More than meets the eye: Papilledema from syphilis posing as idiopathic intracranial hypertension

Introduction

It is well known that Treponema pallidum invades the central nervous system early following infection.^1-3 In 1935, Merritt and Moore described three syndromic variants of acute syphilitic meningitis: hydrocephalus without focal neurologic signs, meningitis of the vertex, and basilar meningitis. ⁴ Acute syphilitic hydrocephalus was predominantly a complication of early syphilis presenting with headache, nausea, vomiting, neck stiffness, and papilledema with elevated opening pressure and lymphocytic pleocytosis on lumbar puncture (LP). ^4-5

There are case reports of syphilis misdiagnosed as idiopathic intracranial hypertension (IIH) in HIV seronegative men who have sex with men. ⁶ , ⁷ IIH is a diagnosis of exclusion, as elevated intracranial pressure (ICP) can result from a variety of causes. ^8,9 We report a case of a heterosexual man presenting with vision changes and headache who was treated for IIH without resolution of his symptoms and eventually diagnosed with syphilitic hydrocephalus that responded rapidly to appropriate treatment.

Case presentation

A 49-year-old obese Caucasian man with a history of depression was referred to the hospital in August after bilateral papilledema was found on outpatient ophthalmologic exam. Initial evaluation with computed tomography (CT) of the head, complete blood count, and serum chemistries were unremarkable. LP showed an opening pressure of 31 cm H₂O, WBC 7 (normal: 0–5) cells per mm³ (cmm), glucose 75 mg/dL (normal: 50–80), and protein 30 mg/dL (normal: 15–45). His headache improved following LP. He was diagnosed with IIH and discharged home with acetazolamide.

Shortly thereafter, headaches worsened with associated photophobia, nausea, and vomiting, prompting return to the hospital. Repeat head CT and magnetic resonance imaging with magnetic resonance venography were interpreted as normal. Repeat LP showed an opening pressure of 23 cm H₂O, glucose of 61 mg/dL, and protein of 43 mg/dL. The LP was traumatic with WBC 10/cmm and RBC 1190/cmm. Symptoms were attributed to migraine headaches and persistent IIH. Topiramate was added.

Due to persistent papilledema, he was monitored weekly by ophthalmology. Visual symptoms progressed with development of blurred peripheral vision. On neurology follow-up in November, topiramate and acetazolamide were tapered off with concomitant initiation of nortriptyline for headaches. He developed tinnitus. Additional workup revealed a positive fluorescent treponemal antibody absorption test with rapid plasma reagin (RPR) titer of >1:1024. Repeat LP revealed an opening pressure of 26 cm H₂O, WBC 7/cmm, protein 28 mg/dL, glucose 56 mg/dL, and non-reactive cerebrospinal fluid (CSF) venereal disease research laboratory test (VDRL). HIV testing was negative. He was then referred to the Infectious Diseases Department for further management.

At Infectious Diseases Department evaluation, his headaches and visual symptoms persisted. He denied a history of sexually transmitted infections, genital or oral ulcers, and reported he was monogamous with his wife. Further history revealed that he was hospitalized in July, just prior to the onset of his visual symptoms, for a diffuse, maculopapular rash associated with fevers and chills. A dermatology consultation had attributed his rash to a drug reaction from lamotrigine (started eight months prior).

Given positive syphilis testing and neuro-ophthalmologic symptoms, treatment commenced with intravenous penicillin G (24 million units per day) for 14 days, followed by three weekly intramuscular benzathine penicillin G injections (2.4 million units each) with rapid improvement of symptoms. Contact tracing was performed by the local public health department. After six months, symptoms completely resolved, visual acuity normalized, and papilledema resolved on ophthalmologic exam. Serum RPR titer fell to 1:128 and continues to be monitored.

Discussion

This case illustrates the importance of considering syphilis in otherwise unexplained elevated ICP. Several factors in this case contributed to delayed diagnosis including only slight pleocytosis without protein elevation in the CSF which may have led providers away from an infectious etiology. However, studies have reported cases of early neurosyphilis with low WBC counts and normal protein in the CSF.^3,4,6,10-12 Furthermore, the preceding rash was likely a manifestation of secondary syphilis that was attributed to a drug reaction possibly due to the patient reporting monogamy with his wife. Sexual histories do not reliably predict STI status. ¹³ , ¹⁴

The diagnosis of neurosyphilis is challenging particularly when CSF VDRL is non-reactive. Furthermore, CSF VDRL sensitivity is only 50–60% for neurosyphilis. ¹ , ¹⁰ , ¹⁵ However, a serum RPR titer of ≥1:32 in HIV-negative patients is associated with greater than 10-fold risk of neurosyphilis regardless of disease stage. ³ , ¹⁰ , ¹⁶ Neurosyphilis diagnosis continues to rely on various combinations of abnormal CSF cell counts, elevated protein, reactive CSF tests, and clinical manifestations. Although not pursued in this case, CSF treponemal tests may help confirm the diagnosis. ¹⁰ , ¹⁷ Our patient’s high RPR titer coupled with resolution of symptoms and papilledema following treatment makes the diagnosis of neurosyphilis highly likely.

With rising rates of syphilis in general and atypical neurosyphilis presentations in particular, ^{17 - 19} this case illustrates the importance of considering syphilis as a cause of elevated ICP in all persons regardless of reported sexual behavior. Novel diagnostic biomarkers like CXCL13 may help clarify suspected cases with negative CSF VDRL in the future.^20,21