Introduction
Syphilis is a sexually transmitted infection caused by the spirochete Treponema pallidum (1,2). Despite its long history, syphilis continues to pose a notable public health challenge due to its ability to mimic a wide array of clinical conditions. Neurosyphilis (NS), a severe complication resulting from the invasion of Treponema pallidum into the central nervous system, can occur at any stage of syphilis. Historically, up to ~30% of untreated patients with syphilis developed NS; however, with antibiotic treatment, symptomatic NS is now estimated to occur in 1.5-13% of syphilis cases, and cohort data indicate that, among individuals with human immunodeficiency virus (HIV) infection, the incidence of NS is twice that of those without HIV infection (3,4). Cerebral syphilitic gummata (CSG) are rare manifestations typically associated with tertiary syphilis (5). In Cushing's (6) frequently cited case series of 2,203 intracranial tumors published in 1932, only 12 cases (0.5%) were identified as CSG. In a review of intracranial tumors by Grant (7) in 1956, which included 2,326 patients, only 5 cases (0.2%) were diagnosed as CSG. Likewise, Katsura et al (8), in a review of all neurosurgical cases in Japan prior to 1959, identified only 12 cases of syphilitic gummas among 3,312 patients, yielding an incidence of 0.4%. Although large-scale retrospective studies from recent years are lacking, the limited number of sporadic case reports published over the past two decades suggests that CSG has become an even rarer disease entity. The gummata are granulomatous lesions that may develop in various organs, including the brain, as a consequence of a chronic inflammatory response to persistent infection (9). Within the central nervous system, these lesions can give rise to diverse neurological symptoms depending on lesion size and location, including headaches, seizures, focal neurological deficits, cognitive impairment and behavioral disturbances. Owing to their rarity and heterogeneous presentation, CSG are frequently misdiagnosed or mistaken for other conditions, such as neoplasms, abscesses or other infectious or inflammatory disorders (10). The present study reports a case of CSG in a 60-year-old male patient who rapidly developed hemiplegia of the right upper and lower limbs over several days. The present case underscores the importance of considering NS in patients presenting with atypical neurological symptoms, particularly those with risk factors for syphilis infection.
Discussion
NS complications occur in 4-10% of untreated or inadequately treated patients with syphilis. The neurological manifestations in advanced NS are diverse (11); early NS often presents without neurological symptoms and primarily affects the meninges and blood vessels, whereas late NS can involve the meninges, blood vessels and brain parenchyma. This progression can lead to conditions such as meningitis, gummas or cerebral infarctions (12-14). CSG is a rare clinical manifestation of NS. In a review of 286 reported cases of NS, Drago et al (4) identified only 10 cases of CSG (3.5%). In a more recent cross-sectional study, the incidence of CSG was found to be 1.8% among 397 patients with NS (15); however, in both large studies, the cases of CSG occurred years or even decades after the initial infection. In the present study, the case is unusual in that the patient developed a gummatous lesion in the brain within just 6 months of being diagnosed with syphilis, representing an atypical and rare presentation of this condition in the early stage of the disease. To the best of our knowledge, this rapid progression is rarely documented in the literature and it underscores the variability in the clinical manifestations of syphilis (16,17).
The radiological appearance of syphilitic gummas frequently mimics other intracranial pathologies. Gliomas, especially high-grade variants, may present with irregular enhancement, marked perilesional edema and a mass effect similar to that observed in gummas. However, gliomas tend to show infiltrative margins and elevated perfusion metrics, whereas gummas more often demonstrate well-circumscribed granulomatous enhancement with a surrounding inflammatory halo.
Reports have suggested that penicillin treatment can reduce the size of CSG lesions, thereby avoiding the need for surgery (18,19). However, in the present case, the condition of the patient deteriorated rapidly, making it impractical to wait for the time required for penicillin therapy. Therefore, in the present case, the decision to pursue surgical intervention was based on the severity of the patient's symptoms and the need to alleviate the mass effect caused by the gummatous lesion. Surgical removal of the lesion not only provided symptomatic relief but also allowed for histopathological confirmation of the diagnosis, revealing granulomatous inflammation consistent with syphilitic gummata. Therefore, surgical biopsy plays a particularly notable role when imaging is inconclusive, allowing definitive histopathological confirmation and exclusion of neoplasia. Decompression may also provide symptomatic relief when rapid deterioration occurs. Nevertheless, once a diagnosis is established, medical therapy alone is often sufficient and unnecessary extensive resections should be avoided (20,21).
The present case is noteworthy as it illustrates that CSG can occur much earlier in the course of syphilis than is typically expected. It emphasizes the importance of considering NS and its atypical manifestations, even in patients with a relatively short history of syphilis. Clinicians should maintain a high degree of suspicion for NS in patients presenting with new-onset neurological symptoms, regardless of the duration since syphilis diagnosis, especially when accompanied by risk factors or inadequate treatment history.
The occurrence of CSG in early syphilis may reflect an aggressive host response or a particularly virulent strain of Treponema pallidum (22). To the best out our knowledge, the pathophysiology behind the formation of gummata in such a short time frame is not well understood. Typically, gummatous lesions result from a chronic granulomatous inflammatory response to persistent infection. In the present patient, elevated Treponema pallidum antibody titers (signal-to-cutoff ratio, 18.84) and cerebrospinal fluid abnormalities, including increased protein and the positive CSF TP-PA test, suggested that the immune response in the present patient might have been unusually robust or dysregulated; this could be due to genetic predisposition, immune status or other unknown factors (23). As part of the present study, a literature review of reported cases of early-onset syphilitic gummas was conducted, as summarized in Table II. Among the cases, a substantial proportion of patients had comorbid conditions associated with immunosuppression, including diabetes, HIV infection or concurrent systemic infections, which may have contributed to the early development of gummatous lesions. Most lesions involved the frontal or temporal lobes, frequently presented with focal neurological deficits such as hemiparesis or speech disturbances, and were generally treated with a combination of surgical resection and antibiotic therapy. Follow-up data indicated that most patients achieved favorable neurological recovery when treated promptly. This detailed overview underscores the importance of considering underlying immunosuppressive conditions and lesion location when evaluating early-onset intracranial syphilitic gummas.
As syphilis rates continue to rise each year, it becomes increasingly more important to consider CSG, a condition that is often overlooked and occurs less frequently (24). There is no definitive standard for diagnosing CSG; although craniocerebral tumors are more common than syphilis, it is crucial to differentiate patients exhibiting nervous system symptoms and positive serological test results for syphilis from those with CSG. Imaging plays a key role in diagnosing CSG; however, when faced with a rapidly deteriorating patient, surgical intervention is often the most effective approach. For patients experiencing severe cerebral edema, decompressive craniectomy can be a viable option.
In conclusion, the present case highlights an atypical and rare presentation of CSG occurring just 6 months after the initial diagnosis of syphilis, challenging the conventional understanding that such manifestations are predominantly associated with tertiary syphilis after numerous years of infection. Clinicians should consider NS in the differential diagnosis of unexplained neurological symptoms, regardless of the duration of syphilis, to facilitate a timely and effective intervention.