A Case of Neuro- and Otosyphilis Successfully Managed with a Sequential Regimen Including Ceftriaxone

Introduction

Syphilis, caused by Treponema pallidum subsp pallidum, is a sexually transmitted infection known as the “great mimicker” due to its ability to affect multiple organ systems and produce a wide range of symptoms.¹ Neurosyphilis occurs when the infection invades the CNS, presents with diverse and nonspecific clinical manifestations that often delay diagnosis² Although neurosyphilis affects only 3–5% of untreated syphilis patients, its incidence has risen globally since 2000, paralleling the resurgence of syphilis cases.³ Otosyphilis, characterized by auditory-vestibular dysfunction, is particularly underrecognized due to overlapping etiologies. According to statistics, among 41,187 syphilis patients in 16 states in the United States in 2019, otosyphilis was only 0.4%, lower than neurosyphilis (1.1%) and ophthalmic syphilis (1.1%), but this may be related to the non-specific manifestations of otosyphilis (such as tinnitus, vertigo and hearing loss).⁴ Although penicillin G remains the first-line therapy, challenges with treatment adherence persist, as it requires hospital admission for intravenous infusion every four hours—a factor contributing to poor adherence in some patients. Additionally, its limited penetration into the CNS underscores the need for practical alternative treatment regimens. Ceftriaxone, for instance, can be administered once daily as an outpatient, making it a feasible alternative for patients who refuse hospitalization. We report a case of neuro- and otosyphilis in an HIV-negative young male successfully managed with a sequential regimen including ceftriaxone, which highlights the diagnostic pitfalls of this comorbidity and the clinical value of alternative sequential treatment regimens. This case provides educational value for clinicians in the diagnosis and management of neuro- and otosyphilis with non-specific symptoms.

Case Report

A 30-year-old male presented to the dermatology department with a complaint of progressive bilateral tinnitus and hearing decrease for three months, and was diagnosed with otitis media in the ENT outpatient department 3 days ago in another hospital, which has not yet been treated. When tracing the medical history, he admitted to having a history of unsafe sexual practices and was diagnosed with syphilis two years prior, treated with penicillin — 1.2 million units IM weekly for 2 weeks, with intermittent follow-up after treatment, and during the process the syphilis serum titer was not regularly monitored. Given the patient’s symptoms of hearing loss, history of syphilis, inadequate initial treatment for syphilis, and lack of regular follow-up with unclear disease progression, the patient was admitted to the dermatology ward for further screening and diagnosis. Following, Neurological examination revealed no abnormality in mental status, memory, or cognitive function. Otolaryngology consultation indicated no external ear deformity, no ear discharge in the examination of the external ear, but audiometry confirmed moderate sensorineural hearing loss in both ears (Figure 1A). Meanwhile, craniocerebral magnetic resonance imaging (MRI) was performed with T1-weighted, T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences with intravenous gadolinium contrast administration, which revealed bilateral cochlear enhancement, with no parenchymal lesions or vascular abnormalities (Figure 1B). Laboratory data for complete blood counts and chemistry were unremarkable, screening tests for hepatitis B virus, hepatitis C virus and HIV yielded negative findings, but there were positive reactions of Treponema Pallidum Particle Agglutination Test (TPPA), and Toluidine Red Unheated Serum Test(TRUST) with a titre of 1:1. Obtaining the patient’s consent, a lumbar puncture was performed to aspirate cerebrospinal fluid. The further CSF analysis showed a positive TPPA, a positive TRUST with a titre of 1:2, and the other concerned results like nucleated cell count, protein level and pandy test were all within the normal reference range. In summary, the diagnosis of otosyphilis combined with neurosyphilis was based on the patient’s history, clinical symptoms, audiometry report, laboratory results and MRI findings. According to clinical treatment guidelines, the management of otosyphilis follows the treatment standards for neurosyphilis. Penicillin is the first-line, typically administered as an intravenous injection of penicillin G, with a treatment course of 10–14 days.⁴

Figure 1 Audiometric and neuroimaging findings before and after treatment. (A) Baseline pure-tone audiogram showing bilateral moderate sensorineural hearing loss at 250–8000 Hz frequencies. (B) Axial T1-weighted post-contrast MRI at presentation showing bilateral cochlear enhancement (red circles indicate the enhanced cochlear structures), with no parenchymal or vascular abnormalities. (C) Follow-up audiogram at 9 months showing normalized hearing thresholds. (D) Follow-up axial T1-weighted post-contrast cranial MRI at 9 months showing resolution of cochlear enhancement, with normal cochlear morphology.

Refusing hospitalization due to personal reasons, the patient received outpatient ceftriaxone (2g IV daily for 14 days) followed by benzathine penicillin (2.4 million units IM weekly for 3 weeks). The sequential regimen was formulated based on the patient’s refusal of inpatient penicillin G therapy, with ceftriaxone used for initial anti-treponemal treatment (outpatient feasible) and benzathine penicillin for subsequent consolidation therapy to ensure sufficient anti-treponemal efficacy. The treatment was well-tolerated with no adverse events, and no steroid or other adjuvant therapies were administered during the entire treatment period. At three-month follow-up, audiological improvement was noted, with complete CSF TRUST seroreversion by six months. At nine-month follow-up, the Cranial MRI examination recovered to no remarkable abnormity, the audiometry test showed hearing had also returned to the normal range (Figure 1C and D). The patient’s hearing recovered, residual nighttime tinnitus persisted and continued monitoring is ongoing. While serum TRUST remained positive at a titer of 1:1 during the follow-up period, which represents a typical serofast state—a common benign condition after adequate anti-syphilitic therapy that does not indicate treatment failure and requires no additional antimicrobial treatment.⁵ Serum and CSF serological and biochemical results during the follow-up period are summarized in Table 1.

Table 1 Serum and CSF Laboratory Results

Discussion

The patient was initially misdiagnosed with otitis media, largely because the presenting symptoms of hearing loss and tinnitus were not correlated with syphilis infection, and a detailed medical history was not thoroughly elicited. With the non-specific manifestations, the actual incidence of otosyphilis is severely underestimated, which is frequently misattributed to other causes, thus delaying diagnosis and treatment.⁶ Depending on the route of pathogen invasion, otosyphilis can either occur as an isolated entity without CSF abnormalities, or coexist with neurosyphilis as a component of the latter’s neurological symptom complex⁷—a clinical scenario that was evident in the present case.

Otosyphilis and neurosyphilis share a common pathogenic basis of Treponema pallidum invasion, and the labyrinthine portion of the inner ear is anatomically connected to the CNS via the vestibulocochlear nerve, which provides a direct route for treponemal spread.⁸ Treponema pallidum can invade the cochlear and vestibular end organs through the meninges surrounding the vestibulocochlear nerve, leading to cochlear inflammation and enhancement (as seen in the patient’s baseline MRI), and can also cross the blood-brain barrier to cause CNS infection, resulting in concurrent neurosyphilis.⁹ The pathological changes mainly include endolymphatic labyrinthitis, vascular inflammation and fibrosis of the inner ear, which are consistent with the sensorineural hearing loss in this patient.⁶ This pathological connection explains why otosyphilis often coexists with neurosyphilis and is regarded as a neurological manifestation of neurosyphilis in clinical practice.^7,8.

This case was featured by tinnitus and hearing loss as the primary complaints, with magnetic resonance imaging (MRI) and audiometry confirming the presence of sensorineural hearing loss (SNHL). However, analogous audiological and radiological alterations can be induced by a wide array of otological disorders, including those triggered by ototoxic medications, noise exposure, non-syphilitic infections, and autoimmune conditions.¹⁰ This underscores the crucial necessity of conducting syphilis serological screening for patients exhibiting unexplained SNHL or tinnitus that deviates from the clinical manifestations of common ear diseases. Such a practice is of utmost importance in reducing misdiagnosis. Given the inherent diagnostic challenges of otosyphilis, close multidisciplinary collaboration between dermatovenereologists and otolaryngologists is indispensable for accurate identification and optimal management of the condition.

Against the backdrop of the global resurgence of syphilis, neurosyphilis has re-emerged as a pressing public health concern.⁸ Nevertheless, a nationwide survey in China has documented substantial discrepancies in the diagnostic criteria adopted by different regions and research institutions, leading to notable confusion in routine clinical practice.¹¹ To date, there is no universally accepted gold standard for the diagnosis of neurosyphilis. Instead, diagnosis hinges on a comprehensive assessment integrating clinical evaluations, CSF analyses, the patient’s human immunodeficiency virus (HIV) infection status, neurological symptomatology, and imaging findings^12,13. For complex cases, the adoption of a multidisciplinary collaborative approach is deemed essential.

In the present case, CSF serological tests for syphilis, including TPPA and TRUST, returned positive results. In contrast, the CSF nucleated cell count, total protein level, and Pandy’s test were all within normal limits. These findings indicate the presence of CSF infection by Treponema pallidum in the absence of significant inflammatory responses or blood-brain barrier disruption. This may imply that the pathogen has not yet caused substantial damage to the CNS, or that the infection is in its early stage.

Ceftriaxone, a third-generation cephalosporin, boasts superior CSF penetration, with CSF concentrations reaching 15–20% of the corresponding serum levels— a figure markedly higher than the 1–2% penetration rate of penicillin.¹⁴ In this case, a sequential regimen including ceftriaxone as the initial treatment and benzathine penicillin as consolidation therapy achieved complete clinical resolution, and we cannot definitively confirm that the therapeutic effect was solely attributable to ceftriaxone monotherapy. Its favorable pharmacokinetic profile, encompassing broad-spectrum antimicrobial activity, a once-daily dosing regimen, and suitability for outpatient administration, renders it a pragmatic alternative to penicillin. Although penicillin remains the first-line agent for syphilis treatment, recent clinical studies have underscored the distinct advantages of ceftriaxone, including shorter hospital stays (a mean of 8.9 days versus 13.8 days with penicillin) and improved neurological outcomes.⁹ The phenomenon of persistent serofast status, which occurs in 10–15% of treated cases,⁴ is thought to stem from residual treponemal antigens or epigenetic modifications rather than active infection. Notably, in this case, the normalization of CSF TRUST titers preceded clinical improvement, highlighting the value of this biomarker as a reliable surrogate endpoint for monitoring treatment response.

This case report has a limitation: the patient received a sequential treatment regimen of ceftriaxone followed by benzathine penicillin, so it is impossible to isolate and confirm the independent therapeutic efficacy of ceftriaxone for neuro- and otosyphilis. The clinical improvement may be the combined effect of the two drugs, and further prospective controlled studies are needed to verify the independent efficacy of ceftriaxone in the treatment of neuro- and otosyphilis.

In summary, this case emphasizes the imperative of integrating syphilis screening into the diagnostic workup of patients with unexplained auditory symptoms, particularly those with a history of potential exposure to syphilis. It further underscores the necessity of prompt and adequate antisyphilitic therapy to achieve definitive cure and prevent irreversible CNS damage. Moreover, the case supports that ceftriaxone is a valuable management for neurosyphilis complicated by otological involvement, providing tangible clinical evidence for its role as a valuable alternative to penicillin in selected cases.

Conclusion

This case describes an immunocompetent young male with neuro-otosyphilis successfully managed with a sequential regimen of ceftriaxone followed by benzathine penicillin. It underscores the risk of otosyphilis misdiagnosis, the necessity of syphilis screening for unexplained auditory symptoms, especially those with a syphilis exposure history. This case supports ceftriaxone as a valuable component of alternative sequential regimens for neuro-otosyphilis in patients intolerant of or refusing first-line penicillin G therapy. And multidisciplinary collaboration among dermatovenereologists, otolaryngologists and neurologists is critical for the accurate diagnosis and optimal management of neuro-otosyphilis.