Annals of B-Pod: Neurosyphilis

History of present illness

The patient is a male in his thirties with a past medical history of Human Immunodeficiency Virus (HIV) who presents to the emergency department (ED) with a rash and eye pain. The rash has been present for the past six weeks and started as red spots on the trunk that spread to the extremities, including his palms and soles. The rash is neither pruritic nor painful, and recently his hands have begun to peel. He denies new sexual or environmental exposures. For the past week, he has been taking oral prednisone that was prescribed by his primary care provider, but his rash has not improved.

The patient also reports bilateral eye pain. The pain started in his right eye with purulent drainage and blurry vision one week ago. The symptoms then spread to his left eye several days later. He was diagnosed with bilateral uveitis at an outside facility and was transferred to a tertiary care center for further work up.

Past Medical History: Human immunodeficiency virus, prior sexually transmitted infection exposures

Past Surgical History: None

Medications: Prednisone

Allergies: None

Vitals: T 98.0°F  HR 103  BP 121/65  RR 22  SpO2 97%

Figure 1. palmar lesions noted on the patient.

Physical Exam: The patient appears thin and older than his stated age but is in no acute distress. He has bilateral conjunctival injection. Visual acuity is 20/150 in the right and left eyes individually. Intraocular pressures are within normal limits. Cell and flare are present bilaterally on slit lamp examination. Examination of the oropharynx shows multiple white patches along the buccal mucosa, uvula, and posterior oropharynx. Bilateral cervical and inguinal adenopathy are present. Lung, cardiac, and abdominal examinations are unremarkable. There is a diffuse erythematous maculopapular rash involving bilateral palms where desquamation is also noted (Image 1). On neurologic exam the patient has a normal mental status, is moving all four extremities, and has normal cranial nerve function.

Hospital Course

Ophthalmology was consulted for the patient’s bilateral uveitis. Their examination revealed pan-uveitis concerning for ocular syphilis. This was additionally supported by his rash consistent with secondary syphilis and untreated HIV. A broad work-up was initiated to evaluate for additional causes of his pan-uveitis. The patient was given prednisolone, cyclopentolate, and phenylephrine eye drops and admitted to the intensive care unit for frequent drop administration. Dermatology and infectious disease were consulted on admission. Shortly into the patient’s hospital course, the patient’s CD4 count resulted at 71 with a high viral load. Trepia (Treponema pallidum agglutination assay) and rapid plasma regain (RPR) studies were also positive. Biopsies of the rash were consistent with secondary syphilis. Lumbar puncture was performed and CSF VDRL titer was 1:4 indicating neurosyphilis. His hospital course was complicated by gram-positive and gram-negative bacteremia. He was discharged with an improvement in his vision and rash after completing two weeks of intravenous penicillin. He continues to be seen by ophthalmology, dermatology, and infectious disease in the outpatient setting for ongoing treatment and monitoring of neurosyphilis and acquired immune deficiency syndrome (AIDS).


Syphilis is a sexually transmitted infection caused by the spirochete Treponema pallidum. If left untreated, the disease can progress through four clinical stages: primary, secondary, latent, and tertiary. After the primary stage of the disease, patients can present with multiple symptoms that mimic other infectious processes and diseases. Syphilis is therefore known as “the great impostor.”

The incidence of syphilis in the United States has varied since rates of infection have been recorded starting in the early 1940s. Penicillin was introduced in the late 1940s and infection rates significantly decreased.[1] In the 1980s, there was a surge secondary to increasing intravenous drug use and prostitution.[1] In 2000, the incidence of syphilis was at an all-time low after programs for aggressive screening and primary prevention were implemented.[1] However, syphilis has since been on the rise in recent years. The annual rate of syphilis has increased every year from 2005 to 2016.[1] In 2016, there were 27,814 cases of primary and secondary syphilis reported in the United States. This was a 17.6% increase from 2015 and 74.0% increased from 2012.[1] Sexually transmitted infections are on the rise in general and research is on-going to determine the cause. Some postulate that the rise of dating apps may play a role.[2] 

table 1. Stages of syphilis based on timing of initial infection and characteristic signs and symptoms.

Primary syphilis classically presents with a chancre at the inoculation site. The chancre initially forms as erythematous papules that progresses to a painless ulcer. Spirochetes are present in these lesions and spread systemically via the lymphatic and hematopoietic systems. Secondary syphilis occurs four to ten weeks after the initial infection and can produce a wide variety of signs and symptoms. It is characterized by a generalized maculopapular rash that frequently involves the palms and soles. Secondary syphilis is classically characterized by condylomata lata which are papules at mucocutaneous junctions. Systemic symptoms such as fever, malaise, headaches, joint pains, and anorexia are common. Hepatic, renal, ocular, and central nervous system involvement also occur at this stage. The latent phase follows the secondary phase, and is a prolonged asymptomatic period following the secondary phase.

The latent stage is dichotomized into early and late stages. Early latent stage occurs less than one year after primary infection and late latent stage occurs greater than one year after primary infection. Tertiary syphilis is due to an obliterative endarteritis that can affect any organ system but is divided into three subtypes: benign, cardiovascular, and central nervous system. Benign tertiary syphilis presents with granulomas anywhere in the body that are called gummatous lesions. The cardiovascular subtype involves the aorta and coronary arteries and patients can present with classic symptoms of acute coronary syndrome. Patients with the central nervous system subtype present with tabes dorsalis and general paresis. Some infectious disease groups also describe a quaternary stage that is an aggressive form of neurosyphilis in patients with AIDS and causes necrotizing encephalitis.[3] 

Neurosyphilis can occur any time after primary infection and is much more common in patients with HIV infection.[4] Infection of the central nervous system begins early, and patients with primary syphilis may have some degree of aseptic meningitis. Over time, the infection may progress and involve more structures in the central nervous system. Early infection generally affects the meninges and vasculature. Late infections progress to involve the parenchyma of the brain and spinal cord. There are six subtypes of neurosyphilis based on the clinical symptoms and structures involved. These include asymptomatic, acute syphilitic meningitis, meningovascular syphilis, tabes dorsalis, general paresis, and optic atrophy. Although described below as separate entities, these syndromes can overlap.[5] 

table 2. subtypes of neurosyphilis and highlights of clinical presentations.

Asymptomatic Neurosyphilis

Asymptomatic neurosyphilis is characterized by positive VDRL serology in the CSF with no signs or symptoms of neurologic disease. CSF studies also show elevated protein and a very mild lymphocytic pleocytosis. This stage may resolve spontaneously without treatment.

Acute Syphilitic Meningitis

Patients with acute syphilitic meningitis present with classic symptoms of meningeal irritation including headache, meningismus, nausea, and vomiting. Fever is not always present, especially if the patient is immunocompromised. Cranial neuropathies can also be present, with cranial nerve seven involved most commonly.

Meningovascular Syphilis

Meningovascular syphilis is a result of neurovascular endarteritis. There is fibroblastic proliferation of the intima of the cerebral blood vessels and luminal narrowing. Patients are more vulnerable to cerebrovascular thrombosis and present with stroke. This occurs about seven years after the initial infection if left untreated.

Tabes Dorsalis

Tabes dorsalis is a slowly progressive degenerative disease of the posterior columns of the spinal cord. It typically develops 20 years after the initial infection. Symptoms include sensory ataxia and neuropathic pain. Pupillary irregularities like Argyll-Robertson pupil are also common in tabes dorsalis. The damage is often irreversible at this stage of infection.

General Paresis

General paresis often develops 10 to 25 years after infection and is also known as general paralysis of the insane, dementia paralytic, or paretic neurosyphilis. It is a progressive dementia with psychotic features. If caught early, symptoms can be reversible with appropriate treatment.[6] 

Optic Atrophy

When syphilis involves the eye, almost any ocular structure can be involved and results in ocular atrophy. Manifestations of ocular syphilis include conjunctivitis, episcleritis, scleritis, interstitial keratitis, iritis, uveitis, chorioretinitis, retinitis, and retinal vasculitis. Posterior uveitis and pan-uveitis are the most common findings. Ocular syphilis can occur at any time during the disease course and most commonly presents with syphilitic meningitis. A report from 2015 showed that the incidence of ocular syphilis is increasing and occurs in about 0.6% of all cases of syphilis.[7] The etiology of the increasing incidence of ocular syphilis remains unclear. Some experts postulate that it could be secondary to the outbreak of a strain of a Treponema pallidum with more affinity for the eye. Other theories include greater awareness of ocular complications or the overall rise in syphilis infections.[7] If ocular syphilis is recognized and treated early in the clinical course, vision is usually fully recovered. If left untreated, chronic progressive intraocular inflammation may result in glaucoma, chronic vitritis, retinal necrosis, and optic atrophy.[8] 


The first step in the diagnosis of syphilis and neurosyphilis is to determine if the patient has ever been infected with T. pallidium. This is accomplished with serologic blood testing with both non-treponemal and treponemal tests. Non-treponemal testing detects antibodies against antigens released by the issue damaged by spirochetes (e.g., cardiolipin). These are the Venereal Disease Research Laboratory (VDRL) and RPR tests. False-positive results can occur in other acute infections, chronic autoimmune disease, and intravenous drug use. These titers decrease after successful treatment and are used to monitor response to treatment as well as reinfection. Treponemal tests detect antibodies against spirochete antigens and are more specific than the non-treponemal tests. These include micro-hemagglutination Treponema pallidum (MHA-TP), fluorescent treponemal antibody absorption test (FTA-ABS), and Treponema pallidum particle agglutination (TPA). Treponemal antibodies remain positive for life, do not correlate with disease activity, and are not useful in monitoring response to treatment. Generally, neither test should be used in isolation when evaluating a patient with syphilis.[9] 

Diagnosis of ocular syphilis is challenging as it can infect any structure of the eye. There is no pathognomonic presentation, and it mimics many other inflammatory conditions of the eye. If an inflammatory eye condition fails to improve with standard therapy, clinicians should consider syphilis in the differential. Emergency physicians need to have a high-index of suspicion and low threshold to obtain serologic testing as ocular syphilis cannot be ruled out by clinical presentation alone.

CSF analysis should be performed in all cases of ocular syphilis or in patients with syphilis and neurologic complaints. Lumbar puncture should be considered in any patient with HIV and syphilis at any stage, regardless of ocular or neurologic disease. Greater than five leukocytes, elevated protein, and presence of treponemal or non-treponemal antibodies in the CSF are diagnostic for neurosyphilis.[9] The preferred treatment of syphilis is parenterally administered penicillin G. The dose and duration of therapy vary by stage. Treatment for neurosyphilis is four million units of penicillin G intravenously every four hours for two weeks followed by 2.4 million units of benzathine penicillin intramuscularly weekly for three weeks. Patients with ocular syphilis should be treated similarly to patients with neurosyphilis even without CSF evidence of neurosyphilis. Intravenous penicillin is required to achieve adequate intraocular levels for bactericidal effects. In penicillin allergic patients, penicillin desensitization should be performed as non-penicillin antibiotic regimens are less effective in the treatment of neurosyphilis.[10] 

Successful treatment of neurosyphilis is confirmed by normalization of CSF studies and nonreactive VDRL serology. Neurologic examination and lumbar puncture should be performed every three to six months following treatment. Patients who do not have normalization of CSF studies by six months or decrease in VDRL titers by fourfold at one year should be retreated.[11]  

Topical and systemic steroids can be used to treat ocular syphilis but only in the setting of appropriate antibiotic therapy. Topical steroids decrease inflammation from interstitial keratitis and anterior uveitis. Oral and intravenous steroids can be used to treat optic neuritis, scleritis, and posterior uveitis.[12] In cases of severe inflammation, topical therapies may need to be administered so frequently that these patients require admission to the intensive care unit.

Emergency physicians must be cognizant that rates of syphilis infections are on the rise and patients can have a wide spectrum of clinical presentations. It is important to ask historical questions to identify patients at risk including sexual behaviors, previous exposures to sexually transmitted infections, and HIV status. Have a low threshold to obtain serology and CSF studies. Ophthalmology should be consulted for further work up and management of inflammation in the eye concerning for ocular syphilis. Neurology should be consulted for patients with neurologic deficits in the setting of neurosyphilis. Patients with findings of ocular syphilis or neurosyphilis should be admitted to receive intravenous penicillin. They will also need to establish care with multiple specialists for long term management.

Syphilis is a sexually transmitted, chronic infection that can affect almost any organ system if untreated. Infection of the central nervous system can occur at almost any time during the infection and patients present with a wide range of symptoms. Ocular syphilis can also occur at any time and can infect any structure in the eye. Diagnosis is confirmed with treponemal and non-treponemal tests and analysis of the CSF. Providers should have a low threshold to perform a lumbar puncture in patients with syphilis and especially those with HIV. If caught early and treated adequately, the majority of neurosyphilis and ocular syphilis can be cured with minimal long term sequelae.

Authored by Eileen Hall, M.D.

Posted by Matthew Scanlon, m.D.


  1. Centers for Disease Control and Prevention (CDC). 2016 Sexually Transmitted Disease Surveillance.
  2. Sharp N. The return of syphilis: why are rates of the once-rare disease now climbing again. The Atlantic. 2015.
  3. Hook EW, M CM. Acquired Syphilis in Adults. New Eng J Med 1992; 326:1060-1069.
  4. Libois A, De Wit S, Poll B, et al. HIV and syphilis: when to perform a lumbar puncture. Sex Transm Dis 2007; 34:141.
  5. Conde-Sendín MA, Amela-Peris R, Aladro-Benito Y, Maroto AA. Current clinical spectrum of neurosyphilis in immunocompetent patients. Eur Neurol 2004; 52:29.
  6. Zheng D, Zhou D, Zhao Z, et al. The clinical presentation and imaging manifestation of psychosis and dementia in general paresis: a retrospective study of 116 cases. J Neuropsychiatry Clin Neurosci 2011; 23:300.
  7. Oliver S, Sahi SK, Tantalo LC, Godornes C, Neblett Fanfair R, Markowitz LE, et al. Molecular typing of Treponema pallidum in ocular syphilis. Sex Transm Dis. 2016; 43:524–7.
  8. Moradi A, Salek S, Daniel E, et al. Clinical features and incidence rates of ocular complications in patients with ocular syphilis. Am J Ophthalmol 2015; 159:334.
  9. Ratnam S. The laboratory diagnosis of syphilis. Can J Infect Dis Med Microbiol 2005; 16:45.
  10. Ghanem KG, Workowski KA. Management of adult syphilis. Clin Infect Dis 2011; 53 Suppl 3:S110.
  11. Workowski KA, Bolan GA; CDC. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015;64(No. RR-03).
  12. Szilárd Kiss, Francisco Max Damico & Lucy H. Young (2009) Ocular Manifestations and Treatment of Syphilis. Seminars in Ophthalmology, 20:3, 161-167.
  13. Centers for Disease Control and Prevention (CDC). Clinical advisory: ocular syphilis in the United States. (Accessed on June  02, 2018).
  14. Hooshmand H, Escobar MR, Kopf SW. Neurosyphilis. A study of 241 patients. JAMA 1972; 219:726.
  15. Karsan N, Barker R, O’Dwyer JP. Clinical reasoning: the “great imitator”. Neurology 2014; 83:e188.
  16. Lukehart SA, Hook EW 3rd, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med 1988; 109:855.
  17. 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.
  18. Oliver SE, Aubin M, Atwell L, et al. Ocular Syphilis - Eight Jurisdictions, United States, 2014-2015. MMWR Morb Mortal Wkly Rep 2016; 65:1185.
  19. Center for Disease Control and Prevention. Rash on the palms of both hands due to secondary syphilis. United States, May 13, 2013