Limbic Encephalitis Caused By Neurospyhilis in a HIV-Positive Male: Case Report and Review

Case

A 51-year-old man presented with a 3-week history of personality changes, progressive amnesia, and bitemporal headaches. On admission, his vital signs and general physical examination were normal. However, he appeared to be experiencing delusions and visual hallucinations. His short term memory was severely impaired and he required frequent reorientation. He confabulated and claimed to have known each of the medical staff at one point in his life. His speech was otherwise fluent and he was able to follow 3-step complex commands. Neurological exam showed impairments in recall, visuospatial, and executive functions. The rest of his examination was normal.

Brain MRI showed increased T2 signal within the bilateral frontal and mesial temporal lobes suspicious for encephalitis (Figure 1a). A lumbar puncture (LP) revealed a cerebrospinal fluid (CSF) glucose of 48 mg/dL, erythrocytes 3/mL, leukocytes 220/mL (lymphocytes 69%, neutrophils 11%, monocytes 20%), and CSF protein of 205 mg/dL. He was started empirically on intravenous acyclovir. CSF analysis for herpes simplex virus (HSV), West Nile virus, and other infectious testing were negative. Malignancy workup including CSF cytology and paraneoplastic antibodies was also negative.

Figure 1a: Brain MRI without contrast: Abnormal T2 and FLAIR signal abnormalities and atrophy within the bilateral frontal and mesial temporal lobes (arrows).

The patient’s wife noted that he was recently engaged in promiscuous sexual behavior. Further testing for syphilis was positive as evidenced by reactive serum rapid plasma reagent (RPR) titer of 1:64), serum and CSF treponema pallidum haemagglutination assay (TPHA) titers were 1:5120 and 1:640, respectively. CSF Venereal Disease Research Laboratory (VDRL) titer was 1:16. The fluorescent treponemal antibody-absorption (FTA-ABS) test also came back positive. Acyclovir was discontinued and he was started on a 21 day course of penicillin G. Further serologic workup revealed that he was HIV-positive with a viral load of 5140 copies and a CD4-lymphocyte count of 396. The CD4 percent was 24% and the CD4/CD8 ratio was 0.6.

His hospital stay was complicated by recurrent generalized tonic-clonic seizures requiring intubation and treatment with Fosphenytoin. Electroencephalogram (EEG) showed independent bitemporal periodic lateralized epileptiform discharges (PLEDs). He was successfully extubated and a repeat LP performed ten days into the course of antibiotic therapy showed marked decrease in the amount of CSF protein (80 mg/dL) and leukocytosis (34/mL).

Prior to his hospital discharge, he was started on highly active antiretroviral therapy with tenofovir, efavirenz, and emtricitabine. Six weeks later during outpatient follow-up, he was able to hold a complex conversation. However, he continued to demonstrate severe short-term memory and confabulated about activities he had done earlier in the day and what he had for breakfast. Repeat MRI of the brain showed improvement of the T2 and FLAIR signal abnormality within the frontal and mesial temporal lobes (Figure 1b). However, there was progression of atrophy of the mesial temporal lobes suggesting irreversible damage. At 6 months follow-up, the patient had a repeat LP that showed no pleocytosis, CSF-protein of 42 mg/dL, and CSF-VDRL was nonreactive. The CD4 count had increased from 396 to 625 and CD4 percent increased from 24% to 42%. The HIV viral load was undetectable.

Figure 1b: Brain MRI performed 2 months after presentation: Progression of atrophy with improvement of the T2 and FLAIR signal abnormality within the frontal and medial temporal lobes since the prior study (arrows).

Neurosyphilis refers to infection of the central nervous system (CNS) by the spirochete Treponema pallidum. This may occur anytime within weeks of the initial inoculation to years during the late stage of tertiary syphilis. If it occurs acutely, it may be latent and asymptomatic or may present as meningitis, strokes, vertigo, optic neuritis, uveitis, or more rarely as basilar meningitis with cranial neuropathies. The pathophysiology involves an acute meningovascular and ocular inflammation caused by small vessel arteritis [1-3].

More commonly, neurosyphilis occurs many years later in the tertiary stage of syphilis manifested by general paresis and tabes dorsalis. In general paresis, chronic infection of the brain parenchyma causes widespread parenchymal damage leading to forgetfulness and personality changes [1]. Tabes dorsalis is caused by demyelination of the posterior columns, dorsal roots, and dorsal root ganglia leading to impaired proprioception and gait imbalance.

Due to its frequent atypical presentations, syphilis has been commonly called "the great imitator”. The case presented describes neurosyphilis mimicking herpes simplex virus (HSV) encephalitis. The subacute presentation of altered mental status, bilateral mesiotemporal T2 hyperintensity on MR images, and temporal PLEDs on EEG have always been thought of as pathognomonic signs for herpes encephalitis. Other uncommon and rare entities have been reported to have similar imaging findings including paraneoplastic limbic encephalopathy, lupus erythematosus, Hurst hemorrhagic leukoencephalitis, and gliomatosis cerebri [4]. An extensive review of the literature demonstrates 29 cases worldwide with mesial temporal lobe encephalitis as a rare manifestation of neurosyphilis [4–26] (Table 1). All the patients presented similarly with confusion, memory disturbance, or change in personality. Scheid et al. and other authors listed in Table 1 recommend including neurosyphilis in the differential diagnosis of limbic encephalitis [25].

Table 1: M: male; F: female; CSF: cerebrospinal fluid; UK: data unknown or unavailable; WBC: white blood cell; VDRL: Venereal Disease Research Laboratory; RPR: Rapid plasma reagin; TPHA: Treponema pallidum haemagglutination assay; microhemagglutination assay for ` Treponema pallidum antibodies (MHA-TP); FTA-ABS: fluorescent treponemal antibody-absorption; TRUST: Toluidine Red Untreated Serum Test.

In addition to serum and CSF laboratory testing, imaging features may help to differentiate between this rare presentation of neurosyphilis and the more common HSV encephalitis. Neurosyphilis may be associated more with atrophy of the medial temporal lobe. On the other hand, gyral enhancement, cortical and subcortical edema, hemorrhage, or areas of restricted diffusion are frequently described in HSV infection [5].

It is unknown what causes the T2 hyperintensity changes in the mesial temporal lobes of patients with this atypical form of neurosyphilis. It is thought that small-vessel ischemic changes and marked meningovascular inflammation cause vasogenic, cytotoxic, and interstitial edema to occur causing parenchymal damage [4]. Another opinion is that abnormal signals are probably related to proliferation of glial cells rather than cytotoxic edema (Wang X). Coinciding seizures may also play a role in causing signal changes of the mesial temporal lobes [25]. In a study examining brain MRI abnormalities in 15 patients with general paresis, abnormal high T2-FLAIR signals were found in nine cases, mainly in the bilateral temporal, insular, and frontal lobes and hippocampus accompanied by cerebral and/or hippocampus atrophy [27]. It is yet to be determined whether mesial temporal encephalitis is part of general paresis or its own distinct manifestation of neurosyphilis.

It is unlikely that the HIV co-infection was an innocent bystander in the case described. The association between syphilis and HIV infection is an important one because both can often present simultaneously [1,28,29]. The genito-ulcerative chancres seen in syphilis increase the risk for viral entry during unprotected sexual intercourse [1]. Also, the increased concentration of T cells at the site of the chancres augments the possibility of the HIV virus infecting and replicating in the host cell [1]. Studies of patients with syphilis co-infected with HIV have described persistent chancres, ulcerative skin lesions, rapid progression to gummatous disease with destructive lesions of the skin, bones or viscera, and a greater frequency of ocular involvement (eg, uveitis, keratitis, optic neuritis, optic atrophy, or chorioretinitis) [30].

Co-infection with HIV may increases the incidence of the neurological complications of syphilis. Neurosyphilis should be considered in the differential diagnosis of any patient with HIV [31]. It has been reported that the incidence of symptomatic neurosyphilis among HIV positive individuals with early syphilis was found to be 3–4 times higher (2.1% vs 0.6%) as compared with HIV-negative persons [32]. In another study, the incidence of neurosyphilis was shown to be 23.5% in HIV-positive patients with untreated syphilis as compared to 10% in HIV-negative patients with untreated syphilis [28].

More so, in HIV positive patients, neurosyphilis may progress in an aggressive and often atypical manner [1,28,29]. It is believed that co-infection with HIV may have potentiating effects on the syphilitic infection [28,29,33]. A more fulminant form of parenchymal disease, referred to as necrotizing neurosyphilis, has also been reported to occur in patients with HIV [34]. None of the cases reports listed in Table 1 were documented as being associated with a concomitant HIV infection. This is the first reported case of neurosyphilis limbic encephalitis in a patient with HIV. It is unknown whether HIV increases the risk of mesial temporal encephalitis in patients with neurosyphilis.

It is important to note that HIV positive patients with neurosyphilis are at least 2.5 times less likely to normalize the CSF-VDRL reactivity after penicillin treatment. This risk is even higher if the CD4+ T-cell count is <200 cells/uL [35]. Thus, the Centers for Disease Control and Prevention treatment guidelines recommend that HIV positive patients with neurosyphilis undergo routine CSF examination every 3–6 months until the cell count normalizes [33,36].

Prognosis of limbic encephalitis due to neurosyphilis varies. Among the 18 patients listed in Table 1 with follow-up data, 11 showed mild to moderate clinical and or radioraphical improvement following antibiotic therapy, 1 required retreatment for recurrent relapses, and 6 had no improvement or worsening of their disease. Early diagnosis and treatment has been shown to improve outcome [22].

Neurosyphilis continues to surprise us with atypical and new presentations. A review of the literature argues that it should be considered in the initial diagnostic workup of limbic encephalitis and not just a mere diagnosis of exclusion. Concomitant HIV infection is common and may change the presentation of neurosyphilis. Clinicians need to be aware of the different manifestations so that early treatment can potentially decrease morbidity in this subgroup of patients.