Longitudinally Extensive Transverse Myelitis and Optic Neuropathy Associated with Syphilitic Meningomyelitis and Human Immunodeficiency Virus Infection: A Case Report and Review of the Literature

Introduction

Syphilis is a sexually-transmitted disease caused by Treponema pallidum infection. Its clinical symptoms include fever, focal or generalized skin lesions, lymph node enlargement, and various neurological disorders, which occur over a period of several years (1). Although tabes dorsalis and progressive paralysis are crucial neurological features of tertiary syphilis, other complications, including meningitis, meningomyelitis, meningovascular syphilis causing stroke and seizure, optic neuritis and/or perineuritis, uveitis, and cranial neuritis, in the earlier stage are also crucial (1-4). Recent reports have shown that the number of patients co-infected with T. pallidum and human immunodeficiency virus (HIV) has been increasing. In the United States, 16% of all syphilis patients, and 28% of male syphilis patients were co-infected with HIV (1). Notably, carrier-stage patients who are co-infected with T. pallidum and HIV are prone to a clinical exacerbation of syphilis and/or acquired immunodeficiency syndrome (1). Syphilitic meningomyelitis is a rare spinal cord syphilis that is pathologically characterized by meningeal inflammation and spinal cord ischemia and edema due to syphilitic vasculopathy (3-13). The clinical symptoms of syphilitic meningomyelitis usually develop at between 1 and 30 years after the initial infection (average: 6 years) (14). These inflammatory and ischemic changes are partially reversible, because treatment with penicillin and corticosteroids can diminish the affected lesions to a certain extent (5, 9, 13).

We herein report a case of a patient with syphilitic meningomyelitis and asymptomatic optic neuropathy accompanied by HIV infection. On magnetic resonance imaging (MRI), the patient was found to exhibit atypical longitudinally extensive transverse myelitis (LETM) at the cervical and thoracic levels that radiologically mimicked neuromyelitis optica (NMO). The patient also had subclinical right optic neuropathy with prolonged P100 latency that was detected using a flash visual evoked potential (VEP) study. Although both T. pallidum and HIV infection can cause myelopathy, it is considered that the elevated treponema pallidum hemagglutination assay (TPHA) index reflected the active syphilitic meningomyelitis under an HIV carrier state in our patient.

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Case Report

A 49-year-old bisexual man had experienced a feeling of residual urine at micturition 5 months before admission. He had also suffered from progressive gait disturbance with spasticity, paresthesia, a loss of pain and temperature sensations in the bilateral lower limbs, and urinary retention for 2 weeks. A previous serological examination when he was in his 20s had revealed an elevated T. pallidum hemagglutination assay (TPHA) titer; however, he had no apparent symptoms of syphilitic infection. In addition, he had no allergic diseases (such as bronchial asthma or atopic dermatitis).

On admission, his cognitive function was normal. A neurological examination, which included examinations of the patient's visual acuity, visual fields, optic fundus, and pupillary light reflex, was normal. He did not exhibit muscle weakness, but the deep tendon reflexes in the arms and legs were brisk, and the patient was bilaterally positive for the Babinski sign. He noticed glove and stocking-type paresthesia in the bilateral extremities. The sensation of vibration was mildly decreased in both legs, but the sense of position was intact. Sensory ataxia was suspected because the patient was positive for the Romberg sign. He experienced gait disturbance with spasticity, but his coordination was intact.

Brain MRI was unremarkable. T2-weighted MRI of the spinal cord revealed partially discontinuous LETM with high-intensity lesions extending from the C4 level to the T6 level (Fig. 1A); in the axial section, the pericentral area was mainly affected (Fig. 1B, C). On T1-weighted images with gadolinium enhancement, spotty contrasted lesions were visible at the surface of the thoracic cord (T2-6, Fig. 1D). On orbital MRI, short T1 inversion recovery images of the coronal section revealed a ring-shaped, high-intense perineural lesion of the right optic nerve (Fig. 2A). Axial T2-weighted MRI revealed a “tram-track sign” on the right optic nerve (Fig. 2B). Flash VEP revealed two bottoms (P1 and P2) and a prolonged P100 latency (P2, 130.6 ms) on right eye stimulation (Fig. 3A) in comparison to the P100 latency (P1, 120.9 ms) on left eye stimulation (Fig. 3B). A blood examination revealed an elevated TPHA titer (×2,560; normal <×80) and a strongly reactive rapid plasma reagin titer (117-fold). The patient's serum was positive for HIV antibodies (HIV-RNA: 3,480 cp/mL). The plasma CD4⁺ lymphocyte count was 837 /μL. Serum antibodies against herpes simplex virus, varicella zoster virus, human T-lymphotropic virus type 1, Epstein-Barr virus, and cytomegalovirus were not detected. The serum IgE level was elevated (1,022 IU/mL; normal, <170 IU/mL), and a specific IgE against mites was detected without eosinophilia. Autoantibodies against aquaporin-4 (AQP4), nuclear, SS-A, SS-B, ribonucleoprotein (RNP), and Sm were not detected. The patient was seronegative for both myeloperoxidase-antineutrophil cytoplasmic antibodies (ANCA) and proteinase 3-ANCA. The levels of angiotensin-converting enzyme, lysozyme, and soluble interleukin-2 receptor were within the normal ranges. A cerebrospinal fluid (CSF) study revealed pleocytosis (202 white blood cells/mm³; 95% lymphocytes) and an elevated total protein level (79 mg/mL). No malignant cells were detected, and oligoclonal bands were not detected in the CSF. The TPHA-albumin index value was elevated (73.3; positive reference value, ≥70). The finding that the CSF-TPHA titer was correlated with the albumin quotient (15), strongly supported the diagnosis of active neurosyphilis. The formulas of these indexes were as follows:

Figure 1.

On contrast abdominal computed tomography, the liver and spleen were normal in size and shape.

Figure 2.

The patient’s clinical course. Serum HBsAg was negative, and HBV-DNA was present at 2.6 log copies/mL before chemotherapy. Entecavir (ETV) was used during R-THP-COP chemotherapy and the subsequent 14 months. Serum HBV-DNA levels remained undetectable, and serum gammaglobulin levels were within the normal range. ETV was discontinued at 14 months after the end of chemotherapy. However, serum HBV-DNA became positive at 24 months and increased to 3.3 log copies/mL at 27 months. In addition, serum HBsAg also reverted. After restarting ETV at 28 months, serum HBV-DNA and HBsAg immediately turned negative. Anti-HBs became positive for the first time at 31 months and remained positive at 46 months, whereas ETV was re-discontinued at 36 months.

Figure 3.

Details of the clinical course from 24 to 29 months after the end of chemotherapy. Serum HBV-DNA became positive at 24 months and increased to 3.3 log copies/mL at 27 months. HBsAg, HBeAg and HBcrAg reverted at the same time. Two weeks later, laboratory data showed a further increase in the serum HBV-DNA levels and reconversion of HBeAg without elevation of serum ALT levels. The patient started taking entecavir (ETV) again at 28 months. After restarting ETV, serum HBV-DNA, HBsAg, HBeAg and HBcrAg immediately turned negative.

The TPHA-albumin index: CSF-TPHA titer/albumin quotient

The albumin quotient: CSF albumin (mg/dL)×10³/serum albumin (mg/dL)

After the intravenous administration of penicillin G potassium (24-million IU/day for 14 days) and methylprednisolone (1,000 mg, daily, for the first 3 days), the symptoms of gait ataxia and sensory disturbance in the lower extremities improved, but the urinary dysfunction remained. Antiretroviral therapy (ART) was not administered because of the patient's high CD4⁺ T-cell count.

At two weeks after the administration of these therapies, MRI revealed a reduction in the size of the cervical and thoracic cord lesions (Fig. 1E, compared with Fig. 1A) but no remarkable change in the optic nerve lesion. A follow-up flash VEP examination that was performed 1 year later showed an improvement in the P100 latency on the right optic nerve (right, 120.3 ms; left, 121.8 ms) (Fig. 3C, D).

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Discussion

The patient, who was an HIV carrier, was diagnosed with syphilitic meningomyelitis with longitudinal spinal cord lesions and asymptomatic unilateral optic neuropathy. NMO and atopic myelitis were ruled out because he was negative for anti-AQP4 antibodies, with no evidence of atopic disorder due to eosinophils in the CSF. The spinal cord involvement in neurosyphilis is classified into three clinical subtypes: meningomyelitis, meningovascular disease, and tabes dorsalis (3). Twelve patients with syphilitic meningomyelitis showing MRI abnormalities have been reported to date. A clinical summary of 13 cases of syphilitic meningomyelitis, including our case, is shown in Table. The mean age at the onset of disease was 42.6 years, and most of the reported patients were male (85%). The common neurological findings in 11 patients with syphilitic meningomyelitis were an impaired superficial sensation (91%), hyperreflexia (82%), extremity weakness (73%), impaired deep sensation (55%), urinary disturbance (55%), and pain (36%) (Table). The duration of symptoms was variable, from 3 days to 6 months, and some patients had a clinical course of chronic myelitis similar to that in our patient (7, 8, 10, 11). However, our patient was the only HIV carrier. Eleven out of 13 patients (85%) exhibited LETM. Gadolinium enhancement in the superficial and/or central part of the spinal cord parenchyma was observed in eight cases (3-5, 7, 8, 12, 13, Fig. 1D), which might reflect direct treponemal invasion into the spinal cord from its surface (4). Most patients underwent antiluetic therapy with penicillin G; in some cases steroids (prednisolone or dexamethasone) were co-administered to prevent Jarisch-Herxheimer reactions, which present as general malaise, myalgia, fever, and headache (5, 8, 11-13). This steroid treatment improved the spinal cord edema caused by primary inflammation (3, 4, 6, and this case). Our patient had presumably been in the latent stage of syphilis before myelopathy, as he had never noticed the initial dermatosclerosis or dermosyphilopathy that are usually seen in early-stage syphilis. Thus, despite being seropositive since his 20s, he had never been treated for syphilis. Based on our patient's clinical history, recent HIV co-infection probably converted his latent syphilis into active meningomyelitis (1), causing urinary disturbance, spastic paraplegia, and sensory disturbance of 5 months in duration. The pathogenesis in this case is primarily considered to be meningomyelitis, according to the clinical course, and the CSF pleocytosis with elevated total protein levels. MRI demonstrated LETM in the cervical and thoracic spinal cord, with several spotty enhanced lesions in the meninges surrounding the spinal cord. However, the high-intensity lesions on T2-weighted MRI partially remained, even after antiluetic therapy, suggesting that the affected cord lesions involved not only reversible edema but also spinal cord ischemia from meningovascular syphilis (13). Although LETM can be observed in the NMO, it is crucial to consider syphilitic meningomyelitis as a radiological differential diagnosis. A meningeal enhancement of the spinal cord is more likely to be seen in infectious meningomyelitis than in NMO.

Table.

Clinical Characteristics in Syphilitic Meningomyelitis and Comparison with HIV Myelitis.

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Ref: reference, M: male, F: female, NA: not applicable, MSM: men who have sex with men, iTPA: intrathecal Treponemapallidum antibody, VDRL: venereal disease research laboratory, FTA: fluorescent treponemal antibody, TPHA: treponema pallidum hemagglutination assay, T: thoracic, WS: whole spinal cord, Con: conus, C: cervical, LETM: longitudinally extensive transverse myelitis, PCG: penicillin G, AB: antibiotics, CTRX: ceftriaxone, mPSL: methyl-prednisolone, DEX: dexamethasone, PSL: prednisolone, HAART: highly activated anti-retroviral therapy

The patient was an HIV carrier. Serum and CSF samples that were taken on admission were positive for HIV-RNA. However, it is unclear when he was co-infected with HIV. The natural course of an HIV patient involves acute viremia, with more than one million copies of HIV-RNA, after viral proliferation in the lymphoid tissue (16). Approximately 50% of HIV patients simultaneously suffer from high fever, rash, and lymph node swelling, and they reach a chronic infectious state after a reduction in HIV by an innate immunological response (16, 17). Our patient did not have acute HIV viremia, but was an HIV carrier; this was evidenced by his normal CD4⁺ cell count remained normal and the relatively low number of serum HIV-RNA copies. Neuropathologically, vacuolar myelopathy is known to be a common finding in advanced HIV myelitis. Four patients with HIV myelitis (16-19) at the time of seroconversion or at the early phase of HIV infection have been reported (Table). Andrade et al. reported the case of a patient with acute HIV myelitis presenting with LETM extending from T2 to T11, CSF pleocytosis (302 /μL), and a large number of HIV-RNA copies in the blood (743,000 cp/mL) (16). HIV myelitis generally exhibits acute and/or subacute spinal cord lesions with less frequent LETM or the uptake of gadolinium and is frequently accompanied by several non-neurological symptoms that are caused by primary HIV infection (Table). In contrast, syphilitic meningomyelitis more frequently exhibits LETM and the gadolinium enhancement of the intrathecal lesions and on the surface of the spinal cord. Our patient exhibited a slower progression of LETM, without any other physical symptoms of HIV. Thus, it was less likely that the patient's LETM was caused directly by his acute HIV infection. Furthermore, the patient's meningomyelitis was improved by antiluetic and steroid pulse therapies but not by ART.

Several studies have reported the prevalence of ocular syphilis to be as high as 10% in HIV-co-infected patients (1). The most common ocular finding in tertiary syphilis is uveitis (2). Optic perineuritis is a relatively uncommon condition and is generally asymptomatic in syphilis (2). The typical clinical features of optic perineuritis include eye pain, mildly decreased visual acuity, and several visual field defects. However, our patient had no remarkable visual symptoms. Orbital MRI revealed a “tram-track sign” on axial T2-weighted images and a ring-shaped area of high intensity on coronal Short tau inversion recovery (STIR) images without gadolinium enhancement in the optic nerves. As the tram-track sign in the optic nerve is a nonspecific radiological feature, it can also be observed in optic perineuritis (20). Unlike optic neuritis, optic perineuritis generally exhibits no apparent gadolinium enhancement in the optic nerve (2). Our patient demonstrated a remarkable improvement in the pathological latencies of flash VEP after antiluetic and steroid therapy. Thus, the optic nerve involvement observed on MRI might be related to subclinical perineuritis.

Syphilitic meningomyelitis is one of many disorders that can cause LETM. If syphilis is detected in a patient with an elevated CSF TPHA-albumin index, it is crucial to check for serum HIV antibodies, especially in patients with a high risk for HIV (e.g., homosexual and/or bisexual individuals). Determining which of the infections, syphilis or HIV, is associated with the LETM lesions in co-infected patients is crucial for allowing for a prompt diagnosis and the initiation of appropriate treatment.

The authors state that they have no Conflict of Interest (COI).

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Acknowledgement

The authors would like to thank Enago (www.enago.jp) for performing the English language review.

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References

1. Zetola NM, Engelman J, Jensen TP, Klausner JD. Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection. Mayo Clin Proc 82: 1091-1102, 2007. [PubMed] [Google Scholar]
2. Parker SE, Pula JH. Neurosyphilis presenting as asymptomatic optic perineuritis. Case Rep Ophthalmol Med 2012: 621872, 2012. [PMC free article] [PubMed] [Google Scholar]
3. Chilver-Stainer L, Fischer U, Hauf M, Fux CA, Sturzenegger M. Syphilitic myelitis: rare, nonspecific, but treatable. Neurology 72: 673-675, 2009. [PubMed] [Google Scholar]
4. He D, Jiang B. Syphilitic myelitis: Magnetic resonance imaging features. Neurol India 62: 89-91, 2014. [PubMed] [Google Scholar]
5. Jacquemin GL, Proulx P, Gilbert DA, Albert G, Morcos R. Functional recovery from paraplegia caused by syphilistic meningomyelitis. J Spinal Cord Med 25: 133-137, 2002. [PubMed] [Google Scholar]
6. Kayal AK, Goswami M, Das M, Paul B. Clinical spectrum of neurosyphilis in North East India. Neurol India 59: 344-350, 2011. [PubMed] [Google Scholar]
7. Kikuchi S, Shinpo K, Niino M, Tashiro K. Subacute syphilistic meningomyelitis with characteristic spinal MRI findings. J Neurol 250: 106-107, 2003. [PubMed] [Google Scholar]
8. Matijosaitis V, Vaitkus A, Pauza V, Valiukeviciene S, Gleizniene R. Neurosyphilis manifesting as spinal transverse myelitis. Medicina (Kaunas) 42: 401-405, 2006. [PubMed] [Google Scholar]
9. Nabatame H, Nakamura K, Matuda M, Fujimoto N, Dodo Y, Imura T. MRI of syphilitic myelitis. Neuroradiology 34: 105-106, 1992. [PubMed] [Google Scholar]
10. Srivastava T, Thussu A. MRI in syphilistic meningomyelitis. Neurol India 48: 196-197, 2000. [PubMed] [Google Scholar]
11. Stom T, Schneck SA. Syphilitic meningomyelitis. Neurology 41: 325-326, 1991. [PubMed] [Google Scholar]
12. Tashiro K, Moriwaka F, Sudo K, Akino M, Abe H. Syphilitic myelitis with its magnetic resonance imaging (MRI) verification and successful treatment. Jpn J Psychiatry Neurol 41: 269-271, 1987. [PubMed] [Google Scholar]
13. Tsui EY, Ng SH, Chow L, Lai KF, Fong D, Chan JH. Syphilitic myelitis with diffuse spinal cord abnormality on MR imaging. Eur Radiol 12: 2973-2976, 2002. [PubMed] [Google Scholar]
14. Bhai S, Lyons JL. Neurosyphilis update: atypical is the new typical. Curr Infect Dis Rep 17: 481, 2015. [PubMed] [Google Scholar]
15. Salamano R, Ballesté R, Perna A, et al. . Cerebrospinal fluid examination may be useful in diagnosing neurosyphilis in asymptomatic HIV+ patients with syphilis. Arq Neuropsiquiatr 74: 128-132, 2016. [PubMed] [Google Scholar]
16. Andrade P, Figueiredo C, Carvalho C, Santos L, Sarmento A. Transverse myelitis and acute HIV infection: a case report. BMC Infect Dis 14: 149, 2014. [PMC free article] [PubMed] [Google Scholar]
17. Denning DW, Anderson J, Rudge P, Smith H. Acute myelopathy associated with primary infection with human immunodeficiency virus. Br Med J 294: 143-144, 1987. [PMC free article] [PubMed] [Google Scholar]
18. Hamada Y, Watanabe K, Aoki T, et al. . Primary HIV infection with acute transverse myelitis. Intern Med 50: 1615-1617, 2011. [PubMed] [Google Scholar]
19. Michou L, Sauve C, Sereni C, Lamotte C, Maillard A, Sereni D. Rapid efficacy of highly active antiretroviral therapy in a case of HIV myelitis. Eur J Intern Med 13: 65-66, 2002. [PubMed] [Google Scholar]
20. Kanamalla US. The optic nerve tram-track sign. Radiology 227: 718-719, 2003. [PubMed] [Google Scholar]

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