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Clinical features and incidence of visual improvement following systemic antibiotic treatment in patients with syphilitic uveitis

The present study reports on the clinical and laboratory findings, and VA outcomes of patients with syphilitic uveitis, with and without HIV coinfection, following systemic antibiotic therapy. We observed that most patients were young MSMs who had HIV co-infection. The majority of patients had high initial serum nontreponemal titers, suggesting that they were likely in earlier disease stages when they experienced ocular symptoms and presented at our clinic, rather than later stages, eg, late latent or tertiary syphilis2,4,25. Following antibiotic therapy, a substantial degree of VA improvement was achieved. Additionally, approximately 70% of eyes were able to achieve a VA ≥ 20/25 by 2 years after presentation. Receiving early antibiotic treatment, absence of HIV coinfection, absence of neurosyphilis, better VA at presentation, and intermediate uveitis as opposed to panuveitis were predictive of achieving a VA of ≥ 20/25.

The demographic profile of our patients is consistent with the epidemiological findings of systemic and ocular syphilis from North America and Western Europe, in which MSM with HIV coinfection represented the majority of the cohort.5. Furthermore, our data adds to the existing information regarding similar epidemiological trends of systemic syphilis in Thailand that have been rising, significantly, since 2005 among Thai MSM with HIV infection.26,27,28. In our study, we found a significantly high rate of HIV coinfection (80%). Furthermore, most patients were newly diagnosed with HIV infection after the syphilis diagnosis. These results support the US Centers for Disease Control and Prevention’s recommendation of conducting HIV testing in all patients diagnosed with ocular syphilis.29. Systemic features of syphilis were observed in roughly one-third of our patients; the proportion found in our study was in the lower range compared to those of earlier studies, which have reported rates ranging from 21 to 70% among patients with syphilitic uveitis10,14,30. This low rate, in particular the rate of genital chancre, could be due to the fact that the data we obtained were mostly based on patient self-reports. A thorough physical examination to document the existence of either active or healed mucocutaneous lesions might have not been performed in all cases.

We found that posterior and panuveitis were the main uveitis presentations. Necrotizing retinitis was predominantly observed in our HIV-infected patients. This observation is consistent with the characteristics of cases that were collected and analyzed in the SUN database to develop classification criteria for syphilitic uveitis. In that study, necrotizing retinitis was observed only in patients with HIV infection and the authors proposed that this retinitis feature may be a variant associated with a compromised immune response.twenty-one. The two distinct retinochoroidal appearances described as a specific presentation of ocular syphilis, which included opacified retinitis with superficial retinal precipitates and acute syphilitic posterior placoid chorioretinopathy (ASPPC)31,32,33, were found in three eyes and one eye in our cohort, respectively (see Supplementary Fig. S1-2). We acknowledge that the prevalence of ASPPC in our study could have been underestimated, as previous studies have reported that the rate of ASPPC varied from 10 to 25% among patients with syphilitic uveitis10,17,21. This underestimation may be explained by the fact that the natural course of ASPPC evolves over time. In addition, the placoid lesions might be difficult to recognize on fundus examination, especially early in the disease course.3. 4. The incorporation of multimodal imaging such as fundus autofluorescence, OCT, or angiogram could be greatly useful for identifying subclinical areas of such lesions. However, they were not systematically performed in all our patients.

The VA results suggest that visual outcomes of syphilitic uveitis are favorable in response to antibiotic treatment. The modeled VA derived from the mixed-effects random-intercept linear regression, which accounted for the propensity of patients with good VA who stop coming to follow-up appointments over time, demonstrated that VA tended to improve shortly after receiving antibiotics and was well maintained at approximately 20/49 for up to two years after presentation. Furthermore, an increased likelihood of recovery of VA to ≥ 20/25 was observed among eyes receiving early antibiotic treatment and eyes with a better presenting VA, which is consistent with previous studies.12,13,17,35. In contrast, eyes with a presenting VA of ≤ 20/200 were less likely to regain VA, which was attributed to the presence of retinal scarring due to extensive retinitis lesions, RD, and recalcitrant CME. The anatomic location of uveitis was predictive of VA improvement. As expected, eyes with intermediate uveitis, wherein the inflammation was primarily localized in the vitreous cavity, were more likely to regain VA compared to those with panuveitis in which the inflammation extended to involve the retina or choroid.

Another notable finding is the presence of HIV coinfection, which decreased the likelihood of VA improvement, and this effect appeared to correlate with the degree of immunosuppression as evidenced by CD4 counts. However, a significant difference was not observed between those HIV patients with CD4 counts ≤ 200 and > 200 cells/µL. The effect of subsequent use of ART and immune recovery in those patients with initially low CD4 count, may assist in their VA restoration, and account for the non-significant result observed. Among 22 HIV-infected patients who were not taking ART at presentation, all subsequently received ART during the follow-up. Some previous studies did not establish HIV coinfection as a predictor of visual outcome, in contrast to the present study1,8,10,32,35. The discrepancy may be due to inconsistencies in the assessment method of VA outcome and variability in the level of immunosuppression among HIV-infected individuals in each study. The more advanced and untreated HIV infection present in our patients might be responsible for the poorer visual prognosis. Approximately half of the HIV-infected patients had baseline CD4 counts of ≤ 200 cells/µL. In HIV-infected patients, reduced opsonic activity of macrophages and decreased clearance of T. pallidum from local sites of infection were observed36. Hence, the impairment of spirochete clearance from ocular tissue may prolong and aggravate the intraocular infectious process and decrease the likelihood of VA recovery in the HIV-infected population, as demonstrated in this study.

The results of this study show a high rate of neurosyphilis (84%) that was almost exclusively observed in HIV-infected patients. The prevalence of neurosyphilis reported earlier varied between 25 and 83%, depending on case selection and diagnostic criteria applied in each study37.38. The high proportion of HIV-infected patients with low CD4 counts and the high initial serum nontreponemal test titers in our patients are likely to be responsible for the high neurosyphilis rate observed.39.40. It is notable that the presence of concomitant neurosyphilis also decreased the likelihood of VA recovery after taking into account HIV status. The results of the analysis did not change when four patients diagnosed as neurosyphilis with only elevated CSF protein concentrations were excluded. To date, limited evidence exists on the relationship between neurosyphilis and visual outcomes in ocular syphilis cases. We hypothesized that neurosyphilis might result in an occlusive/ischemic microvasculopathy involving the optic nerve and the associated visual pathway and contribute to the poorer recovery of VA in these patients. Our data suggest that performing LP to establish whether neurosyphilis is present may add a benefit in providing patients’ visual prognoses. This finding may be worthy of consideration in light of the 2021 updated guideline by the US Centers for Disease Control and Prevention which states that CSF examination is not always needed before treatment for persons with ocular syphilis if there is no evidence of cranial nerve dysfunction or other neurological abnormalities, as the result of CSF analyzes does not alter the initial management and follow-up29.

Our study did not observe the significant difference on VA recovery between those who did or did not receive adjunctive oral prednisolone following systemic antibiotic therapy. However, this result should be interpreted with caution owing to the non-standardized doses and duration of prednisolone prescribed in our patients. Further, the decision to initiate systemic steroids was typically based on the severity of intraocular inflammation. Patients with more severe inflammation were more likely to be prescribed prednisolone which could have introduced indication bias. Randomized controlled trial would be the most suitable study design to explore the benefit of adjunctive systemic steroid treatment.

Our results demonstrated that the female patient had a greater probability of achieving VA recovery than the male patients. It is important to note that this result was based on only one female participant. Therefore, no conclusion can be drawn on this association. Further studies with a larger number of female patients are required to provide evidence and confirm such associations. We observed an increased likelihood of achieving VA recovery among the MSM compared to the non-MSM population. This finding may be attributed to a shorter median duration of ocular symptoms prior to treatment (4.3 vs. 17.1 weeks, p= 0.64, Mann–Whitney U test), better median presenting VA (0.74 logMAR vs. 1.3 logMAR, p= 0.46, Mann–Whitney U test), and higher median baseline CD4 counts among those who were co-infected with HIV (329 vs 142 cells/µL, p= 0.057, Mann–Whitney U test) in the MSM group compared to the non-MSM group.

This study has several. First, the retrospective nature and relatively small sample, mainly consisting of men living with HIV who presented with early syphilis, used in the study may limit its generalizability. Second, other predictive factors of VA improvement may be unrecognized. These include HIV viral load and multimodal imaging findings, such as OCT imaging and angiography, which were not included due to insufficient data. Third, we only used VA as the measure of visual function, which does not completely represent all aspects of vision-related to functioning. Fourth, there may be referral bias since the study was conducted at a tertiary center. However, few, if any, other hospitals in our region comprehensively manage patients with uveitis involving the posterior segment. Hence, we believe that our data are fairly representative of uveitis caused by syphilis in southern Thailand and are not limited to only a tertiary setting. The results of the present study could contribute to the data on ocular syphilis from developing countries located in the South East Asia region where HIV and STIs are currently a high burden.

In summary, men with HIV coinfection represented the majority of our patients with syphilitic uveitis. These demographic characteristics were consistent with the current epidemiological data of syphilis resurgence in western countries. Bilateral uveitis with posterior segment involvement was a common presentation. Substantial degree of VA improvement was achieved in most eyes with a short course of antibiotic therapy, this finding highlights the importance of accurately diagnosing syphilis. Delayed treatment with poor VA at presentation, presence of HIV coinfection, and concomitant neurosyphilis decreased the likelihood of VA restoration. In the era of rapidly evolving multimodal ocular imaging, future studies that focus on the combination of different imaging modalities are warranted for identification of potential biomarkers to serve as reliable predictors of disease severity and functional outcomes post-therapy.

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