Abstract
A previously healthy 35-year-old man suffering from behavioral and mental deterioration for three months was referred to our facility. On admission, the patient was dysphasic and had tonic-clonic seizures. Neurological examination showed mental confusion, euphoric mood, mania, paranoia, and mild motor dysphasia. Magnetic resonance imaging (MRI) was performed twice but no abnormalities were revealed. His acute confusional state, elevated cerebrospinal fluid (CSF) protein, epileptic seizure and electroencephalogram showing intermittent frontal slowness were all suggestive of encephalitis. The patient was treated with acyclovir without significant improvement in his condition. Testing for herpes simplex virus and human immunodeficiency virus was negative. Limbic encephalitis was suspected and the patient was treated with intravenous immunoglobulin (IVIG) for five days. Venereal disease research laboratory and Treponema pallidum hemagglutination assay were both tested positive in serum and CSF. Neurosyphilis was diagnosed, and the patient received a 14-day course of penicillin G with gradual improvement. Anti-N-methyl-D-aspartate-receptor (anti-NMDAR) antibodies were positive in serum, confirming the presence of encephalitis. The atypical clinical presentation of neurosyphilis with symptomatology mimicking encephalitis and no MRI abnormalities made the diagnosis challenging. Coexistence of neurosyphilis with anti-NMDAR encephalitis has been reported only in one recent study. Our case demonstrates the importance of testing for syphilis in patients with unexplained neurologic deficits and suspected encephalitis.
Keywords
Neurosyphilis is caused by the invasion of a microorganism, Treponema pallidum, into the central nervous system. This rare infection is observed in 5–10% of untreated patients and may occur at any stage. We report here the case of a young man suffering from neurosyphilis with signs of encephalitis as first clinical presentation but without magnetic resonance imaging (MRI) abnormalities and highlight the importance of considering this disease in patients with specific or non-specific neurologic symptomatology.
Case report
A previously healthy 35-year-old man suffering from gradually-progressing abnormal behavior, personality changes, and mental deterioration for three months was referred to our emergency room. There was no relevant medical history, and no alcohol or drug abuse. He did not have any history of seizures, epileptic attacks, or sexually transmitted infection. On his way to the hospital, he had tonic-clonic seizures with excessive salivation and was treated with valproic acid. Neurological examination at admission showed a personality change with mental confusion, attention and short-term memory impairments, euphoric mood, mania, paranoia, and mild motor dysphasia. The patient’s score on the Montreal Cognitive Assessment examination was 26/30. Two MRIs were performed but no abnormalities were observed. Blood tests revealed elevated levels of leukocytes (14,000 cells/mm3), Creatine phosphokinase (CPK) (447 U/L), and C-reactive protein (CRP) (2.51 mg/dL). Creatine (1.3 mg/dL) and Blood urea nitrogen (BUN) (13 mg/dL) were in the normal range. Lumbar puncture revealed clear cerebrospinal fluid (CSF) with protein levels of 146 mg/dL without pleocytosis and glucose content of 0.59 CSF/serum. Confusional state, elevated protein concentration, epileptic seizures, and electroencephalogram (EEG) with intermittent frontal slowness were suggestive of encephalitis (Figure 1). The patient was treated initially with acyclovir intravenously for ten days without significant improvement in his condition. When the results of CSF polymerase chain reaction (PCR) for herpes simplex virus (HSV) 1 and 2 and varicella zoster virus (VZV) were found to be negative, acyclovir was discontinued and an alternative diagnosis was sought. A second CSF analysis revealed 52 white blood cells/µL, of which 96% were monocytes and protein levels of 143 mg/dL. Due to subacute psychiatric manifestation, new onset of epileptic seizures and abnormal EEG, limbic encephalitis was suspected, and the patient was treated with IVIG for five days without any improvement. Immunological markers, such as antinuclear antibody, protein electrophoresis, anticardiolipin antibody, lupus anticoagulant, beta 2-glycoprotein and infectious pathogen testing, such as Mycobacterium tuberculosis, Epstein-Barr virus, cytomegalovirus, toxoplasma, Mycoplasma pneumoniae, Brucella, human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus tests were all negative. The venereal disease research laboratory (VDRL) test and Treponema pallidum hemagglutination assay (TPHA) both tested positive in serum and CSF. Consequently, neurosyphilis was diagnosed, and the patient received a 14-day intravenous course of penicillin G. To avoid the Jarisch-Herxheimer reaction, prednisone (50 mg) was administered orally. His general condition improved gradually, and EEG also improved (Figure 2). Anti-neuronal antibodies such as anti-HU, anti-MA, anti-RI, and anti-YO were negative, except for anti-N-methyl-D-aspartate-receptor (anti-NMDAR) that was positive in serum and CSF confirming the presence of autoimmune limbic encephalitis.
Intermittent delta slowness activity.
Resolution of slowing.
Discussion
Neurosyphilis leads to a slow and progressive destruction of the brain and spinal cord. It can be latent and asymptomatic or present a wide variety of signs and non-specific clinical symptoms mimicking many types of medical disorders, including headaches, meningitis, seizures, stroke, insomnia, personality change, decreased memory, disorientation, irritability, visual loss, dysphasia, and mental confusion. 1 Furthermore, various neuroradiological findings make the diagnosis challenging. Early recognition and appropriate treatment are particularly crucial to prevent further cognitive decline, improve the outcome, and decrease the risk of neurologic sequelae. 2 The pathophysiology involves an acute meningovascular and ocular inflammation resembling other infectious, inflammatory, or autoimmune processes in the CNS. 2 The radiological findings of neurosyphilis include cerebral infarctions or non-specific white matter lesions, cerebral gummas, or arteritis. 3 Late or tertiary neurosyphilis is characterized by chronic infection of the brain parenchyma or the posterior columns of the spinal cord and may lead to dementia, impaired proprioception, and gait imbalance. 2 VDRL-CSF, the standard serological test for CSF, is highly specific but is not 100% sensitive; i.e. a negative VDRL-CSF result does not rule out neurosyphilis. In our case, VDRL and treponemal test were positive both in serum and CSF, confirming the presence of neurosyphilis. The TPHA test is highly specific and sensitive in all stages of the disease except, possibly, in early primary syphilis. False positives, although rare, have been observed in some patients with connective tissue disease, autoimmune disease, with HIV infection and in the presence of antiphospholipid antibodies. 4 False-positive cases have not been reported and are not expected with NMDAR antibodies. NMDAR encephalitis is an autoimmune disorder associated with poor outcome and even death if not treated; however, when treated, there is a high probability of recovery. This clinically heterogeneous disorder is characterized by psychosis, memory deficits, epileptic seizures, dyskinesia, consciousness impairments, and autonomic instability. Symptoms may be various and sometimes the disorder presents in milder or incomplete forms. 5 Subacute onset of memory deficits, psychiatric picture, personality change, and abnormal EEG with seizures not explained by a previously known seizure disorder suggest, in our case, the diagnosis of an autoimmune encephalitis. The atypical clinical presentation of neurosyphilis with symptomatology mimicking limbic encephalitis, NMDAR antibody positivity, and no MRI abnormalities challenged the diagnosis. This demonstrates that neither normal neuroimaging findings nor the presence of neuronal autoantibodies exclude neurosyphilis. It is therefore important to take neurosyphilis into consideration and test routinely for syphilis in patients with psychiatric and neurologic deficits. Only one study has reported two cases of anti-NMDAR encephalitis coexisting with neurosyphilis. 5 We present here an atypical case of neurosyphilis concomitant with anti-NMDAR encephalitis strengthening the possibility of comorbidity of these diseases. As immune encephalitis is an unusual manifestation in neurosyphilis and only rare cases have been reported, it is difficult to suggest a special pathological mechanism. The fact that autoimmune encephalitis does not appear in neurosyphilis in HIV-infected patients supports that a competent immune system is required. 6 In our opinion, neurosyphilis might act as a chronic infection and mimic not only the clinical pattern but also shows cross-reaction with autoimmune encephalitis, leading to a false-positive anti-NMDAR encephalitis. The efficacy of antibiotic therapy and no response to immune therapy in our patient suggests that neurosyphilis might lead to a secondary immunological response of anti-NMDAR antibody production. It is well known that deterioration several weeks after herpes simplex encephalitis (HSE) presents an immune response related to NMDAR antibodies with their intrathecal synthesis starting shortly after HSE, and a clinical picture resembling limbic encephalitis with regard to behavior, personality, and memory deficits. We propose a similar mechanism for our patient. T. pallidum neuroinfection might also trigger brain autoimmunity. Further studies assessing antibodies against synaptic receptors and intracellular antigens are needed in patients with neurosyphilis.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.