Ocular Immunology & Inflammation, 2014; 22(3): 170–174 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2013.819928
ORIGINAL ARTICLE
Acute Retinal Necrosis: Clinical Features, Management and Outcomes – a 10 Year Consecutive Case Series Rupak Roy, MBBS, MS1, Bikramjit P. Pal, MBBS, DO, DNB2, Gaurav Mathur, MBBS, MS2, Chetan Rao, MBBS, MS2, Debmalya Das, MBBS, DO, DNB1, and Jyotirmay Biswas, MBBS, MS3
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1
Vitreo Retina Services, Aditya Birla Sankara Nethralaya, Kolkata, West Bengal, India, 2Shri Bhagwan Mahavir Vitreoretinal Services, and 3L and T Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
ABSTRACT Purpose: To determine the viral diagnosis and clinical outcome of eyes with acute retinal necrosis (ARN). Method: A retrospective analysis was done of 62 eyes of 53 patients presenting to a tertiary care ophthalmic institute between 1997 and 2007 with features of ARN. All patients with active disease were started immediately on intravenous acyclovir followed by oral antivirals along with systemic steroids. A prophylactic laser retinopexy was performed in patients with a clear media to areas posterior to the necrotic retina. Results: The aqueous and the vitreous sample revealed herpes simplex virus in 19 (30.60%) and varicella zoster virus in 28 patients (45.16%). Forty-one (66.12%) eyes had retinal detachment. Prophylactic laser photocoagulation was given in 19 (30.64%) eyes. Surgical intervention was required in 32 (51.61%) eyes. Favorable functional outcome was seen in 28 (45.1%) eyes. Conclusion: ARN is a fulminant disorder, which if treated early and aggressively gives good results. Keywords: Acute, clinical features, India, management, outcome, retinal necrosis
Acute retinal necrosis (ARN), described first by Urayama and co-workers of Japan in 1971, was initially referred to as ‘‘Kirisawa’s uveitis.’’1 The term acute retinal necrosis was introduced by Young and Bird in 1978.2 This devastating condition, usually occurring in immunocompetent individuals, has also been reported to occur in the immunocompromised host.3 The causative organisms have been debated but of late the consensus has been mainly on varicella zoster virus (VZV) and herpes simplex virus (HSV);4–6 other organisms, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), have also been implicated from time to time.7 The diagnostic criteria for ARN as put forward by the American Uveitis Society in 19948 comprises (1) one or more discrete foci of peripheral retinal necrosis, (2) circumferential spread, (3) occlusive arteriolar retinopathy, (4) a prominent vitreous or anterior
chamber inflammatory reaction, and (5) rapid disease progression in the absence of therapy. The visual outcome is generally poor if diagnosed late due to its propensity to cause complications like retinal detachment (RD).9,10 Lau et al.11 recommended prophylactic lasers and early vitrectomy to reduce chances of developing complications like retinal detachment. They also showed improvement of vision after surgery, though the visual prognosis remains guarded. Hillenkamp et al.12 indicated poor functional outcomes even in cases where early vitrectomy was performed. Various reports9-12 from the West provide us with the outcome of this infectious retinitis, although none are very encouraging. Apart from a few case reports13 no Indian study has reported the visual outcomes in ARN. Hence, the aim of the present study is to provide clinical
Received 17 March 2013; revised 17 June 2013; accepted 24 June 2013; published online 16 April 2014 Correspondence: Rupak Roy, Vitreo Retina Services, Aditya Birla Sankara Nethralaya, 147, E.M. Bypass, Kolkata – 700099, West Bengal, India. E-mail: [email protected]
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Acute Retinal necrosis: management and outcomes. outcomes in patients presenting with classic features of ARN in an Indian scenario.
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MATERIALS AND METHODS This retrospective study was conducted in a tertiary eye care hospital in South India and included data from 1997 to 2007. All patients were diagnosed cases of acute retinal necrosis. Clinical diagnosis of ARN was based on the presence of (1) acute panuveitis, (2) occlusive retinal vasculitis (arteritis and phlebitis) with or without retinal hemorrhage, and (3) peripheral patchy necrotizing retinitis (usually multifocal). Other symptoms and signs, when present, were supportive of the diagnosis: ocular or periocular pain, conjunctivitis, episcleritis, scleritis, rapid circumferential spreading and coalescence of the necrotizing retinitis, and rhegmatogenous retinal detachments (RRD). Data were collected pertaining to age and gender, date of onset assessed by symptoms and signs (blurred or reduced vision, floaters, photophobia, pain, red eye), visual acuity at presentation and during follow-up (1-week, 1-month, 3-month, 6-month, and last follow-up), aqueous or vitreous tap for diagnostic PCR DNA analysis or cell culture, duration between onset of symptoms and appropriate treatment, extent of retinal involvement, occurrence of RD, type of treatment, and final functional and anatomical outcomes. Permission was granted by the Institutional Review Board to retrospectively review medical records. Prophylactic laser treatment was applied on the normal retina to surround the posterior edge of the necrotic retina by 3 consecutive rows of confluent and circumferential laser burns for extensive necrosis or diffuse patchy necrosis, or up to the ora serrata for sectoral necrosis. Prophylactic laser treatment was not applied when there was severe media opacity or presence of RD. All patients received intravenous antiviral treatment (acyclovir, 10 mg/kg thrice daily) for 7–10 days, followed by oral antiviral therapy (valacyclovir 1 g thrice daily or acyclovir 800 mg 5 times a day) for a further 6–8 weeks. Systemic corticosteroid treatment was instituted in all patients. The dosage of oral prednisolone was 1 mg/kg/day and was tapered by 10 mg every 5 days. Systemic corticosteroids were started 48–72 h after institution of anti viral therapy. Those eyes that had RRD underwent 20 G 3-port pars plana vitrectomy, induction of a posterior vitreous detachment if not already present— with 360-degree encircling and silicone oil or gas tamponade. A favorable functional outcome was deemed if the eyes achieved best-corrected visual acuity greater than 3/60 at final follow-up. Anatomical success was achieved if the eye had attached retina, clear media, and normal intraocular pressure at final follow !
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up. Regression analysis was performed with visual outcome as the final dependent variable and the various independent factors assessed were age, sex, presence of retinal detachment, extent of retinal involvement, and time delay between onset and treatment of disease. Statistical analysis was performed using the statistical software SPSS, version 11 (Chicago, IL, USA). A p value of less than 0.05 was considered statistically significant.
RESULTS A total of 62 eyes of 53 patients were evaluated for the study. The demographic data are enumerated in Table 1. Of a cohort of 53 Indian patients, 38 (71.7%) were males and 15 (28.3%) were females. The mean age of our patients was 36.04 years (range 6–70 years). The right eye was affected in 24 (38.7%) patients, whereas 38 (61.3%) had affliction in the left eye. Fortyfour (83.01%) patients had unilateral involvement, whereas 9 (16.98%) had bilateral involvement. In the bilateral cases the average duration between involvement of the fellow eye was 210.43 days (range 0–2190 days). The mean duration of follow-up was 820.02 days (180–3650 days). After analyzing the various referral diagnoses we found ARN to be diagnosed as posterior uveitis in 13 (24.5%), retinal vasculitis in 5 (9.45%), pars planitis in 5 (9.45%), panuveitis in 3 (5.66%), ischemic neuropathy in 3 (5.66%), glaucoma in 2 (3.77%), conjunctivitis 1 (1.88%), and sarcoidosis in 1 patient (1.88%). Acute retinal necrosis was a referral diagnosis in 10 (18.86%) of our patients. Ten (18.86%) patients did not have a referral diagnosis. Fifty-five eyes (88.7%) had active disease at presentation and 7 (11.2%) had inactive disease. All of our patients presented with a chief complaint of hazy vision. Ten (18.86%) of our patients had associated complaints such as headache and periocular pain, whereas rest did not have any associated complaints. Only 4 (7.54%) patients gave a history of varicella zoster (chicken pox) infection. On inquiring about any preceding features before the visual loss, only 4 (7.5%) gave a history of viral fever;
TABLE 1. Baseline characteristics of study subjects. Gender Eyes Laterality Age (mean years) Duration between onset and treatment (mean days) Duration of follow-up (mean days)
Male n (%) 38 (71.7) Right eye n (%) 24 (38.7%) Unilateral n (%) 44 (83.01) 36.04 (6–70) 27 (1–120)
820 (180–3650)
Female n (%) 15 (28.3) Left eye n (%) 38 (61.3%) Bilateral n (%) 9 (16.98)
172 R. Roy et al TABLE 2. Extent of retinal involvement and clinical outcome. Extent of involvement Up to 90 degrees 90–180 degrees 180–270 degrees 270–360 degrees Total retinal necrosis ARN sequlae
Number of eyes n (%) 4 9 7 32 3 7
(6.45) (14.51) (11.29) (51.61) (4.83) (11.29)
Anat scs n (%) 3 5 2 15 1 6
(75) (55.55) (28.57) (46.87) (33.33) (85.71)
Fn scs n (%) 3 4 2 14 0 5
(75) (44.44) (28.57) (43.75) (0) (71.42)
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Anat scs, attached retina, clear media and normal intraocular pressure; Fn scs, best-corrected visual acuity 43/60.
one had a history of herpes encephalitis. Among our cohort 2 patients were HIV positive. The mean visual acuity at the presentation was 2.02 logMAR units and the mean visual acuity at the final follow-up was 1.78 logMAR units. The difference between initial and final visual acuity was statistically significant (paired t test, p50.03). Mean duration of starting of appropriate treatment after the onset of the symptoms was 27 days (1–120 days). Table 2 enumerates the extent of retinal involvement at presentation and its correlation with the final outcome. Retinal involvement of 90 degrees or less in periphery was observed in 4 (6.45%) eyes; 90–180 degrees of peripheral retina was involved in 9 (14.51%) eyes. Lesions involving 180–270 degrees were observed in 7 (11.29%) eyes and 360 degrees of peripheral retinal involvement was seen in 32 (51.61%) eyes. Involvement of the whole retina was seen in 3 (4.83%) eyes. Seven (11.29%) eyes presented with ARN sequelae. Out of the cohort of 62 eyes 41 (66.12%) eyes had retinal detachment. Eighteen (29.03%) eyes had RD at presentation, whereas 23 (37.09%) eyes developed RD during the course of the disease. The mean duration between the onset of complaints and retinal detachment occurred on an average of 71.35 days (range 7–365). The aqueous and the vitreous samples revealed HSV in 19 (30.60%) and VZV in 28 (45.16%) eyes. The investigations did not reveal any organisms in 9 (14.51%) eyes. No samples were taken in 6 (9.67%) eyes. Polymerase chain reaction yielded a diagnosis in 37 (59.67%) of organism-positive patients, whereas in 9 (17.74%) cases the cell culture method yielded the diagnosis. Prophylactic laser photocoagulation was given in 19 (30.64%) eyes. Among the lasered eyes, 12 (23%) developed retinal detachment. In the nonlasered cohort of 43 (69.35%) eyes 29 (67.44%) developed RD. There was no significant difference in retinal detachment rates among lasered and nonlasered eyes (p value 0.43). Surgical intervention was required in 32 (51.61%) eyes. The indication for surgery was RD in 31 (98%) eyes, whereas vitreous haze was the indication in 1 (2%) eye. Ten eyes with RD did not undergo surgical procedure because 6 had retinal detachment with
optic atrophy with negative light perception at time of diagnosis, 2 had exudative RD that subsided with oral steroids and systemic acyclovir, 1 was phthisical, and 1 eye of a patient was best left alone without any surgical intervention in view of inoperable RD. In the RD group proliferative vitreoretinopathy (PVR) was seen in 14 (35%) eyes. Recurrent RD was seen in 14 of 31 eyes (45%); 6 of these had attached retina at final follow-up and the other 8 retinas remained detached with or without repeat surgeries. Silicon oil of 1300 and 5000 cSt was used in 21 and 6 eyes, respectively. C3F8 was used as tamponade in 1 eye. In 3 cases no tamponade was used as they were abandoned intraoperatively. Two cases were abandoned due to multiple large posterior breaks and the other case was abandoned due to posterior closed funnel configuration. Among all eyes favorable anatomical outcome (attached retina, clear media, and normal IOP) was present in 32 (51.61%) eyes. However, among the patients who underwent RD surgery, a successful anatomical outcome was seen in 17 of the 41 (41.46%) eyes. A favorable functional outcome (visual acuity better than 3/60) was seen in 28 (45.1%) eyes. In the 34 eyes with poor functional outcome, the major causes for poor visual potential were RD in 16 (47.05%), secondary optic atrophy in 10 (29.41%), phthisis in 4 (11.7%), hypotony in 3 (8.8%), and macular scar in 1 (2.9%) eyes. Regression analysis showed that the extent of involvement and time interval between onset of disease and start of the treatment were significant parameters that affected the visual potential (p value 0.03 and 0.01, respectively).
DISCUSSION In this retrospective study we analyzed the clinical outcomes of 62 eyes of 53 patients. To the best of our knowledge this is the first reported case series from India on acute retinal necrosis, its clinical presentation, management, and outcomes. We found that ARN has a slight gender predilection, male gender being affected more, and it typically affects patients who are between 20 and 60 years of age.14,15 In our study we found a male predilection (70%) and the age group ranged from 6 to 70 years. ARN is generally thought to be associated with an immunocompetent state,3 but we found this condition in 2 of our patients who were HIV positive, both of whom had unilateral but extensive involvement of retina. One had an associated HSV detected on PCR but the other had no isolation. Both of our patients were on HAART therapy at the time of presentation with a CD4 count of 400 and 300, respectively. Several cases have been reported in HIV-infected patients presenting with acute retinal necrosis Ocular Immunology & Inflammation
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Acute Retinal necrosis: management and outcomes. syndrome in association with skin manifestations of VZV infection.16 Chess and Marcus17 reported a case of bilateral acute retinal necrosis syndrome associated with unilateral herpes zoster ophthalmicus as the presenting sign of HIV infection. The etiology of ARN in HIV has been a matter of debate but one of the postulated mechanisms, other than defective cellmediated immunity and infection with VZV, has been a hypercoagulable state.18,19 Recently, occurrences of an ocular inflammatory syndrome identical in all respects to ARN have been recognized in immunosuppressed patients. This suggests that features of the specific etiologic agent(s), rather than the immune status of the infected individual, are responsible for producing the pattern of posterior segment infection known as ARN.20 Bilateral involvement occurs in approximately onethird of patients, but both eyes may not be affected simultaneously.21,22 A fellow eye involvement of 13.6% has been reported in a recent study.23 Our results showed that 9 (16.98%) had a bilateral involvement, of which 6 had bilateral involvement at the time of presentation, whereas 3 had the other eye involved during the course of treatment. Two of those patients had skipped the acyclovir therapy, whereas one was on a lower dose of acyclovir. Our study did not identify any risk factors for the bilaterality apart from a lower dose of acyclovir or treatment defaulters, suggesting need for optimal antiviral therapy and a close follow-up. Antiviral treatment is therefore essential to contain unilateral disease and minimize progression to bilateral retinitis. The virological results in our study are in accordance with those of Lau et al.24 and Hillenkamp et al.,12 indicating VZV as the most frequent organism causing ARN, followed by HZV. PCR has allowed rapid diagnosis in small ocular samples and has generally overtaken other local and systemic methods of virusspecific antibody detection. One of the important findings in our study was the importance of the extent of retinal involvement as a predictor of visual outcome. Eyes with less than 90% involvement had the best prognosis functionally, whereas total retinal necrosis had the worst functional outcomes. A recent study by Meghpara et al.25 supports our finding that the initial extent of retinal involvement can be a useful tool for predicting the visual potential of the affected eye. According to his work, eyes with 25% retinitis had better visual acuities at both the initial visit and the subsequent follow-up intervals. Visual acuity progressively deteriorated as the extent of retinitis increased to 25–50% and 100%. Similarly, in our patients best outcomes were achieved in eyes with less than 90-degree necrosis and worsened as the extent of involvement increased (Table 2). The other important factor influencing the final visual outcome is the time duration between the !
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presentation and start of treatment. A favorable functional outcome in only 28 (45.1%) of the study eyes could be attributed to delayed diagnosis and treatment (p value 0.01), which could lead to increased extent of necrosis in retina and subsequent retinal detachments. Our institute being a tertiary care center and ARN still being an underdiagnosed disease probably accounts for this delay. Overall the incidence of RD in our study was high (66%) and the rate was comparable to that found by Lau et al. (60%).24 Other studies25 have reported a lower prevalence of RD. The mean duration for the RD to occur in our study was 71 days, with other studies reporting the range from 32 to 65 days.12,24,25 The increased incidence of secondary retinal detachment could be because 35 (56.45%) of the eyes had involvement of all retinal quadrants or more and greater extent of retinal necrosis predisposes to increased chances of RD.25 Eyes without RD fared better compared to eyes with RD in terms of final anatomical and functional outcome (Table 3). The value of laser photocoagulation in ARN has always been a matter of debate. Some studies have reported it to be a useful modality in prevention of RD,26 whereas others have not found it to be beneficial.27 We did not find any protective role of laser photocoagulation in preventing retinal detachment. The comparison of lasered and nonlasered eyes is biased because in many eyes with severe ARN, vitreous inflammatory opacification precludes the application of laser, whereas eyes with mild ARN often present with relatively clear media that allows the application of laser. Prophylactic laser retinopexy also fails to prevent secondary RD when, after laser retinopexy, the involved retinal area continues to extend posteriorly beyond the demarcation of the laser burns. Eyes in which laser treatment is possible obviously have less retinitis and hence vitritis, which ultimately gives them a better chance at the final visual prognosis. Late-stage complications of ARN can only be managed by surgical intervention. In the present study surgical intervention was needed for 32 (51.6%) eyes. Predominant indication for surgery in our series was RD 31 (96.87%) eyes, whereas vitreous opacification necessitated surgery in 1 case.
TABLE 3. Outcomes related to retinal detachment. Anat scs
Patients with RD Patients without RD
Fn scs
No.
%
No.
%
17/41 15/21
41 71
16/41 12/21
39 57
Anat scs, attached retina, clear media and normal intraocular pressure; Fn scs, best-corrected visual acuity43/60; RD, retinal detachment.
174 R. Roy et al TABLE 4. Comparison with previous studies. Study
Year
N
Follow-up (days)
Predominant organism
RD (%)
Lau24 Tibbets28 Meghpara25 Present
2007 2010 2010 2012
22 58 20 53
1460 1020 622 820
Varicella zoster NA Varicella zoster Varicella zoster
51.9 50 20 66
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N, number of patients, RD, retinal detachment; NA, data not available.
Though in our study an early vitrectomy was not performed for acute retinal necrosis, Hillenkamp et al.12 have reported the role of early vitrectomy in prevention of secondary RD. Lau et al. reported24 better visual acuities in patients who underwent surgical interventions for retinal detachments. In our series, eyes without RD fared better both, anatomically and functionally, compared to those eyes with RD, but the difference was not statistically significant (Table 3). A comparative study with review of literature from published articles is shown in Table 4. In terms of visual acuity, organisms isolated and retinal detachments remain nearly the same in all the studies. In conclusion, we showed that a greater involvement of the retina at the onset portends a worse visual outcome. In addition, the use of laser retinopexy did not affect the chances of RD. The important thing to remember is the early diagnosis and referral of ARN suspected cases because early and aggressive treatment is the cornerstone of its management.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Urayama A, Yamada N, Sasaki T. Unilateral acute uveitis with periarteritis and detachment. J Clin Ophthalmol. 1971; 25:607–619. 2. Young NJ, Bird AC. Bilateral acute retinal necrosis. Br J Ophthalmol. 1978;62:581–590. 3. Freeman WR, Lerner CW, Mines JA. A prospective study of the ophthalmologic findings in the acquired immune deficiency syndrome. Am J Ophthalmol. 1984; 97:133–142. 4. Culbertson WW, Blumenkranz MS, Pepose JS. Varicella zoster virus is a cause of the acute retinal necrosis syndrome. Ophthalmology. 1986;93:559–569. 5. Matsuo T, Nakayama T, Koyama T, et al. Cytological and immunological study of the aqueous humor in acute retinal necrosis syndrome. Ophthalmologica. 1987;195:38–44. 6. Lewis ML, Culbertson WW, Post JD. Herpes simplex virus type 1: a cause of the acute retinal necrosis syndrome. Ophthalmology. 1989;96:875–878.
7. De Boer JH, Luyendijk L, Rothova A. Detection of intraocular antibody production to herpesviruses in acute retinal necrosis syndrome. Am J Ophthalmol. 1994;117: 201–210. 8. Holland GN. Executive Committee of the American Uveitis Society. Standard diagnostic criteria for the acute retinal necrosis syndrome. Am J Ophthalmol. 1994;117: 663–667. 9. Aizman A, Johnson MW, Elner SG. Treatment of acute retinal necrosis syndrome with oral antiviral medications. Ophthalmology. 2007;114:307–312. 10. Clarkson JG, Blumenkranz MS, Culbertson WW. Retinal detachment following the acute retinal necrosis syndrome. Ophthalmology. 1984;91:1665–1668. 11. Lau KK, Scott IU, Chaudhry NA. Intravitreal antiviral injections as adjunctive therapy in the management of immunocompetent patients with necrotizing herpetic retinopathy. Am J Ophthalmol. 2000;129:811–813. 12. Hillenkamp J, No¨lle B, Bruns C, et al. Acute retinal necrosis: clinical features, early vitrectomy, and outcomes. Ophthalmology. 2007;114:756–762. 13. Prasad P, Upadhaya NS. Unilateral acute retinal necrosis-a case report. Indian J Ophthalmol. 1992;40:96–98. 14. Fisher JP, Lewis ML, Blumenkranz M, et al. The acute retinal necrosis syndrome—clinical manifestations. Ophthalmology. 1982;89:1309–1316. 15. Nussenblatt RB, Palestine AG. Uveitis: Fundamentals and Practice. Chicago: Year Book Med; 1989:407–415. 16. Batisse D, Eliaszewicz M, Zazoun L. Acute retinal necrosis in the course of AIDS: study of 26 cases. AIDS. 1996;10: 55–60. 17. Chess J, Marcus DM. Zoster-related bilateral acute retinal necrosis syndrome as presenting sign in AIDS. Ann Ophthalmol. 1988;20:431–435. 18. Ando F, Kato M, Goto S. Platelet function in bilateral acute retinal necrosis. Am J Ophthalmol. 1983;96:27–32. 19. Simon V, Ho DD, Abdool Karim Q. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet. 2006;368:489–504. 20. Hayasaka S, Asano T, Yabata K, et al. Acute retinal necrosis. Br J Ophthalmol. 1983;67:455–460. 21. Palay DA, Sternberg Jr P, Davis J. Decrease in the risk of bilateral acute retinal necrosis by acyclovir therapy. Am J Ophthalmol. 1991;112:250–255. 22. Cardine S, Chaze PA, Bourcier F. Bilateral acute retinal necrosis syndrome associated with meningoencephalitis caused by herpes simplex virus 2: a case report. J Fr Ophtalmol. 2004;27:795–800. 23. Okunuki Y, Usui Y, Kezuka T, et al. Four cases of bilateral acute retinal necrosis with a long interval after the initial onset. Br J Ophthalmol. 2011;95:1251–1254. 24. Lau CH, Missotten T, Salzmann J, et al. Acute retinal necrosis: features, management, and outcomes. Ophthalmology. 2007;114:756–762. 25. Meghpara B, Sulkowski G, Kesen MR, et al. Longterm follow-up of acute retinal necrosis. Retina. 2010;30: 795–800. 26. Hudde T, Althaus C, Sundmacher R. Acute retinal necrosis syndrome: argon laser coagulation for prevention of rhegmatogenic retinal detachment. Ophthalmologe. 1998; 95:473–477. 27. McDonald HR, Lewis H, Kreiger AE. Surgical management of retinal detachment associated with the acute retinal necrosis syndrome. Br J Ophthalmol. 1991;75: 455–458. 28. Tibbetts MD, Shah CP, Young LH, et al. Treatment of acute retinal necrosis. Ophthalmology. 2010;117:818–824.
Ocular Immunology & Inflammation
ORIGINAL ARTICLE
Acute Retinal Necrosis: Clinical Features, Management and Outcomes – a 10 Year Consecutive Case Series Rupak Roy, MBBS, MS1, Bikramjit P. Pal, MBBS, DO, DNB2, Gaurav Mathur, MBBS, MS2, Chetan Rao, MBBS, MS2, Debmalya Das, MBBS, DO, DNB1, and Jyotirmay Biswas, MBBS, MS3
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1
Vitreo Retina Services, Aditya Birla Sankara Nethralaya, Kolkata, West Bengal, India, 2Shri Bhagwan Mahavir Vitreoretinal Services, and 3L and T Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
ABSTRACT Purpose: To determine the viral diagnosis and clinical outcome of eyes with acute retinal necrosis (ARN). Method: A retrospective analysis was done of 62 eyes of 53 patients presenting to a tertiary care ophthalmic institute between 1997 and 2007 with features of ARN. All patients with active disease were started immediately on intravenous acyclovir followed by oral antivirals along with systemic steroids. A prophylactic laser retinopexy was performed in patients with a clear media to areas posterior to the necrotic retina. Results: The aqueous and the vitreous sample revealed herpes simplex virus in 19 (30.60%) and varicella zoster virus in 28 patients (45.16%). Forty-one (66.12%) eyes had retinal detachment. Prophylactic laser photocoagulation was given in 19 (30.64%) eyes. Surgical intervention was required in 32 (51.61%) eyes. Favorable functional outcome was seen in 28 (45.1%) eyes. Conclusion: ARN is a fulminant disorder, which if treated early and aggressively gives good results. Keywords: Acute, clinical features, India, management, outcome, retinal necrosis
Acute retinal necrosis (ARN), described first by Urayama and co-workers of Japan in 1971, was initially referred to as ‘‘Kirisawa’s uveitis.’’1 The term acute retinal necrosis was introduced by Young and Bird in 1978.2 This devastating condition, usually occurring in immunocompetent individuals, has also been reported to occur in the immunocompromised host.3 The causative organisms have been debated but of late the consensus has been mainly on varicella zoster virus (VZV) and herpes simplex virus (HSV);4–6 other organisms, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), have also been implicated from time to time.7 The diagnostic criteria for ARN as put forward by the American Uveitis Society in 19948 comprises (1) one or more discrete foci of peripheral retinal necrosis, (2) circumferential spread, (3) occlusive arteriolar retinopathy, (4) a prominent vitreous or anterior
chamber inflammatory reaction, and (5) rapid disease progression in the absence of therapy. The visual outcome is generally poor if diagnosed late due to its propensity to cause complications like retinal detachment (RD).9,10 Lau et al.11 recommended prophylactic lasers and early vitrectomy to reduce chances of developing complications like retinal detachment. They also showed improvement of vision after surgery, though the visual prognosis remains guarded. Hillenkamp et al.12 indicated poor functional outcomes even in cases where early vitrectomy was performed. Various reports9-12 from the West provide us with the outcome of this infectious retinitis, although none are very encouraging. Apart from a few case reports13 no Indian study has reported the visual outcomes in ARN. Hence, the aim of the present study is to provide clinical
Received 17 March 2013; revised 17 June 2013; accepted 24 June 2013; published online 16 April 2014 Correspondence: Rupak Roy, Vitreo Retina Services, Aditya Birla Sankara Nethralaya, 147, E.M. Bypass, Kolkata – 700099, West Bengal, India. E-mail: [email protected]
170
Acute Retinal necrosis: management and outcomes. outcomes in patients presenting with classic features of ARN in an Indian scenario.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Emory University on 06/23/14 For personal use only.
MATERIALS AND METHODS This retrospective study was conducted in a tertiary eye care hospital in South India and included data from 1997 to 2007. All patients were diagnosed cases of acute retinal necrosis. Clinical diagnosis of ARN was based on the presence of (1) acute panuveitis, (2) occlusive retinal vasculitis (arteritis and phlebitis) with or without retinal hemorrhage, and (3) peripheral patchy necrotizing retinitis (usually multifocal). Other symptoms and signs, when present, were supportive of the diagnosis: ocular or periocular pain, conjunctivitis, episcleritis, scleritis, rapid circumferential spreading and coalescence of the necrotizing retinitis, and rhegmatogenous retinal detachments (RRD). Data were collected pertaining to age and gender, date of onset assessed by symptoms and signs (blurred or reduced vision, floaters, photophobia, pain, red eye), visual acuity at presentation and during follow-up (1-week, 1-month, 3-month, 6-month, and last follow-up), aqueous or vitreous tap for diagnostic PCR DNA analysis or cell culture, duration between onset of symptoms and appropriate treatment, extent of retinal involvement, occurrence of RD, type of treatment, and final functional and anatomical outcomes. Permission was granted by the Institutional Review Board to retrospectively review medical records. Prophylactic laser treatment was applied on the normal retina to surround the posterior edge of the necrotic retina by 3 consecutive rows of confluent and circumferential laser burns for extensive necrosis or diffuse patchy necrosis, or up to the ora serrata for sectoral necrosis. Prophylactic laser treatment was not applied when there was severe media opacity or presence of RD. All patients received intravenous antiviral treatment (acyclovir, 10 mg/kg thrice daily) for 7–10 days, followed by oral antiviral therapy (valacyclovir 1 g thrice daily or acyclovir 800 mg 5 times a day) for a further 6–8 weeks. Systemic corticosteroid treatment was instituted in all patients. The dosage of oral prednisolone was 1 mg/kg/day and was tapered by 10 mg every 5 days. Systemic corticosteroids were started 48–72 h after institution of anti viral therapy. Those eyes that had RRD underwent 20 G 3-port pars plana vitrectomy, induction of a posterior vitreous detachment if not already present— with 360-degree encircling and silicone oil or gas tamponade. A favorable functional outcome was deemed if the eyes achieved best-corrected visual acuity greater than 3/60 at final follow-up. Anatomical success was achieved if the eye had attached retina, clear media, and normal intraocular pressure at final follow !
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up. Regression analysis was performed with visual outcome as the final dependent variable and the various independent factors assessed were age, sex, presence of retinal detachment, extent of retinal involvement, and time delay between onset and treatment of disease. Statistical analysis was performed using the statistical software SPSS, version 11 (Chicago, IL, USA). A p value of less than 0.05 was considered statistically significant.
RESULTS A total of 62 eyes of 53 patients were evaluated for the study. The demographic data are enumerated in Table 1. Of a cohort of 53 Indian patients, 38 (71.7%) were males and 15 (28.3%) were females. The mean age of our patients was 36.04 years (range 6–70 years). The right eye was affected in 24 (38.7%) patients, whereas 38 (61.3%) had affliction in the left eye. Fortyfour (83.01%) patients had unilateral involvement, whereas 9 (16.98%) had bilateral involvement. In the bilateral cases the average duration between involvement of the fellow eye was 210.43 days (range 0–2190 days). The mean duration of follow-up was 820.02 days (180–3650 days). After analyzing the various referral diagnoses we found ARN to be diagnosed as posterior uveitis in 13 (24.5%), retinal vasculitis in 5 (9.45%), pars planitis in 5 (9.45%), panuveitis in 3 (5.66%), ischemic neuropathy in 3 (5.66%), glaucoma in 2 (3.77%), conjunctivitis 1 (1.88%), and sarcoidosis in 1 patient (1.88%). Acute retinal necrosis was a referral diagnosis in 10 (18.86%) of our patients. Ten (18.86%) patients did not have a referral diagnosis. Fifty-five eyes (88.7%) had active disease at presentation and 7 (11.2%) had inactive disease. All of our patients presented with a chief complaint of hazy vision. Ten (18.86%) of our patients had associated complaints such as headache and periocular pain, whereas rest did not have any associated complaints. Only 4 (7.54%) patients gave a history of varicella zoster (chicken pox) infection. On inquiring about any preceding features before the visual loss, only 4 (7.5%) gave a history of viral fever;
TABLE 1. Baseline characteristics of study subjects. Gender Eyes Laterality Age (mean years) Duration between onset and treatment (mean days) Duration of follow-up (mean days)
Male n (%) 38 (71.7) Right eye n (%) 24 (38.7%) Unilateral n (%) 44 (83.01) 36.04 (6–70) 27 (1–120)
820 (180–3650)
Female n (%) 15 (28.3) Left eye n (%) 38 (61.3%) Bilateral n (%) 9 (16.98)
172 R. Roy et al TABLE 2. Extent of retinal involvement and clinical outcome. Extent of involvement Up to 90 degrees 90–180 degrees 180–270 degrees 270–360 degrees Total retinal necrosis ARN sequlae
Number of eyes n (%) 4 9 7 32 3 7
(6.45) (14.51) (11.29) (51.61) (4.83) (11.29)
Anat scs n (%) 3 5 2 15 1 6
(75) (55.55) (28.57) (46.87) (33.33) (85.71)
Fn scs n (%) 3 4 2 14 0 5
(75) (44.44) (28.57) (43.75) (0) (71.42)
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Anat scs, attached retina, clear media and normal intraocular pressure; Fn scs, best-corrected visual acuity 43/60.
one had a history of herpes encephalitis. Among our cohort 2 patients were HIV positive. The mean visual acuity at the presentation was 2.02 logMAR units and the mean visual acuity at the final follow-up was 1.78 logMAR units. The difference between initial and final visual acuity was statistically significant (paired t test, p50.03). Mean duration of starting of appropriate treatment after the onset of the symptoms was 27 days (1–120 days). Table 2 enumerates the extent of retinal involvement at presentation and its correlation with the final outcome. Retinal involvement of 90 degrees or less in periphery was observed in 4 (6.45%) eyes; 90–180 degrees of peripheral retina was involved in 9 (14.51%) eyes. Lesions involving 180–270 degrees were observed in 7 (11.29%) eyes and 360 degrees of peripheral retinal involvement was seen in 32 (51.61%) eyes. Involvement of the whole retina was seen in 3 (4.83%) eyes. Seven (11.29%) eyes presented with ARN sequelae. Out of the cohort of 62 eyes 41 (66.12%) eyes had retinal detachment. Eighteen (29.03%) eyes had RD at presentation, whereas 23 (37.09%) eyes developed RD during the course of the disease. The mean duration between the onset of complaints and retinal detachment occurred on an average of 71.35 days (range 7–365). The aqueous and the vitreous samples revealed HSV in 19 (30.60%) and VZV in 28 (45.16%) eyes. The investigations did not reveal any organisms in 9 (14.51%) eyes. No samples were taken in 6 (9.67%) eyes. Polymerase chain reaction yielded a diagnosis in 37 (59.67%) of organism-positive patients, whereas in 9 (17.74%) cases the cell culture method yielded the diagnosis. Prophylactic laser photocoagulation was given in 19 (30.64%) eyes. Among the lasered eyes, 12 (23%) developed retinal detachment. In the nonlasered cohort of 43 (69.35%) eyes 29 (67.44%) developed RD. There was no significant difference in retinal detachment rates among lasered and nonlasered eyes (p value 0.43). Surgical intervention was required in 32 (51.61%) eyes. The indication for surgery was RD in 31 (98%) eyes, whereas vitreous haze was the indication in 1 (2%) eye. Ten eyes with RD did not undergo surgical procedure because 6 had retinal detachment with
optic atrophy with negative light perception at time of diagnosis, 2 had exudative RD that subsided with oral steroids and systemic acyclovir, 1 was phthisical, and 1 eye of a patient was best left alone without any surgical intervention in view of inoperable RD. In the RD group proliferative vitreoretinopathy (PVR) was seen in 14 (35%) eyes. Recurrent RD was seen in 14 of 31 eyes (45%); 6 of these had attached retina at final follow-up and the other 8 retinas remained detached with or without repeat surgeries. Silicon oil of 1300 and 5000 cSt was used in 21 and 6 eyes, respectively. C3F8 was used as tamponade in 1 eye. In 3 cases no tamponade was used as they were abandoned intraoperatively. Two cases were abandoned due to multiple large posterior breaks and the other case was abandoned due to posterior closed funnel configuration. Among all eyes favorable anatomical outcome (attached retina, clear media, and normal IOP) was present in 32 (51.61%) eyes. However, among the patients who underwent RD surgery, a successful anatomical outcome was seen in 17 of the 41 (41.46%) eyes. A favorable functional outcome (visual acuity better than 3/60) was seen in 28 (45.1%) eyes. In the 34 eyes with poor functional outcome, the major causes for poor visual potential were RD in 16 (47.05%), secondary optic atrophy in 10 (29.41%), phthisis in 4 (11.7%), hypotony in 3 (8.8%), and macular scar in 1 (2.9%) eyes. Regression analysis showed that the extent of involvement and time interval between onset of disease and start of the treatment were significant parameters that affected the visual potential (p value 0.03 and 0.01, respectively).
DISCUSSION In this retrospective study we analyzed the clinical outcomes of 62 eyes of 53 patients. To the best of our knowledge this is the first reported case series from India on acute retinal necrosis, its clinical presentation, management, and outcomes. We found that ARN has a slight gender predilection, male gender being affected more, and it typically affects patients who are between 20 and 60 years of age.14,15 In our study we found a male predilection (70%) and the age group ranged from 6 to 70 years. ARN is generally thought to be associated with an immunocompetent state,3 but we found this condition in 2 of our patients who were HIV positive, both of whom had unilateral but extensive involvement of retina. One had an associated HSV detected on PCR but the other had no isolation. Both of our patients were on HAART therapy at the time of presentation with a CD4 count of 400 and 300, respectively. Several cases have been reported in HIV-infected patients presenting with acute retinal necrosis Ocular Immunology & Inflammation
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Acute Retinal necrosis: management and outcomes. syndrome in association with skin manifestations of VZV infection.16 Chess and Marcus17 reported a case of bilateral acute retinal necrosis syndrome associated with unilateral herpes zoster ophthalmicus as the presenting sign of HIV infection. The etiology of ARN in HIV has been a matter of debate but one of the postulated mechanisms, other than defective cellmediated immunity and infection with VZV, has been a hypercoagulable state.18,19 Recently, occurrences of an ocular inflammatory syndrome identical in all respects to ARN have been recognized in immunosuppressed patients. This suggests that features of the specific etiologic agent(s), rather than the immune status of the infected individual, are responsible for producing the pattern of posterior segment infection known as ARN.20 Bilateral involvement occurs in approximately onethird of patients, but both eyes may not be affected simultaneously.21,22 A fellow eye involvement of 13.6% has been reported in a recent study.23 Our results showed that 9 (16.98%) had a bilateral involvement, of which 6 had bilateral involvement at the time of presentation, whereas 3 had the other eye involved during the course of treatment. Two of those patients had skipped the acyclovir therapy, whereas one was on a lower dose of acyclovir. Our study did not identify any risk factors for the bilaterality apart from a lower dose of acyclovir or treatment defaulters, suggesting need for optimal antiviral therapy and a close follow-up. Antiviral treatment is therefore essential to contain unilateral disease and minimize progression to bilateral retinitis. The virological results in our study are in accordance with those of Lau et al.24 and Hillenkamp et al.,12 indicating VZV as the most frequent organism causing ARN, followed by HZV. PCR has allowed rapid diagnosis in small ocular samples and has generally overtaken other local and systemic methods of virusspecific antibody detection. One of the important findings in our study was the importance of the extent of retinal involvement as a predictor of visual outcome. Eyes with less than 90% involvement had the best prognosis functionally, whereas total retinal necrosis had the worst functional outcomes. A recent study by Meghpara et al.25 supports our finding that the initial extent of retinal involvement can be a useful tool for predicting the visual potential of the affected eye. According to his work, eyes with 25% retinitis had better visual acuities at both the initial visit and the subsequent follow-up intervals. Visual acuity progressively deteriorated as the extent of retinitis increased to 25–50% and 100%. Similarly, in our patients best outcomes were achieved in eyes with less than 90-degree necrosis and worsened as the extent of involvement increased (Table 2). The other important factor influencing the final visual outcome is the time duration between the !
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presentation and start of treatment. A favorable functional outcome in only 28 (45.1%) of the study eyes could be attributed to delayed diagnosis and treatment (p value 0.01), which could lead to increased extent of necrosis in retina and subsequent retinal detachments. Our institute being a tertiary care center and ARN still being an underdiagnosed disease probably accounts for this delay. Overall the incidence of RD in our study was high (66%) and the rate was comparable to that found by Lau et al. (60%).24 Other studies25 have reported a lower prevalence of RD. The mean duration for the RD to occur in our study was 71 days, with other studies reporting the range from 32 to 65 days.12,24,25 The increased incidence of secondary retinal detachment could be because 35 (56.45%) of the eyes had involvement of all retinal quadrants or more and greater extent of retinal necrosis predisposes to increased chances of RD.25 Eyes without RD fared better compared to eyes with RD in terms of final anatomical and functional outcome (Table 3). The value of laser photocoagulation in ARN has always been a matter of debate. Some studies have reported it to be a useful modality in prevention of RD,26 whereas others have not found it to be beneficial.27 We did not find any protective role of laser photocoagulation in preventing retinal detachment. The comparison of lasered and nonlasered eyes is biased because in many eyes with severe ARN, vitreous inflammatory opacification precludes the application of laser, whereas eyes with mild ARN often present with relatively clear media that allows the application of laser. Prophylactic laser retinopexy also fails to prevent secondary RD when, after laser retinopexy, the involved retinal area continues to extend posteriorly beyond the demarcation of the laser burns. Eyes in which laser treatment is possible obviously have less retinitis and hence vitritis, which ultimately gives them a better chance at the final visual prognosis. Late-stage complications of ARN can only be managed by surgical intervention. In the present study surgical intervention was needed for 32 (51.6%) eyes. Predominant indication for surgery in our series was RD 31 (96.87%) eyes, whereas vitreous opacification necessitated surgery in 1 case.
TABLE 3. Outcomes related to retinal detachment. Anat scs
Patients with RD Patients without RD
Fn scs
No.
%
No.
%
17/41 15/21
41 71
16/41 12/21
39 57
Anat scs, attached retina, clear media and normal intraocular pressure; Fn scs, best-corrected visual acuity43/60; RD, retinal detachment.
174 R. Roy et al TABLE 4. Comparison with previous studies. Study
Year
N
Follow-up (days)
Predominant organism
RD (%)
Lau24 Tibbets28 Meghpara25 Present
2007 2010 2010 2012
22 58 20 53
1460 1020 622 820
Varicella zoster NA Varicella zoster Varicella zoster
51.9 50 20 66
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N, number of patients, RD, retinal detachment; NA, data not available.
Though in our study an early vitrectomy was not performed for acute retinal necrosis, Hillenkamp et al.12 have reported the role of early vitrectomy in prevention of secondary RD. Lau et al. reported24 better visual acuities in patients who underwent surgical interventions for retinal detachments. In our series, eyes without RD fared better both, anatomically and functionally, compared to those eyes with RD, but the difference was not statistically significant (Table 3). A comparative study with review of literature from published articles is shown in Table 4. In terms of visual acuity, organisms isolated and retinal detachments remain nearly the same in all the studies. In conclusion, we showed that a greater involvement of the retina at the onset portends a worse visual outcome. In addition, the use of laser retinopexy did not affect the chances of RD. The important thing to remember is the early diagnosis and referral of ARN suspected cases because early and aggressive treatment is the cornerstone of its management.
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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