Insights Into Treatment Alternatives for Neurosyphilis: Systematic Literature Review and Meta-Analysis.

ABSTRACT: We conducted a systematic literature review and meta-analysis to assess the efficacy of alternative treatments for neurosyphilis. We searched MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Embase, Cochrane, Scopus, and Web of Science from database inception to September 2023, for studies in neurosyphilis that compared penicillin monotherapy with other treatments. We focused on the impact of these therapies on treatment response, but also assessed data regarding reinfection and adverse drug events. Random-effect models were used to obtain pooled mean differences. Of 3415 screened studies, 6 met the inclusion criteria for the systematic literature review. Three studies provided quantitative data that allowed for inclusion in the meta-analysis. Our analysis revealed that the efficacy of intravenous (IV) ceftriaxone 2 g daily for 10 days (51 patients) did not appear statistically different compared with IV penicillin G 18 to 24 million units daily for 10 days (185 patients) for neurosyphilis (pooled odds ratio, 2.85; 95% confidence interval, 0.41-19.56; I 2 = 49%). No statistical difference between ceftriaxone and penicillin was identified in people living with human immunodeficiency virus (HIV) (pooled odds ratio, 4.51; 95% confidence interval, 0.50-40.49; I 2 = 34%). We concluded that alternative therapy with IV ceftriaxone appears similar to penicillin, potentially expanding treatment options for neurosyphilis. Other treatment options including doxycycline warrant further study.

An observational prospective study based on a large cohort of HIV-negative neurosyphilis patients with particular reference to the Jarisch-Herxheimer reaction.

PURPOSE: The purpose of this study is to outline a complete picture of Jarisch-Herxheimer reaction (JHR) in the central nervous system among HIV-negative neurosyphilis patients. METHODS: A prospective study cohort of 772 cases with almost all stages of neurosyphilis depicted the features of JHR including occurrence rate, risk profiles, clinical manifestations, medical management and prognosis. RESULTS: The total occurrence rate of JHR was 9.3% (95% CI, 7.3-11.4%), including 4.1% (95% CI, 2.7-5.6%) with severe JHR. The reaction started 5 h after treatment initiation, peaked after 8 h, and subsided after 18 h. Patients with severe JHR experienced a longer recovery time (26 h). Patients with general paresis (OR = 6.825), ocular syphilis (OR = 3.974), pleocytosis (OR = 2.426), or a high CSF-VDRL titre (per log2 titre increase, OR = 2.235) were more likely to experience JHR. Patients with general paresis had an 11.759-fold increased risk of severe JHR. Worsening symptoms included cognitive impairment, mania, nonsense speech, and dysphoria, while symptoms of hallucination, urination disorder, seizures, myoclonus, or aphasia appeared as new-onset symptoms. Neurosyphilis treatment did not need to be interrupted in most patients with JHR and could be reinstated in patients with seizures under supportive medication when JHR subsided. CONCLUSION: Severe JHR displayed a 4.1% occurrence rate and clinicians should pay particular attention to patients at a higher risk of JHR. The neurosyphilis treatment regime can be restarted under intensive observation for patients with severe JHR and, if necessary, supportive medication should be initiated and continued until the end of therapy.

Novel and characteristic radiological features of neurosyphilis: a case series.

BACKGROUND: Treponema pallidum can invade the central nervous system (CNS) early in its infection, causing neurosyphilis. Neurosyphilis typically presents with meningovasculitis in the acute or subacute phase, while tabes dorsalis and dementia paralytica are classical conditions in the later stages. However, syphilis is often misdiagnosed as other conditions such as tumors or autoimmune diseases including vasculitis and encephalitis, which is why the condition is known as "The Great Mimicker." The increasing incidence of syphilis in recent years emphasizes the importance of early diagnosis and treatment; however, its multiple clinical manifestations impose diagnostic challenges for clinicians because it resembles other diseases. In this case series, we present the impressive manifestations of neurosyphilis through three unique radiological presentations. CASE PRESENTATION: Case 1 details optic nerve involvement in an HIV-positive male, where MRI and fundoscopic findings confirmed syphilitic optic neuritis. Case 2 describes a patient in her pregnancy initially suspected of acoustic neuroma on MRI, later diagnosed with syphilitic gumma affecting the inner ear canal. Case 3 is a young male with clinical features mimicking temporal arteritis, ultimately identified as skull osteomyelitis secondarily causing inflammation of the musculus temporalis and meningitis. CONCLUSIONS: These cases underscore the necessity of considering syphilis in differential diagnoses, given the diversity of its clinical presentations. Radiology plays an important role in avoiding unnecessary interventions. The increasing prevalence of recurrent syphilis imposes diagnostic challenges, emphasizing the importance of the early diagnosis and treatment of neurosyphilis by clinicians.

Neurosyphilis in a young man having HIV infection, blurring of vision and skin rash.

We report a 22-year-old homosexual man, a known case of HIV-1 infection but non-compliant to medications, who presented with a 5-month history of progressive painless non-pruritic coin-shaped skin lesions and recent gradual bilateral blurring of vision. His history divulged a primary syphilitic event 1 year prior to the present clinical manifestations. Investigation led to the diagnosis of neurosyphilis with ocular involvement with concurrent signs of secondary syphilis. Treatment with aqueous crystalline penicillin G, ophthalmic steroid and tropicamide drops, and topical emollients resulted in significant clinical improvement of ocular symptoms and skin lesions. The diagnosis of neurosyphilis requires a high degree of clinical suspicion and should be included in the differential diagnosis of unexplained ocular symptoms, particularly in men who have sex with men and HIV-infected patients. This is necessary for the early diagnosis, appropriate management, and good outcome of these patients.

Imaging features of neurosyphilis.

Syphilis is an infectious disease caused by the spirochete Treponema pallidum, subspecies pallidum. Although its incidence has declined after the widespread availability of penicillin, it has recently re-emerged, especially in men who have sex with men and in people living with human immunodeficiency virus (HIV). The neurological manifestations of syphilis, generally known as neurosyphilis, may appear at any time during the infection, including the initial years after the primary infection. Neurosyphilis can be asymptomatic, only with cerebrospinal fluid abnormalities, or symptomatic, characterized by several different clinical syndromes, such as meningitis, gumma, meningovascular, brain parenchyma involvement, meningomyelitis, tabes dorsalis, and peripheral nervous system involvement. However, these syndromes may simulate several other diseases, making the diagnosis often a challenge. In addition, syphilis can also be vertically transmitted from mother to child during pregnancy, leading to neurological manifestations. Neuroimaging is essential to demonstrate abnormal brain or spinal cord findings in patients with neurosyphilis, aiding in the diagnosis, treatment, and follow-up of these patients. This article aims to review the imaging features of neurosyphilis, including the early and late stages of the infection.

[Neurosyphilis or not - a case of a differential diagnostic challenge]. / Neurosyphilis vagy nem ­ egy differenciáldiagnosztikai kihívás esete.

We report the case of a 42-year-old woman with paraparesis associated with transverse myelitis. For differential diagnostics detailed microbiological, cerebrospinal fluid (CSF) and neuroimaging examinations were performed. Syphilis was confirmed, but diagnosis of neurosyphilis was only probable based on the CSF microbiological test results. The beneficial treatment response to application of the therapeutic protocol for syphilis supported the supposed diagnosis of syphilis-associated myelitis in our case. In this case report we reviewed the differential diagnostic tools of myelopathies/myelitis.
Nowadays regarding to growing prevalence of syphilis worldwide physicians should face on its presence and medical consequences.

Neurosyphilis in disguise.

PURPOSE: Neurosyphilis can mimic different diseases, not only in its clinical presentation but also on imaging. Treponema pallidum is also known as the "great imitator." Having an ultimate diagnosis of neurosyphilis is quite critical as this can affect management drastically. Herein, we discuss the case of a 69-year-old female who was treated for neurosyphilis, while having an atypical imaging finding of anterior temporal lobe enhancement that simulated an infection with herpes simplex virus (HSV); we also review the available literature on different imaging findings in both the early and late stages of the disease. METHODS: We performed a literature search using the new PubMed in June 2021. The terms "neurosyphilis", "MRI", and "neuroimaging" were used either alone or in combination with "early neurosyphilis" or "late neurosyphilis". Data on neurosyphilis and imaging findings was mainly derived from review articles, cohort studies, case series, and individual reports. CONCLUSION: Neurosyphilis can present with an extensive variation and different patterns on the MRI, and clinicians must be aware of the wide variety in radiological presentations. Anterior temporal lobe involvement is a rare presentation and requires evaluating for neurosyphilis to prevent a missed diagnosis and treatment.

Neurosyphilis Mimicking Behavioral Variant of Frontotemporal Dementia in a 59-Year-Old Man.

We present the case of a man exhibiting a clinical phenotype of behavioral variant of frontotemporal dementia (bvFTD). The man had developed psychiatric disturbances with verbal aggressiveness over a few months, followed by cognitive and frontal behavioral disorders, fulfilling the clinical criteria for bvFTD. Atrophy and hypometabolism in frontotemporal regions were consistent with the diagnosis. However, serum-screening exams for syphilis infection were positive, and CSF analysis, despite a negative Venereal Disease Research Laboratory Test, suggested the diagnosis of neurosyphilis. After specific antibiotic therapy, the man's behavioral abnormalities and cognitive deficits notably improved, confirming neurosyphilis as the cause of the clinical phenotype. The cognitive deficits completely recovered 1 year post therapy and remained stable for 2 years. After ∼2½ years from the first treatment, the man's behavioral disorders mildly worsened, at which time we re-evaluated him. His cognition was stable, and a positive Venereal Disease Research Laboratory Test confirmed the diagnosis of neurosyphilis. With this case, we demonstrated that in some instances, neurosyphilis can mimic frontotemporal dementia. As a cause of treatable dementia, it should be considered in the differential diagnosis of bvFTD, particularly when psychiatric symptoms and a rapid cognitive decline are noted, even in the presence of brain atrophy and/or hypometabolism.

[Other Central Nervous System Infections(Including Fungal Infection, Tuberculosis, and Parasitic Infection)].

This review describes cryptococcal meningoencephalitis, tuberculous meningitis, neurosyphilis, and toxoplasma encephalitis. Central nervous system infections are neurological emergencies associated with mortality or other outcomes. Therefore, early diagnosis and treatment are critical. Fungal or gondii infections are rare and affect compromised hosts who are HIV positive, have diabetes, or take immunosuppressive or anticancer drugs. Cryptococcal antigens in the serum and cerebrospinal fluid are useful for the diagnosis of cryptococcal meningoencephalitis. RPR and TPHA tests are useful for the diagnosis of neurosyphilis. Cryptococcal meningoencephalitis and tuberculous meningitis often develop into hydrocephalus, making VP shunt necessary. Antifungal drugs for cryptococcal meningitis are limited by the blood-brain barrier, making a full recovery difficult; in such situations, intraventricular antifungal treatment is required.

Neurosyphilis and Lyme neuroborreliosis.

PURPOSE OF REVIEW: Neurosyphilis (NS) and Lyme neuroborreliosis (LNB) are spirochetal diseases with distinct clinical manifestations. The diagnosis of NS remains challenging due to imperfect diagnostic criteria and testing modalities. With LNB, misconceptions about diagnosis and treatment lead to considerable morbidity and drug related adverse effects. RECENT FINDINGS: Although studies continue investigating alternate approaches and new diagnostic tests for NS, few data exist to change current approaches to diagnosis, management or follow up. In the diagnosis of LNB, the chemokine CXCL13 shows promising diagnostic accuracy. A systematic review discourages the use of cell-based assays when investigating Lyme disease. Clinical studies show no benefit from extended antibiotic treatment for patients with unspecific symptoms labelled as having Lyme disease. SUMMARY: The diagnosis of NS may be delayed due to a lack of specificity of findings, low suspicion for syphilis, and/or similarities in presentation to other diseases. A high index of suspicion for syphilis is required provide timely diagnosis and management of NS. Fortunately, penicillin remains the treatment of choice. Overdiagnosis and overtreatment in patients labelled as having Lyme disease can be avoided by an evidence-based approach towards diagnosis and treatment.

Clinical and serological outcomes in patients treated with oral doxycycline for early neurosyphilis.

OBJECTIVES: Penicillin-based antibiotic treatment for syphilis infection with CNS involvement (early neurosyphilis) is not always a suitable treatment option. We compared outcomes of patients diagnosed with early neurosyphilis and treated with doxycycline or procaine G penicillin. METHODS: Serological and clinical outcomes were analysed in patients diagnosed with early neurosyphilis between January 2015 and October 2019 at 56 Dean Street, a combined sexual health and HIV service based in London, UK. Acute onset of CNS, ocular and/or otic symptomatology and a documented seroconverting syphilis serology or a >4-fold increase in rapid plasma reagin ('RPR)' test titre within the previous 12 months were criteria used to define a case. Mann-Whitney U-test and χ2 tests were used to test distributions between baseline characteristics and outcomes according to treatment administered. RESULTS: Eighty-seven patients were included: median age = 35 years (IQR = 31-45), 98% MSM, 79% white ethnicity, 53% HIV-1 positive and 40% previously diagnosed with syphilis at any stage. They were treated exclusively with either intramuscular (IM) procaine G penicillin (71%) or oral doxycycline (18%). Patients received doxycycline treatment over a penicillin-based regimen due to IM treatment declined (31%), inability to attend for IM injections (31%) or penicillin allergy (19%). Serological response was achieved by all patients; 91% reported full symptom resolution at 30 days from end of treatment. Similar rates of clinical and serological response and seroreversion were observed in the groups treated with procaine G penicillin versus doxycycline. CONCLUSIONS: The clinical and serological outcomes seen with penicillin-based versus doxycycline treatments were similar. A randomized controlled trial is needed to establish the effectiveness of doxycycline in the treatment of early neurosyphilis.

Clinical and Ophthalmological Characteristics of Ocular Syphilis in a Retrospective Tertiary Hospital Cohort.

BACKGROUND: Data on ocular syphilis (OS) and its clinical presentation are currently insufficient. This study aimed to investigate the characteristics of a cohort with a high OS incidence at a university hospital in Germany, focusing on the clinical presentation of OS. METHODS: This single-center cohort study retrospectively analyzed data on 90 patients with 109 episodes of syphilis between 2008 and 2018. Cases of OS were identified and additionally reevaluated through a study-specific secondary assessment by an ophthalmologist specializing in uveitis. RESULTS: Twenty-three patients (26%) were diagnosed with OS, 16 (70%) of whom were with binocular involvement. Uveitis, especially that of the posterior segment, showed a high prevalence. Lumbar puncture was performed in 20 OS patients (87%), of whom 17 (85% of those with lumbar puncture/74% in total) met the 2018 Centers for Disease Control and Prevention criteria for likely neurosyphilis. Five (22%) of 23 patients had HIV infection, of whom 2 did not receive antiretroviral therapy. The preferred syphilis treatment regimens were benzylpenicillin and ceftriaxone, which yielded favorable serological, clinical, and ophthalmological outcomes. CONCLUSIONS: A high incidence of OS was identified, and physicians should be aware of uveitis as a manifestation of syphilis. Most patients presented with uveitis and syphilis in an early or late latent stage and showed central nervous system involvement.

Neurosyphilis: a series of 178 cases at the 3rd-level hospital of Marrakesh (Morocco).

Neurosyphilis (NS) is an infection of the central nervous system (CNS), caused by Treponema pallidum. Up to 4-10% of patients with untreated syphilis may develop NS which still constitutes a health challenge. The aim of this study is to analyze epidemiological, clinical, paraclinical, therapeutic, and progression profiles of NS in the south of Morocco. Authors analyzed retrospectively 178 files of patients with neurosyphilis, collected in the Neurology Department of Marrakesh over 25 years from January 1994 to March 2019. In our study, the mean age was 46 years (17-75 years). The number of males was dominant (87.6%). The most common presentation was meningoencephalitis. Four cases were atypical (late congenital syphilis, amyotrophic lateral sclerosis, neurosyphilis associated with neuro-Behcet's disease, and acute polyradiculoneuropathy). All patients had positive TPHA and VDRL serologies in blood; CSF-TPHA was positive in all patients, and CSF-VDRL was positive in 64.0% of patients. CT scan and brain MRI showed cortical atrophy in the majority of cases. One hundred seventy-seven patients were treated with intravenous injection of aqueous penicillin G. Neurosyphilis is still a significant medical problem in developing countries, and its occurrence in HIV infection is the reason for a growing number of new cases in developed countries. Given the frequent atypical manifestations of the disease, screening for neurosyphilis should be considered in all patients with neurological or psychiatric symptoms.

Neurosyphilis and the Jarisch-Herxheimer reaction: A therapy concern with HIV disease.

Jarisch-Herxheimer reaction (JHR) should be anticipated in treating neurosyphilis with coexistent human immunodeficiency virus (HIV) encephalitis. In that context we have devised a staging classification for JHR. In addition, an illustrative case is provided to emphasize the need to consider the diagnosis of neurosyphilis in HIV patients, and if delineated, to be prepared for a severe JHR.

Incidental finding of neurosyphilis with intracranial hemorrhage and cerebral infarction: A case report.

Syphilis has recently increased in prevalence in Japan. Neurosyphilis is a special pathological condition of syphilis well known to cause cerebral vasculitis and ischemic stroke. Neurosyphilis in the meningovascular stage rarely causes caliber irregularity of the cerebral blood vessels or cerebral hemorrhage. We describe the case of a 49-year-old Japanese man with neurosyphilis. Cerebral hemorrhage, multiple cerebral infarctions, and caliber irregularity of the cerebral blood vessels were observed, the patient underwent surgery for cerebral hemorrhage on the day of admission, all of which were suspected to be caused by syphilis. He was started on an antibacterial treatment of penicillin on the day of admission and was diagnosed with neurosyphilis the following week based on his serum and spinal fluid test results. His condition improved, and he was transferred to another hospital after 4 weeks of treatment consisting of 3 weeks of infusion treatment with benzylpenicillin followed by oral treatment with amoxicillin. To the best of our knowledge, this is a rare case of neurosyphilis in conjunction with cerebral hemorrhage and cerebral infarction. Clinicians should consider syphilis in the differential diagnosis of cerebral hemorrhage and cerebral infarction and test patients for sexually transmitted diseases, in addition to cerebrospinal fluid testing, when cerebral hemorrhage occurs with an unknown cause. This is especially pertinent when patients present with cerebral infarction or caliber irregularity of the cerebral blood vessels.

Ocular syphilis - a case series of four patients.

Ocular manifestations of syphilis with visual impairment symptoms may occur already at the stage of secondary syphilis. They may also be the only manifestation of syphilis and mimic other diseases of the eye. Therefore, in all patients with uveitis, optic neuritis, optic atrophy, acute ocular muscle paresis, or loss of visual acuity, syphilis infection should be ruled out, even if the medical history does not initially raise suspicion. Ocular involvement should be treated as neurosyphilis. Delayed diagnosis and inadequate therapy are often associated with irreversible consequences for the affected patient. As with any syphilis infection, HIV infection should be considered and excluded, especially in the case of ocular manifestations.

Syphilis with diplopia. / Syfilis med dobbeltsyn.

BACKGROUND: Syphilis is a sexually transmittable infectious disease caused by the spirochaete Treponema pallidum, which classically causes symptoms in three stages. CASE PRESENTATION: A previously healthy male in his thirties was admitted to our department after suffering from diplopia and unilateral ptosis for two days. Clinical examination revealed a left-sided oculomotor palsy with an ipsilateral ptosis. Supplementary cerebral computer tomography with angiography and magnetic resonance imaging was normal except for lymphadenopathy in the neck and mediastinum. As the patient was homosexual, we chose to test for HIV. The doctor on duty, being from Belarus where syphilis was recognised as endemic during her studies, also screened for syphilis. The HIV test was negative, while the syphilis test was positive. Lumbar puncture showed moderate pleocytosis and positive serology for syphilis, confirming the diagnosis of neurosyphilis. The patient recovered fully after a course of penicillin. INTERPRETATION: Even though syphilis remains uncommon in Norway, the incidence has been increasing in recent decades, especially in male homosexual communities. Patients may subsequently present with a diversity of symptoms.

Secondary syphilis with ocular involvement in a HIV-infected patient - case report.

We describe the case of a HIV-infected patient, in whom a secondary syphilis with skin lesions and ocular involvement developed. On admission papular skin rash and partial visual loss with left eye were observed. Serological tests for syphilis were positive in very high titers. Ophthalmological examination revealed ocular abnormalities indicating ocular syphilis. Cerebrospinal fluid (CSF) tests showed elevated concentration of immunoglobulin G (IgG) with normal white blood count and albumin concentration, serological treponemal tests for syphilis were positive. Intravenous therapy with Penicillinum Crystallisatum (Benzylpenicillinum kalicum) was administered, according to the neurosyphilis treatment schedule, achieving resolution of the skin lesions and partial vision improvement, a month after the end of the treatment a complete recovery of the vision was noted. Serological tests` for syphilis titers decreased fourfold. Described case confirms reasonability of examination for syphilis in patients with sudden vision disturbances, especially those HIV-infected. It also indicates that early appropriate treatment of the ocular syphilis prevents permanent loss of vision.

Neurosyphilis Treatment Outcomes After Intravenous Penicillin G Versus Intramuscular Procaine Penicillin Plus Oral Probenecid.

BACKGROUND: Data comparing neurosyphilis treatment regimens are limited. METHODS: Participants were enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis that was conducted at the University of Washington between April 2003 to May 2014. They were diagnosed with syphilis and referred by their providers due to concerns for neurosyphilis. We evaluated 150 people with CSF abnormalities who were treated with either intravenous aqueous penicillin G (PenG) or intramuscular aqueous procaine penicillin G plus oral probenecid (APPG-P). An abnormal CSF diagnosis was defined as a white blood cell (WBC) count >20/µL, a CSF protein reading >50 mg/dL, or a reactive CSF-Venereal Disease Research Laboratory test (VDRL). Hazard ratios for normalization of CSF or serum measures were determined using Cox regression. RESULTS: In individuals treated with either PenG or APPG-P, CSF WBCs and CSF-VDRL reactivity normalized within 12 months after treatment, while protein normalized more slowly and less completely. There was no relationship between treatment regimen or human immunodeficiency virus (HIV) status and likelihood of normalization of any measure. Among those living with HIV, CSF WBC counts and CSF-VDRL reactivity were more likely to normalize in those treated with antiretrovirals. Unexpectedly, CSF WBCs were more likely to normalize in those with low CD4+ T cell counts. When neurosyphilis was more stringently defined as a reactive CSF-VDRL, the relationship with the CD4+ T cell count remained unchanged. CONCLUSIONS: In the current antiretroviral treatment era, neurosyphilis treatment outcomes are not different for PenG and APPG-P, regardless of HIV status. The relationship between the normalization of CSF WBC counts and CD4+ T cell counts may indicate continued imprecision in neurosyphilis diagnostic criteria, due to HIV-related CSF pleocytosis.