Diagnostic Challenges and Clinical Insights of Neurosyphilis

Background: US cases of syphilis have increased by nearly 80% between 2018 and 2022 despite an overall decline in other sexually transmitted infections. Neurosyphilis, a serious complication of untreated syphilis, can cause irreversible sequelae, including vision loss, hearing loss, and paralysis. It often presents with nonspecific neurologic or ophthalmologic symptoms that complicate timely diagnosis.Discussion: A 62-year-old male with untreated syphilis, polysubstance use, and social instability presented to the emergency department with headaches, fluctuating vision changes, cognitive disturbances, and a remote history of suspected seizure activity. Serologic testing confirmed active syphilis infection. While his presentation was complicated by personal and social factors that led to delays in care, these did not adversely affect the clinical outcome. The patient was treated with intravenous penicillin G and his vision and headaches markedly improved within days. Conclusions: Nonspecific neurologic and ophthalmologic presentation of neurosyphilis can delay recognition. This case illustrates the role of a thorough social and sexual history in identifying patients at risk, particularly those with histories of unstable housing, substance use, or incarceration. Clinicians should maintain a high index of suspicion for neurosyphilis in patients with unexplained headaches, vision changes, or cognitive symptoms, especially those with risk factors for untreated syphilis. Prompt recognition and treatment with penicillin G are essential to prevent permanent neurologic and visual sequelae.Syphilis has grown in prevalence in recent years, posing renewed diagnostic and public health challenges. Between 2018 and 2022, cases in the United States grew by nearly 80%, reflecting gaps in prevention, early detection, and treatment adherence.[1,2] Neurosyphilis, a severe and potentially irreversible manifestation of Treponema pallidum infection, can occur at any stage of the disease and often presents with vague or nonspecific neurologic or ophthalmologic symptoms, making diagnosis particularly challenging. This report of a patient with a history of substance use and unhoused status underscores the importance of clinical vigilance, comprehensive history-taking, and early empiric treatment in patients with risk factors for untreated syphilis. Case PresentationAn African American male aged 62 years with a medical history of untreated hypertension, polysubstance use, and multiple emergency department (ED) visits presented to the Edward Hines Jr. Veterans Affairs Hospital (EHJVAH) ED with headaches, vision changes, and inguinal lymphadenopathy. He reported using about 3 to 4 bags of intranasal heroin daily and smoking as much cocaine as he could afford but no alcohol or injection drug use. He requested treatment for cocaine and heroin use. Two days prior to ED presentation, the patient reported substance use abstinence. However, he experienced a suspected seizure with loss of consciousness lasting about 5 minutes, as described by a friend. He had no recollection of the event. The patient believed he had experienced seizure-like activity over the previous 2 years. At presentation, he reported fluctuating visual symptoms, including difficulty focusing his vision and a persistent sense of confusion. He reported no difficulty with depth perception or gait and no fever, chills, gastrointestinal symptoms, chest pain, dyspnea, dysuria, or penile discharge. He noted bilateral inguinal lumps for about 2 years that were not painful and did not drain. The patient was not engaged with any primary care or outpatient clinicians. The patient’s history included social instability, including housing and financial insecurity. He reported multiple sexual partners over the past decade. He had been incarcerated 8 times over the past 10 years. Physical examination at presentation was unremarkable, and he had a body mass index of 19.2. The patient’s cranial nerves were found to be intact. His visual acuity was intact bilaterally, visual fields were full to confrontation, pupils were of equal size and exhibited both normal direct and consensual responses to light, and extraocular movements were intact in all directions. No ptosis was observed, and the patient’s facial sensation was intact bilaterally, and his facial expression was symmetrical, with no weakness noted. Hearing acuity was intact to conversation. Palatal movements were symmetrical, with no uvular deviation. Sternocleidomastoid and trapezius muscle strength was full and symmetric. His tongue protruded in the midline. The patient did not exhibit any motor drift in his upper extremities. Reflexes were all present and symmetrical throughout without any pathological clonus. Sensation was intact throughout. Finger-to-nose testing was unremarkable. The patient’s cardiovascular, pulmonary, abdominal, and skin examinations were also unremarkable. He had noted bilateral, nonpainful inguinal lymphadenopathy. Initial laboratory workup revealed leukocytosis with a white blood cell count of 15.1 x 103/uL, predominantly neutrophils. The patient also had acute kidney injury: his creatinine level was 3.7 mg/dL (reference range, 0.73-1.18 mg/dL) compared with 1.2 mg/dL 5 years earlier. Urinalysis was positive for cocaine and fentanyl. A chest X-ray was unremarkable, but a computed tomography without contrast of the head showed chronic small vessel disease and diffuse cerebral atrophy.Extensive chart review revealed that during a 2022 ED visit, the patient was evaluated for penile cellulitis and an early penile abscess after a bite sustained during oral sex. A sexually transmitted infection (STI) workup was performed, and rapid plasma reagin (RPR) testing was positive. However, at that time the patient refused treatment and left against medical advice and was not seen again before the current presentation. The patient had no prior hospital admissions; after his ED evaluation, he was admitted to the EHJVAH general medicine service and remained hospitalized for 6 days. Given his history of untreated syphilis, reported visual changes, and changes in cognition, the infectious disease team recommended the patient be treated for neurosyphilis. While lumbar puncture (LP) could help confirm neurosyphilis, a normal LP would not rule out ocular syphilis or preclude treatment. As a result, it was not conducted. The patient underwent a thorough evaluation by the ophthalmology team to assess for ocular manifestations of neurosyphilis given his vision changes. Comprehensive assessments, including visual acuity tests, slit-lamp examination, and fundoscopy, were performed. The evaluation revealed no evidence of active or past syphilitic involvement in the eyes. Visual acuity was normal, and there were no signs of uveitis, optic neuropathy, or any other ocular pathology associated with neurosyphilis. Over the first 2 hospital days, the patient’s acute kidney injury improved with intravenous (IV) fluids, and creatinine returned toward baseline. Once renal function improved, IV penicillin G was initiated, at a dosage of 4 million units every 4 hours for a planned 10-day duration. After 2 days of IV penicillin, the patient’s vision and headache greatly improved. He was also followed closely by mental health services and was admitted to the EHJVAH inpatient substance use rehabilitation program.DiscussionNeurosyphilis is a manifestation of Treponema pallidum infection resulting from invasion of the central nervous system (CNS), which can occur shortly after infection and at any stage of the infection.[1] It can present with a diverse range of neurologic and ophthalmologic manifestations. The most clinically significant symptoms are thought to be headaches and visual disturbances, which often serve as early indicators of CNS involvement, particularly in untreated or late-stage syphilis.[2] Headache is a common, although nonspecific, symptom of neurosyphilis. The underlying pathophysiology varies by clinical subtype. In meningovascular neurosyphilis, headache often reflects chronic meningitis with concomitant cerebral vasculitis. These headaches may be persistent and progressive and can be associated with focal neurologic deficits due to cerebral infarction.[3] In general paresis, headaches are usually accompanied by neuropsychiatric symptoms such as personality changes, irritability, and cognitive decline, reflecting diffuse cortical involvement.[4] Less commonly, in late-stage disease, syphilitic gummas can cause hydrocephalus due to impaired cerebrospinal fluid (CSF) flow, which can elevate intracranial pressure and contribute to headaches and papilledema.[5] Vision changes in neurosyphilis often reflect ocular syphilis or optic nerve involvement. These presentations are clinically urgent and can range from transient visual blurring to irreversible blindness. Optic atrophy, optic neuritis, and retrobulbar neuritis are also commonly observed.[6] Posterior uveitis, panuveitis, and chorioretinitis also may occur as isolated findings or with CNS symptoms.[7] In patients with immunocompromised states—particularly those with HIV—ocular manifestations may be more severe.[8]SerologyThe diagnostic evaluation includes serologic and CSF testing. Initial serologic screening with nontreponemal tests (eg, RPR and Venereal Disease Research Laboratory test [VDRL]) and confirmatory treponemal tests (eg, fluorescent treponemal antibody test and Treponema pallidum particle agglutination [TP-PA]) is essential. CSF abnormalities may include lymphocytic pleocytosis, elevated protein levels, and a reactive CSF-VDRL, which remains the gold standard for diagnosis despite limited sensitivity.[9] Cerebral imaging may reveal parenchymal or meningeal involvement, and ophthalmologic assessment with slit-lamp examination and optical coherence tomography can aid in the diagnosis of ocular syphilis.[10] During the patient’s inpatient stay, an infectious disease workup was negative for HIV, hepatitis C, hepatitis B, chlamydia, and gonorrhea. The serologic evaluation revealed a positive RPR and a positive TP-PA. RPR is a nontreponemal test: a reactive result indicates an active or recent syphilis infection. The RPR titer is clinically significant because it can be monitored over time to assess treatment response and disease activity.[2] TP-PA is a treponemal test and a positive result confirms exposure to Treponema pallidum, since treponemal-specific antibodies typically remain positive for life regardless of treatment or disease activity.[3] The combined interpretation of reactive RPR and positive TP-PA strongly supported an ongoing syphilis infection. In contrast, an isolated positive TP-PA test may indicate past, treated infection, while isolated nontreponemal reactivity could represent a false positive.[2] HIV and syphilis share transmission routes and biological interactions. Both infections share common risk factors, including sexual exposure. Individuals with 1 infection are at increased risk of having the other.[9] Syphilis can facilitate the acquisition and transmission of HIV through mucosal disruption and increased inflammatory cells in genital secretions.[11] HIV coinfection can alter the natural history of syphilis, potentially accelerating its progression and increasing the risk of neurosyphilis, even at earlier stages.[9,12] The Centers for Disease Control and Prevention (CDC) and World Health Organization recommend HIV testing in all patients with newly diagnosed syphilis to guide prognosis and tailor management.[3,13] Serologic responses in patients with HIV infection may be atypical, showing unusual titers or slower declines following therapy, complicating interpretation. Therefore, management of these patients may require closer follow-up and a lower threshold for LP to evaluate for neurosyphilis.[9,14]TreatmentThe 2021 CDC STI guidelines recommend aqueous crystalline penicillin G administered in 3 to 4 million units every 4 hours, for a total of 18 to 24 million units daily, via continuous infusion or IV for the treatment of neurosyphilis, ocular syphilis, and otosyphilis.[2,11] This recommendation is based on the effectiveness of penicillin in rapidly clearing Treponema pallidum, with prolonged therapy ensuring adequate penetration into the CSF and complete eradication of the infection. While a 10-day course is generally sufficient for treatment in many cases, a 14-day regimen is often preferred, particularly in clinical practice involving patients with advanced disease, HIV coinfection, or high-risk features due to concerns about relapse or persistent CSF abnormalities.[3,9]Evidence for a 10-day regimen suggests that it achieves adequate CSF sterilization in immunocompetent patients. Pharmacokinetic data indicate that therapeutic levels in CSF can be maintained with this regimen, and relapse rates are low with appropriate follow-up, offering advantages such as shorter hospitalization and reduced treatment costs.[11] Historically, neurosyphilis treatment regimens have involved a 14-day course due to concerns about incomplete clearance and the difficulty of monitoring patients posttherapy. Patients with HIV infection, notably those with low CD4 counts or detectable viral loads, may have a higher risk of relapse, prompting many clinicians to opt for the 14-day course. Complex presentations such as meningovascular syphilis, parenchymal disease, and ocular or otic involvement are also often treated with a 14-day regimen to maximize the likelihood of cure. In clinical practice, a 10-day regimen may be considered reasonable for immunocompetent patients with early neurosyphilis, provided there is reliable follow-up and access to repeat CSF examination if necessary. However, a 14-day regimen is preferred for patients with HIV coinfection; severe, late, or atypical neurosyphilis presentations; or those with poor follow-up or a higher risk of treatment failure.[3,9] Both 10-day and 14-day regimens of IV penicillin G are acceptable for the treatment of neurosyphilis, though the 14-day regimen is favored in higher-risk cases, such as those involving HIV, severe neurological involvement, or poor follow-up. While evidence does not show clear inferiority of a 10-day regimen in immunocompetent patients, guideline-based and pragmatic practice trends typically lean toward the longer regimen in complex or uncertain scenarios. The mainstay of treatment for neurosyphilis remains aqueous crystalline penicillin G, due to its proven ability to achieve treponemicidal levels in CSF. This regimen ensures sustained CSF concentrations above the minimal inhibitory concentration for Treponema pallidum, thereby eradicating the organism from the CNS.[2,9] As an alternative regimen, if adherence and close monitoring can be assured, procaine penicillin G 2.4 million units intramuscularly daily, plus probenecid 500 mg orally 4 times daily for 10 to 14 days, is considered acceptable. However, this regimen is less commonly used in modern practice due to the need for frequent dosing and adherence concerns. In patients with a documented severe penicillin allergy, the preferred approach is penicillin desensitization followed by standard therapy, given the limited evidence for the efficacy of nonpenicillin alternatives.[2] While IV or intramuscular 2 g ceftriaxone daily for 10 to 14 days has demonstrated some efficacy and adequate CSF penetration in small studies, evidence remains limited, and treatment failures have been reported.[3,15] As such, the CDC considers ceftriaxone a possible alternative, though not equivalent to penicillin.[2] Doxycycline and azithromycin, which may be used in some cases of early syphilis, are not effective in neurosyphilis due to poor CSF penetration and inadequate clinical outcomes.[3,11]Corticosteroids are sometimes administered adjunctively in neurosyphilis to reduce the inflammatory response triggered by rapid spirochete lysis during antibiotic therapy, particularly with IV penicillin. Acute inflammation, known as the Jarisch–Herxheimer reaction (JHR), can cause clinical worsening, especially in patients with neurologic or ophthalmic involvement. However, the use of steroids in this context is supported by limited data and expert opinion rather than by large, controlled clinical trials.[2] Certain patients may benefit from steroid treatment. Patients with ocular syphilis (eg, optic neuritis, uveitis, retinitis, or other vision-threatening involvement) may receive corticosteroids in conjunction with antibiotics to reduce inflammation and preserve visual function.[3,6] Patients with otosyphilis experiencing hearing loss, tinnitus, or vestibular dysfunction may find steroids helpful in mitigating inflammation of the inner ear structures, although the evidence is largely anecdotal.[1,6] In patients with meningeal or meningovascular neurosyphilis with a high risk of JHR, patients with high CSF treponemal burden or symptomatic meningitis may benefit from a short course of steroids (ie, prednisone 40-60 mg daily for 3-5 days, starting 24 hours before antibiotics) to blunt the inflammatory response. Patients with severe parenchymal involvement, such as advanced neurosyphilis (eg, general paresis or tabes dorsalis), rarely can be considered for short courses of steroids to prevent acute worsening; however, the supporting data are sparse.[2,3] There are situations in which steroids should be avoided. Patients with isolated latent or asymptomatic neurosyphilis, without acute inflammatory risk factors, derive no benefit from steroids and may be unnecessarily exposed to immunosuppression.[2] Similarly, patients with severe immunosuppression without careful monitoring (eg, advanced HIV/AIDS) could face worsened infection control or an increased risk of opportunistic infections if given corticosteroids. Patients with inactive, uncontrolled infections, such as tuberculosis or cryptococcosis, should avoid steroids because they can exacerbate the disease. Additionally, patients with contraindications to corticosteroid therapy, including those with poorly controlled diabetes, severe hypertension, psychiatric instability, or gastrointestinal ulcer disease, may be harmed by unnecessary corticosteroid exposure.[3] Patients with asymptomatic neurosyphilis and with specific contraindications should not receive steroids. The clinical decision to use corticosteroids should be individualized, weighing the potential benefits in preventing inflammatory complications against the risks posed by immunosuppression. ConclusionsNeurosyphilis should be considered in the differential diagnosis of patients presenting with unexplained headaches or visual symptoms, particularly in individuals with risk factors such as HIV infection, prior untreated syphilis, or substance use. Early identification and prompt treatment are critical to prevent irreversible neurologic and visual sequelae. The patient in this report had seizures that posed a diagnostic challenge, as they could have been related to substance use, syphilis, or a synergistic pathway involving both conditions. Ultimately, an in-depth chart review determined that his seizures were directly related to previously untreated syphilis. This case emphasizes the importance of considering a diagnosis of syphilis or neurosyphilis in patients presenting with unexplained neurologic or visual symptoms, especially those with risk factors such as substance use, social instability, and incomplete STI treatment. Early recognition and prompt antibiotic therapy are essential to prevent permanent, debilitating neurologic sequelae.