Clinical Outcomes of Ocular Syphilis within the Great Plains Region: Potential Syndemic Impact of Methamphetamine Use

Abstract

Background/Objectives

To characterise the clinical spectrum of ocular syphilis and its visual acuity impact in patients with and without methamphetamine use.

Subjects/Methods

This retrospective observational case series of patients with ocular syphilis was conducted at a tertiary referral centre within the Midwest United States. Patients diagnosed with ocular syphilis between 2021 and 2023 at the University of Nebraska Medical Center were included in the study. Patients were stratified into methamphetamine use and non-methamphetamine use groups. Paired, non-parametric comparisons of visual characteristics and visual outcomes at baseline, month-3, and month-6 were performed between the two groups.

Results

A total of 34 eyes of 21 patients were included in the analysis. The median age was 44 years (39 – 53), and fifteen patients (71%) were male. The median baseline visual acuity (VA) was 6/60 (6/45.7 – LP) in the methamphetamine group (11 eyes, n=7), which was significantly worse than the non-methamphetamine group (23 eyes, n=14) with the median VA of 6/18 (6/7.5 – 6/45.7), p=0.0136. While the non-methamphetamine group exhibited a significant VA improvement from baseline to month-3 follow-up (6/18 to 6/7.5, p=0.001) and from baseline to month-6 follow-up (6/21 to 6/6, p=0.002), this was not seen in the methamphetamine group (6/120 to 6/24, p=0.225). Duration from symptom onset to presentation was shorter within the methamphetamine group compared to the non-methamphetamine group (7 days vs 36 days, p=0.024).

Conclusions

Methamphetamine use was associated with worse visual acuity at presentation and follow-up despite patients presenting sooner for evaluation.

Introduction

Syphilis is a growing public health concern with a rising incidence globally and nationally. In the United States, rates of primary and secondary syphilis have increased every year since 2001, with nearly 134,000 new cases reported in 2020 representing a 52% increase from 2016.¹ In Nebraska, the incidence of syphilitic cases reported to the Nebraska Department of Health and Human Services increased by 364% from 2017 to 2021.² Of the 255 cases reported in 2021, 15 people reported experiencing vision impairment, and 8 of these patients had a confirmed diagnosis of uveitis. The reported spectrum of ocular symptoms ranged from floaters and blurry vision to partial or complete vision loss.³

The diagnosis of ocular syphilis can be technically challenging due to its variable clinical presentations that mimic phenotypes of other diseases.³ Syphilis may affect various parts of the ocular anatomy leading to anterior segment (episcleritis/scleritis, keratitis, and conjunctivitis), posterior segment (vitritis, chorioretinitis, pyramidal inflammatory deposits of the outer retina,⁴ and neuroretinitis), or neuro-ophthalmologic manifestations (Argyll Robertson pupil, and optic neuropathy).⁵ Posterior or panuveitis are the most commonly seen ophthalmic manifestations of ocular syphilis and can occur at any stage of the disease.⁶ Due to its difficult diagnosis and variable clinical manifestations, a laboratory evaluation for syphilis is recommended for any patient with unexplained intraocular inflammation.⁷ A delay in the diagnosis of syphilitic uveitis could potentially lead to progressive disease and either subacute or more rapid deterioration of vision.

Several risk factors associated with syphilis have been studied, including human immunodeficiency virus (HIV), men-who-have-sex-with-men (MSM), multiple sexual partners, and drug use disorders.⁸ Historically, studies have shown a high rate of heterosexual syphilis transmission among people who use methamphetamine, specifically 9.6% of patients diagnosed with primary or secondary syphilis had used methamphetamine in 2017.⁹ Methamphetamine use is hypothesised to contribute to engagement in unsafe sexual practices and therefore increased risk of sexually transmitted infections (STIs) such as syphilis.^10,11 Overlap of risky behaviours including drug use disorder and unsafe sexual practices in certain patient populations could constitute a syndemic, methamphetamine use disorder and syphilis, that highlights underlying trends in socioeconomic and structural disparities. In addition to behavioural effects, the sympathomimetic properties of methamphetamine facilitate diffuse vasoconstriction, which may disrupt immune response and contribute to disease progression.¹²

Intravenous penicillin remains the mainstay therapy for ocular syphilis.³ Adjunctive systemic corticosteroids have shown varying results in improving patient outcomes.^3,13,14 While immunologic response may contribute to the disease manifestations, previous studies found no additional benefit of co-administering corticosteroids with antibiotics.³ Over 90% of ocular syphilis respond to first line antibiotic therapy,^3,14 however, there remains a risk of recurrence. Even among patients with adequate follow-up, as many as 9% of previously treated ocular syphilis may develop recurrent ophthalmic disease.¹⁵ These data highlight the importance of prompt risk factor identification and regular ophthalmologic follow-up in this group of patients.

Given the consequences of ocular syphilis on vision impairment, its association with HIV, and the potential for poorer outcomes in methamphetamine users, we described the spectrum of ocular syphilis and its visual acuity (VA) impact observed in our tertiary referral in patients with and without methamphetamine use. Specifically, we hypothesised that methamphetamine use may predispose patients with syphilis to more severe ocular involvement and varying anatomic and functional consequences compared to non-methamphetamine users.

Materials and Methods

The study was conducted in compliance with the Declaration of Helsinki, and informed consent was obtained from the patients participating in the study. The Institutional Review Board approval was obtained from the University of Nebraska Medical Center.

Patient population and demographic characteristics

A retrospective study was performed to investigate the association between methamphetamine use and disease severity in patients with ocular syphilis treated at the University of Nebraska Medical Center between 2021–2023. Demographic data including age, sex, risk factors (HIV, high-risk sexual behaviour, other drug use disorders, and incarceration), and history of methamphetamine use were collected for analysis. Patients were stratified into the methamphetamine use group and non-methamphetamine use group for comparison of disease and VA outcomes.

Ophthalmic examination and disease characteristics

All patients underwent a comprehensive ophthalmic examination at our uveitis service. Baseline (initial visit), month-3 (2 weeks to 4 months after the initial visit), and month-6 (6 months to 10 months after the initial visit) VA were collected for analysis. Visual impairment was stratified according to mild (VA 6/7.5 – 6/12), moderate (VA 6/15 – 6/60), and severe vision loss (VA < 6/60). Uveitis was classified according to Standardization of Uveitis Nomenclature (SUN) guidance for the anatomic location of uveitis, including anterior, intermediate, posterior, and panuveitis, and anterior chamber (AC) cells and vitreous cells were collected for analysis.¹⁶ Ophthalmic manifestations including retinal findings, and optic nerve disease were also reviewed. Placoid features were identified by dilated fundus examination and multimodal imaging, while optic nerve involvement was evaluated by dilated fundus examination and/or fluorescein angiography. Optical coherence tomography (OCT) findings such as ellipsoid zone (EZ) loss, retinal pigment epithelium (RPE) deposits, and subretinal fluid (SRF)/intraretinal fluid (IRF) were analysed. The received treatments for ocular syphilis were also reviewed and collected for analysis.

Statistical analysis

Microsoft Excel (Microsoft Corp., Redmond, WA, USA) with additional SPC (https://www.spcforexcel.com/) and XLSTAT (https://www.xlstat.com/en/) statistical software for Excel were used for statistical analysis. VA was further converted to a Logarithm of the Minimum Angle of Resolution (LogMAR) VA score for statistical analysis.¹⁷ Categorical values were expressed as frequencies and percentages. Median was calculated for numerical values and expressed as median (IQR). Chi-squared test of proportions was used to compare the categorical values between the two groups, and Man-Whitney U test was used to compare the numerical values between the two groups. Wilcoxon signed-rank test was used for BCVA comparisons over time in each group. A p-value <0.05 was considered statistically significant for all analyses.

Results

Demographic characteristics

A total of 34 eyes of 21 patients with ocular syphilis were included in the study. The median age was 44 (39 – 53) years. Fifteen patients (71%) were male, and six patients (29%) were female. Documented risk factors including history of HIV, high-risk sexual behaviours (unprotected intercourse, multiple partners, MSM), illicit drug use, and a history of incarceration are summarised in Table 1.

Table 1.

Baseline characteristics and treatments administered in patients diagnosed with ocular syphilis (n=21)

Characteristics	Methamphetamine use (n=7)	No methamphetamine use (n=14)	Total (n=21)
Median age, years (IQR)	45 (40, 51.5)	43.5 (36.5, 52.8)	44 (39, 53)
Sex, n (%)
Male	5 (71)	10 (71)	15 (71)
Female	2 (29)	4 (29)	6 (29)
Risk factors, n (%)
HIV	4 (57)	3 (21)	7 (33)
High-risk sexual behaviours*
Illicit drug use	4 (57)	9 (64)	13 (62)
Incarceration	7 (100)	6 (43)#	13 (62)
	3 (43)	2 (14)	5 (24)
Symptom duration prior to presentation, weeks (IQR)	1 (1, 4)	5.15 (3.33, 43.35)	4.3 (3, 13)
Laterality, n (%)
Unilateral	3 (43)	5 (36)	8 (38)
Bilateral	4 (57)	9 (64)	13 (62)
Anatomic diagnosis
Anterior uveitis	1 (14)	3 (21)	4 (19)
Intermediate uveitis	1 (14)	5 (36)	6 (29)
Posterior uveitis	1 (14)	-	1 (5)
Panuveitis	4 (57)	6 (43)	10 (48)
Optic nerve involvement
Yes	5 (71)	7 (50)	13 (62)
No	2 (29)	7 (50)	8 (38)
Placoid features
Yes	2 (29)	2 (14)	4 (19)
No	5 (71)	12 (86)	17 (81)
Treatment
IV penicillin, patients (%)	5 (71)	10 (71)	15 (71)
Antibiotic alternative to penicillin, patients (%)**	1 (14)	4 (29)	5 (24)
Declined treatment, patients (%)	1 (14)	0 (0)	1 (5)

^*High-risk sexual behaviours include unprotected intercourse, multiple partners, and men-who-have-sex-with-men.

^**ceftriaxone, doxycycline

^#Drugs aside from methamphetamine

Abbreviations: IQR: interquartile range, HIV: human immunodeficiency virus, IV: intravenous

Spectrum of syphilitic uveitis

Thirteen patients (62%) had bilateral ocular involvement, and eight patients (38%) had unilateral ocular involvement. A spectrum of anatomic locations of uveitis and disease presentations were observed including anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis. Intermediate uveitis (n=6, 29%) and panuveitis (n=10, 48%) were the most common diagnoses. Thirteen patients (62%) had optic nerve involvement, meanwhile, four patients (19%) had placoid features (Table 1). Multimodal imaging of a patient with syphilitic uveitis in our study is shown in Figure 1.

Figure 1.

Right eye: A) Fundus photograph shows disc oedema, poor macular reflex, segmental perivascular sheathing, and intraretinal infiltrates; B) Fluorescein angiogram shows optic disc hyperfluorescence with leakage and staining of the placoid lesion; C) Optical coherence tomography (OCT) highlights retinal pigment epithelial elevations and ellipsoid zone attenuation. Left eye: D) Fundus photograph shows yellow subfoveal lesion (blue arrow); E) Fluorescein angiogram shows optic disc hyperfluorescence with leakage; F) OCT shows subfoveal hyperreflective material of the corresponding subfoveal lesion on fundus photograph with ellipsoid zone attenuation.

Visual outcomes after treatments between two groups

The median VA of the cohort was 6/30 (6/12 – 6/120) at the initial visit. It improved to 6/9.1 (6/6 – 6/24) at month-3 visit (p=0.0073) and to 6/6 (6/6 – 6/9.1) month-6 visit (p=0.0001) following treatment, often in conjunction with the infectious disease team and hospital medicine consultation (Table 1, Figure 2A). Baseline, month-3, and month-6 LogMAR VA and severity of visual impairment are summarised in Table 2. At the initial visit, the median VA was 6/60 (6/45.7 to LP) in the methamphetamine group (n=11), which was significantly worse than the non-methamphetamine group (n=23) with the median VA of 6/18 (6/7.5 – 6/45.7), p=0.0136 (Table 3). At month-3 follow-up, the median VA of the methamphetamine group was 6/24 (6/15 – 6/60), and the median VA for the non-methamphetamine group was 6/7.5 (6/6 – 6/12), and this difference was also statistically significant (p=0.0052). While the non-methamphetamine group exhibited a significant VA improvement from baseline to month-3 follow-up (6/18 to 6/7.5, p=0.001) (Figure 2C) and from baseline to month-6 follow-up (6/21 to 6/6, p=0.002) (Figure 2D), this improvement was not seen in the methamphetamine group at (6/120 to 6/24, p=0.225) (Figure 2B).

Figure 2.

Effects of treatment of ocular syphilis on visual acuity over time. For all patients included in the study, median LogMAR visual acuity improvement was significant 3 months and 6 months after treatment completion (A). In the cohort of methamphetamine users, the median LogMAR at month 3 follow-up did not exhibit a significant improvement (B). Significant improvements were observed in the cohort of non-methamphetamine users at month 3 follow-up (C) and month 6 follow-up (D).

Table 2.

Degree of visual impairment at presentation and progression of visual acuities over time by eyes (n=34)

	Methamphetamine use (n=11)	No methamphetamine use(n=23)	Total (n=34)
Median LogMAR visual acuities (IQR)
Baseline	1 (0.88, 1.9)	0.48 (0.1, 0.88)	0.7 (0.3, 1.27)
3 months	0.65 (0.4, 1)	0.1 (0, 0.301)	0.18 (0, 0.6)
6 months	-	0.05 (0, 0.12)	0.05 (0, 0.12)
Severity of visual impairment*, n (%)
None	-	5 (22)	5 (15)
Mild	1 (9)	5 (22)	6 (18)
Moderate	5 (45)	8 (35)	13 (38)
Severe	5 (45)	5 (22)	10 (29)

^*World Health Organization criteria: Mild: VA 20/25–20/40, Moderate: VA 20/50–20/200, Severe: VA < 20/200

Abbreviations: LogMAR: Logarithm of the Minimum Angle of Resolution, IQR: interquartile range

Table 3.

Effect of methamphetamine use on visual acuity, clinical features, and ocular inflammation by eyes (n=34)

Dependent variable	Methamphetamine use (n=11)	No methamphetamine use (n=23)	p-value
Median LogMAR VA at baseline (IQR)	1 (0.88, 1.9)	0.48 (0.1, 0.88)	0.0136*
Median LogMAR VA at month 3 (IQR)	0.65 (0.40, 1)	0.1 (0, 0.3)	0.0052*
Optic nerve involvement, n (%)	5 (71)	7 (50)	0.185
Placoid features, n (%)	2 (29)	2 (14)	0.329
EZ loss on OCT, n (%)	7, (64)	4, (17)	0.023*
RPE deposits on OCT, n (%)	9, (82)	7, (30)	0.018*
SRF/IRF on OCT, n (%)	2, (18)	5, (22)	0.562
Anterior chamber cells, SUN grade (IQR)	2 (0.25, 2)	1 (0, 2)	0.246
Vitreous cells, SUN grade (IQR)	1 (0, 2)	1 (0.5, 2)	0.589
Median symptom duration before presentation, weeks (IQR)	1 (1, 4)	5.15 (3.33, 43.35)	0.024*

^*p<0.05 is significant; Mann-Whitney U test and Pearson Chi-Square test

Abbreviations: LogMAR VA: Logarithm of the Minimum Angle of Resolution Visual Acuity, IQR: interquartile range, EZ: Ellipsoid zone, RPE: retinal pigment epithelium, SRF: subretinal fluid, IRF: intraretinal fluid, SUN: Standardisation of Uveitis Nomenclature

Disease characteristics between the two groups

The methamphetamine group presented earlier following symptom onset than non-users (7 days vs 36 days, p=0.024) (Table 3). The proportion of eyes presenting with optic nerve involvement in the methamphetamine group was slightly higher than compared to the non-user group, but the difference was not statistically significant (73% vs 57%, p=0.465). Similarly, the proportion of individuals with placoid syphilis also appeared greater in the methamphetamine group, although no clear difference was observed between groups (27% vs 13%, p=0.363). On OCT, the methamphetamine group demonstrated a significantly greater proportion of EZ loss (64% vs 17%, p=0.023), and RPE deposits (82% vs 30%, p=0.018) as compared to the non-methamphetamine group. Intraocular inflammation was similar between groups (anterior chamber and vitreous cells as defined by the SUN criteria¹⁶) and summarised in Table 3.

Discussion

Given the potential contribution of methamphetamine use to neurologic manifestations of syphilis and the high prevalence of ocular syphilis, we assessed the impact of methamphetamine use on VA and disease characteristics of syphilitic uveitis. The mean age of patients in our cohort was 47.6 years, which is consistent with data reported in population-based studies of ocular syphilis patients reporting a mean age of 41–53 years.^18–21 The male preponderance of 71% also parallels prior reports.²² Intermediate uveitis (29%) and panuveitis (48%) were the most common diagnoses among our patients, while the literature reports posterior uveitis as the most frequent ocular manifestation.²³

There was a high rate of patient-reported methamphetamine use in our cohort, with seven patients (33%) reporting a remote or recent history of methamphetamine use. The two groups revealed similar baseline demographic and historical characteristics overall, aside from a significantly shorter period of symptom duration in the methamphetamine group. However, the baseline VA among methamphetamine users was notably poorer compared to non-users despite a shorter duration before presentation. The median VA from baseline in the methamphetamine use group did not improve significantly at month-3 follow-up, and additional follow-up was unavailable for several individuals at month-6 follow-up for further analyses. In contrast, within the patients with ocular syphilis in the non-methamphetamine use group, a significant improvement in VA was observed at month-3 follow-up, and this improvement was sustained at month-6 follow-up. These findings highlight the potential impact of methamphetamine use on patient outcomes despite antimicrobial therapy. Whether methamphetamine may be associated with underlying social factors or pathobiology related to this effect in ocular syphilis warrants further investigation.

When stratified by level of vision impairment, patients with methamphetamine use presented with moderate or severe visual impairment more frequently. Interestingly, methamphetamine users tended to present earlier than non-users, which could be due to more rapid disease progression or severe ocular manifestation leading to more prompt referral. While the precise reason for this observation is unknown, this significant finding may support an underlying mechanistic contribution of methamphetamine use and disease progression. The paradoxical earlier presentation but worse visual outcomes in the methamphetamine group highlight the potential for additive effects from methamphetamine augmenting the disease burden or severity of syphilis. Interestingly, two prior case series report the association between methamphetamine use and syphilitic uveitis.^24,25 In a study by Thomas et al, four cases of syphilitic uveitis with methamphetamine use were described with symptoms of blurry vision after an average of 3 weeks.²⁴ All four patients presented with bilateral syphilitic uveitis; of these patients, 3 presented with bilateral panuveitis, and 1 presented with bilateral posterior uveitis.²⁴ Notably, four eyes of 3 patients demonstrated significant vision loss (VA < 6/60).²⁴ In another study by Zhang et al, one patient with bilateral syphilitic uveitis in the setting of methamphetamine use had a VA of 6/12 in both eyes.²⁵ However, the patient demonstrated persistent cystoid macular oedema in both eyes despite treatment with penicillin.²⁵ These findings suggest that methamphetamine use can exacerbate the disease severity of syphilitic uveitis leading to significant, and potentially irreversible vision loss.

Notably, we also observed a slightly greater proportion of optic nerve involvement in patients with reported methamphetamine use. Although syphilitic optic nerve involvement has an excellent prognosis if it is detected promptly and treated properly,²⁶ blindness associated with syphilitic optic nerve involvement was reported.¹⁴ In a study by Gu et al, 213 patients with ocular syphilis were included in the study, and 67 eyes of 50 patients met the WHO definition of blindness (VA<6/60).¹⁴ Of 67 eyes, the most common cause of blindness was optic nerve involvement (n=37, 55.2%) (optic atrophy and optic neuritis).¹⁴ Unfortunately, several patients in our study presented with severe visual acuity impairment to the level of legal blindness as well as severe optic disc oedema. Further studies investigating the correlation between methamphetamine use and optic nerve disease are needed to understand this unique relationship.

Based on our analysis, the precise mechanism of exacerbation of ocular syphilis in methamphetamine users may be multifactorial. There is ongoing investigation regarding purported mechanisms that may explain the potential effect of methamphetamine use on these findings. Methamphetamine may trigger pathways such as apoptosis induction and inhibition of antigen-presenting cell function, which results in immunosuppression and increases patient susceptibility to blood-borne pathogens and STIs.²⁷ Methamphetamine may also damage the integrity of the blood-brain barrier, thereby increasing the likelihood of central nervous system involvement during infection.²⁸ Direct damage to the vascular endothelium is compounded by downstream neuroinflammatory signalling, leading to chronic dysfunction of the barrier and intensifying neuronal damage.²⁹ Evidence also suggests that methamphetamine has a neurotoxic effect on the retina, specifically in animal models that have demonstrated loss of retinal neurons associated with methamphetamine administration.^30,31 Investigations into effects of remote methamphetamine use showing residual neurotoxicity even years after cessation suggest that some of the drug-induced degeneration may be permanent.³² In patients, a statistically significant association was observed between chronic methamphetamine use and retinal nerve fibre layer thickness³³ and Bruch’s membrane opening minimum rim width.³⁴ This phenomenon may result from inflammation and a disturbed balance of the antioxidative/oxidative system, which interferes with visual function.³¹ In addition, microvascular damage arising from chronic methamphetamine use leads to progressive neuronal loss.³⁵ While drug-induced neuronal death results in permanent ocular changes, further research is warranted to determine whether the burden or severity of ocular syphilis risk may be worse with chronic methamphetamine use versus a remote history of methamphetamine use.

Our study has several limitations, including the retrospective nature of the study, the small sample size, the limited duration of follow-up in some patients in the methamphetamine use group, the lack of the relative timeframe of methamphetamine use (remote versus recent), the frequency of methamphetamine use, and the possibility of other confounding factors. Recorded data regarding the presence of additional risk factors, such as high-risk sexual behaviours, is also affected by patient willingness to disclose this sensitive information. Other potential confounding factors include social determinants of health such as housing, transportation, health literacy or employment status. Given known behavioural influences, it is probable methamphetamine use contributed to negative social determinants, reinforcing the socio-cultural aspects of this potential syndemic. Despite these limitations, our early observations suggest that within our cohort, methamphetamine use was associated with more severe disease with worse vision on presentation. In addition, we observed limited visual recovery in the methamphetamine group during follow-up when compared to the patients in the non-methamphetamine use group.

One consideration for future investigation includes longer longitudinal follow-up of the current cohort to evaluate long-term trends in visual outcomes. Further analysis of prognostic factors and their influence on VA improvement, including high-risk sexual behaviours and concurrent STI, could be conducted. Multicentre studies could also address the issue of limited sample size and determine whether the trends delineated in our investigation are mirrored in various geographic areas.

Conclusion

In this study, we demonstrated the role of methamphetamine use as a potential detriment to disease outcomes in patients with syphilitic uveitis. Given the potential syndemic represented by concurrence of the ongoing methamphetamine epidemic and resurgence of syphilis, methamphetamine use as a prognostic factor warrants further investigation. Future interventions should aim to address both issues to achieve sustainable positive outcomes for patients.

What was known before:

• The incidence of syphilis has increased in recent years • Ocular syphilis can have anterior segment, posterior segment, or neuro-ophthalmologic manifestations • Early detection and treatment of ocular syphilis improve patient outcomes • Identification of common concurrent health conditions that contribute to ocular syphilis disease progression can help address particularly vulnerable patient populations

What this study adds:

• Methamphetamine use was associated with significantly worse visual acuity at presentation of ocular syphilis (compared to individuals not using methamphetamine) • Individuals with ocular syphilis not using methamphetamine saw significantly improved visual acuity at 3 month and 6 month follow-up visits- an observation not seen among individuals using methamphetamine • These findings support a potential syndemic relationship between ocular syphilis and methamphetamine use

Data Sharing Statement

Data requests can be made to the corresponding author with a supplemental proposal outlining the proposed analysis. If permission is granted, deidentified study participant data in an Excel format will be made available. Data requests will be reviewed pending publication.