity. Urgent treatment is required for ocular syphilis to prevent retinal involvement and blindness. Early forms of neurosyphilis are most frequently observed in individuals with HIV.

CNS involvement in the late stages of syphilis includes general paresis and tabes dorsalis. General paresis (previously known as general paralysis of the insane) usually presents 10–25 years after the initial infection and is a progressive dementia that may or may not be accompanied by abnormal findings on physical exam (e.g., dysarthria, hypotonia, intention tremor).

Symptoms of tabes dorsalis, which is a disease of the posterior columns of the spinal cord and dorsal roots, include sensory ataxia, absent lower extremity reflexes, Argyll Robertson pupil (small, contracts to accommodation but not to light, lack of dilation to painful stimuli), and lancinating back, limb, or face pains. Common non-neurologic manifestations of tertiary syphilis include cardiovascular involvement (particularly aortitis) and gummatous syphilis, which typically involves nodular, granulomatous lesions of the skin and bones. Late syphilis is uncommon, and its incidence may have been reduced partially due to the use of antibiotics for other infections in asymptomatic individuals with untreated early syphilis.

Laboratory testing protocols vary. Nontreponemal tests, such as the rapid plasma reagin (RPR) test and the venereal disease research laboratory (VDRL) test, are based on the reactivity of serum to a cardiolipin-cholesterol-lecithin antigen. Although they are sensitive screening tests, there is an elevated false-positive rate associated with other conditions (e.g., pregnancy, recent immunization, rickettsial disease, autoimmune disorders, HIV). Nontreponemal tests have the advantage of being quantitative tests. As a result, the value of the titer may be helpful in determining whether an infection is acute and whether treatment is effective. However, nontreponemal tests may be nonreactive in very early or late syphilis, as well as in immunocompromised individuals (particularly HIV infected). In the case described above, ocular symptoms represent the secondary stage of syphilis but early stage of neurosyphilis, at which time a nontreponemal test would be expected to demonstrate an elevated titer, and a treponemal test would also be positive.

Treponemal tests, such as the fluorescent treponemal antibody absorption test (FTA-ABS), Treponema pallidum enzyme immunoassay (TP-EIA), and microhemagglutination test for antibodies to Treponema pallidum (MHA-TP), are qualitative tests and are specific for syphilis. Treponemal tests remain positive after initial infection and thus are not able to clarify whether there is an acute infectious process present. Confirming the presence of active syphilis is based on the results of both a nontreponemal and treponemal test. Diagnosing neurosyphilis requires clinical suspicion and a spinal fluid examination, including a VDRL, lymphocyte count, and protein level. Consultation with laboratory or infectious disease experts is important in selecting appropriate diagnostic testing. The mainstay of treatment for all stages of syphilis is penicillin.

A reactive fluorescent treponemal antibody absorption test and a rash on the soles of the feet (A) is consistent with secondary syphilis. Even as the initial chancre heals, there is widespread dissemination of the infectious agent within the body. This sets the stage for progression to secondary, tertiary, and neurosyphilis. Approximately 25% of infected individuals will demonstrate systemic symptoms consistent with secondary syphilis, such as fever, rash, and adenopathy. The classic rash involves the entire trunk and extremities and is diffuse, symmetric, and macular or papular. Involvement of the palms and soles should alert the clinician to the possibility of secondary syphilis.

A reactive Treponema pallidum particle agglutination assay and a genital chancre (C) is consistent with primary syphilis, which generally presents with a painless papule at the site of inoculation. Subsequent ulceration reveals a 1–2 cm ulcer with a raised and indurated margin, the classic syphilitic chancre. Lesions develop at the site of inoculation, which is most frequently on the genitals. Other sites include the posterior pharynx, vagina, or anus. Since the chancre is typically painless, may not be visible, and heals spontaneously without treatment, it may go unrecognized by the individual and result in transmission to others.

A reactive venereal disease research laboratory test and a palpable epitrochlear node (D) is consistent with secondary syphilis. Palpable epitrochlear nodes indicate a disease process and, in particular, forearm or hand infection, secondary syphilis, lymphoma, tularemia, or sarcoidosis. In the context of syphilis, the epitrochlear nodes are typically firm, rubbery, and only minimally tender.

References:

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