Chronic Pseudophakic Endophthalmitis After Uneventful Phakoemulsification: A Case Series and Review of Litterature


 Purpose: To report a retrospective case series of patients with chronic post operative endophthalmitis (CPE) after uneventful phacoemulsification (PKE) with intraocular lens (IOL) implantation. Methods: this study was conducted between January 2011 and June 2020, including patients with delayed-onset endopthalmitis occurring at least 2 weeks after uneventful PKE+IOL. Diagnosis was based on typical clinical features associated or not to proven sample culture. Treatment was based on step-by-step management, depending on results of microbiology and response of treatment. It consisted in first line medical treatment with a two-approach intraocular and systemic antiobiotics, followed, if necessary, by a second line conservative-IOL surgical treatment with pars plana vitrectomy (PPV), and a third line non-conservative-IOL surgical treatment with re-PPV associated to IOL explantation. Results: Seven patients were included with a mean age of 62,5 years. Mean duration interval between cataract surgery and diagnosis of CPE was 31,3 weeks. All patients presented a decrease of visual acuity with white intracapsular plaques. Only one patient had positive IOL culture. Medical treatment was sufficient in three cases. In the four other cases, PPV with IOL explantation and total capsular bag removal was conducted. Mean final BCVA was 20/160 with a gain of 4 lines and was ≥ 20/40 in 4 cases. Conclusion: The diagnosis of CPE is still challenging especially for difficulties in isolating microorganisms. It should always be considered in cases of recurrent ocular inflammation resistant to conventional treatment in operated eyes. Non-conservative IOL surgical treatment may be directly necessary in severe cases.


Introduction
Infectious endophthalmitis is a rare complication occurring days, weeks or even years after cataract surgery (1,2). Chronic postoperative endophthalmitis (CPE) is de ned as a delayed-onset intra-ocular in ammation occurring more than 6 weeks, months or even years after surgery. It is less common than acute endophthalmitis representing 12 % to 24% of post-operative endophtalmitis (3)(4)(5)(6). CPE can present a diagnostic and therapeutic challenge. After phacoemulsi cation (PKE) and intraocular lens (IOL) implantation, it is characterized clinically by a delayed-onset of a chronic unilateral in ammation responding partially to topical steroids with phases of recurrence when treatment is interrupted. The presence of whitish capsular plaque (WCP) is the most frequent clinical feature (2,7). The most frequent causative microorganisms are staphylococcus epidermidis and propionic bacterium acnes (P.acnes), noted in 42,86% and 28,57% of cases by Moloney, respectively [5]. Their identi cation by culture of intraocular specimen facilitates the management of CPE, including medical and surgical therapeutic treatment depending on severity of clinical presentation (2,7,8). The purpose of this study was to describe the clinical features of CPE following uneventful PKE with IOL implantation and to highlight its treatment challenges in the absence of proven culture causative germ.

Materials And Methods
The current study was an observational retrospective case series, conducted over a 10-year period between January 2011 and June 2020, in the department of ophthalmology of Charles Nicolle's Hospital, a tertiary care center in Tunis. Patients with CPE after uneventful PKE with IOL implantation were included. CPE was de ned by the following clinical features: history of chronic ophthalmic in ammation responding partially to topical steroids occurring at least 2 weeks after uncomplicated PKE, decrease of visual acuity after surgery, anterior chamber cells and white capsular plaque [7].
Prior ethics committee approval was obtained and the study was carried out in accordance with the tenets of the Declaration of Helsinki.
A chart review of medical and microbiological records of the included patients were reviewed and the following initial data was collected for each patient: age, gender, clinical features, interval between cataract surgery and diagnosis of CPE, interval between onset of signs and diagnosis of CPE, initial best corrected visual acuity (BCVA), details of slit-lamp examination, medical and/or surgical treatment, nal BCVA and follow-up after treatment. All patients underwent, before any treatment, under sterile conditions, an aqueous sampling (AS) with needle aspiration of aqueous uid until attening of the anterior chamber. At any time of follow-up, liquid or tissue or material taken from eye, such as aqueous humor (AH) collected before intraocular antibiotics (IOAB) injection, vitreous samples collected at the time of the therapeutic pars plana vitrectomy (PPV), tissues samples of removed capsular bag (CB), explanted IOL were processed for microbiological identi cation with special culture media and prolonged incubation time, with Gram Stain, inoculated into Blood, Chocolate and Sabouraud's Dextrose agar.
Treatment modalities were based on step-by-step management, depending on severity of CPE, results of microbiology and response to treatment (9,10). First line treatment for all patients was medical with a « two-compartment » approach of IOAB injection with systemic antibiotics (SATB). The IOAB was preceded by CB washing. It included simultaneous intracamelar vancomycine (1mg/0.1 ml) injection, and intravitreal antibiotics injection (IVAB) of vancomycine (1mg/0,1 ml) and ceftazidine (2,25 mg/0,1 ml). SATB consisted of intravenous cefazoline (3g/ day) and oral o oxacine (400mg/day) during at least one week. Topic steroids were associated in all cases. This conservative medical treatment was repeated weeklywhen necessary in case of persistent or improved in ammation. Second and third line treatments were considered in case of worsening or persistent or recurrence of the in ammation during follow-up. The second line treatment was a conservative IOL surgical treatment with PPV. It was associated with partial posterior capsulectomy, irrigation of the CB and IOAB injection. The third line treatment was a non-conservative IOL surgical treatment, consisting in an IOL explantation with an additional PPV and a complete removal of the CB and IOAB injection. It may be considered as direct surgical procedure in severe cases. After a minimum follow-up of 3 months without recurrence of endophthalmitis, the infection was considered as resolved.

Results
Seven eyes from 7 patients were included in this study. Four patients underwent uncomplicated PKE and IOL in our department. The three other patients were operated elsewhere and referred to us, for management of a corticosteroid resistant uveitis with unknown etiology. There were four males and three females, with a mean age of 73.4 years (range: 61-83 years). Demographic data and clinical features of patients are summarized in Table 1. The mean interval between cataract surgery and the diagnosis of CPE was 30.7 weeks (range 2 -108 weeks). The mean duration of symptoms before diagnosis was 10.9 weeks (range 2 days-8 months). At presentation, all patients were under topic corticotherapy.
In four patients (cases n°3, 5,6 and 7), medical treatment was su cient and infection resolved after a single IOAB injection in 3 eyes (cases 3, 6 and 7) ( g 2-b, 2-e, 2-f) , and a second IOAB injection in 1 eye (case 5) ( g 2-d). In case 1, persistence of the WCP was noted after the third ( g 1-b) and the fourth ( g 1-c) IOAB injections. In three cases, intraocular in ammation didn't respond to medical treatment and a surgical treatment was required 8 days to 8 weeks after initial treatment. (Cases n°1, 2 and 4). In case 1, second line conservative-IOL surgical treatment was performed and followed by non-conservative IOL surgical treatment (Fig 1-d). In case 2 and 4, third line non-conservative IOL surgical treatment was performed directly following medical treatment. All treatment modalities are represented in table 2. In ammation was resolved in all cases with a mean follow-up period of 39 months (range 12-80 months).

Discussion
In most cases of CPE, patients are referred for the management of a cortico-dependent anterior uveitis, as noted in 4/7 of our patients. According to Fardeau et al, the partially response to steroid represented one of the item of the de nition of CPE (9). Typical clinical presentation is unilateral granulomatous uveitis involving the anterior chamber with a possible later progression into the vitreous. Most frequent ocular symptoms are a recurrent eye pain, a progressive decrease vision, a red eye, isolated or associatedto eye pain. An anterior chamber in ammation was present in 85,7% of our cases, with different grade of in ammation. Hypopion was noted in one of our cases, this clinical feature was reported by several authors in approximately 46% of the cases of CPE (8, [11][12][13][14]. A white plaque on the anterior surface of the IOL or on the posterior capsule, was noted in all our patients, this nding was reported in 28.5% to 100% of CPE (11,14,15) and was found to be mostly associated with P.acnes (12,(16)(17)(18)(19)(20). Others clinical features were noted in literature, suggesting fungal infection, such as a stirringly white in ltrates or clumps in the anterior chamber (16, 21,22).
In this series the mean interval between cataract surgery and the diagnosis of CPE was 30.7 weeks. This interval was extremely variable in literature: 2 weeks, 3 weeks, 6 weeks (9,14,23,24), 3 months (12,13) or 6 months (25) . The mean time interval between cataract surgery and the diagnosis of CPE was relatively shorter in Onchobactrum Anthropi (O.anthropi) endophthalmitis and non tuberculous mycobacterium than in P. acnes endophthalmitis or Pseudomonas oryzihabitans, 6.8, 2, 36 and 16 weeks reported by previous studies, respectivelly (21,26) . This difference of delay, and the onset of clinical manifestations are probably related to average time of growth of the microorganisms (18,26,27).
In our study, AH culture was negative in 6 out of 7 patients, and only one case was culture-proven CPE, with an IOL microbiological diagnosis. The most cases series in literature provide from culture-proven cases from clinical and microbiology laboratory database (8,28-31). However, a negative culture result does not necessarily imply a bacteria-free infection (22,26,32). These results might be due to the nature of the cases being referred to our institution. These patients had been treated before being referred, thus the initial microbial pro le might have been altered (33) . In addition, most of the microorganisms responsible for CPE are widely distributed in the natural environment, such as the water sources for O.anthropi, water and soil for Alacaligines faecalis or eyelid for P.acnes (22,23,34). They are generally not virulent but the production of a bio lm on the arti cial devices, such as in the surface of the IOL or on its haptics, may lead to these sequestration of microorganisms into the CB (1,13,17,(17)(18)(19)(20)(32)(33)(34)(35)(36). Furthermore, vitreous taps have a higher rate of culture positivity than AS. However, in cases of negative cultures of both samples, the best result is the culture of the removed CB and IOL, as found in the single culture proven case of our series. Identi cation of the microorganism may need special culture media and prolonged incubation time. An aerobic and fungal culture is highly recommended (14,15). More recently, the role of molecular testing by polymerase chain reaction or "PCR", is essential, and allows a microbiological diagnosis in 71% of cases of postoperative acute and delayed-onset endophthalmitis as demonstrated by Chiquet (37-39). However, diagnosis based on clinical ndings should be performed, without waiting for the microbiological results the to treat (22,29). E.faecalis was the only identi ed microorganism in our study. It is a gram positive bacterium that is part of the normal human gastrointestinal track ora (40,41). It is a relatively rare cause of endophthalmitis, found in 1.23% of acute post-cataract surgery endophthalmitis cases in the Endophthalmitis Vitrectomy Study (41,42). In a reported case series of E.faecalis endophthalmitis, the onset of clinical signs was within 4 days in 61,53%, between 4 days and 6 weeks in 7,69% and after 6 weeks in 19,23% of cases (36,41). As we noted in our series, it is usually related to a poor visual outcome with only 15% achieving a visual acuity better than 6/60, probably related to the bacterial virulence. Table 3 describes reported microbiological proven CPE after PKE and IOL implantation in literature (8, 23,24,28,[30][31][32]39, The management of CPE is controversial. The sequestration of microorganisms into the CB, their different virulence proprieties and the possibility of polymycrobial infection have made it di cult to establish a unique protocol treatment (13,45). However, regardless of the clinical presentation and its severity, its management has to be prompt. A sample of intraocular uid for microbiological investigation is mandatory in any suspected CPE before initiating treatment. In our series, the treatment of CPE was based on a "step by step approach". The rst line treatment was medical, followed by the IOL-conservative surgical treatment, and the non-conservative-IOL surgical treatment, as recommended in literature (9,10,12). As described by Güler and Aldave, IOAB were based on a "two-compartment approach" that included a simultaneous injection in the humor aqueous and vitreous (71,72). Vancomycine (1mg/0.1 mL) and ceftazidim (2,25mg/0.1 mL) were used for empiric coverage of gram-positive and gram-negative organisms in the primary procedure (12,73,73). Cipro oxacin (0.2 mg/0.1 mL) was used in non-responding cases and/or resistance to Ceftazidim (49,56). We performed an irrigation and washing of the CB, associated to the IOAB, as recommended in some studies (9,12). The use of SATB remains controversial (13,15,21,74,75). The slow growth of most common microorganisms isolated in CPE and their sequestration in the CB justify the need of repeated IOAB injection as we observed in cases n°3, 5, 6. (9,12,49,71). The association of steroids to IOAB injection and SATB administration depends on severity of in ammation and are proposed in different routes of administration. When in ammation recurs or increases, surgical treatment based on PPV is required to eliminate the contaminating foci, and may include two types of approaches, depending on whether the IOL is explanted or not. The IOL-conservative surgical treatment is generally associated to capsulotomy of the most in ltrated areas of the CB, and the IOL is preserved (1,10). This treatment strategy allows the removal of localized infectious sources while leaving enough capsular support for the IOL(26) . If the conservative-IOL surgical treatment is not e cient, as observed in our case 1, removal of the entire CB and the IOL is required to eradicate all sites of intraocular infection (9,13,15,17,19,23,26,27,34,(43)(44)(45)(46)(47)(48)73,76). Surgical treatments were observed in 50% of this case series, which agrees with other studies that reported it in approximately 30% to 73% of cases (12,15,16,27,41). A de nitive initial surgical procedure should be considered in any patient with strong clinical evidence of severe or refractory CPE, or when the clinical features are suggestive or microbiologically proven aggressive microorganisms, such as fungal infection, Onchobactrum Anthropi, P.Acnes, or polymicrobial infection (15,22,26,34,45,52,(72)(73)(74)77).
In this series, the mean nal BCVA was 20/160 with a gain of 4 lines (ranging from 1/80 to 20/32), poor visual outcome was observed in case 2 and 4 where postoperative complications were noted such as CME (case 4) and ERM (case 2). The visual prognosis of CPE is various from one report to another, with a better visual prognosis than acute-onset endophthalmitis (16). Hsu et al noted that a long incubation (>1 month) would be associated with favorable visual outcomes compared to acute cases (18). However, CPE can lead to poor visual outcome despite the two-compartment approach of IOAB, and safe technics of complete non-conservative IOL surgical therapy, mainly related to the causative organism, specially fungal and/or nontuberculous mycobacterium infection (18, 33,74). In another hand, polymycrobial infection has been associated with failure of IOL-conservative treatment (14,26,48,56,78).
Based on the literature, and the results observed in this study, we propose the following algorithm for the management of CPE (Table 3). First line treatment is medical, given at presentation and repeated if needed based on IOAB and associated to an AC and CB wash. If in ammation persists or recurs, the second step is an IOL-conservative surgical treatment, based on PPV, associated with CB partial removal and IOAB injection. The third step is a non-conservative-IOL surgical treatment, based on an additional PPV, associated to residual CB removal and IOL explantation. At any step of treatment, we start with an ocular sample for microbiological analyses, whether it concerns the intraocular uids, humor and vitreous, CB or/and IOL when they have been removal. The surgical treatment is proposed as rst line approach in particular situations (Figure 3).
The limitations of the current study include its retrospective design, a relatively small number of patients, the absence of performance of vitreous tap and inclusion of cases with negative aqueous humor cultures. Nevertheless, we addressed non-proven culture CPE after uneventful PKE, an issue that is encountered in our daily practice and we tried to extrapolate from our experience an algorithm that can help to manage such an entity.

Conclusion
The diagnosis of CPE is still challenging especially for di culties in isolating microorganisms. It should always be considered in cases of recurrent ocular in ammation resistant to conventional treatment in operated eyes. The rst diagnosis, based on clinical ndings, should be performed to start a prompt management, beginning with ocular samples for microbiological diagnostic. Treatment is based on step-by-step approach. Medical treatment with intraocular antibiotic injections associated to capsular bag washing is e cient in most of cases. Nevertheless, rst line non-conservative IOL surgical treatment may be necessary in severe cases associated to poor visual outcome. The study was carried out in accordance with the tenets of the Declaration of Helsinki.

Consent for publication
Patients have given informed consent for the publication of their data and photo

Availability of data and material
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.