Syphilitic Keratitis
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Syphilitic keratitis results from congenital or late acquired syphilis. The incidence of disease has decreased dramatically since the penicillin era, however in recent years rates of the disease have been rising in the US. Therefore, it is important to consider the diagnosis in a patient presenting with bilateral stromal keratitis, especially with other systemic signs or symptoms of syphilis. Prevention of congenital syphilis is best achieved by treating syphilis positive, pregnant patients with penicillin in their second semester or earlier. Treatment for syphilitic keratitis is topical corticosteroids with cyclosporine or tacrolimus used for refractory or recurrent cases, and penetrating keratoplasty for surgical management.
Disease
Syphilitic keratitis is a non-ulcerative interstitial keratitis that typically manifests as a late sequela of congenital or acquired syphilis. Syphilitic keratitis is seen more commonly in patients with congenital syphilis than in those who acquire syphilis later in life. In congenital syphilis, the keratitis is typically bilateral in up to 80% of cases and presents in children or adolescents most often between ages 5 and 15. Involvement of the second eye is typically seen within a few weeks following onset of disease in the first eye, but may also occur simultaneously. Syphilitic keratitis can be the only manifestation of late congenital syphilis, but it can also present as part of the Hutchinson's triad of interstitial keratitis, sensorineural deafness (damage to the eighth cranial nerve), and Hutchinson's teeth (notched incisors).[1] Syphilitic keratitis primarily involves the deep stroma of the cornea, and can present as a stromal haze or focal infiltrate. The inflammation appears most commonly in the superior cornea, and can lead to corneal thickening. Neovascularization of the cornea often occurs after the onset of stromal haze and edema. Neovascularization occurs as extension of both the limbal and anterior ciliary vessels often coinciding with increased lymphatic extension into the peripheral cornea.[1] The combination of neovascularization and lymphatic extension results in the classic salmon-colored patch seen in the disease.
Syphilitic keratitis is uncommon in patients with acquired syphilis. When it does occur in acquired syphilis, presentation is typically a unilateral keratitis in 60% of cases, and most commonly in the late latent phase of infection.[2] Syphilitic keratitis has similar a clinical appearance in acquired syphilis as in congenital syphilis with a few noted exceptions. Besides the unilateral preference, the keratitis from acquired syphilis is usually more localized, and is characterized by less corneal neovascularization. When bilateral involvement occurs in keratitis from acquired syphilis, the second eye typically has less severe involvement.[1]
Etiology
Prior to the era of penicillin, syphilitic keratitis was estimated to have a prevalence of >1 million individuals worldwide, placing 1 in every 1,000 newborns at risk of acquiring the disease, and overall disease prevalence has decreased exponentially since the development of penicillin.[1] Prevention is focused on decreasing the incidence of congenital syphilis, as pregnant women conventionally undergo screening and treatment during the first prenatal visit, second trimester of pregnancy (28 weeks' gestation), and at delivery, particularly in higher risk women.[1][3] This has shown to be effective with syphilitic keratitis incidence in the United States decreasing 22% per year between 1990 and 1999.[2] However, rates of congenital syphilis remain high and have been rising in recent years in the US. The Center of Disease Control reports that in the US from 2015 to 2019 the rate of congenital syphilis increased 291.1% (12.4 to 48.5 per 100,000 live births). This mirrors increases in the rate of acquired syphilis among reproductively-aged females in the US (15–44 years), a 171.9% increase, from 3.2 to 8.7 per 100,000 females.[3] Congenital syphilis remains a public health challenge to improve and expand prenatal care to further decrease rates and sequelae of the disease including keratitis.
Pathophysiology
The pathophysiology of syphilitic keratitis is incompletely understood. While laboratory studies have shown that Treponema pallidum can attach to keratocytes and can also enter the eye via hematogenous spread, the inability to find these spirochetes in eyes with syphilitic keratitis has led to other theories on the mechanism of disease.[1] The prevailing theories focus on an auto-inflammatory response to T. pallidum as the mechanism of disease in syphilitic keratitis.[1] This is supported by the lack of treatment response of the disease to antibiotics alone and the response to treatment by immunosuppressive agents like corticosteroids and cyclosporine. The findings of mononuclear cells and angiogenesis in the disease also point to an immune-mediated response. The prevailing theory is that the immune-mediated process is triggered by a response to hidden antigens and molecular mimicry of self-antigens leading to syphilitic keratitis.[1]
Prevention
Prevention of congenital syphilis is best achieved by treating syphilis positive, pregnant patients with penicillin in the second trimester or earlier of pregnancy.
Physical Examination
Clinical exam findings include corneal opacification, chronic corneal edema, astigmatism, amyloid degeneration, and calcific band keratopathy.[1] On exam, syphilitic keratitis can be classified as active or inactive with active disease showing stromal inflammation without ulceration. This typically coincides with an anterior uveitis. Inactive syphilitic keratitis presents with stromal scarring and thinning as well as ghost vessels and deposition of collagenous material on the Descemet membrane.[4] Complications of syphilitic keratitis include glaucoma, cataracts, and choroidal atrophy.[1][5] Hemorrhagic Descemet membrane detachment as a result of syphilitic keratitis has also been reported.[6] Classically, ghost vessels are also seen on exam which appear as phantom vessels that weave through the stroma. While these ghost vessels are most often phantom vessels, some of the ghost vessels are patent and can carry red blood cells.[7]
Diagnostic procedures and Laboratory test
Diagnostic testing of syphilis is a combination of clinical exam and laboratory findings. Laboratory testing centers on treponemal and nontreponemal serologic tests. Classically algorithms have suggested starting with a nontreponemal test and following it with a treponemal test if the former is positive. However, because nontreponemal serologic titers decrease over time, it has been suggested that for latent syphilis and syphilitic keratitis the testing should start with a treponemal test.[1]
Management
The preferred treatment of all stages of syphilis is penicillin. However, antibiotics alone have shown to be ineffective at treating syphilitic keratitis.[7] First-line treatment of syphilitic keratitis is topical corticosteroids. Topical corticosteroids shorten the duration of the keratitis and lead to improved vision in the large majority of cases. For patients who fail topical corticosteroid treatment, evidence shows immunosuppression therapy with cyclosporine or tacrolimus is an effective alternative treatment.[8] Treatment is important in the active stage of the disease to limit the neovascularization and lymphatic extension by inhibiting the inflammatory response. After appropriate treatment, recurrence can occur in 5-15% of patients.[1] Antibiotics should be used in patients with syphilic keratitis if there is laboratory evidence of active infection or a history of no treatment or an incomplete treatment course. It has been argued that any ocular manifestations of syphilis should be treated with a neurosyphilis regimen of penicillin therapy (10-14 days of penicillin G) to prevent further systemic or ocular complications including optic neuritis and Argyll Robertson pupils.[1][9]
Orsoni, et al. argues for immunosuppression therapy (oral cyclosporine) over topical corticosteroids for recurrent syphilitic keratitis due to the risk of cataracts and glaucoma with chronic corticosteroid use. Additionally, the efficacy of immunosuppressive agents is superior in recurrent syphilitic keratitis at preventing relapses.[8] Finally, protocols for immunosuppression and their safety profile have already been developed and studied for multiple other conditions including uveitis.[8] Surgical treatment for severe syphilitic keratitis presenting with corneal opacity is penetrating keratoplasty.[1][10] The outcomes of penetrating keratoplasty have shown that at 10-year follow-up the graft survival rate is just under 80%. Penetrating keratoplasty results in increased visual acuity in most patients, however, 20/20 vision is not always achieved.[10]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 Wilhelmus KR. Syphilitic stromal keratitis. In: Mannis MJ, Holland EJ, ed. Cornea. United States: Elsevier Inc; 2017: 996-1012. Print.
- ↑ 2.0 2.1 Aldave AJ, King JA, Cunningham ET. Ocular syphilis. Curr Opin Ophthalmol. 2001;12:433–441.
- ↑ 3.0 3.1 Centers for Disease Control and Prevention. (2021, July 22). Congenital syphilis. https://www.cdc.gov/std/treatment-guidelines/congenital-syphilis.htm
- ↑ Schwartz GS, Harrison AR, Holland EJ. Etiology of immune stromal (interstitial) keratitis. Cornea 1998;17:278–81.
- ↑ Bodh SA, et al. Inflammatory glaucoma. Oman J Ophthalmol. 2011 Jan-Apr; 4(1): 3–9. doi: 10.4103/0974-620X.77655.
- ↑ Höllhumer R, Zairani Mz A, Watson S. Hemorrhagic Descemet Membrane Detachment Following Syphilitic Interstitial Keratitis. Cornea. 2016 Sep;35(9):1255-6.
- ↑ 7.0 7.1 Lee ME, Lindquist TD. Syphilitic Interstitial Keratitis. JAMA. 1989; 262(20):2921. doi:10.1001/jama.1989.03430200169047.
- ↑ 8.0 8.1 8.2 Orsoni JG, Zavota L, Manzotti F, Gonzales S. Syphilitic interstitial keratitis: treatment with immunosuppressive drug combination therapy. Cornea. 2004 Jul;23(5):530-2.
- ↑ Gaudio PA. Update on ocular syphilis. Curr Opin Ophthalmol, 2006;17(6), 562-566.
- ↑ 10.0 10.1 Goegebuer A, Ajay L, Claerhout I, et al. Results of penetrating keratoplasty in syphilitic interstitial keratitis. Bull Soc Belge Ophtalmol 2003; 290:35–9.
