Prevalence of Ocular Manifestations and Visual Outcomes in Patients with Herpes Zoster Ophthalmicus

CLINICAL SCIENCE

Prevalence of Ocular Manifestations and Visual Outcomes in Patients With Herpes Zoster Ophthalmicus

Simon K. H. Szeto, MRCS,*† Tommy C. Y. Chan, FRCS,*† Raymond L. M. Wong, MRCS,*† Alex L. K. Ng, MRCS,‡ Emmy Y. M. Li, FRCS,*† and Vishal Jhanji, MD*†

associated with increased health care utilization, impact on Purpose: To investigate the prevalence of ocular manifestations and daily social and physical functioning, and work place pro- visual outcomes in patients with herpes zoster ophthalmicus (HZO). ductivity.2 Zoster vaccine has been shown to reduce the 3 Methods: Consecutive cases diagnosed with HZO who attended 2 incidence of herpes zoster by 50%. According to the Centers for Disease Control and Prevention, routine vaccination is hospitals between July 1, 2011, and June 30, 2015, were retrospec- $ tively reviewed. Patient demographics, clinical presentations, and recommended to all immunocompetent individuals aged 60 management were reviewed. The logistic regression model was used years. Herpes zoster ophthalmicus (HZO) is caused by to estimate the odds ratio of visual loss with ocular manifestations. reactivation of latent varicella zoster virus. It presents as painful vesicular rashes along the skin supplied by the Results: A total of 259 patients were included. Of these, 110 (42.5%) ophthalmic branch of the trigeminal nerve. It is believed that patients were ,60 years old and 149 patients (57.5%) were $60 years viral reactivation occurs as a result of declining cell-mediated old. None of the patients had received zoster vaccination before immunity, which can be associated with aging, impaired presentation. Ocular manifestations were present in 170 (65.6%) immunity, trauma, and psychological stress.4 HZO is associ- patients with no difference between both age groups (P = 0.101). ated with ocular and systemic morbidities including keratitis, Conjunctivitis was the most common ocular manifestation, followed uveitis, glaucoma, stroke, and depression secondary to by anterior uveitis and keratitis. After resolution of HZO, 58.7% of postherpetic neuralgia.5–8 patients had a visual acuity of 6/12 or worse. Epithelial keratitis and This study aims to investigate the prevalence of ocular stromal keratitis were independent risk factors for visual loss after manifestations and visual outcomes in patients with HZO at 2 resolution of HZO (P = 0.003 and P = 0.004, respectively). The hospitals in Hong Kong. corresponding odds ratio was 6.59 [95% confidence interval (CI): 1.87–23.19] and 7.55 (95% CI: 1.88–30.30), respectively. The number of ocular manifestations was also associated with an increased risk of visual loss with an odds ratio of 1.49 (95% CI: 1.01–2.20; P = 0.043). MATERIALS AND METHODS Conclusions: A substantial proportion of patients with HZO were This is a retrospective study of patients diagnosed with ,60 years old in this study. The absence of zoster vaccination across HZO at Hong Kong Eye Hospital and Queen Elizabeth the study cohort was noteworthy. Keratitis was the main reason for Hospital, the largest tertiary care ophthalmic hospital and poor visual outcome in these patients. largest general hospital in Hong Kong, respectively, between July 1, 2011, and June 30, 2015. Patients with incomplete Key Words: herpes zoster ophthalmicus, ocular manifestations, follow-up until resolution of HZO were excluded. The study visual outcome, postherpetic neuralgia was conducted in accordance with the tenets of the Declara- (Cornea 2017;36:338–342) tion of Helsinki. The study protocol was approved by the Institutional Review Board of Kowloon Central Cluster, Hospital Authority, Hong Kong. erpes zoster affects approximately 30% of the population Patient demographics, medical history, clinical presen- Hin the United States.1 The burden of herpes zoster makes tations, treatment, and outcomes were reviewed and analyzed. it a sizeable public health problem including expenses All patients were referred from physicians or private ophthalmologists for management of acute HZO. All patients were followed up and monitored for possible development or Received for publication July 17, 2016; revision received August 19, 2016; progression of HZO-related ocular complications. For the accepted August 24, 2016. Published online ahead of print October 12, purpose of this study, HZO was defined as the presence of 2016. From the *Hong Kong Eye Hospital, Kowloon, Hong Kong, China; typical vesicular rashes affecting the dermatome supplied by †Department of Ophthalmology and Visual Sciences, Chinese University the ophthalmic branch of the trigeminal nerve. Postherpetic of Hong Kong, Hong Kong, China; and ‡Department of Ophthalmology, neuralgia was defined as any symptom of pain or the use of The University of Hong Kong, Hong Kong, China. pain medications documented in medical records at least 3 The authors have no funding or conflicts of interest to disclose. Reprints: Tommy C. Y. Chan, FRCS, Hong Kong Eye Hospital, Kowloon, months after the onset of HZO. A search in the shared Hong Kong, China (e-mail: [email protected]). database by ophthalmologist, physicians, and psychiatrists Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. was performed to identify patients who had postherpetic

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Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cornea Volume 36, Number 3, March 2017 Herpes Zoster Ophthalmicus neuralgia or stroke. The patients were divided into 2 groups based on the age at onset of HZO (,60 and $60 years). Statistical analyses were performed using IBM/SPSS software version 21 (IBM/SPSS Inc, Chicago, IL). Group means were compared with the Mann–Whitney U test. Cat- egorical parameters were evaluated using the x2 test or Fisher exact test. Visual acuity was quantified as logarithm of the minimum angle of resolution for analysis. A multivariate logistic regression model with visual loss as the dependent variable was constructed. Visual loss was defined as reduction in the best-corrected visual acuity by $1 line after resolution of HZO or completion of antiviral medications and topical corticosteroids, compared with the best-corrected visual acuity at the time of presentation. The univariate logistic regression model was also used to estimate the odds ratio of visual loss and postherpetic neuralgia with the number of ocular manifestations. P , 0.05 was considered statistically significant. A false discovery rate, which measures the percentage of false discovery due to random errors, was evaluated for multiple statistical tests by the threshold of P ,0.05. It is estimated by the below formula

ðnumber of testsÞ · ðhighest P value obtained less than 0:05Þ · 100%: ðnumber of significant discoveriesÞ FIGURE 1. Distribution of HZO and its associated ocular manifestation among different age groups. The number of patients with or without ocular involvement for each age RESULTS group is indicated in each bar graph. The percentage of pa- A total of 259 patients (259 eyes) with HZO were tients with ocular involvement for each age group is shown on included. Thirty-three cases were excluded during the study the top of each bar graph. There was no significant difference period. The mean age was 62.7 6 17.5 years (range: 22–96 in the likelihood of ocular involvement among different age years). The mean follow-up duration was 9.3 6 10.2 months groups (P = 0.135). (range: 6 months–4 years). One hundred ten (42.5%) patients were ,60 years old, and 149 (57.5%) patients were $60 discovery rate of #0.9%. None of the cases had posterior years old. Male to female ratio was 1.07. The right-to-left uveitis or acute retinal necrosis. ratio was 1.19. Only 2 (0.8%) patients had a history of HZO. Oral antiviral medications (acyclovir or famciclovir) Fourteen patients (5.4%) had concomitant involvement of the were prescribed either by primary physicians or by ophthalmol- dermatome supplied by the maxillary branch of the trigeminal ogists in 250 (96.5%) patients within 72 hours of onset of nerve. The average duration from onset of symptoms to symptoms. None of our patients had received zoster vaccination examination by an ophthalmologist was 4.0 6 2.3 days before. The treatment profile of HZO is shown in Table 2. No (range: 0–14 days). Ninety-two (35.5%) patients had hyper- difference was observed between both age groups (P $ 0.14). tension, 34 (13.1%) had diabetes mellitus, 14 (5.4%) had The average duration of HZO, defined as the time between previous stroke, and 7 (2.7%) had underlying drug-induced onset of rashes and resolution of zoster disease or stopping of immunodeficiency. Hypertension, diabetes mellitus, and antiviral medications and topical steroids, was 28.3 6 28.2 a history of stroke were more common in patients aged days (range: 14–227 days) with no intergroup difference (P = $60 years (P , 0.006). None of the patients tested positive 0.645). None of the patients required acute surgical intervention for human immunodeficiency virus. due to HZO-related ocular involvement. Ocular manifestations were present in 170 (65.6%) The best-corrected visual acuity was 6/12 or worse in patients. There was no significant difference by age in decades 42.7% of the patients at the time of presentation and in 58.7% in terms of ocular involvement (P = 0.135) (Fig. 1). The of the patients after disease resolution. Visual loss was noted distribution of HZO-associated ocular manifestations is sum- in 12.4% of patients. Visual loss was not associated with sex marized in Table 1. The commonest ocular manifestation was (P = 0.867) and immune status (P = 1). The relationship conjunctivitis followed by anterior uveitis and keratitis. There between visual loss and different HZO-related ocular mani- was a significant difference in prevalence of conjunctivitis festations is shown in Table 3. A statistically significant between both age groups (P = 0.008) with a false discovery rate association was found between the presence of corneal of #7.2%. The Hutchinson sign was present in 57 (22.0%) (epithelial and stromal) involvement and visual loss (P # patients with no difference between age groups (P =0.397).It 0.01) with a false discovery rate of #4.0%. A multiple was associated with ocular involvement (P = 0.001), conjunc- logistic regression model was constructed with visual loss as tivitis (P = 0.003), and anterior uveitis (P = 0.002) with a false the dependent variable and age of the patients, presence of

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TABLE 1. Frequency of Ocular Manifestation in Patients With TABLE 3. Distribution of Age-Related and HZO-Related HZO Ocular Involvement With Visual Loss All ,60 Years ‡60 Years Visual No Visual (n = 259, %) (n = 117, %) (n = 149, %) P* Loss Loss P* Ocular 170 (65.6) 66 (56.4) 104 (69.8) 0.101 Age group (,60/$60), yrs 9/23 101/126 0.079 involvement Hutchinson sign (presence/absence) 4/28 53/174 0.166 Conjunctivitis 147 (56.8) 52 (44.4) 95 (63.8) 0.008 Ocular involvement Anterior 46 (17.8) 20 (17.1) 26 (17.4) 0.879 Conjunctivitis (presence/absence) 20/12 127/100 0.484 uveitis Scleritis (presence/absence) 0/32 8/219 0.601 Stromal 17 (6.6) 8 (6.8) 9 (6.0) 0.692 Epithelial keratitis (presence/ 6/26 7/220 0.002 keratitis absence) Epithelial 13 (5.0) 4 (3.4) 9 (6.0) 0.381 Stromal keratitis (presence/absence) 6/26 11/216 0.01 keratitis Endothelial keratitis (presence/ 1/31 2/225 0.328 Scleritis 8 (3.1) 3 (2.6) 5 (3.4) 1 absence) Endothelial 3 (1.2) 1 (0.9) 2 (1.3) 1 Anterior uveitis (presence/absence) 5/27 41/186 0.736 keratitis Optic neuritis (presence/absence) 0/32 1/226 1 Cranial nerve 3 (1.2) 2 (1.7) 1 (0.7) 0.575 palsy Cranial nerve palsy (presence/ 1/31 2/224 0.329 absence) Optic neuritis 1 (0.3) 0 (0) 1 (0.7) 1 , fi , $ , *P 0.05 represents statistical signi cance. *Comparison between patients aged 60 and 60 years with P 0.05 represents Note: Patients were counted more than once if presenting with .1 manifestation of HZO. statistically significant. Note: Patients were counted more than once if presenting with .1 manifestation of HZO. uveitis (P = 0.017) with a false discovery rate of #13.6% (Table 4). The number of ocular manifestation was also not conjunctivitis, epithelial keratitis, stromal keratitis, and ante- associated with postherpetic neuralgia (P = 0.218). There was rior uveitis as independent variables with backward selection no case of stroke after HZO during the follow-up period. by the Akaike information criterion. Epithelial keratitis and stromal keratitis were identified as risk factors for visual loss after resolution of HZO (P = 0.003 and P = 0.004, DISCUSSION respectively). The corresponding odds ratio was 6.59 [95% Ocular manifestations were present in 65.6% of patients confidence interval (CI): 1.87–23.19] and 7.55 (95% CI: with HZO in this study. Previous studies have shown the 1.88–30.30), respectively. None of the other independent variables were significantly associated with visual loss (P . 0.064). According to the univariate logistic regression model, the number of ocular manifestations was associated with an TABLE 4. Distribution of Age-Related and HZO-Related elevated risk of visual loss with an odds ratio of 1.49 (95% Ocular Involvement With Postherpetic Neuralgia CI: 1.01–2.20; P = 0.043). Postherpetic No Postherpetic P All cases resolved with treatment except 1 patient who Neuralgia Neuralgia * developed relapse of anterior uveitis after stopping topical Age group (,60/$60), yrs 9/8 140/102 0.692 steroids and required chronic antiglaucoma medications. There Hutchinson sign (presence/ 7/10 50/192 0.066 were 17 (6.6%) patients with postherpetic neuralgia, all of absence) whom required second-line analgesics (amitriptyline and Ocular involvement gabapentin) for pain control. The only ocular manifestation Conjunctivitis (presence/ 10/7 137/105 0.859 absence) that was associated with postherpetic neuralgia was anterior Scleritis (presence/ 1/16 7/235 0.424 absence) TABLE 2. Epithelial keratitis 0/17 13/229 1 Treatment Profile of Patients With HZO (presence/absence) All ,60 Years ‡60 Years Stromal keratitis 2/15 15/227 0.309 (n = 259, %) (n = 117, %) (n = 149, %) P* (presence/absence) Oral antiviral ,72 250 (96.5) 108 (93.4) 142 (95.3) 0.309 Endothelial keratitis 0/17 3/239 1 hours from onset (presence/absence) Topical antiviral 103 (39.7) 38 (32.5) 65 (43.6) 0.14 Anterior uveitis (presence/ 7/10 39/203 0.017 absence) Topical steroid 94 (36.3) 39 (33.3) 55 (36.9) 0.809 IOP-lowering 15 (5.8) 5 (4.3) 10 (6.7) 0.461 Optic neuritis (presence/ 0/17 1/241 1 medications absence) Cranial nerve palsy 0/17 3/239 1 *Comparison between patients aged ,60 and $60 years with P , 0.05 represents (presence/absence) statistically significant. Note: Patients were counted more than once if .1 medication was used. *P , 0.05 represents statistical significance. IPO, intraocular pressure. Note: Patients were counted more than once if presenting with .1 manifestation of HZO.

Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cornea Volume 36, Number 3, March 2017 Herpes Zoster Ophthalmicus prevalence of ocular manifestations ranging from 20% to complication. Prompt administration of systemic antiviral 90%.6,9–11 Keratitis and conjunctivitis have been reported as may also be the reason. common ocular manifestation of HZO in previous studies.6,9– Aging is a known risk factor for development of herpes 13 Anterior uveitis has also been reported as a common zoster,1 which is believed to be the result of declining specific intraocular manifestation of HZO.11 It was estimated that the cell-mediated immunity against varicella zoster virus.19 The relative risk of anterior uveitis for patients with HZO was Shingles Prevention Study Group conducted a double- 13.1 times greater than that of herpes zoster in general.14 In blinded, randomized controlled trial and concluded that the our cohort, conjunctivitis was the most prevalent ocular zoster vaccine reduced the incidence of herpes zoster by manifestation followed by anterior uveitis and keratitis. The 51.3% and postherpetic neuralgia by 66.5%.3 Routine same pattern persisted in patients who were below or above vaccination is recommended for all immunocompetent indi- the age of 60 years, although the prevalence of conjunctivitis viduals aged $60 years according to the Centers for Disease was significantly higher in the older age group. Ghaznawi Control and Prevention. The Food and Drug Administration et al reported that dendriform keratitis and recurrent inflam- licensed the use of zoster vaccine for individuals aged $50 mation were more common in patients less than 60 years. years after a report showing a 69.8% reduction in herpes Neurotrophic keratitis was common in older patients.12 zoster in individuals aged 50 to 59 years.20 However, one Unfortunately, corneal sensation was not tested in our routine third of our patients with HZO were aged below 60 years with practice, but we did not find any patient who had a persistent ocular manifestations, and most of our cases were immuno- epithelial defect after HZO. Early diagnosis of HZO and competent. A substantial number of our patients with ocular initiation of therapy can reduce the duration of symptoms and manifestation were among the younger age groups (Fig. 1). It prevent ocular complications.15 With prompt oral antiviral has also been shown that half of the patients with HZO with therapy and referral, the average duration of HZO of our ocular involvement are under the age of 60 years, and over patients was short, and only 1 patient had recurrent anterior 90% are immunocompetent.12 A recently published study uveitis and persistently elevated intraocular pressure. We reported declining age at presentation in over 900 patients believed that the short duration between disease onset and with HZO with the immunodeficiency status remaining administration of antiviral therapy in most (96.5%) of our unchanged over the study period.21 Furthermore, the risk of patients might explain the low rate of chronic zoster disease in stroke after herpes zoster was found to be greatest among the patients. individuals younger than 40 years,22 supporting the potential Mild to moderate visual loss has been reported in 10% role of zoster vaccination in the younger population. Cohen of patients with HZO at 6-month follow-up.16 In the present commented that vaccination for young patients can be study, visual loss was noted in 12.4% of the patients after considered but more research is needed using revised cost– HZO. Epithelial and stromal keratitis significantly reduced the benefit models.23 The vaccine is generally safe with local visual acuity despite treatment. This was mainly caused by inflammatory reactions being the most common complication the presence of corneal scars or haze after resolution of acute within the first week of vaccination.24 However, it is con- disease. Although we did not investigate the visual outcomes traindicated in individuals with impaired cellular immunity. compared with the premorbid state in our cohort, we noted This study was limited by its retrospective nature. It is that 58.7% of the patients had a best-corrected visual acuity of known that dermatomal pain without a rash is not uncommon, 6/12 or worse after disease resolution. It has been shown that and the diagnosis of HZO may be missed.15,25 Furthermore, not nasociliary nerve and lacrimal nerve involvement were all patients had eye involvement diagnosed during the initial associated with poor visual outcomes, whereas isolated visit to the ophthalmologist, as ocular manifestations could frontal nerve involvement was associated with good vision develop weeks to months after the initial diagnosis of HZO.9 after HZO.17 In another report by the same group, increasing Our study design also missed the patients who may have age, positive Hutchinson sign, absent corneal sensation, received further management elsewhere after the acute episode. corneal epithelial lesions, and uveitis were risk factors for This precluded analysis of patients is complicated with chronic poor visual outcomes.18 Although we did not observe or recurrent zoster disease and its associated complications. a significant association of poor visual outcomes with age, Because we were unable to obtain the premorbid visual acuity Hutchinson sign, and anterior uveitis, we noticed that the total of our patients, it is likely that some of the patients had HZO- number of ocular manifestation was weakly associated with induced acute visual loss at presentation. Nevertheless, we visual loss with an odds ratio of 1.49. demonstrated further visual loss after disease resolution We observed a lower rate of postherpetic neuralgia compared with vision at presentation. This study characterized (6.6%) compared with other studies in the literature, ranging only the marginal distribution of ocular manifestations with and from 13.3% to 20.9%.6,11–13 It has been demonstrated that without visual loss. The joint distribution of various ocular advanced age, presence of ocular involvement, severe initial manifestations was not reported. There may be a correlation rashes, and neuralgia are risk factors for this complication.6 between the various ocular manifestations. Apart from anterior uveitis, other ocular involvement and In conclusion, this study provided epidemiological data advanced age were not associated with higher incidence of regarding the demographics, clinical presentation, and visual postherpetic neuralgia in our patients. In our setting, most outcomes of patients with HZO in Hong Kong. A substantial patients who had postherpetic neuralgia were not managed by portion of patients with HZO and ocular manifestation was ophthalmologists. Patients may consult private physicians for among the younger age group. Corneal involvement was the the pain symptoms, leading to an underestimation of this main reason for poor visual outcomes.

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