Morning report: Syphilis

1. Morning report: Syphilis Liz Thomas July 18, 2007

2. “He who knows syphilis, knows medicine.”- William Osler

3. Overview History Pathophysiology Clinical manifestations Diagnosis Neurosyphilis Ocular syphilis Treatment Prognosis

4. History The first description of syphilis occurred during and after the 1494 seige of Naples. Charles VIII invaded with 30,000 mercenary soldiers who spread out over Europe after the army was disbanded. They brought with them a mysterious new illness known first as “the Neopolitan disease,” later as the “French sickness” and “great pox.” During the 19th century the term syphilis became universally accepted.

5. There are differing theories regarding the origin of syphilis. Columbian Exchange theory describes syphilis as a New World disease brought back by Columbus, citing as evidence the timing of the outbreak and skeletal evidence of syphilis in the Americas. Pre-Columbian theory holds that syphilis was present in Europe before the voyage of Columbus, using evidence of descriptions of disease consistent with syphilis in the Bible and by Hippocrates in Classical Greece. Another theory asserts that precursors to the syphilis bacterium existed in both the New and Old Worlds, and that differing environmental conditions produced different strains. Native Americans thus had some immunity against the more virulent European strain.

6. Epidemiology Worldwide ~ 12 million new syphilis cases/year >90% in the developing world In the US the rate of primary and secondary syphilis infection decreased through the 1990s to lowest recorded rate in 2000. However, there was a 29% increased annual rate of primary and secondary syphilis in 2004 (2.7 per 100,000) from 2000 (2.1 per 100,000) Nearly all of the increase is in men MSM account for most of the increase One study in Chicago reported transmission via oral sex may constitute as much as 13.7% of contagion

7. Pathophysiology Syphilis is caused by the spirochete Treponema pallidum. It initiates infection after gaining access to subcutaneous tissues via abrasions that occur during sexual intercourse

8. Pathophysiology After invading the subcutaneous tissue the organism establishes the chancre. Some organisms also establish infection in regional lymph nodes during early local replication.

9. Pathophysiology Nearly all cases of syphilis are sexually acquired (aside from congenital syphilis) Transmission rate during primary and secondary syphilis is about 30% and requires exposure to open lesions – either primary chancre or mucocutaneous lesions. The incubation period varies but ranges from 10 – 90 days.

10. Clinical manifestations: Primary syphilis The initial clinical manifestations is the primary chancre. Usually painless, which distinguishes it from other causes of genital ulcers: herpes simplex (genital herpes) and Hemophilus ducreyi (chancroid). Most often heals without treatment over a period of a few weeks.

11. Secondary syphilis If untreated, approximately 25% of patients will go on to develop systemic symptoms Rash Fever Headache Malaise Diffuse lymphadenopathy Alopecia

12. Late vs. Latent syphilis Latent syphilis refers to patients without symptoms who have positive serologic testing for syphilis. Early latent refers to duration less than one year Late latent refers to duration greater than one year or of unknown duration Late or tertiary syphilis refers to the group of clinical manifestations that may occur anywhere between 1 and 30 years after infection when the infection is not treated.

13. Tertiary syphilis Patients may not have experienced symptomatic primary or secondary syphilis prior to developing tertiary syphilis Most common manifestations are central nervous system, the cardiovascular system, or the skin and subcutaneous tissues (gummas).

14. Diagnosis T. pallidum cannot be grown in culture, so other methods must be used to identify organisms Dark field microscopy allows direct visualization of spirochetes taken directly from lesions Direct fluorescent antibody testing can also be used; it is specific T. pallidum antigens More often, serologic tests are used Nontreponemal tests (VDRL and RPR) measure reactivity of serum from patients with syphilis to a cardiolipin-cholesterol-lecithin antigen. They measure IgG and IgM antibodies and are reported as titers. Treponemal tests (FTA-ABS, MHA-TP and TPPA) are based upon the detection of antibodies directed against treponemal cellular components.

15. Neurosyphilis Neurosyphilis refers to invasion of the CSF by T. pallidum and can occur at any stage of disease Early in the disease the most common manifestations are asymptomatic meningitis, symptomatic meningitis, and meningovascular disease. Late in disease, the most common forms involve the brain and spinal cord parenchyma (general paresis of the insane and tabes dorsalis).

16. Asymptomatic neurosyphilis By definition, no symptoms or signs of CNS involvement Can occur within weeks of infection Characterized by lymphocytic pleocytosis typically <100 cells/µL, an elevated protein concentration usually <100 mg/dL, a reactive VDRL, or a combination of these. WBC count >5 lymphocytes per microliter or a protein concentration >45 mg/dL in patients with suspected neurosyphilis (without HIV) is diagnostic In HIV positive patients with a negative CSF VDRL there is no consensus regarding CSF findings, as mild pleocytosis and elevated protein are typical in HIV infected patients.

17. Symptomatic neurosyphilis Usually occurs within 1 year of infection Symptoms include headache, confusion, nausea and vomiting, and stiff neck; may have decreased visual acuity if there is concomitant uveitis, vitritis, retinitis, or optic neuritis. Patients can have cranial neuropathies, particularly of the optic, facial, or auditory nerves. Can cause small, medium or large vessel arteritis leading to ischemia or infarction Syphilitic gummas may present as mass lesions and can cause seizures Uncommonly affects spinal cord with meningomyelitis or hyperplastic pachymeningitis with polyradiculopathy CSF abnormalities are more severe, with cell count between 200-400, protein between 100-200, and almost always positive VDRL.

18. Meningovascular syphilis Syphilis can cause an infectious arteritis that may affect any vessel in the subarachnoid space and result in thrombosis, ischemia, and infarction. Can develop at any time from first months to several years after infection. May present as an ischemic stroke in a young person.

19. Late neurosyphilis General paresis Progressive dementing illness initially with forgetfulness and personality changes Usually occurs 10 to 25 years after infection In the first half of the 20th century, it accounted for about 10% of admissions to psychiatric hospitals.

20. Syphilis and HIV HIV and syphilis are prevalent in the same risk groups: men who have sex with men, injection drug users, and individuals engaging in sex in exchange for drugs or money. Both infections have been reported to enhance the acquisition and transmission of each other Neurosyphilis may be more common in persons co-infected with HIV; there have been many case reports of such patients who have rapidly progressed from early syphilis to neurosyphilis. For this reason, many experts recommend performing LP on all HIV-infected patients with syphilis.

21. Ocular syphilis All structures of the eye may be affected Uveitis is most common Nothing is pathognomonic Uveitis Anterior uveitis: granulomatous or nongranulomatous. Posterior segment involvement: posterior placoid chorioretinitis, vitritis, focal retinitis, retinal vasculitis, and papillitis, periphlebitis, retinal hemorrhages, and serous and exudative retinal detachments Panuveitis: often granulomatous Other eye manifestations Optic neuritis, neuroretinitis, arterial and venous occlusion

22. Ocular Syphilis Acute syphilitic posterior placoid chorioretinitis Interstitial keratitis Anterior uveitis Extensive retinitis with multifocal satellite lesions

23. Ocular syphilis and HIV With untreated HIV coinfection Bilateral eye involvement and posterior segment may be more common Retrospective review of HIV+ on HAART with ocular syphilis in Georgetown HIV clinic No correlation with CD4 count Mean=408 (Range: 388-594) No cases of CMV retinitis during the same period

24. Treatment Early syphilis is a reportable disease and should be brought to the attention of the department of public health T. pallidum remains highly sensitive to penicillin and no resistance has been reported to date despite several decades of use

25. Treatment Standard therapy for primary, secondary, or early latent syphilis is benzathene penicillin G (one dose 2.4 million units IM) If the patient has had syphilis of greater than 1 year duration or if duration is unknown, treatment should be benzathene penicillin G 2.4 million units IM x 3 doses, 1 week apart. Neurosyphilis and ocular syphilis: 18 to 24 million units per day, administered as 3 to 4 million units IV every four hours or continuous infusion, for 10 to 14 days For penicillin allergic patients Early syphilis: Doxycyline 100mg BID x 14 days, or tetracycline 500mg QID x 14 days. Ceftriaxone and azithromycin have both been studied but are not currently recommended. Gummatous syphilis: Doxycycline 100mg BID for 28 days. Cardiovascular syphilis: Ceftriaxone 1g daily for 10-14 days (if history of mild PCN allergy) Neurosyphilis: Patients should undergo desensitization and treatment with PCN

26. Jarisch-Herxheimer Reaction Dramatic but usually mild reaction consisting of fever, chills, myalgias, headache, tachycardia, increased respiratory rate, increased circulating neutrophil count and vasodilation with mild hypotension may follow initiation of treatment Occurs in nearly 50% with primary, 90% with secondary, and 25% with early latent syphilis. Defervescence occurs within 12 to 24 hours Treatment of the reaction is symptomatic

27. Prognosis Monitor response to treatment using RPR or VDRL titers After treatment of first episode primary or secondary syphilis the VDRL titer declines, becoming negative by 12 months in 40-75% in primary and 20-40% in secondary cases. Re-treatment should be considered if serologic responses are not adequate or if clinical signs persist or recur. CSF should be examined in patients with suspected treatment failure, and if abnormal the patient should be treated for neurosyphilis. Patients with late latent syphilis may not have a dramatic drop in antibody titers but should not be retreated unless titers rise or symptoms recur. Most patients with ocular syphilis will have improvement in vision, but not necessarily to baseline. Even delayed treatment can improve vision. Prolonged disease can ultimately result in eye destruction.

28. References 2007 UpToDate Workowski, KA, Berman, SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006; 55:1. Balba, GP, Kumar, PN, James, AN, et al. Ocular syphilis in HIV-positive patients receiving highly active antiretroviral therapy. Am J Med 2006; 119:448. Bordon J, Martinez-Vasquez, C, et al. Eur J Clin Microbiol Infect Dis. 1999 Oct;18(10):729-32. Kasper, Braunwald, et al. Harrison’s Principles of Internal Medicine. 16th Edition. 2005: 977-988.