Neurosyphilis in the Time of COVID-19: Avoiding Anchoring Heuristics
1Resident Physician, Department of Internal Medicine, Saint Peter’s University Hospital
2Internist, Department of Internal Medicine, Saint Peter’s University Hospital
Thota G, Shah M, Chandna S, Rosenthal M. Neurosyphilis in the time of COVID-19: avoiding anchoring heuristics. Consultant. 2023;63(6):e1. doi:10.25270/con.2022.11.000008
Received April 13, 2022. Accepted September 1, 2022. Published online November 30, 2022
The authors report no relevant financial relationships and declare no conflicts of interest.
Monarch Shah, Saint Peter’s University Hospital, 254 Easton Avenue, New Brunswick, NJ 08901 (email@example.com)
Syphilis is known as the "great masquerader," as it may present with atypical symptoms or occasionally as asymptomatic. Being a great imitator, neurosyphilis should be high on the differentials in patients presenting with neurologic symptoms, particularly in those with high risk, including men who have sex with men and individuals who have HIV. The presentation of neurosyphilis may also be asymptomatic or can include focal dermatologic changes, meningeal, meningovascular events, such as acute strokes, as well as general paresis or tabes dorsalis. We describe a case of an immunosuppressed patient amid the COVID-19 pandemic presenting with a headache, which has been reported as a presenting symptom of COVID-19 infection. This case emphasizes the importance of avoiding anchoring heuristics when encountering nonspecific symptoms in a patient amid the COVID-19 pandemic, even when accounting for the current public health landscape, diagnostic and radiographic limitations, and overlapping symptomatology.
Neurosyphilis is due to infection of the cerebrospinal fluid (CSF), a process that occurs after the acquisition of Treponema pallidum infection. Infection of the CSF with this spirochete may sometimes resolve spontaneously without causing persistent infection. Persistent meningitis is due to failure to clear organisms from the CSF.
Prior to the invention of antibiotics, about one-third of untreated individuals were thought to develop tertiary syphilis; of these, 15% went on to develop gummatous disease (1–46 years after infection), 10% developed cardiovascular syphilis (20–30 years after infection), and 4% to 14% developed late neurosyphilis (2–50 years after infection).1 Depending on whether pathologic criteria or clinical criteria were employed to make the diagnosis, 3.2% to 15% of individuals infected with syphilis experienced meningovascular symptoms.2
In the current antibiotic era, neurosyphilis, particularly the early forms, is seen in people who have HIV.3 This association suggests that syphilis is common in men who have sex with men, many of whom have HIV or due to differences in susceptibility.3 For persons with HIV, the risk of neurosyphilis is increased in those with low peripheral CD4+ T-cell counts, detectable HIV RNA in plasma, and individuals who are not receiving antiretroviral therapy (ART). The frequency of the late forms of neurosyphilis, particularly tabes dorsalis, has declined in the current antibiotic era and are now very uncommon.
A 40-year-old man with HIV and AIDS presented to our hospital when the COVID-19 pandemic was at its peak during spring 2020, reporting headaches that lasted for 4 weeks. He described his headache as gradual in onset, progressively worsening, intractable, sharp, constant, and bifrontal with associated pain in both eyes. He did not report any fever, cough, dyspnea, rashes, fatigue, or lesions anywhere on his body. He did not seek any medical attention when his headache first started and was taking over-the-counter naproxen as needed without significant relief. The patient had not taken a COVID-19 test when the headaches began.
History. The patient was receiving ART and had a history of cytomegalovirus (CMV) colitis. He was in a monogamous relationship with a male partner. HIV infection and AIDS were diagnosed in 2019, at the same time when his CMV was diagnosed and treated with valacyclovir. At that time, the patient's CD4 count was 69. He was started on ART with a combination of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir 300 mg; his CD4 counts steadily improved to 233. He was adherent to his medications and no further changes were made to his regimen.
Clinical findings. The patient's vital signs were all within normal limits and physical examination, including a comprehensive neurological examination, was normal. The findings of a complete blood count and a complete metabolic panel were as follows: CD4 count, 227 (25% CD4 cell); HIV viral load, 23 copies/mL; erythrocyte sedimentation rate, 68 mm/hour (range, 0 – 15 mm/hour); lactate dehydrogenase, 341 u/L (range, 140 – 271 u/L); D-dimer, 346 ng/mL (range, 0 – 211 ng/mL); and positive COVID-19 nasal polymerase chain reaction test. A noncontrast computerized tomography of the head was negative for an acute intracranial process. The patient declined to undergo further imaging of the brain or a lumbar puncture (LP).
Patient outcome. The patient's headache improved with symptomatic treatment and he was discharged on day 2 with an outpatient follow-up with an infectious diseases physician. He did not develop any respiratory symptoms due to COVID-19 infection during his hospital stay and since he had been symptomatic for 4 weeks, treatment for COVID-19 was deferred. He had not been vaccinated for COVID-19 prior to presentation and after subsequent follow up visits when COVID-19 vaccinations became available, he was advised to get vaccinations as an outpatient, which he did.
At the outpatient follow-up, the patient was asymptomatic. Routine screening showed serum rapid plasma reagin (RPR) was reactive (1:128), as well as the fluorescent treponemal antibody absorption. Subsequently, the patient agreed to undergo an LP. CSF analysis (Table) showed lymphocytic pleocytosis. A reactive venereal disease research laboratory (VDRL) test confirmed the diagnosis of early symptomatic neurosyphilis.
Treatment was initiated with intravenous penicillin-G 18 million units/day for 10 days, and a follow-up CSF analysis was done after 6 months of initial treatment.
CSF Analysis, Pre- and Post-treatment
40 – 70 mg/dL
15 – 45 mg/dL
White blood cells, 20
1 red blood cells/microL
White blood cells, 7
1 red blood cells/microL
0 – 5 cells/microL
0 - 5 lymphocytes
Reactive, 1:2 titers
Table. CSF analysis, pre- and post-treatment.
At the follow-up visit, the patient remained headache-free, with a normal neurologic examination. Six months after treatment, there was a decline in the CSF white blood cell count, the CSF-VDRL test was nonreactive, and there was a decline in serum RPR from 1:128 to 1:8, which indicated successful treatment. The patient’s partner was tested and had a nonreactive RPR test and was treated with intramuscular penicillin 1.2 million units weekly for a total of 3 doses.
Headache is a nonspecific and minor symptom of many diseases. It has been reported as a minor symptom associated with the presentation of COVID-19 infection in different case reports. Coronavirus tends to have neuroinvasive potential as patients have shown neurologic symptoms, such as headaches, nausea, vomiting, myalgia, fatigue, impaired consciousness and confusion, ageusia, anosmia, neuropathic or radicular pain, occipital neuralgia, visual impairment, seizure, and ataxia.3,4 Based on a growing number of case reports and series, the central nervous system (CNS), peripheral nervous system, and skeletal muscles may be involved in COVID-19, presenting with a variety of neurologic conditions, including Guillain-Barre syndrome, myopathy, encephalopathy, meningoencephalitis, encephalomyelitis, and acute myelitis, which may overlap with other disease processes, such as neurosyphilis.
At the onset of the COVID-19 pandemic, several case studies established CNS involvement during COVID-19 infection leading to a specific manifestation of the disease referred to as “neuro-COVID,” with neuroinvasive potential presenting with similar symptoms.3 Some reports provide evidence for a direct viral invasion of the nervous system. The neural injury could be due to a systemic inflammatory response triggered by the SARS-CoV-2 virus.3 Both viral and autoimmune meningoencephalitis have been reported in patients with COVID-19.4 Studies of post-COVID-19 manifestations showed that neurologic symptoms persisted for at least 6 weeks; the most frequent symptoms reported were "brain fog" (81%), headache (68%), numbness/tingling (60%), dysgeusia (59%), anosmia (55%), and myalgias (55%).5
This case highlights the importance of including neurosyphilis on the list of differentials when encountering a patient presenting with a headache, particularly in patients with risk factors such as HIV and men who have sex with men.6,7 Clinical suspicion combined with CSF analysis are keys to establishing the diagnosis of neurosyphilis.8 Patients presenting in the asymptomatic or early neurosyphilis stage return to baseline with adequate treatment, and those with late stages may improve but do not usually return to their baseline functional status. Thus, the earlier the identification, the better the prognosis.
Persons with HIV infection and syphilis presenting with neurologic symptoms should undergo immediate CSF examination.6,8 Some studies have demonstrated that clinical suspicion and CSF abnormalities that are consistent with neurosyphilis are seen among persons with HIV who have a diagnosis of syphilis and a CD4 count of less than 350 cells/mL, a RPR titer of greater than 1:32, or both.9 Follow-up CSF analysis should be repeated every 6 months until the cell count is within normal limits if CSF pleocytosis is present during the initial CSF examination.10 The leukocyte count is a sensitive measure of the effectiveness of the treatment.9
Follow-up CSF-VDRL and protein testing can also be done, but changes in these two parameters occur more slowly than cell counts.10 If the cell count has not decreased after 6 months of treatment or if the CSF cell count or protein level is not within normal limits after 2 years of treatment, then retreatment should be considered in these cases.9
In 2020, 133,945 cases of all stages of syphilis were reported, including 41,655 cases of primary and secondary (P&S) syphilis, the most infectious stages of the disease. Since reaching a historic low in 2000 and 2001, the rate of P&S syphilis has increased almost every year, increasing 6.8% from 2019 to 2020.11 These statistics highlight that although there is effective treatment for syphilis, the number of cases has increased since the beginning of the COVID-19 pandemic.
- Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA. 2003;290(11):1510-1514. doi:10.1001/jama.290.11.1510
- Ghanem KG. Review: Neurosyphilis: A historical perspective and review. CNS Neurosci Ther. 2010 Oct;16(5):e157-68. doi: 10.1111/j.1755-5949.2010.00183.x.
- Tancheva L, Petralia MC, Miteva S, et al. Emerging neurological and psychobiological aspects of COVID-19 infection. Brain Sci. 2020;10(11):852. doi: 10.3390/brainsci10110852
- Davis AP, Stern J, Tantalo L, et al. How well do neurologic symptoms identify individuals with neurosyphilis? Clin Infect Dis. 2018;66;3(1):363-367. doi: 10.1093/cid/cix799
- Graham EL, Clark JR, Orban ZS, et al. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 "long haulers". Ann Clin Transl Neurol. 2021;8(5):1073-1085. doi: 10.1002/acn3.51350
- Hobbs E, Vera JH, Marks M, Barritt AW, Ridha BH, Lawrence D. Neurosyphilis in patients with HIV. Pract Neurol. 2018;18(3):211-218. doi:10.1136/practneurol-2017-001754
- Centers for Disease Control and Prevention. Diagnoses of HIV infection in the United States and dependent areas, 2018 (Updated). HIV Surveillance Report. Published May 2020. Accessed October 24, 2022. https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2018-updated-vol-31.pdf
- Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis. 2004;189(3):369-376. doi:10.1086/381227
- Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 2004;38(7):1001-1006. doi:10.1086/382532
- Marra CM, Maxwell CL, Tantalo LC, et al. Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clinical abnormalities after treatment of neurosyphilis. Clin Infect Dis. 2008;47(7):893-899. doi:10.1086/591534
- Sexually transmitted disease surveillance 2020. Centers for Disease Control and Prevention. Published 2022. Accessed October 24, 2022. https://www.cdc.gov/std/statistics/2020/overview.htm#Syphilis