Neurosyphilis Concurrently Presenting With Limbic Encephalitis and Normal Pressure Hydrocephalus: A Case Report

ABSTRACT

Background

Neurosyphilis may present with a variety of clinical symptoms and neuroimaging findings and is thus likely to be overlooked. We report a case of neurosyphilis presenting with dementia, limbic encephalitis, and normal pressure hydrocephalus.

Case Presentation

A 47‐year‐old man had gradually experienced cognitive decline for over a year. He was admitted to a psychiatric hospital. Brain computed tomography imaging showed ventricular enlargement. Serological tests for syphilis were positive. He was transferred to our hospital, where he exhibited gait disturbance, cognitive impairment, and urinary incontinence. Brain magnetic resonance imaging showed high signal intensity in both medial temporal lobes. Treponemal cerebrospinal fluid testing was positive. He was treated with intravenous benzylpenicillin for 36 days and two courses of intravenous methylprednisolone pulse therapy. His psychomotor agitation required physical restraint for 37 days and treatment with risperidone. Although his gait disturbance and urinary incontinence improved, no clinically meaningful change in cognitive impairment was observed. The high signal intensity on repeat imaging was attenuated. He was transferred back to the psychiatric hospital 3 months after admission.

Conclusion

This case of neurosyphilis was characterized by early‐onset dementia with limbic encephalitis and normal pressure hydrocephalus. Psychiatrists should be aware of the possibility of neurosyphilis in such cases.

We report a case of neurosyphilis characterized by early‐onset dementia, limbic encephalitis, and normal pressure hydrocephalus. Psychiatrists should be aware of the possibility of neurosyphilis in such cases.

1. Introduction

Syphilis is a sexually transmitted disease caused by Treponema pallidum [1]. More than 10 000 cases of syphilis have been reported every year since 2022 in Japan [2]. Neurosyphilis is a condition in which T. pallidum infects the central nervous system. It is typically classified as asymptomatic early neurosyphilis, syphilitic meningitis, meningovascular syphilis, general paresis, or tabes dorsalis, based on clinical manifestations and laboratory findings [3]. Neurosyphilis may cause neurocognitive impairment, personality changes, and mood disorders, mimicking various psychiatric conditions [4]. Moreover, it can exhibit diverse clinical presentations, such as limbic encephalitis (LE) [5, 6] and normal pressure hydrocephalus (NPH) [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]. However, sufficient attention may not be paid to neurosyphilis as a potential cause of these manifestations. We report a case of neurosyphilis presenting with dementia, LE, and NPH in a 47‐year‐old man.

2. Case Presentation

A 47‐year‐old Japanese man was admitted to a psychiatric hospital with a 14‐month history of behavioral changes. He worked as an office worker, lived alone, and had a gentle personality. His medical and family history were unremarkable. He had been sending incoherent emails at work and was washing cars with a brush on the taxi company's premises. In addition, he was unable to unlock the automatic door of his apartment building. Brain computed tomography imaging showed ventricular enlargement. Both rapid plasma reagin (RPR) and T. pallidum hemagglutination assay (TPHA) tests were positive.

Nine days after admission, he was transferred to our hospital (Figure 1). His gait was slightly wide and unsteady, and he was unable to stand on one leg. He mistook our hospital for a hotel, and his speech was incoherent. He urinated in his room and kept his soiled clothes together with his clean clothes. His Mini‐Mental State Examination (MMSE) score was 16 on Day 2. He had urinary incontinence. Examination of his cranial nerves, motor strength, sensory pathways, and deep tendon reflexes was unremarkable. On Day 3, cerebrospinal fluid (CSF) analysis showed pleocytosis and a positive TPHA (Table 1). The CSF opening pressure was 170 mmH₂O. CSF anti‐N‐methyl‐d‐aspartate receptor antibodies and blood anti‐thyroid peroxidase antibodies were negative. Quantitative nucleic acid testing for herpes simplex virus (HSV) and varicella‐zoster virus in the CSF was negative. Blood human immunodeficiency virus type 1/2 antibody testing was negative. He denied high‐risk sexual behaviors (such as having multiple sexual partners and having sex with men), international travel, and injection drug use. Brain magnetic resonance imaging (MRI) on Day 1 showed abnormal signal intensity in both medial temporal lobes (Figure 2a) and ventricular enlargement (Evans index = 0.41; Figure 2b). Electroencephalography demonstrated diffuse slow wave activity (6–7 Hz). He was diagnosed with major neurocognitive disorder due to neurosyphilis in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria.

FIGURE 1.

Clinical course of the patient. The patient was treated with benzylpenicillin (PCG) 24 million units/day for 36 days and two courses of methylprednisolone (mPSL) pulse therapy. His psychomotor agitation required physical restraint for 37 days and up to 2 mg/day of risperidone (RIS). His gait disturbance and urinary incontinence improved, but his Mini‐Mental State Examination (MMSE) score did not. He was transferred back to the referring hospital on Day 85.

TABLE 1.

Laboratory data before and during treatment for neurosyphilis.

Test	Before treatment		During treatment
	Day 1	Day 3	Day 41
Blood
Glucose (mg/dL)	—	99	95
Albumin (mg/dL)	—	4740	3670
Immunoglobulin G (mg/dL)	—	1110	742
Rapid plasma reagin (R.U.)	44.6	—	13.8
Treponema pallidum hemagglutination assay (T.U.)	77.3	—	127.2
Cerebrospinal fluid
Cell counts (/μL)	—	15	3
Mononuclear cell counts (/μL)	—	15	3
Multinuclear cell counts (/μL)	—	< 1	< 1
Glucose (mg/dL)	—	46	54
Albumin (mg/dL)	—	75	117
Immunoglobulin G (mg/dL)	—	23.5	17.2
Total protein (mg/dL)	—	132	182
Treponema pallidum hemagglutination assay	—	1:10 240	1:5120
Immunoglobulin G index	—	1.34	0.73

Abbreviations: R.U., reagin units; T.U., titer units.

FIGURE 2.

Brain magnetic resonance imaging findings of the patient before (a, b) and after (c, d) treatment for neurosyphilis. T2‐weighted fluid‐attenuated inversion recovery imaging showed abnormal high signal intensity in both medial temporal lobes (arrows) before treatment (a), which was attenuated after treatment (c). The lesions were not associated with edema or mass effect. T1‐weighted imaging showed that ventricular enlargement did not change before (b) and after (d) treatment (Evans index = 0.41 for each).

He was treated with intravenous benzylpenicillin (PCG) 24 million units/day for 36 days (Figure 1). We also administered steroid pulse therapy (methylprednisolone 1 g/day) from Day 10 to Day 12. His psychomotor agitation worsened and he removed an intravenous cannula. Physical restraint was initiated on Day 13, and risperidone 1 mg/day was initiated on Day 14. He then received a second course of steroid pulse therapy from Day 24 to Day 26. RPR decreased from 44.6 reagin units on Day 1 to 13.8 on Day 41 (Table 1). Therefore, intravenous PCG was discontinued on Day 45. His psychomotor agitation fluctuated but persisted. The dose of risperidone was increased to 1.5 mg/day on Day 36, and 2 mg/day on Day 45. Physical restraint was ended on Day 49.

His gait became stable and his urinary incontinence had nearly resolved. His MMSE scores on Day 24 and Day 57 were 12 and 18, respectively. Brain MRI on Day 52 showed attenuation of the abnormal signal intensity (Figure 2c), but the ventricular enlargement was unchanged (Evans index = 0.41; Figure 2d). He was transferred back to the psychiatric hospital on Day 85.

3. Discussion

3.1. Neurosyphilis Presenting With LE and NPH

The PubMed and Ichushi‐Web databases were searched for cases of neurosyphilis presenting with LE and/or NPH, using the terms “neurosyphilis,” “LE,” and “NPH.” We identified no case of neurosyphilis presenting with both LE and NPH. Psychiatrists should be aware of this possibility because patients with neurosyphilis may initially present to a psychiatrist, such as our case.

For the differential diagnosis of LE, we ruled out HSV infection, varicella‐zoster virus infection, and anti‐N‐methyl‐d‐aspartate receptor encephalitis; however, we did not perform a comprehensive diagnostic work‐up for other autoimmune or paraneoplastic conditions, which is a limitation regarding the diagnosis of LE in our patient. Neurosyphilis was the most likely cause of LE in our patient because it may present with LE and mimic autoimmune LE [5, 6]. Several cases of concurrent neurosyphilis and autoimmune LE have been reported [18, 19]. Therefore, it is important to differentiate the two. In a literature review of 60 cases of neurosyphilis presenting with LE [6], only 3 patients met all 3 criteria for a definite diagnosis of autoimmune LE [20]. Our patient did not meet the first criterion because he developed chronic but not subacute onset (rapid progression of less than 3 months). He met the second criterion (bilateral brain abnormalities on T2‐weighted fluid‐attenuated inversion recovery MRI highly restricted to the medial temporal lobes) and the third criterion (CSF pleocytosis and electroencephalogram with slow‐wave activity involving the temporal lobes). In patients presenting with atypical manifestations of autoimmune LE, as in this case, clinicians should consider neurosyphilis.

Our patient was diagnosed with NPH based on clinical symptoms (cognitive decline and urinary incontinence) and ventricular enlargement on brain computed tomography. Onset in his 40s suggested secondary NPH rather than Hakim's disease (idiopathic NPH) [21]. To screen for neurosyphilis as the cause of secondary NPH, blood tests for syphilis were performed and were positive, as was a CSF TPHA test. Additionally, MRI did not indicate disproportionately enlarged subarachnoid‐space hydrocephalus, which is characteristic of Hakim's disease. A tap test was not performed because it is not generally indicated in cases of secondary NPH [22].

Table 2 shows the symptoms and treatment in our patient and 11 previously reported cases of neurosyphilis presenting with NPH [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]. Nine of the 12 patients were under age 65 years. Eight exhibited the classic triad of NPH symptoms. PCG was the most frequently used antibiotic, followed by ceftriaxone and doxycycline. In three patients [11, 12, 15], neurosyphilis was diagnosed after ventriculoperitoneal shunting, which is associated with the risk of spreading T. pallidum from the CSF into the abdominal cavity. Therefore, it is important to consider neurosyphilis as a possibility in patients diagnosed with NPH, especially those who are middle aged.

TABLE 2.

Twelve cases of neurosyphilis presenting with normal pressure hydrocephalus.

Author	Age	Sex	Triad			Treatment
			Gait disturbance	Cognitive impairment	Urinary incontinence	Antibiotics	VP shunt
Heinz et al. [7]	52	F	NA	+	NA	NA	NA
Pedersen et al. [8]	54	M	+	+	NA	PCG	+
Kamei et al. [9]	68	M	+	+	+	PCG + DOXY	−
Cosottini et al. [10]	44	M	+	+	NA	PCG	−
Ishizaki et al. [11]	54	M	+	+	+	PCG	−
Fadil et al. [12]	61	M	+	+	+	PCG	+
Mok et al. [13]	76	M	+	+	+	PCG	−
Souza et al. [14]	79	M	+	+	+	PCG	−
Roman‐Filip et al. [15]	38	M	NA	+	NA	CTRX	+
Abdool et al. [16]	46	M	+	+	+	PCG	−
Baskar et al. [17]	40	M	+	+	+	PCG + CTRX	−
Obata et al.	47	M	+	+	+	PCG	−

Abbreviations: CTRX, ceftriaxone; DOXY, doxycycline; F, female; M, male; NA, not available; PCG, benzylpenicillin; VP, ventriculoperitoneal.

3.2. Antibiotic and Steroid Therapy for Neurosyphilis

In the 2021 Sexually Transmitted Infections Treatment Guidelines [23], intravenous PCG 18–24 million units/day for 10–14 days is the recommended treatment regimen for neurosyphilis. However, this treatment duration is shorter than that recommended for latent syphilis. Therefore, additional intramuscular benzathine PCG 2.4 million units/week for 1–3 weeks can be considered. However, benzathine PCG is not indicated for neurosyphilis in Japan. Intravenous PCG has been commonly used for more than 14 days in patients with latent syphilis of unknown duration [24], although there is no robust evidence for this practice. In our patient, blood RPR and CSF pleocytosis improved, whereas CSF protein increased from 132 to 182 mg/dL. We were unsure as to how to interpret this discordant response, and decided to terminate intravenous PCG after 36 days. The lack of non‐treponemal CSF findings (e.g., CSF‐RPR) limited our ability to assess diagnostic certainty and the treatment response. A previous longitudinal study reported normalization of blood RPR in 57%, 85%, and 88% of patients 4, 7, and 13 months after treatment of neurosyphilis, respectively [25]. In addition, normalization of blood RPR titer predicts normalization of CSF abnormalities except for CSF protein [25]. Therefore, it may be acceptable to use blood RPR as an indicator for assessing the efficacy of neurosyphilis treatment.

Interaction between infection and autoimmunity might be involved in the pathophysiology underlying neurosyphilis presenting with LE [5]. Bhai et al. [26] reported such a patient whose clinical symptoms improved with steroid pulse therapy. That patient, a 64‐year‐old woman with declining cognitive function over a 7‐month period, was treated with intravenous methylprednisolone 1 g/day for 5 days, which resulted in improvement in her memory, attention, and concentration. Subsequent serological tests for syphilis were positive and intravenous PCG 4 million units/day was administered for 2 weeks. Akashi et al. [27] reported a 52‐year‐old man with neurosyphilis presenting with LE, who showed sudden onset disorganized behaviors and developed a generalized seizure. Blood and CSF tests for syphilis were positive, and intravenous PCG 24 million units/day was administered for 14 days. He was also treated with intravenous acyclovir 1500 mg/day for 14 days and two courses of steroid pulse therapy (intravenous methylprednisolone 0.5 g/day for 3 days) until a second negative result for quantitative nucleic acid CSF testing for HSV was confirmed. Additionally, amoxicillin 3000 mg/day was administered for 14 days. He returned to work 6 months after diagnosis. The authors speculated that steroid pulse therapy might be effective against the autoimmune mechanism underlying LE [27]. In our patient, steroid pulse therapy was also conducted in combination with PCG, considering the presentation of LE. His psychomotor agitation worsened despite approximately 2 weeks of PCG treatment. At that time, we were unable to conclude that the first course of steroid pulse therapy had exacerbated his agitation. Although the evidence is limited, there have been several case reports of neurosyphilis presenting with LE in whom the patient's clinical symptoms may have improved owing to steroid pulse therapy, as described above. Therefore, we administered the second course of steroid pulse therapy. In retrospect, however, its effectiveness was unclear, and it may have worsened his agitation. Steroid therapy should be only considered in patients with neurosyphilis mimicking autoimmune LE if the potential benefits outweigh the risks.

We acknowledge the short follow‐up period as a limitation of this case report, as cognitive impairment and ventricular enlargement may change over a longer period after treatment. However, the clinical, serological, CSF, and radiological data after the patient was transferred back to the referring hospital are unavailable. MMSE scores fluctuated from 16 on Day 2 to 12 on Day 24, and then to 18 on Day 57. Agitation and/or steroid pulse therapy may have caused the decline in MMSE score on Day 24. Nevertheless, cognitive impairment did not meaningfully change in the short‐term period.

4. Conclusion

This case of neurosyphilis was characterized by dementia presenting with LE and NPH in a 47‐year‐old man. Psychiatrists should be aware of the possibility of neurosyphilis in such cases.

Author Contributions

N.O. wrote the first draft. K.T., G.M., Y.M., S.I., and Y.W. critically revised the manuscript. All authors have read and approved the final manuscript.

Funding

The authors have nothing to report.

Disclosure

No material from other sources was reproduced in this manuscript.

Ethics Statement

This study was approved by the Clinical Ethics Committee of Uonuma Kikan Hospital.

Consent

The patient and his family provided written informed consent for the publication.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

No datasets were generated or analyzed for this case report.