Neurosyphilis: When an Antipsychotic Is Not Enough

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TALES FROM THE CLINIC

-Series Editor Nidal Moukaddam, MD, PhD

In this installment of Tales From the Clinic: The Art of Psychiatry, we visit the emergency department (ED) and discuss a case of psychosis likely due to neurosyphilis, known in the literature as “the great imitator,” as it can mimic symptoms of other diseases. Syphilitic infection rates are on the rise in the US, and more cases of antibiotic resistance are reported. Of interest for this series is the reminder that a thorough medical workup is necessary before symptoms are labeled as being of primary psychiatric origin.

Case Vignette

“Ms Kate” is a 45-year-old woman with a history of hypertension, polysubstance use, and no past psychiatric history of psychotic disorder, who was brought to the ED by emergency medical services after exhibiting bizarre behavior at her apartment. She called 911 to report dead bodies in her neighbor's apartment, but when police arrived, they found nothing unusual except Ms Kate, an irascible 911 caller complaining about the tracker in her ear, alleged dead bodies in the building, and that her husband was going to kill her. In the ED, Ms Kate is unable to participate in an interview and demands that you “take the tracker out of my ear and discharge me.” She is cooperative with labs but is displaying agitated behavior while interacting with staff and is observed to verbally respond to internal stimuli when left alone.

On physical exam, she has poor dentition, is disheveled, malodorous, and has dilated pupils that are unresponsive to light. Her disorganized and agitated behavior, along with her history, places her at an acutely elevated risk of self-harm. Despite wanting to leave, she is kept for observation and further work-up. Becoming increasingly angry, Ms Kate begins yelling, threatening staff, and throwing things. She is restrained and given 2 mg of lorazepam, 10 mg of haloperidol, and 50 mg of diphenhydramine intramuscularly. Despite this, she continues to be agitated and responds to internal stimuli for 2 hours even after receiving an additional dose of haloperidol. Only a dose of midazolam finally helps her sleep. Lab results show an elevated white count, a urine drug screen positive for amphetamines, and a positive rapid plasma reagin (RPR) test. Chart review reveals a prior positive RPR more than 10 years ago, and it was later confirmed that Ms Kate never got treatment.

What Is Neurosyphilis?

Table. Stages of Neurosyphilis

Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum. Syphilis has been referred to as “the great imitator,” as it can present many different ways¹; however, there are certain key features that are commonly associated with each stage of infection. Primary infection presents as a chancre, a painless ulcer forming within 3 to 4 weeks of exposure.² If untreated, it progresses to secondary syphilis, characterized by a diffuse, rough, red or brown rash that can spread to the whole body and can include the palms and soles.³ Neurosyphilis occurs when the infection invades the blood-brain barrier and colonizes the cerebrospinal fluid (CSF).⁴ Neurosyphilis may occur during any stage of syphilis (Table). Approximately 25% to 40% of patients experience neuroinvasion during the course of the disease with a majority of patients clearing the infection without developing symptoms of or requiring treatment for neurosyphilis.¹ Late forms of syphilis causing general paresis and tabes dorsalis are considered a tertiary infection.⁵ Essentially, the more mature the infection, the more pervasive the symptoms become. Latent syphilis occurs when primary and secondary stages of the disease’s presentation improve despite no treatment and patients become asymptomatic but still positive on serologic studies. Approximately one third of patient without treatment develop tertiary syphilis 20 to 40 years after primary infection, with cardiovascular and/or neurological involvement. Neurosyphilis is considered tertiary only when it develops during the late latent course of the disease, otherwise neurological symptoms may occur during any phase of infection including primary and secondary stages.¹

Syphilis has been prevalent throughout modern society and has a long, complex history across the globe. Some hypotheses suggest that the endemic infection we know today, or something very closely related, first emerged in 7000 BC, and spread to Europe from South-Western Asia in 3000 BC.⁶ Many argue that syphilis was brought to the Americas from Europe in 1492, but other studies suggest the existence of the organism prior to the arrival of colonialism.⁶ Over the past 600 years or so, T. pallidum was not unique to any one group, as it has infected common folk, royalty, artists, philosophers, and more. Even Al Capone allegedly developed neurosyphilis in his later years.⁶ That said, the landscape radically changed with the widespread adoption of penicillin. Before antibiotics, asymptomatic neurosyphilis was developed in 25% to 35% of patients with early syphilis and 13.5% of those with tertiary syphilis.⁵ Following World War II, and coinciding with the widespread availability of antibiotics, the incidence in the US and other industrial countries decreased from 76 per 100,000 people in 1945 to 4 per 100,000 almost a decade later.¹ Today, it is most frequently diagnosed in those coinfected with HIV.⁷

When T. pallidum colonizes the CSF and invades the central nervous system, patients can present with severe neurological complications.⁴ Symptoms can include headache, neck stiffness, sensory ataxia, bladder dysfunction, severe neuralgia, incontinence, and Argyll Robertson pupils—an appropriate pupillary constriction to accommodation, but not to light.² Severe neurosyphilis can lead to dementia and other neuropsychiatric symptoms years after the initial infection.³ If untreated, neurosyphilis can lead to severe and permanent neurological damage, psychiatric symptoms, and cognitive decline. The prognosis of neurosyphilis largely depends on the stage of diagnosis and treatment.^2,3,5 When treated too late, or not at all, it can have life-long complications.

Discussion

Severe T. pallidum infection may be asymptomatic for years but can present with a variety of nonspecific psychiatric symptoms.⁴ Early symptoms may include personality changes and emotional instability, which can be confused with other psychiatric disorders.^2,3 Later symptoms may progress to depression, manic-like behavior, and even psychosis.³ To complicate matters further, those with histories of homelessness, sex work, or polysubstance abuse are at higher risk of contracting an initial infectionand should be tested for syphilis if presenting with bizarre behavior and psychosis.⁸

Polysubstance use and syphilis are common comorbidities, and treatment of one often needs to be considered in the context of the other. Substances like methamphetamine and phencyclidine (PCP) can exacerbate symptoms of neurosyphilis specifically, leading to severe neurotoxicity, cognitive decline, paranoia, anxiety, and psychosis.^3,5,9,10 Drug-induced psychosis, such as that from PCP or methamphetamine, typically responds to antipsychotic medication, which blocks D2 dopamine receptors and reduces symptoms.¹¹

Psychosis secondary to neurosyphilis, on the other hand, is often caused by structural damage to the brain. Direct infection and subsequent inflammation, immune response, neuronal damage, and general encephalopathy may result in psychotic features that are not directly caused by a neurotransmitter imbalance, and therefore can be refractory to antipsychotic medication.^11,12 Overall, chronic infection and inflammation can lead to permanent CNS changes, making the brain less responsive to antipsychotic medications.¹² These drugs may temporarily mitigate symptoms but will not treat the infection or significantly improve CNS damage.

A standard psychiatric workup in the ED should include vital signs, a metabolic panel, a complete blood count, a urinalysis with microscopic analysis, a urine drug screen, a TSH with free T4, and a treponemal and/or nontreponemal tests. Serum nontreponemal tests include venereal disease research laboratory (VDRL) or rapid plasma reagin (RPR). The serum treponemal tests include fluorescent treponemal antibody absorption (FTA-ABS), T. Pallidum particle agglutination assay (TPPA), and T. Pallidum enzyme immunoassay (TP-EIA). Confirmation of active syphilis infection is very likely when tests from both categories are positive; however, nontreponemal tests may be nonreactive in late neurosyphilis.¹³ For this reason, serum treponemal tests should always be performed as they should remain reactive for life regardless of treatment history. That said, if neurosyphilis is truly suspected, definitive diagnosis is confirmed with a lumbar puncture (LP) and CSF examination.^3,5

Neurosyphilis can occur at any time during a T. Pallidum infection, but its management requires significantly more comprehensive treatment than that for primary syphilis. In early syphilis, a since intramuscular dose of 2.4 million units of Penicillin G is sufficient for treatment.^2,3,5,14 To achieve adequate CNS penetration, the treatment of neurosyphilis, on the other hand, consists of aqueous penicillin G 3 to 4 million units IV every four hours for 10 to 14 days.^3,5 Early treatment with penicillin can prevent disease spread, but chronic syphilis may be refractory to single doses and persist despite treatment. In some instances of late neurosyphilis, those with severe symptoms, an additional IM dose of 2.4 million units may be recommended after the IV course. Neurological examination and LP should be repeated every 6 months following treatment until the CSF white blood cell count (WBC) is normal and the CSF-VDRL is nonreactive.³ Retreatment may be indicated if the follow up CSF WBC is seen to be increased or the CSF-VDRL shows a significant increase in titer.³ The mainstay of treatment is penicillin, and the more pervasive the infection, the more involved the treatment must be to combat it.

The psychiatric management of psychosis secondary to neurosyphilis ultimately involves treating the underlying infection.^3-5 Antipsychotics may help manage symptoms, but can be less effective than in psychosis secondary to neurotransmitter imbalance.^11,12,15 Patients with concurrent illicit substance abuse pose additional challenges, requiring careful management to ensure adherence to treatment and observation to avoid misuse of vascular access sites. Close monitoring and a comprehensive care plan involving addiction specialists and regular follow-up are recommended.

Concluding Thoughts

Neurosyphilis, though less common today, remains a critical diagnostic consideration in patients presenting with neuropsychiatric symptoms, particularly those with risk factors such as polysubstance abuse, homelessness, and sex work. Differentiating neurosyphilis from substance-induced psychosis involves a comprehensive workup, including serologic and CSF tests. Early and appropriate treatment with penicillin is crucial to prevent long-term neurological damage. Managing neurosyphilis requires a multidisciplinary approach, addressing both the infection and any concurrent psychiatric and substance use issues, to improve patient outcomes and quality of life.

Mr Hendricks is a medical student at Texas A&M EnMed and he is interested in emergency medicine. Dr Safavi is the system director of emergency psychiatry at Houston Methodist, an assistant professor of Psychiatry & Behavioral Sciences at Baylor College of Medicine, and attending physician at Methodist Hospital, Houston.

References

1. Hobbs E, Vera JH, Marks M, et al. Neurosyphilis in patients with HIV. Pract Neurol. 2018;18(3):211-218.

2. Hotson JR, Jose S. Modern neurosyphilis: a partially treated chronic meningitis. West J Med. 1981;135(3):191-200.

3. Tso MK, Koo K, Tso GY. Neurosyphilis in a non-HIV patient: more than a psychiatric concern. McGill J Med. 2008;11(2):160-163.

4. Gonzalez H, Koralnik IJ, Marra CM. Neurosyphilis. Semin Neurol. 2019;39(4):448-455.

5. Ha, T., Tadi, P., Leslie, S. W. & Dubensky, L. Neurosyphilis. StatPearls (2024).

6. Tampa M, Sarbu I, Matei C, et al. Brief history of syphilis. J Med Life. 2014;7(1):4-10.

7. Ho EL, Spudich SS. Neurosyphilis and the impact of HIV infection. Sex Health. 2015;12(2):148-154.

8. Jennings JM, Wagner J, Tilchin C, et al. Methamphetamine use, syphilis, and specific online sex partner meeting venues are associated with HIV status among urban black gay and bisexual men who have sex men. Sex Transm Dis. 2021;48(8S):S32-S39.

9. McKetin R, Dawe S, Burns RA, et al. The profile of psychiatric symptoms exacerbated by methamphetamine use. Drug Alcohol Depend. 2016;161:104-109.

10. Ellison G. The N-methyl-d-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Res Rev. 1995;20(2)250-267.

11. Ham S, Kim TK, Chung S, Im HI. Drug abuse and psychosis: new insights into drug-induced psychosis. Exp Neurobiol. 2017;26(1):11-24.

12. Najjar S, Steiner J, Najjar A, Bechter K. A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis. J Neuroinflammation. 2018;15(1):40.

13. Oboho IK, Ghanem KG. Blissful ignorance when managing pregnant women with syphilis and nonreactive nontreponemal tests? Sex Transm Dis. 2013;40(4):316-317.

14. Brown DL, Frank JE. Diagnosis and management of syphilis. Am Fam Physician. 2003;68(2):283-290.

15. Kaur B, Khanna D. A narrative review of the many psychiatric manifestations of neurosyphilis: the great imitator. Cureus. 2023;15(9):e44866.