Case Presentation
A 43-year-old homosexual white man who was diagnosed with HIV type 1 (HIV-1) infection in 2000 was referred from the HIV primary care center in December 2002, with complaints of blurry vision in the right eye, decreased hearing and ringing in both ears, and a prickling sensation and tingling in the legs for the past 4 weeks. He admitted to intermittent fever, chills, and night sweats but denied diplopia, photophobia, vertigo, headaches, or changes in appetite or weight. He had no previous episodes with similar symptoms. He was diagnosed with bipolar depression a few months after being diagnosed with HIV infection. He had stopped taking his highly active antiretroviral drugs and psychiatric medications for financial reasons and was taking gabapentin (Neurontin) and lorazepam (Ativan) intermittently. He abused tobacco, alcohol, and cocaine.

Physical examination revealed a comfortable, non–ill-looking man. He was alert and oriented to person, place, and time. His vital signs were: temperature, 101°F; pulse, 120 beats/min; respirations, 20 breaths/min; blood pressure, 122/76 mm Hg. Pertinent findings on physical examination were confined to the neurologic examination, which included a positive Romberg sign, irregular right pupil that was unresponsive to light, and increased light touch and pain sensation in both legs. The motor system and deep-tendon reflexes were normal, and the Babinski reflex was absent. Results of the cardiorespiratory, abdominal, genital, anal, and oral examinations were normal.

Test results from the referring center included: CD4⁺ cell count, 244/µL; HIV-1 RNA viral load, >750,000 copies/mL; purified protein derivative induration, 0 mm; serum rapid plasma reagin (RPR), 1:128, which was confirmed by the Treponema pallidum particle agglutination test. Test results on admission showed liver function abnormalities, including an elevated alkaline phosphatase level (358 IU/L) and an elevated gamma-glutamyl transpeptidase level (964 IU/L). Serum aspartate aminotransferase and alanine aminotransferase concentrations were normal. Serum hepatitis C antibody and B surface antigen were negative, but hepatitis B surface antibody and core antibody were positive.

Abdominal ultrasound and computed tomography of the head were normal. Lumbar puncture revealed clear, colorless cerebrospinal fluid (CSF), with glucose, 68 mg/dL (serum glucose, 99 mg/dL); protein, 43 mg/dL; 0 white blood cells (WBC); 0 red blood cells; and negative Gram’s stain. The CSF venereal disease research laboratory (VDRL) test was negative. CSF bacterial and fungal cultures were negative, as were CSF cryptococcal antigen and India ink tests. The CSF fluorescent treponemal antibody absorption (FTA-ABS) test was not performed. CSF JC virus by polymerase chain reaction (PCR) was negative. A magnetic resonance imaging scan of the head revealed mild cerebral atrophy and no focal masses.

A diagnosis of neurosyphilis was made based on the patient’s symptoms, neurologic findings, and strongly positive serum RPR. He did not recall having any symptoms associated with primary syphilis (eg, chancre) or any of the classic signs of secondary syphilis (eg, rash on the palms and soles). His RPR was negative in 2000 at the time of his HIV diagnosis; however no further serologies to determine the time of syphilis exposure were available. Central nervous system (CNS) toxoplasmosis, primary CNS lymphoma, and progressive multifocal leukoencephalopathy were ruled out by the clinical presentation, laboratory investigations, and neuroimaging.

The patient was started on intravenous (IV) aqueous crystalline penicillin G, 3 million units every 4 hours. The ophthalmology service diagnosed right syphilitic uveitis with posterior synechia and recommended prednisone eyedrops and atropine eyedrops in addition to the IV penicillin. Audiology studies revealed bilateral sensorineural hearing loss consisting of borderline to mild at lower frequencies and mild to moderate at higher frequencies, with the left ear being worse than the right. The ear, nose, and throat (ENT) clinic made the diagnosis of otosyphilis and concurred with the use of IV penicillin, but it added oral prednisone. The psychiatry consultant recommended olanzapine (Zyprexa) and lorazepam for the patient’s bipolar depression and panic attacks.

Fever and tachycardia resolved within 36 hours of beginning use of IV penicillin. By the fourth day of therapy the patient reported feeling symptomatically better, and his hearing and vision improved. Levels of serum alkaline phosphatase and gamma-glutamyl transpeptidase returned to normal by 2 weeks. The patient was discharged to our long-term care facility to complete 2 weeks of IV penicillin therapy. He had follow-up appointments with the neurology, ENT, psychiatry, and ophthalmology clinics. When he came to the HIV primary care center 5 weeks after presentation, he had no complaints, and his original symptoms had resolved.

Discussion
Recently released data from the Centers for Disease Control and Prevention show that the incidence of syphilis in men increased by nearly 12% between 2003 and 2004. In addition, 64% of syphilis cases in adults in 2004 were in men who have sex with men, an increase of nearly 60% since 1999.¹ Because of the high rate of coinfection, all patients with syphilis should be tested for HIV infection.

In addition, neurosyphilis, a CNS infection caused by the spirochete T pallidum, must always be considered in any patient infected with HIV-1 who presents with neurologic signs and symptoms. The clinical presentation, serology, and other laboratory test results may be atypical in an HIV-seropositive patient.

This patient’s clinical presentation and neurologic findings, including sensorineural hearing loss, an irregular and fixed right pupil, tinnitus, and paresthesia, warranted the inclusion of neurosyphilis in the differential diagnosis, which was aided by an elevated serum RPR test (Table).^2,3 However, the CSF findings were atypical in that the cell count and protein level were normal, and the CSF-VDRL was negative. Normal CSF findings in the setting of symptomatic neurosyphilis are uncommon, and such findings have been described in only up to 4% of patients.²

Neurosyphilis
Neurosyphilis is classified as acute or chronic (late).² Acute neurosyphilis occurs most commonly during the secondary phase of syphilis, when spirochetemia is most prominent; CNS seeding during spirochetemia can occur in up to 40% of patients, and acute aseptic meningitis develops in 1% to 2%.²

Late neurosyphilis is divided into asymptomatic or symptomatic. By definition, patients with asymptomatic neurosyphilis lack clinical symptoms but demonstrate CSF abnormalities, such as an elevated CSF protein concentration, CSF pleocytosis, and/or a positive CSF-VDRL.

The symptomatic phase of late neurosyphilis is further subdivided into meningovascular or parenchymatous.^2,3 In meningovascular neurosyphilis, the pathogenesis of disease results from endarteritis obliterans, which causes microinfarcts of the cortex and spinal cord. In parenchymatous neurosyphilis, there is destruction of the nerve cells from direct invasion of the spirochetes. The various clinical features of neurosyphilis are presented in the Table.

Diagnosis
The diagnosis of neurosyphilis is made in the presence of a reactive serologic test for syphilis with either neurologic manifestations consistent with neuro­syphilis, as in our patient, or CSF evidence with one or more of the following findings: mononuclear pleocytosis (>10-20 WBC/mm³), elevated protein concentration (>45 mg/dL), and/or positive CSF-VDRL test results. The CSF-VDRL is a specific but not sensitive test, with sensitivity ranging from 30% to 70%.^2,4,5 A reactive CSF-VDRL test establishes the diagnosis of neurosyphilis, but a negative test does not rule it out. In contrast, the CSF FTA-ABS test is sensitive but not specific. Identification of T pallidum in the CSF by PCR is not recommended as a diagnostic test for neurosyphilis.^4,6-8

The laboratory test results of HIV-1–infected patients with syphilis should be interpreted the same way as in HIV-seronegative patients, but responses to nontreponemal serologic tests, such as the RPR and the VDRL, may be different; serology results may be higher, lower, or delayed in those infected with HIV-1.⁴ If serologic test results are inconsistent with clinical suspicions, other techniques should be used, such as lesion biopsy, dark-field microscopy, or direct fluorescent antibody staining.⁴

Similarly, the CSF results in HIV-infected patients with neurosyphilis should be interpreted the same way as in seronegative patients. However, HIV infection itself may cause CSF abnormalities, such as mildly elevated protein levels or lymphocytic pleocytosis, which can persist after therapy for neurosyphilis.^9,10

Therapy
The mainstay of treatment for neurosyphilis is IV aqueous crystalline penicillin G, 18 million to 24 million units daily, administered in 3 million to 4 million unit-doses every 4 hours, for 10 to 14 days. Alternative treatment includes procaine penicillin, 2.4 million units intramuscularly, once daily, with oral proben­ecid, 500 mg every 6 hours, for 10 to 14 days.

Some experts also recommend benzathine penicillin, 2.4 million units intramuscularly weekly for 3 weeks, following the completion of neurosyphilis treatment. However, there is no consensus on the addition of benzathine penicillin in the management of neurosyphilis.⁴ Patients allergic to penicillin should undergo penicillin desensitization, followed by penicillin treatment.⁴

Patients should be warned of the possibility of a Jarisch-Herxheimer reaction that can occur, usually 1 to 2 hours after the initial dose of penicillin. A reaction is characterized by an abrupt onset of fever, chills, tachycardia, hyperventilation, malaise, and mild hypotension.² This is believed to be due to a hypersensitivity reaction to killed treponemes and their liberated toxins. The reaction is most common in the secondary phase of syphilis but can occur in any stage. It is self-limited and can be treated with aspirin for 1 to 2 days. Alternatively, oral prednisone can help curb the reaction.²

Symptoms of syphilitic meningitis and some cases of meningovascular syphilis usually resolve with treatment. Symptoms of ocular syphilis usually resolve if treated early enough. If treatment is delayed, the patient may be left with vision loss. Symptoms of tabes dorsalis or general paresis are the result of irreversible CNS damage and are unlikely to abate. Consequently, the goal of therapy in such cases is to halt further progression of the disease.

Patients with neurosyphilis should have repeat lumbar puncture at 3 and 6 months after therapy, and then at 6-month intervals until CSF pleocytosis resolves and/or the CSF-VDRL test is nonreactive.⁴ If the CSF WBC count does not decrease after 6 months of treatment, or if the CSF-VDRL remains positive 2 years after treatment, repeating treatment for neurosyphilis should be considered.

Conclusion
Because the incidence of syphilis is increasing, and since CNS involvement can occur during any stage of infection, it is likely that physicians will be encountering increasing numbers of neurosyphilis cases in HIV-negative and HIV-positive patients. Diagnosis requires lumbar puncture. When other potential causes have been ruled out, a positive CSF result on VDRL assay or pleocytosis, with or without elevated protein levels, establishes the diagnosis. Treatment is the same in persons with or without HIV infection and usually consists of IV aqueous crystalline penicillin G. All patients presenting with syphilis or neurosyphilis should be encouraged to undergo HIV testing.

References
1. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2004. November 8, 2005. Available at www.cdc.gov/STD/stats/default.htm.

2. Tramont EC. Spirochetes. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000:2474-2490.

3. Bartlett JG, Gallant JE. 2004 Medical Management of HIV Infection. Baltimore, Md: Johns Hopkins University; 2004.

4. Benson CA, Kaplan JE, Masur H, et al. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. Clin Infect Dis. 2005;40(suppl 3):S131-S235.

5. Malessa R, Agelink MW, Hengge U, et al. Oligosymptomatic neurosyphilis with false-negative CSF-VDRL in HIV-infected individuals? Eur J Med Res. 1996:1:299-302.

6. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Recomm Rep. 2002;51(RR-6):1-78.

7. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis. 2004;189: 369-376.

8. Lukehart SA, Hook EW III, Baker-Zander, et al. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med. 1988;109:855-862.

9. Collier AC, Marra C, Coombs RW, et al. Central nervous system manifestations in human immunodeficiency virus infection without AIDS. J Acquir Immune Defic Syndr. 1992;5:229-241.

10. Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis. 2004;38: 1001-1006.