Ocular Immunology & Inflammation, 2014; 22(6): 439–443 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2014.949780
ORIGINAL ARTICLE
Spectral-domain Optical Coherence Tomography Findings after Severe Exogenous Endophthalmitis
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 02/11/15 For personal use only.
Martin Sebastian Zinkernagel, MD, PhD, Chantal Dysli, MD, Sebastian Wolf, and Andreas Ebneter, MD, PhD
MD, PhD,
Department of Ophthalmology, University of Bern, Bern, Switzerland
ABSTRACT Purpose: To report outcomes and assess structural changes in the retina in patients with severe endophthalmitis. Methods: Retrospective, nonrandomized, interventional case series at a tertiary referral centre. Spectral domain optical coherence tomography (OCT) images of both eyes were acquired at least 5 months after pars plana vitrectomy. OCT images were analyzed using retinal layer segmentation. Results: Nine patients (46–80 years of age) were included in this study. Average ETDRS visual acuity before treatment was 23 letters and improved to 74 letters. In our cohort we did not find a generalized reduction of retinal layers using automated layer segmentation. Conclusion: Our findings suggest that prompt treatment of severe endophthalmitis with intravitreal antibiotics followed by pars plana vitrectomy may lead to excellent visual outcomes with minimal damage to the retinal architecture. Keywords: Endophthalmitis, OCT, retina, segmentation
Acute postoperative endophthalmitis following cataract surgery is a devastating condition, despite major advances in medical and surgical treatment in the last decades. With modern cataract surgery the incidence of postoperative endophthalmitis ranges from 0.05 to 0.5%.1–3 Rapid treatment to obtain sufficiently high antimicrobial levels in the vitreous is decisive as prolonged intraocular infection and inflammation may lead to irreversible structural and functional damage of the retina. Although the endophthalmitis vitrectomy study (EVS)4 has clearly shown the benefit of pars plana vitrectomy in conjunction with intravitreal antibiotics in eyes with visual acuity of less than hand movements, the treatment regimens in regards to treatment on arrival, the timing of vitreous tapping for microbiology, and the choice of antibiotics vary widely. Furthermore, the indication for vitrectomy derived from the EVS in regards to visual acuity has been a matter of controversy with reports arguing for
a more aggressive management employing pars plana vitrectomy.5,6 At our institution the standard operating procedure for postoperative endophthalmitis is immediate anterior chamber tap with intravitreal injection of vancomycin (1 mg/0.1 mL) and amikacin (400 mg/0.1 mL) followed by same-day pars plana vitrectomy and a second injection of vancomycin (1 mg/0.1 mL) and dexamethasone (4 mg/0.1 mL) in painful eyes with anterior chamber (AC) cell and flare reaction, hypopyon, or vitreous opacification. This has the advantage of providing a rapid therapeutic intravitreal antimicrobiotic level even if surgery has to be delayed for some hours and allows for intravitreal injection of a steroid under previously applied antibiotic cover. Whereas vancomycin (1 mg/0.1 mL) is considered the drug of choice for gram-positive organisms, there is some degree of controversy regarding the choice against gram-negative bacteria. This is mainly because
Received 6 June 2014; revised 10 July 2014; accepted 25 July 2014; published online 27 August 2014 Correspondence: Martin Zinkernagel, Dept. Ophthalmology, Inselspital, Bern University Hospital, Universita¨t Bern, CH-3010 Bern, Switzerland.Email: [email protected]
439
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 02/11/15 For personal use only.
440 M. S. Zinkernagel et al. some aminoglycosides have shown macular toxicity. This has been shown for gentamycin, but concerns have been voiced with amikacin as well.7,8 However, in the context of intraocular infection it is often difficult to differentiate between structural damage caused by infection, collateral damage caused by the immune system, and structural changes caused by toxicity. Little is known about long-term structural changes in the retina after severe acute endophthalmitis and treatment with intravitreal antibiotics followed by pars plana vitrectomy. We sought to address this question with the use of noninvasive, cross-sectional analysis of the retina with a spectraldomain optical tomography coherence tomogram (SD-OCT) to investigate possible long-term structural changes after endophthalmitis with intravitreal injection of vancomycin (1 mg/0.1 mL) and amikacin (0.4 mg/0.1 mL) followed by pars plana vitrectomy and a second injection of vancomycin (1 mg/0.1 mL) and dexamethasone (4 mg/0.1 mL) using fully automated segmentation algorithms.9
MATERIAL AND METHODS All records from the surgical database, including intravitreal injections, between 2007 and 2012 of the Department of Ophthalmology at the University Hospital Bern were screened and patients requiring pars plana vitrectomy for endophthalmitis were identified (Figure 1). All patients diagnosed with severe postoperative endophthalmitis were treated with immediate intravitreal antibiotics on arrival in an
outpatient setting according to standard operating procedures of the Department of Ophthalmology of the University Hospital Bern, Switzerland. This entailed immediate anterior chamber tap followed by intravitreal injection with 1.0 mg of vancomycin and 400 mg of amikacin, followed within 12 h of arrival in eyes with anterior chamber (AC) cell and flare reaction (3+ to 4+ corresponding to 26–50 and 450 cells in a 1-mm2 slit beam), hypopyon, or vitreous opacification, by pars plana vitrectomy in conjunction with vitreous tap and a second intravitreal injection of vancomycin 1.0 mg and dexamethasone 4 mg. Visual acuity was measured with the use of Snellen charts at baseline and at least 5 months later when obtaining the OCT. The Snellen values were converted into ETDRS visual acuity. Only patients having had an OCT at least 3 months after vitrectomy were included in this study. All scans were acquired using a Heidelberg spectralis OCT with acquisition software (version 5.4.6.0). Infrared images used averaged data of 9 images that were acquired with a scan angle 30 . OCT image stacks were acquired with a scan angle of 20 usually with 49 B-scans resulting in a field size of 20 20 (5.8 5.8 mm) with a distance between B-scans of 121 mm. For the analysis of retinal layers, we used custom-built segmentation software9 (ARTORG Center for Biomedical Engineering Research, University of Bern, Bern, Switzerland). The local thickness was determined for each B-scan of the volume scan. The automatic segmentation was verified by an experienced retinologist. All statistical analyses were performed using GraphPad InStat version 6.05 for Windows (GraphPad Software, San Diego, CA). A p value of5.05 was considered to be statistically significant.
RESULTS
FIGURE 1. Study flow chart.
Fifty-five patients were identified as requiring pars plana vitrectomy for exogenous endophthalmitis. Out of these patients 24 were excluded due to concomitant maculopathy (including intravitreal injections), glaucoma, or diseases potentially affecting the optic nerve, such as trauma due to confounding factors using automated segmentation. Furthermore, patients with endophthalmitis due to corneal procedures were excluded because of alterations of the visual axis, potentially interfering with optical coherence tomography and visual acuity outcomes. Of the 21 remaining patients, who all had postcataract endophthalmitis, we identified 9 with an OCT at least 5 months after treatment for endophthalmitis (Figure 1). All patients were pseudophakic and their demographic data are summarized in Table 1. BCVA improved in all patients when compared to baseline (Table 1). Funduscopy in some patients showed Ocular Immunology & Inflammation
SD-OCT Findings after Exogenous Endophthalmitis
441
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 02/11/15 For personal use only.
TABLE 1. Patient characteristics and ETDRS final visual acuity. Patient age
Gender
BCVA at discharge
final BCVA
Microorganism
72 72 80 73 75 70 71 74 46
Female Male Female Male Female Male Female Female Female
0 3 5 5 25 34 35 50 51
70 65 70 35 85 85 85 85 85
coag-neg Staph coag-neg Staph S. aureus Nil Nil Nil Nil NA Nil
Best corrected visual acuity (BCVA) at the final visit had improved in all eyes compared to postoperative vision at discharge. Causative microorganisms were identified in 3 of 8 eyes, whereas no growth was found in cultures of 5 samples. In one patient no sample was available for laboratory testing.
marked pigmentary changes at the posterior pole (Figure 2).
Anatomical Characteristics In some patients OCT showed marked atrophy of the outer retinal layers even with development of rosettes or focal outer layer defects (Figure 3). In 2 patients intraretinal cysts were found. Furthermore, focal RNFL defects were seen (Table 2). As the RNFL lies at the forefront of potential damage to the retina due to infection or inflammation, we sought to systematically analyze the RNFL using the Spectralis OCT RNFL protocol. However, analysis of RNFL data did not show any statistically significant difference of the RNFL layers in eyes having had endophthalmitis compared with the contralateral healthy eye. More subtle changes, such as fuzziness of the Henle’s layer or thickening of the vitreous–retinal interface, were sometimes associated with thinning of the inner retinal layers.
Layer Analysis The segmentation algorithm determined the border between (a) the internal limiting membrane, (b) nerve fiber/ganglion cell layer junction, (c) IPL/INL junction, (d) outer nuclear layer (ONL)/Henle’s fiber junction, (e) ellipsoid zone, and (f) pigment epithelium/Bruch’s complex (Figure 4). A thickness value for each layer and each sector of a superimposed grid, which was initially defined in the Early Treatment Diabetic Retinopathy Study, was exported. The primary analysis compared the average retinal layer thickness of the affected eye with the contralateral eye using a paired t test. Furthermore, the retinal nerve fiber layer thickness was compared using data from the image acquisitions with the RNFL protocol of the !
2014 Informa Healthcare USA, Inc.
FIGURE 2. Final fundus appearance in representative cases. In the first case with full visual acuity the final fundus color image of the affected left eye appears normal (A). Minor structural changes, such as hyporeflective outer retinal bands, intraretinal cysts, irregularity of the Henle’s layer, not necessary, and a discrete epiretinal membrane in the peripapillary area, are discernible on spectral domain optical coherence tomography. In the second case (B) widespread perifoveal pigmentary changes are visible, while the unaffected eye shows only minor signs of dry age-related macular degeneration. Accordingly, the spectral domain optical coherence tomography shows clumping of the retinal pigment epithelium in the affected regions. The outer layers of the fovea are well preserved. However, some cysts and structural irregularities are present centrally. TABLE 2. Quantification of structural alterations found with optical coherence tomography in eyes after infectious postcataract surgery endophthalmitis. Structural alteration Henle’s layer fuzziness ILM thickening with GCC thinning Focal outer layer defect Nerve fiber layer defect Intraretinal cysts Henle’s layer cleft Rosette formation
Occurrence
%
7 7 3 2 2 1 1
78 78 33 22 22 11 11
ILM, internal limiting membrane; GCC, ganglion cell complex (retinal nerve fiber layer + ganglion cell layer + inner plexiform layer).
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 02/11/15 For personal use only.
442 M. S. Zinkernagel et al.
FIGURE 3. Spectral domain optical coherence tomography changes. The range of structural alterations was widely variable, and both outer retina as well as inner retina disturbances were found. In some eyes the retina structure appeared almost normal like in image (A), where only some fuzziness of the Henle’s layer was seen in parts of the retina. Microphotograph (B) shows some focal parafoveal ILM thickening with thinning of the inner plexiform and ganglion cell layers. In image (C) a cleft in the Henle’s layer is displayed. Some focal ganglion cell layer defect is highlighted (arrow) in picture (D), which also shows some more widespread irregularities. In another eye (E) a focal outer layer defect (arrow) with an intact external limiting membrane was found. Much more significant alterations of the retinal pigment epithelium photoreceptor complex are shown in photograph (F) from the eye shown in Figure 2(B). In an area with missing retinal pigment epithelium a rosette formation (arrow) is present.
DISCUSSION
FIGURE 4. Layer thickness measurements of the central retina and the inner retinal ring according to the standard ETDRS grid. The definition of the layers is shown on a representative image after automated segmentation by the software (A). No significant differences were found between the affected and the contralateral control eyes for the center (B) and the inner retinal ring (C) as per standard ETDRS grid. ILM, internal limiting membrane; NFL, nerve fiber layer; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; HFL, Henle’s layer; ONC, outer nuclear complex (OPL + HFL); IS, inner photoreceptor segments; OS, outer photoreceptor segments; EZ, ellipsoid zone; RPE, retinal pigment epithelium.
Endophthalmitis is a devastating condition and can be one of the most challenging indications for the vitreoretinal surgeon. Although it is well known that intraocular infection may lead to permanent retinal damage, a systematic analysis of retinal architecture after endophthalmitis has, to our knowledge, not been reported in the literature. Several factors can contribute to structural damage of the retina during or after endophthalmitis. Postoperative endophthalmitis caused by species of streptococci, Staphylococcus aureus, enterococci, Bacillus, or gram-negative bacteria can cause a more explosive and fulminant endophthalmitis, whereas Propionibacterium acnes and coagulase-negative staphylococci usually display a more benign course.10,11 In animal models it has been shown that supernatants from B. cereus and S. aureus can cause retinal damage due to release of
inflammatory stimuli.12 In an experimental rabbit model intravitreal application of Bacillus cereus led to a disruption of retinal architecture and photo receptor layer folding as early as 12 h postinfection, mainly attributed to hemolysin BL. Other reports showed that Staphylococcus aureus secretes cytolytic toxins and stimulates release of proinflammatory cytokines, such as interleukin-8.13,14 As such, bacterial endophthalmitis may not only lead to retinal tissue damage due to endotoxins produced by bacteria but also through bystander damage caused by leukocyte infiltration into the vitreous and retina.15 Although we found no systematic changes within the retinal layers in our cases after endophthalmitis, there were focal areas of retinal damage in SD-OCT. In the first instance we found foci of damage in the
classic glaucoma application using spectral domain OCT. Layer analysis revealed that the RNFL and the ganglion cell layer were not significantly thinner in eyes having had endophthalmitis compared to healthy control eyes. No difference of INL, ONL thickness was found between eyes with endophthalmitis and healthy eyes (Figure 4).
Ocular Immunology & Inflammation
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 02/11/15 For personal use only.
SD-OCT Findings after Exogenous Endophthalmitis inner retinal layers in the area of the inner nuclear layer and dent-like changes in the retinal nerve fiber layer (Figure 3). In addition, we found areas of atrophy in the outer retinal layers with formation of microholes and formation of tubules probably corresponding to focal areas of necrosis. The absence of generalized structural retinal changes and the excellent visual outcomes support our clinical protocol of immediate intravitreal treatment with antibiotics by pars plana vitrectomy. The first allows for adding intravitreal steroids, while the latter may clear the vitreous of the potentially toxic aminoglycoside. Another finding that merits further discussion is the incidence of postoperative endophthalmitis cases. As our department is a tertiary referral center, the majority of patients with postoperative endophthalmitis were referred from primary caretakers. There are limitations of this study. The number of the patients was small, such as mainly due to stringent exclusion criteria due to macular or glaucomatous disease, both frequently encountered in the age group undergoing ophthalmic surgery. Furthermore, less than half of the patients had positive microbiology results. However, this is in keeping with other studies.16 The excellent clinical outcomes reported here may possibly be attributed to little virulence or the absence of gram-negative bacterial strains in our cohort. Therefore, we cannot correlate our findings with other bacterial strains. Furthermore, with the small number of patients no general conclusion can be made on amikacin toxicity affecting the RNFL. Endophthalmitis remains an infrequent but sightthreatening complication of intraocular surgery. In our case series immediate treatment with intravitreal antibiotics in eyes presenting with endophthalmitis followed by same-day pars plana vitrectomy and intravitreal injection of steroids resulted in excellent visual outcome with minimal structural changes seen on SD-OCT.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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2014 Informa Healthcare USA, Inc.
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REFERENCES 1. Keay L, Gower EW, Cassard SD, et al. Postcataract surgery endophthalmitis in the United States: analysis of the complete 2003 to 2004 Medicare database of cataract surgeries. Ophthalmology. 2012;119:914–922. 2. Taban M, Behrens A, Newcomb RL, et al. Acute endophthalmitis following cataract surgery: a systematic review of the literature. Arch Ophthalmol. 2005;123:613–620. 3. Garcia-Arumi J, Fonollosa A, Sararols L, et al. Topical anesthesia: possible risk factor for endophthalmitis after cataract extraction. J Cataract Refract Surg. 2007;33: 989–992. 4. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol. 1995;113:1479–1496. 5. Sternberg Jr P, Martin DF. Management of endophthalmitis in the post-endophthalmitis vitrectomy study era. Arch Ophthalmol. 2001;119:754–755. 6. Kuhn F, Gini G. Vitrectomy for endophthalmitis. Ophthalmology. 2006;113:714. 7. Campochiaro PA, Lim JI. Aminoglycoside toxicity in the treatment of endophthalmitis. The Aminoglycoside Toxicity Study Group. Arch Ophthalmol. 1994;112:48–53. 8. Conway BP, Tabatabay CA, Campochiaro PA, et al. Gentamicin toxicity in the primate retina. Arch Ophthalmol. 1989;107:107–112. 9. Dufour PA, Ceklic L, Abdillahi H, et al. Graph-based multi-surface segmentation of OCT data using trained hard and soft constraints. IEEE Trans Med Imaging. 2013;32: 531–543. 10. Josephberg RG. Endophthalmitis: the latest in current management. Retina. 2006;26:S47–S50. 11. Al-Rashaed SA, Abu El-Asrar AM. Exogenous endophthalmitis in pediatric age group. Ocul Immunol Inflamm. 2006; 14:285–292. 12. Callegan MC, Jett BD, Hancock LE, Gilmore MS. Role of hemolysin BL in the pathogenesis of extraintestinal Bacillus cereus infection assessed in an endophthalmitis model. Infect Immun. 1999;67:3357–3366. 13. Otto M. Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Annu Rev Microbiol. 2010;64:143–162. 14. Hume E, Sack R, Stapleton F, Willcox M. Induction of cytokines from polymorphonuclear leukocytes and epithelial cells by ocular isolates of Serratia marcescens. Ocul Immunol Inflamm. 2004;12:287–295. 15. Kalogeropoulos CD, Malamou-Mitsi VD, Asproudis I, Psilas K. The contribution of aqueous humor cytology in the differential diagnosis of anterior uvea inflammations. Ocul Immunol Inflamm. 2004;12:215–225. 16. Bhoomibunchoo C, Ratanapakorn T, Sinawat S, et al. Infectious endophthalmitis: review of 420 cases. Clin Ophthalmol. 2013;7:247–252.
ORIGINAL ARTICLE
Spectral-domain Optical Coherence Tomography Findings after Severe Exogenous Endophthalmitis
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 02/11/15 For personal use only.
Martin Sebastian Zinkernagel, MD, PhD, Chantal Dysli, MD, Sebastian Wolf, and Andreas Ebneter, MD, PhD
MD, PhD,
Department of Ophthalmology, University of Bern, Bern, Switzerland
ABSTRACT Purpose: To report outcomes and assess structural changes in the retina in patients with severe endophthalmitis. Methods: Retrospective, nonrandomized, interventional case series at a tertiary referral centre. Spectral domain optical coherence tomography (OCT) images of both eyes were acquired at least 5 months after pars plana vitrectomy. OCT images were analyzed using retinal layer segmentation. Results: Nine patients (46–80 years of age) were included in this study. Average ETDRS visual acuity before treatment was 23 letters and improved to 74 letters. In our cohort we did not find a generalized reduction of retinal layers using automated layer segmentation. Conclusion: Our findings suggest that prompt treatment of severe endophthalmitis with intravitreal antibiotics followed by pars plana vitrectomy may lead to excellent visual outcomes with minimal damage to the retinal architecture. Keywords: Endophthalmitis, OCT, retina, segmentation
Acute postoperative endophthalmitis following cataract surgery is a devastating condition, despite major advances in medical and surgical treatment in the last decades. With modern cataract surgery the incidence of postoperative endophthalmitis ranges from 0.05 to 0.5%.1–3 Rapid treatment to obtain sufficiently high antimicrobial levels in the vitreous is decisive as prolonged intraocular infection and inflammation may lead to irreversible structural and functional damage of the retina. Although the endophthalmitis vitrectomy study (EVS)4 has clearly shown the benefit of pars plana vitrectomy in conjunction with intravitreal antibiotics in eyes with visual acuity of less than hand movements, the treatment regimens in regards to treatment on arrival, the timing of vitreous tapping for microbiology, and the choice of antibiotics vary widely. Furthermore, the indication for vitrectomy derived from the EVS in regards to visual acuity has been a matter of controversy with reports arguing for
a more aggressive management employing pars plana vitrectomy.5,6 At our institution the standard operating procedure for postoperative endophthalmitis is immediate anterior chamber tap with intravitreal injection of vancomycin (1 mg/0.1 mL) and amikacin (400 mg/0.1 mL) followed by same-day pars plana vitrectomy and a second injection of vancomycin (1 mg/0.1 mL) and dexamethasone (4 mg/0.1 mL) in painful eyes with anterior chamber (AC) cell and flare reaction, hypopyon, or vitreous opacification. This has the advantage of providing a rapid therapeutic intravitreal antimicrobiotic level even if surgery has to be delayed for some hours and allows for intravitreal injection of a steroid under previously applied antibiotic cover. Whereas vancomycin (1 mg/0.1 mL) is considered the drug of choice for gram-positive organisms, there is some degree of controversy regarding the choice against gram-negative bacteria. This is mainly because
Received 6 June 2014; revised 10 July 2014; accepted 25 July 2014; published online 27 August 2014 Correspondence: Martin Zinkernagel, Dept. Ophthalmology, Inselspital, Bern University Hospital, Universita¨t Bern, CH-3010 Bern, Switzerland.Email: [email protected]
439
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 02/11/15 For personal use only.
440 M. S. Zinkernagel et al. some aminoglycosides have shown macular toxicity. This has been shown for gentamycin, but concerns have been voiced with amikacin as well.7,8 However, in the context of intraocular infection it is often difficult to differentiate between structural damage caused by infection, collateral damage caused by the immune system, and structural changes caused by toxicity. Little is known about long-term structural changes in the retina after severe acute endophthalmitis and treatment with intravitreal antibiotics followed by pars plana vitrectomy. We sought to address this question with the use of noninvasive, cross-sectional analysis of the retina with a spectraldomain optical tomography coherence tomogram (SD-OCT) to investigate possible long-term structural changes after endophthalmitis with intravitreal injection of vancomycin (1 mg/0.1 mL) and amikacin (0.4 mg/0.1 mL) followed by pars plana vitrectomy and a second injection of vancomycin (1 mg/0.1 mL) and dexamethasone (4 mg/0.1 mL) using fully automated segmentation algorithms.9
MATERIAL AND METHODS All records from the surgical database, including intravitreal injections, between 2007 and 2012 of the Department of Ophthalmology at the University Hospital Bern were screened and patients requiring pars plana vitrectomy for endophthalmitis were identified (Figure 1). All patients diagnosed with severe postoperative endophthalmitis were treated with immediate intravitreal antibiotics on arrival in an
outpatient setting according to standard operating procedures of the Department of Ophthalmology of the University Hospital Bern, Switzerland. This entailed immediate anterior chamber tap followed by intravitreal injection with 1.0 mg of vancomycin and 400 mg of amikacin, followed within 12 h of arrival in eyes with anterior chamber (AC) cell and flare reaction (3+ to 4+ corresponding to 26–50 and 450 cells in a 1-mm2 slit beam), hypopyon, or vitreous opacification, by pars plana vitrectomy in conjunction with vitreous tap and a second intravitreal injection of vancomycin 1.0 mg and dexamethasone 4 mg. Visual acuity was measured with the use of Snellen charts at baseline and at least 5 months later when obtaining the OCT. The Snellen values were converted into ETDRS visual acuity. Only patients having had an OCT at least 3 months after vitrectomy were included in this study. All scans were acquired using a Heidelberg spectralis OCT with acquisition software (version 5.4.6.0). Infrared images used averaged data of 9 images that were acquired with a scan angle 30 . OCT image stacks were acquired with a scan angle of 20 usually with 49 B-scans resulting in a field size of 20 20 (5.8 5.8 mm) with a distance between B-scans of 121 mm. For the analysis of retinal layers, we used custom-built segmentation software9 (ARTORG Center for Biomedical Engineering Research, University of Bern, Bern, Switzerland). The local thickness was determined for each B-scan of the volume scan. The automatic segmentation was verified by an experienced retinologist. All statistical analyses were performed using GraphPad InStat version 6.05 for Windows (GraphPad Software, San Diego, CA). A p value of5.05 was considered to be statistically significant.
RESULTS
FIGURE 1. Study flow chart.
Fifty-five patients were identified as requiring pars plana vitrectomy for exogenous endophthalmitis. Out of these patients 24 were excluded due to concomitant maculopathy (including intravitreal injections), glaucoma, or diseases potentially affecting the optic nerve, such as trauma due to confounding factors using automated segmentation. Furthermore, patients with endophthalmitis due to corneal procedures were excluded because of alterations of the visual axis, potentially interfering with optical coherence tomography and visual acuity outcomes. Of the 21 remaining patients, who all had postcataract endophthalmitis, we identified 9 with an OCT at least 5 months after treatment for endophthalmitis (Figure 1). All patients were pseudophakic and their demographic data are summarized in Table 1. BCVA improved in all patients when compared to baseline (Table 1). Funduscopy in some patients showed Ocular Immunology & Inflammation
SD-OCT Findings after Exogenous Endophthalmitis
441
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 02/11/15 For personal use only.
TABLE 1. Patient characteristics and ETDRS final visual acuity. Patient age
Gender
BCVA at discharge
final BCVA
Microorganism
72 72 80 73 75 70 71 74 46
Female Male Female Male Female Male Female Female Female
0 3 5 5 25 34 35 50 51
70 65 70 35 85 85 85 85 85
coag-neg Staph coag-neg Staph S. aureus Nil Nil Nil Nil NA Nil
Best corrected visual acuity (BCVA) at the final visit had improved in all eyes compared to postoperative vision at discharge. Causative microorganisms were identified in 3 of 8 eyes, whereas no growth was found in cultures of 5 samples. In one patient no sample was available for laboratory testing.
marked pigmentary changes at the posterior pole (Figure 2).
Anatomical Characteristics In some patients OCT showed marked atrophy of the outer retinal layers even with development of rosettes or focal outer layer defects (Figure 3). In 2 patients intraretinal cysts were found. Furthermore, focal RNFL defects were seen (Table 2). As the RNFL lies at the forefront of potential damage to the retina due to infection or inflammation, we sought to systematically analyze the RNFL using the Spectralis OCT RNFL protocol. However, analysis of RNFL data did not show any statistically significant difference of the RNFL layers in eyes having had endophthalmitis compared with the contralateral healthy eye. More subtle changes, such as fuzziness of the Henle’s layer or thickening of the vitreous–retinal interface, were sometimes associated with thinning of the inner retinal layers.
Layer Analysis The segmentation algorithm determined the border between (a) the internal limiting membrane, (b) nerve fiber/ganglion cell layer junction, (c) IPL/INL junction, (d) outer nuclear layer (ONL)/Henle’s fiber junction, (e) ellipsoid zone, and (f) pigment epithelium/Bruch’s complex (Figure 4). A thickness value for each layer and each sector of a superimposed grid, which was initially defined in the Early Treatment Diabetic Retinopathy Study, was exported. The primary analysis compared the average retinal layer thickness of the affected eye with the contralateral eye using a paired t test. Furthermore, the retinal nerve fiber layer thickness was compared using data from the image acquisitions with the RNFL protocol of the !
2014 Informa Healthcare USA, Inc.
FIGURE 2. Final fundus appearance in representative cases. In the first case with full visual acuity the final fundus color image of the affected left eye appears normal (A). Minor structural changes, such as hyporeflective outer retinal bands, intraretinal cysts, irregularity of the Henle’s layer, not necessary, and a discrete epiretinal membrane in the peripapillary area, are discernible on spectral domain optical coherence tomography. In the second case (B) widespread perifoveal pigmentary changes are visible, while the unaffected eye shows only minor signs of dry age-related macular degeneration. Accordingly, the spectral domain optical coherence tomography shows clumping of the retinal pigment epithelium in the affected regions. The outer layers of the fovea are well preserved. However, some cysts and structural irregularities are present centrally. TABLE 2. Quantification of structural alterations found with optical coherence tomography in eyes after infectious postcataract surgery endophthalmitis. Structural alteration Henle’s layer fuzziness ILM thickening with GCC thinning Focal outer layer defect Nerve fiber layer defect Intraretinal cysts Henle’s layer cleft Rosette formation
Occurrence
%
7 7 3 2 2 1 1
78 78 33 22 22 11 11
ILM, internal limiting membrane; GCC, ganglion cell complex (retinal nerve fiber layer + ganglion cell layer + inner plexiform layer).
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 02/11/15 For personal use only.
442 M. S. Zinkernagel et al.
FIGURE 3. Spectral domain optical coherence tomography changes. The range of structural alterations was widely variable, and both outer retina as well as inner retina disturbances were found. In some eyes the retina structure appeared almost normal like in image (A), where only some fuzziness of the Henle’s layer was seen in parts of the retina. Microphotograph (B) shows some focal parafoveal ILM thickening with thinning of the inner plexiform and ganglion cell layers. In image (C) a cleft in the Henle’s layer is displayed. Some focal ganglion cell layer defect is highlighted (arrow) in picture (D), which also shows some more widespread irregularities. In another eye (E) a focal outer layer defect (arrow) with an intact external limiting membrane was found. Much more significant alterations of the retinal pigment epithelium photoreceptor complex are shown in photograph (F) from the eye shown in Figure 2(B). In an area with missing retinal pigment epithelium a rosette formation (arrow) is present.
DISCUSSION
FIGURE 4. Layer thickness measurements of the central retina and the inner retinal ring according to the standard ETDRS grid. The definition of the layers is shown on a representative image after automated segmentation by the software (A). No significant differences were found between the affected and the contralateral control eyes for the center (B) and the inner retinal ring (C) as per standard ETDRS grid. ILM, internal limiting membrane; NFL, nerve fiber layer; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; HFL, Henle’s layer; ONC, outer nuclear complex (OPL + HFL); IS, inner photoreceptor segments; OS, outer photoreceptor segments; EZ, ellipsoid zone; RPE, retinal pigment epithelium.
Endophthalmitis is a devastating condition and can be one of the most challenging indications for the vitreoretinal surgeon. Although it is well known that intraocular infection may lead to permanent retinal damage, a systematic analysis of retinal architecture after endophthalmitis has, to our knowledge, not been reported in the literature. Several factors can contribute to structural damage of the retina during or after endophthalmitis. Postoperative endophthalmitis caused by species of streptococci, Staphylococcus aureus, enterococci, Bacillus, or gram-negative bacteria can cause a more explosive and fulminant endophthalmitis, whereas Propionibacterium acnes and coagulase-negative staphylococci usually display a more benign course.10,11 In animal models it has been shown that supernatants from B. cereus and S. aureus can cause retinal damage due to release of
inflammatory stimuli.12 In an experimental rabbit model intravitreal application of Bacillus cereus led to a disruption of retinal architecture and photo receptor layer folding as early as 12 h postinfection, mainly attributed to hemolysin BL. Other reports showed that Staphylococcus aureus secretes cytolytic toxins and stimulates release of proinflammatory cytokines, such as interleukin-8.13,14 As such, bacterial endophthalmitis may not only lead to retinal tissue damage due to endotoxins produced by bacteria but also through bystander damage caused by leukocyte infiltration into the vitreous and retina.15 Although we found no systematic changes within the retinal layers in our cases after endophthalmitis, there were focal areas of retinal damage in SD-OCT. In the first instance we found foci of damage in the
classic glaucoma application using spectral domain OCT. Layer analysis revealed that the RNFL and the ganglion cell layer were not significantly thinner in eyes having had endophthalmitis compared to healthy control eyes. No difference of INL, ONL thickness was found between eyes with endophthalmitis and healthy eyes (Figure 4).
Ocular Immunology & Inflammation
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SD-OCT Findings after Exogenous Endophthalmitis inner retinal layers in the area of the inner nuclear layer and dent-like changes in the retinal nerve fiber layer (Figure 3). In addition, we found areas of atrophy in the outer retinal layers with formation of microholes and formation of tubules probably corresponding to focal areas of necrosis. The absence of generalized structural retinal changes and the excellent visual outcomes support our clinical protocol of immediate intravitreal treatment with antibiotics by pars plana vitrectomy. The first allows for adding intravitreal steroids, while the latter may clear the vitreous of the potentially toxic aminoglycoside. Another finding that merits further discussion is the incidence of postoperative endophthalmitis cases. As our department is a tertiary referral center, the majority of patients with postoperative endophthalmitis were referred from primary caretakers. There are limitations of this study. The number of the patients was small, such as mainly due to stringent exclusion criteria due to macular or glaucomatous disease, both frequently encountered in the age group undergoing ophthalmic surgery. Furthermore, less than half of the patients had positive microbiology results. However, this is in keeping with other studies.16 The excellent clinical outcomes reported here may possibly be attributed to little virulence or the absence of gram-negative bacterial strains in our cohort. Therefore, we cannot correlate our findings with other bacterial strains. Furthermore, with the small number of patients no general conclusion can be made on amikacin toxicity affecting the RNFL. Endophthalmitis remains an infrequent but sightthreatening complication of intraocular surgery. In our case series immediate treatment with intravitreal antibiotics in eyes presenting with endophthalmitis followed by same-day pars plana vitrectomy and intravitreal injection of steroids resulted in excellent visual outcome with minimal structural changes seen on SD-OCT.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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