Neurosyphilis Is a Long-forgotten Disease but Still a Possible Etiology for Dementia

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1 CASE REPORT Neurosyphilis Is a Long-forgotten Disease but Still a Possible Etiology for Dementia Hideharu Hagiya 1, Kentaro Deguchi 2, Kiyohiro Kawada 3 and Fumio Otsuka 1 Abstract We herein report a heterosexual Japanese man in his forties who had been suffering from advanced dementia and personality change for 4 years. Positive results of a serological test for syphilis, Treponema pallidum hemagglutination assay, and fluorescent treponemal antibody-absorption test of both serum and cerebral spinal fluid led to the diagnosis of neurosyphilis. Jarisch-Herxheimer reaction was seen shortly after the first dose of penicillin was administered to the patient. His cognitive function did not recover after treatment. The incidence of syphilis has been reported to be increasing. Neurosyphilis should not be overlooked as an etiology for progressive dementia even in this post-antibiotic era. Key words: dementia, Jarisch-Herxheimer reaction (JHR), spirochete, syphilis, Treponema pallidum (Intern Med 54: , 2015) () Introduction Syphilis is an ancient disease that was first described more than 500 years ago but remains a constant threat (1). With the introduction of antibiotics, the number of patients with syphilis has dramatically declined, but it has recently been increasing (2). The remerging disease is caused by Treponema pallidum, which infects people mainly through sexual contact. The organism is difficult to identify by conventional methods of staining and culture, and its infection yields wide-spectrum symptoms mimicking various diseases over a long duration. Thus, the clinical diagnosis of syphilis is challenging for physicians. Neurosyphilis develops by invasion of the pathogen into cerebrospinal fluid (CSF). It has been thought that the disease develops long after T. pallidum infection, but it is now considered to develop at any stage of the infection. According to a previous report, T. pallidum was detected in CSF samples in one-quarter of untreated patients with early syphilis (3). With a decrease in newly infected people, neurosyphilis might have been forgotten as one of the etiologies for central nervous system disorder. We herein report an otherwise previously healthy, young adult patient who developed advanced dementia and personality change that was diagnosed with neurosyphilis 4 years after onset. Case Report A previously healthy heterosexual man in his forties had attended a psychiatric hospital for four years with a diagnosis of bipolar affective disorder. During that period, the patient showed disturbance of memory and personality change. He was abnormally fixated on money; he counted money all day long. In addition, he always had his eyes on the clock and made a note of his own behaviors. He frequently experienced nighttime incontinence. For the past 9 months, his attention and interest had been gradually impaired. Ventricular enlargement was indicated by head computed tomography and a tap test was performed with the suspicion of normal pressure hydrocephalus. However, his symptoms did not resolve at all. For further investigation, the patient was referred to the department of neurosurgery in our hospital. The patient was alert but dementia accompanying memory disturbance was seen. In the admission ward, he wandered Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan, Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan and Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan Received for publication January 13, 2015; Accepted for publication March 1, 2015 Correspondence to Dr. Hideharu Hagiya, e_dai_for_all@hotmail.com 2769

2 Table. Results of Blood Tests. White blood cells 9,480 /mm 3 LDH 242 IU/L Cerebrospinal fluid Nt 76.9 % AST 24 IU/L Cell 1 Lym 16.9 % ALT 29 IU/L Protein 91 mg/dl Mono 5 % ALP 255 IU/L Glucose 54 mg/dl Eo 0.8 % GTP 19 IU/L Culture negative Baso 0.4 % T-bil 0.71 mg/dl STS 6.8 R.U. Hemoglobin 13.4 g/dl BUN 12.1 mg/dl TPHA 32,450 T.U. Platelet /mm 3 Cre 0.79 mg/dl FTA-ABS 2+ ESR 15 mm/h TP 7.8 g/dl Alb 5 g/dl PT-INR 0.96 CRP 0.06 mg/dl APTT 31.1 sec Na 140 meq/l Fibrinogen 325 mg/dl K 3.8 meq/l D dimer <0.5 Cl 105 meq/l Glucose 75 mg/dl HBs-Ab negative HbA1c 5.4 % HCV-Ab negative Vit B1 46 ng/ml HIV-Ab negative Vit B pg/ml STS 7.2 R.U. ANA negative TPHA 37,300 T.U. FT ng/ml FTA-ABS 2+ TSH 5.86 IU/mL Except for high titers of STS and TPHA in both serum and cerebrospinal fluid, results of blood examinations were almost normal. A result of cytology for cerebrospinal fluid showed a small quantity of lymphocyte. ANA: antinuclear antibody, FTA-ABS: fluorescent treponemal antibody-absorption test, STS: serological test for syphilis, TPHA: Treponema pallidum hemagglutination assay in and out of rooms. He had never received a blood transfusion. His physical examination did not reveal any evidence of a genital ulcer or skin rash on the trunk, palm, or plantar surface. Meningeal irritation signs were absent. He showed spastic gait, but motor paralysis was not apparent. Results of the Mini-Mental State Examination (MMSE) and Revised Hasegawa s dementia scale (HDS-R) were 14/30 and 8/30, respectively. His laboratory examination revealed no remarkable findings. However, the results of a serological test for syphilis (STS) and T. pallidum hemagglutination assay (TPHA) were elevated: 7.2 RPR unit (R.U.) and 37,300 titer unit (T.U.), respectively (latex method). Specific antibodies for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus (HIV) were all negative. There was no finding of thyroid dysfunction or vitamin deficiency. Neurosyphylis was suspected, therefore, the patient s CSF was examined. There was no elevation of cell count, but his protein level, STS, and TPHA of CSF were all elevated: 91 mg/dl, 6.8 R.U., and 32,450 T.U., respectively. Positive results of a fluorescent treponemal antibody-absorption (FTA- ABS) test were also obtained in both serum and cerebral spinal fluid samples (Table). Cerebral atrophy was observed by brain magnetic resonance imaging (MRI) (Fig. 1A, B), but there was no signal abnormality in the cerebral parenchyma or cortex. His magnetic resonance angiography (MRA) was not indicative of arteritis or an aneurysm. A decreased cerebral blood flow was prominent, particularly in frontal lobes (Fig. 1D). His spinal MRI did not show any evidence of spinal cord lesions including tabes dorsalis. With an elevation of protein and positive results of STS and FTA-ABS in CSF, a diagnosis of neurosyphilis was made and an intravenous administration of penicillin G was started with a dose of 4 million units per 4 hours for the patient. Soon after the first dose, a high fever emerged with a peak at 6 hours but spontaneously resolved within one day (Fig. 2). The condition was considered to be a Jarisch- Herxheimer reaction (JHR) and antibiotic therapy was continued. Five days after initiating penicillin G therapy, a systemic rash emerged and the administration of the drug was discontinued because of the suspected drug-induced eruption.afewdayslater,therashdisappeared,and2gperday of ceftriaxone was administered instead. The alternative therapy was given for 2 weeks without other adverse events. At the end of the antibiotic therapy, STS and TPHA declined in both serum (STS, 7.2 to 5.0 R.U.; TPHA, 37,300 to 26,100 T.U.) and CSF (STS, 6.8 to 1.4 R.U.; TPHA, 32,450 to T.U.). However, the patient s cognitive function and abnormal behaviors did not improve after the treatment. Discussion The present case showed the importance of careful examination for treatable dementia, especially in young adult patients. In general, common diseases for dementia include degenerative disorders such as Alzheimer s disease, frontotemporal lobar degeneration, and dementia with Lewy bodies (4). Vascular dementia is also frequently encountered in elderly people (5). These conditions are, however, difficult to treat once they develop. In contrast, there are many treatable diseases or conditions causing dementia symptoms; i.e., possibly reversible dementia. Representative conditions include endocrine disorders (thyroid or adrenal diseases), electrolyte disorders (hyponatremia, hypernatremia, hypercalcemia), vitamin deficiency (vitamin B1, B12, nicotinate), conditions induced by drugs (benzodiazepines, antipsychotic, 2770

3 A B C D Figure 1. The radiological findings of the patient. The brain atrophy was entirely recognized. The sylvian fissures were enlarged (A, arrow head) and medial temporal lobes were markedly atrophic (B, arrow heads). No parenchymal or vascular abnormalities were detected. The Evans index was calculated to be 0.36 (>0.30) and a narrowing of cerebral sulcus was observed at the parietal lobes (C, arrow head), suggesting hydrocephalus. Results of an ezis analysis indicated hypoperfusion on the surface of the brain, especially on the frontal lobes and posterior cingulate gyri (D). A-C: magnetic resonance imaging (MRI). D: easy Z-score imaging system (ezis). antiparkinson, anticholinergic and antihistaminic agents), intoxication (alcohol and heavy metals), encephalopathy (hepatic, uremic and blood sugar abnormality), metabolic disease (lipoidosis), intracranial structural diseases (chronic subdural hematoma, hydrocephalus and brain tumor), sleep apnea syndrome and infection of the central nervous system (syphilis, tuberculosis, Cryptococcus and HIV) (6, 7). Therefore, the differential diagnosis of dementia covers a broad range of disease spectrums. With medical progress, the number of patients with possibly reversible dementia is decreasing (7). However, the above-mentioned nondegenerative or nonvascular etiologies for dementia are common in younger patients (8). Patients under 60 years of age with sub-acute to chronic course, neurologic focal symptoms, and gait disturbance have been reported to be indicative for intracranial lesions (9). Our patient was in his early forties when he developed cognitive impairment. Investigation should have been performed more eagerly for such a young patient with newly-onset dementia. Neurosyphilis is one of the forms of possibly reversible dementia and a screening examination for syphilis should be considered. For our patient, syphilis was not suspected and specific tests were not submitted at all before referring him to our hospital. The clinical manifestation of neurosyphilis is classified into two forms: early and late neurosyphilis. The former includes asymptomatic or symptomatic neurosyphilis, both of which occur within the first year after infection. Symptomatic neurosyphilis causes meningeal irritation signs with cranial neuropathies: ocular syphilis, otosyphilis, and meningovascular syphilis. On the other hand, late neurosyphilis, which mainly causes general paresis and tabes dorsalis, occurs a few to twenty years after the initial infection. These conditions often overlap and a distinct diagnosis is sometimes difficult. Our patient suffered from an abnormal cognitive function for four years, thus indicating late neurosyphilis. A recent guideline mentioned that there is no single reliable examination for the diagnosis of neurosyphilis (10). 2771

4 4 million units of P G every 4 hours ( o C) (bpm) 39.5 JHR Heart Rate Body Temperature Time a er administering an (hour) Figure 2. A fever pattern of the case. Prior to antibiotic therapy, the patient was afebrile. Shortly after being given parenteral penicillin G, he developed a high fever which indicates a Jarisch-Herxheimer reaction (JHR). Although the administration of penicillin G was continued, the febrile reaction showed spontaneous remission. The patient was hemodynamically stable during the febrile period. Therefore, the diagnostic process should be carefully followed up with combinations of serum and CSF RPR/TPHA, CSF cell count, and protein level. CSF pleocytosis (>5 cells/ mm 3 ) is usually seen in patients with neurosyphilis (10); however, according to a previous report, CSF pleocytosis (>20 cells/μl) was seen in only 67% of patients with neurosyphilis (74/110 cases) (11). T. pallidum can latently infect the central nervous system from an early stage of the clinical course (5 to 10% of untreated patients) (12) without any apparent inflammatory reaction (3, 13), leading to asymptomatic neurosyphilis. Considering the chronic course in our patient, the negative result of CSF pleocytosis can be possible. A lesson learned from this case is that a normal CSF cell count alone should not lead to the ruling out of neurosyphilis. Neuroimaging findings can also be of help in evaluating patients with neurosyphilis. A previous report involving 35 cases including both HIV-positive and HIV-negative showed that a normal radiographic finding was seen in 31%, cerebral infarctions in 23%, nonspecific white matter lesions in 20%, cerebral gummas and extraaxial enhancement indicating meningitis in 6% (14). Arteritis was also observed in a few cases. Another report summarizing 14 HIV-negative patients demonstrated cerebral atrophy in 50%, nonspecific white matter lesion in 50%, cerebral infarction in 43%, arteritis in 29%, acute syphilitic meningitis and normal finding only in 7% (15). According to an investigation by Kodama et al., atrophy of the medial temporal lobe was seen in 3 of 7 cases (16), which was related to a prolonged personality change, general dementia, and general paresis (17). The brain MRI of our patient showed marked atrophy in the medial temporal lobe and the prognosis of his cognitive function was assumed to be poor. In addition to the increased Evans index, the cerebral sulcus of the parietal lobes was narrowed and the sylvian fissures were enlarged, which were indicative of disproportionately enlarged subarachnoid-space hydrocephalus (DESH). Thus, neurosyphilis should be listed as one of the differential diagnoses of DESH. Early diagnosis of neurosyphilis followed by appropriate antibiotic therapy yields better clinical outcomes. Neuroimaging would also be useful in the follow-up for such patients (18). The treatment regimen for syphilis has been thoroughly summarized in various articles (10, 19). Generally, the parenteral administration of penicillin G is the most common choice of therapy; ceftriaxone, doxycycline and azithromycin can be alternatively used (19). For the treatment of late syphilis, however, reliable evidence is unavailable. JHR is an immunologic reaction that is often seen when treating patients with spirochaetal infection (20). The incidence rate of JHR in patients with neurosyphilis has been reported in about less than 10% (21); however, the reaction may lead to exacerbation of neurologic symptoms (22). In conclusion, syphilis is still an existing concern. Neurosyphilis should therefore be included as a possible etiology for progressive dementia, especially in non-elderly patients. The authors state that they have no Conflict of Interest(COI). References 1. Patton ME, Su JR, Nelson R, et al. Primary and secondary syphilis--united States, MMWR Morb Mortal Wkly Rep 63: , Larson EB, Yaffe K, Langa KM. New insights into the dementia epidemic. N Engl J Med 369: , Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group. N Engl J Med 337: ,

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