Case reports of neurosyphilis: neurological and psychiatric aspects of the great imitator

Abstract

Neurosyphilis (NS) is a severe complication of syphilitic infection, in which Treponema pallidum invades the central nervous system (CNS), causing a wide range of clinical manifestations that can vary from behavioral disorders and cognitive decline to paresis and death. Without proper treatment, NS can lead to irreversible sequelae and death, and early initiation of specific treatment is essential for a favorable prognosis. Syphilis, caused by the spirochete Treponema pallidum, is most commonly transmitted through mucous membranes and disseminates systemically via hematogenous and lymphatic pathways [1]. If untreated, syphilis progresses through three clinical stages: primary, secondary, and tertiary, alternating with asymptomatic periods of variable duration. CNS invasion by T. pallidum can occur within the first few days of infection [2,3], meaning that NS, although often perceived as a late complication, can appear in any of the three stages of the disease. The development of NS depends on the complex interaction between bacterial invasion of the CNS and the immune system’s ability to eliminate the pathogen [4]. There are five forms of NS: three early forms – asymptomatic, meningeal, and meningovascular; and two late forms – general paresis (affecting the brain) and tabes dorsalis (affecting the spinal cord) [3]. The first three forms are classified as early NS, and the last two as late NS. Additionally, late NS can mimic various psychiatric disorders, including depression, mania, psychosis, hallucinations, euphoria, dementia, and schizophrenic disorders [5]. The diagnosis of NS is based on neurological clinical manifestations and changes in cerebrospinal fluid (CSF). Because there is no gold standard for diagnosing NS and no clear consensus on diagnostic criteria [4], careful correlation of clinical symptoms with CSF and serological changes is necessary, which can pose a challenge for dermatovenerologists, neurologists, and psychiatrists. The presented clinical cases illustrate the neurological and psychiatric manifestations of NS in three male patients, whose symptoms developed over a relatively short period of 1-2 years. The objective was to evaluate the clinical features and management of neurosyphilis in adults. Materials and Methods A retrospective study was conducted on a series of neurosyphilis cases. Case 1. A 42-year-old man lost consciousness in a public place and presented with speech disorders. He was transported to the hospital with a suspected cerebrovascular accident, which was not confirmed. The RPR (Rapid Plasma Reagin) test was positive, and the patient was referred to the Dermatology and Communicable Diseases Hospital in Chișinău, Moldova. Upon hospitalization, he exhibited slow speech, confusion, spatial disorientation, and difficulty answering questions about himself and his past, but without obvious neurological signs. Neurological examination showed isochoric pupils, positive direct and indirect reflexes bilaterally, no motor or sensory deficits, and negative meningeal signs. The MoCA cognitive test score was 9/30, indicating significant cognitive impairment. The diagnosis of acute cerebrovascular accident was excluded, as the cranial CT scan showed no pathological foci, only punctate atheromatous deposits in the carotid siphons bilaterally. Given the clinical signs and RPR positivity, a CSF analysis was performed, which was VDRL positive with a titer of 1:8, TPHA (passive hemagglutination) positive ++++, Western blot IgG for syphilis positive, ELISA IgG and IgM positive. The patient was HIV-negative. Based on clinical and paraclinical data, the diagnosis of NS was established, and treatment with penicillin G 2.4 million units daily for 14 days was initiated. No Jarisch-Herxheimer reaction occurred. The treatment was complemented with Piracetam 20% IV, Cinnarizine 0.025 mg in the evening, and Memantine 0.01 mg in the morning. Upon discharge, the patient showed slight improvement, but cognitive functions remained severely impaired, with a repeated MoCA score of 11/30. Cognitive re-evaluation at 6-12 months post-treatment is recommended to assess the reversibility of neural impairment. Case 2. A 32-year-old man presented to the Institute of Neurology and Neurosurgery after losing consciousness following a traumatic brain injury. He was temporospatially disoriented, with slow speech, concentration difficulties, auditory hallucinations, and headaches. According to relatives, behavioral disorders, including psycho-emotional lability, apathy, aggression, and memory disturbances, had started about a year prior. The neurological diagnosis was structural atrophic post-traumatic encephalopathy, meningovascular NS, rare non-convulsive epileptic seizures, and cognitive disorders. Neurological examination was normal, with non-systematized postural instability and palmar hyperhidrosis. Serologically, RPR ++++ titer 1:8, TPHA ++++, specific IgG antibodies 3.2, titer 1:1280, IgM negative. CSF examination was VDRL positive, Anti T. pallidum IgG 3.39 (reference values 0.21) titer 1:40, Anti T. pallidum IgM 0.39 (reference values 0.16), Pandy test positive. Cranial CT showed marked cerebral atrophy. The mini-cognitive test score was 8/30. The diagnosis of symptomatic NS, meningovascular form, was established, and treatment with penicillin G 2.4 million units daily for 14 days was initiated. The neurologist also recommended Carbamazepine 200 mg daily for 3 months, hypothalamic phospholipids 28 mg/2 ml IV daily for 10 days, and B vitamins for 10 days. No improvement in cognitive and behavioral disorders was observed during treatment. Case 3. A 33-year-old man presented to the hospital with left-sided muscle weakness, headache, periodic nausea, and fatigue. Anamnesis revealed he had lost consciousness while driving and was diagnosed with RPR positive. Objective examination showed left-sided hemiparesis, bilateral bradykinesia, isochoric pupils, and preserved bilateral light reflexes. The MoCA cognitive test score was 12/30. Serologically, RPR ++++, TPHA ++++, specific IgG antibodies positive, IgM negative. CSF examination was VDRL positive, RPR ++++, TPHA ++++, specific IgM antibodies ++, IgG positive ++++. The diagnosis of NS was established, and treatment with benzathine benzylpenicillin 2.4 million units daily for 14 days was initiated, with no notable changes in neurological and psychiatric symptoms during treatment. Discussions In the three patients, CT scans excluded cerebrovascular accident and intracranial volume formation diagnoses. Primary dementia was excluded due to the rapid cognitive decline (1-2 years) and the young age of the patients (32, 33, and 42 years). Serological tests for hepatic viruses and HIV were negative. During treatment, no clinical evolution was observed in these patients. A narrative review of the literature revealed a low level of clinical awareness of NS as a possible cause of various psychiatric disorders [5]. Early diagnosis and subsequent treatment are crucial in cases of NS, directly influencing the reversibility of manifestations. In this context, routine testing of psychiatric and neurological patients for syphilitic serological markers is mandatory. When clinical suspicion is supported by relevant anamnesis (young age, male sex, rapid development of psychiatric condition, altered social relationships, living alone), CSF evaluation is considered useful. However, due to potential complications from CSF collection, this test has limitations. The screening tests for syphilis remain the non-treponemal serological tests VDRL and RPR [4,9]. To establish the diagnosis of NS, the presence of treponemes in the nervous system must be confirmed by CSF analysis. The Centers for Disease Control and Prevention (CDC) emphasize two categories of NS diagnosis: the first is “confirmed” NS, in which NS is present at any stage of syphilis with a reactive CSF-VDRL test; the second is “presumptive” NS, where CSF-VDRL is non-reactive but CSF abnormalities such as pleocytosis or increased proteins are present, along with clinical signs characteristic of syphilis [5]. Polymerase chain reaction (PCR) testing would be a complementary method, but it has unclear sensitivity in CSF or blood analysis (sensitivity ranged between 40 and 70%) [6]. PCR can be used as an additional screening test for syphilis, especially in the early stage when the serological reaction is negative [7]. According to an epidemiological study from 2022 [8], the syphilis rate is continuously increasing compared to 2013, with a male-to-female ratio of 7.8:1. The data from this study state that 74% of syphilis cases with known transmission mode were among MSM (Men Who Have Sex with Men). Strengthening epidemiological screening and treatment measures in these groups, as well as increasing disease awareness at the population level, is necessary. Conclusions Diagnosing NS is complicated due to its varied manifestations. Clinical evaluation and meticulous anamnesis collection are crucial in establishing the diagnosis. Considering NS as a differential diagnosis in young patients, especially males, with rapidly developing cognitive decline and behavioral disorders is notable. Interdisciplinary collaboration – dermatovenerologist, neurologist, psychiatrist – could expedite diagnosis. Diagnosis is based on objective examination, serological data, and CSF changes. Early administration of treatment influences the reversibility of manifestations and reduces the risk.