Symptomatic neurosyphilis is considered to be a rare complication of syphilis, but modern estimates of its prevalence have been based largely on retrospective studies of health department syphilis records.1,21,2 Standard syphilis case-report forms and investigations might incompletely capture cases of neurosyphilis. To our knowledge, no contemporary studies have sought to prospectively identify symptoms of neurologic, otologic, or ocular complications in patients with syphilis. The objective of this study was to determine the prevalence of symptoms of complicated syphilis and the prevalence of confirmed symptomatic complicated syphilis in a population-based sample.
Disease intervention specialists (DIS) conducting syphilis partner services in Seattle & King County have asked all persons with syphilis about symptoms of complicated infection as part of routine case investigations since February 2012. Disease intervention specialist interviews of patients with early and unknown duration syphilis include a questionnaire that captures symptoms of vision changes, hearing changes, and tinnitus using a standardized protocol and interview form. For all persons with these symptoms, DIS recommend follow-up with a medical provider for additional evaluation. In addition to the interview record, the Washington state sexually transmitted disease case-report form includes a field for medical providers reporting a syphilis case to indicate a diagnosis of neurosyphilis. Although DIS do not routinely interview patients with late latent syphilis, neurosyphilis in those cases can be captured through the case report, provider interview to confirm treatment, or review of the treatment regimen used.
We reviewed the records of all syphilis cases at any stage of infection reported in King County for the period of March 2012 to September 2013 that met one of the following criteria (categories are mutually exclusive and hierarchical as listed): (1) neurosyphilis diagnosed by the reporting medical provider, (2) treatment with a regimen recommended by Centers for Disease Control and Prevention (CDC) for otologic, ocular, or neurosyphilis,3 (3) a record of cerebrospinal fluid (CSF) testing, or (4) neurologic symptoms recorded in the partner services interview. Partner services staff document the results of CSF testing when available in medical records or from conversation with the reporting provider. We reviewed each record to determine whether the patient had symptoms of complicated syphilis, which we defined as a change in vision or hearing, including tinnitus. We assumed that all cases that did not meet the criteria for review, including cases for which no partner services data were available, did not have complicated syphilis. When cases we reviewed had no information about the presence or absence of symptoms in the case report, partner services interview, or medical record, we excluded the case from further analysis (n = 6).
We calculated the prevalence of vision and hearing symptoms with binomial confidence intervals (CIs). We separately analyzed a strict definition of confirmed symptomatic complicated syphilis, which we defined as either (1) vision or hearing symptoms and an abnormal CSF or (2) vision symptoms and an ophthalmologic examination consistent with ocular syphilis. Presence of one of the following criteria defined abnormal CSF4,54,5: (1) reactive Venereal Diseases Research Laboratory test, (2) leukocyte count greater than 5/μL in HIV-seronegative persons or greater than 20/μL in HIV-seropositive persons, or (3) protein greater than 45 mg/dL and reactive CSF–fluorescent treponemal antibody absorption test.
A total of 573 individuals with early or unknown duration syphilis were reported during the study period; 468 (82%) completed partner services interviews. As shown in Figure 1, 68 (12%) of the total 573 cases met the criteria for this case review; 48 (71%) were early-stage syphilis and 20 (29%) were late- or unknown-stage syphilis. We excluded from the calculation of symptom prevalence 6 cases with no data on symptoms. Of the 567 remaining cases, 45 (7.9% [95% CI, 5.8%–10.5%]) had vision or hearing symptoms; 20 (3.5% [95% CI, 2.2%–5.4%]) of 567 met the criteria for confirmed symptomatic complicated neurosyphilis with either abnormal CSF testing or an ophthalmologic examination consistent with ocular syphilis. Symptoms of complicated syphilis were more common among patients with late- or unknown-stage syphilis (13.1% [11/84]) than patients with early syphilis (7.0% [34/489]; P = 0.05), as was confirmed complicated syphilis (7.1% in late/unknown vs. 2.9% in early [P = 0.048]). Among patients with early syphilis, symptoms of complicated syphilis were most common in the secondary stage (10.3%), followed by early latent (7.1%) and primary (0.9%; P = 0.01). Confirmed complicated syphilis was also more common in secondary (3.8%) and early latent (3.1%) than primary (0.9%) syphilis, but the differences were not statistically significant (P = 0.36).
Overall, the most commonly reported symptoms were vision changes (n = 27; 4.8% of 567 cases), followed by hearing loss (n = 22; 3.9%), and tinnitus (n = 15; 2.7%). Among the 27 persons with vision symptoms, 15 (56%) had confirmed complicated neurosyphilis; thus, 2.7% (95% CI, 1.5%–4.3%) of the 567 total cases had vision symptoms and objective findings consistent with ocular syphilis. Among the 499 (88%) cases with documented HIV serostatus, 281 (56%) were HIV infected. The proportion of cases with complicated syphilis did not significantly differ by HIV status, with complicated syphilis defined by symptoms (9.3% in HIV infected vs. 7.8% in HIV uninfected; P = 0.2) or symptoms plus objective confirmation (4.3% in HIV infected vs 3.2% in HIV uninfected; P = 0.5).
One limitation of this study is that we could not confirm or exclude the possibility of neurosyphilis for all patients with neurologic symptoms because not all patients with symptoms received a lumbar puncture, and not all patients with vision changes completed an ophthalmologic examination in the course of their clinical care. Because we did not have access to the medical records for a few of the patients during the partner services process or the conduct of this review, it is possible that we missed a small number of cases of confirmed symptomatic complicated syphilis. Because DIS do not routinely interview persons with late latent syphilis, we may have underestimated the prevalence of symptomatic complicated syphilis in late-stage cases. Our study might have excluded patients who had otosyphilis with normal CSF results because most patients with hearing changes did not complete audiometric evaluation. Nonetheless, even our conservative estimate of confirmed symptomatic complicated syphilis suggests that complicated syphilis is more common than previously estimated.
Taylor and colleagues1 reviewed 7083 syphilis cases diagnosed in Los Angeles among persons aged 19 to 65 years in 2001 to 2004; 109 (1.5%) had probable or confirmed neurosyphilis. A CDC analysis of reported cases of neurosyphilis among HIV-positive men who have sex with men in 4 US cities over a 30-month period in 2002 to 2004 estimated the prevalence of symptomatic early neurosyphilis in HIV-infected men who have sex with men with syphilis to be 1.7%. A report from the Netherlands estimated the prevalence of neurosyphilis to be 11% among persons with syphilis in 1999 to 2010, but that study used different methods than the 2 previous US studies and relied on hospital discharge data to enumerate cases of neurosyphilis.6
Our finding that approximately 3.5% to 8% of persons with syphilis have complicated syphilis compared with estimates less than 2% in previous US studies could be due, at least in part, to systematic ascertainment of symptoms in partner services interviews. Descriptions of complicated syphilis in the older literature support this hypothesis. In 1931, Moore7 reported that 111 (4.5%) of 2413 patients with early secondary syphilis in the Johns Hopkins Hospital syphilis clinic had iritis, and in 1932, Stokes et al.8 described ocular syphilis in 91 of 3244 (2.8%) of patients with early syphilis in the Cooperative Clinical Group. These estimates are similar to the 2.7% of cases we found with vision symptoms and objective findings consistent with ocular syphilis. Alternatively, the difference between our estimate and those of Taylor's team and the CDC could indicate a temporal or geographic difference in the prevalence of Treponema pallidum strain types with a propensity to cause neurological disease,9,109,10 a possibility also addressed in the historic syphilis literature.11 Indeed, recent public health alerts about a possible increase in ocular syphilis suggest that the epidemiology of complicated syphilis may be evolving.12 Our analysis was limited to a single jurisdiction and a relatively short period, both of which limit the generalizability of our findings.
Our results suggest that neurosyphilis, otosyphilis, and ocular syphilis are more common than previously estimated in the United States. Routine evaluation of all persons with syphilis for symptoms of complicated syphilis—and prompt CSF examination, complete clinical evaluation, and empiric treatment when appropriate—is crucial for quality clinical care and accurate syphilis surveillance.
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