Shift Work: a Risk Factor for Central Serous Chorioretinopathy

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Shift Work: A Risk Factor for Central Serous Chorioretinopathy

ELODIE BOUSQUET, MYRIAM DHUNDASS, MATHIEU LEHMANN, PIERRE-RAPHAE¨L ROTHSCHILD, VIRGINIE BAYON, DAMIEN LEGER, CIARA BERGIN, ALI DIRANI, TALAL BEYDOUN, AND FRANCINE BEHAR-COHEN

PURPOSE: To investigate if shift work or sleep distur- and focal serous detachments of the neurosensory retina bances are risk factors for central serous chorioretinop- and retinal pigment epithelium alterations. The role of athy (CSCR). choroid hyperpermeability in the pathogenesis of CSCR DESIGN: Prospective case-control study. has been well documented recently with multimodal imag- 2 METHODS: Forty patients with active CSCR and 40 ing modalities. In CSCR patients, a thick choroid has controls (age- and sex-matched) were prospectively been reported not only in the affected eye but also in the recruited from the Ophthalmology Department of Hoˆtel fellow eye, which is consistent with bilateral choroidal Dieu Hospital, Paris, between November 2013 and hyperpermeability.2,3 December 2014. All patients were asked to complete a To date, several risk factors for CSCR have been questionnaire addressing previously described risk factors identified,3 and the most consistent is corticosteroid and working hours, as well as the Insomnia Severity exposure from therapeutic administration or from endog- Index (ISI), a validated instrument for assessing sleep enous overproduction, as in Cushing syndrome.4–6 disturbances. Corticosteroids were recently shown to induce RESULTS: The mean age of the CSCR group was 44 ± 9 choroidal vasodilation through mineralocorticoid years, whereas the mean age of the control group was receptor activation in animal models.3 CSCR has also 43 ± 10 years. By use of multivariate analysis, shift been associated with increased sympathetic activity7 work (odds ratio [OR] [95% confidence interval]: 5 and sympathomimetic medication.8 Psychological stress9 [1.2–20.4]; P [ .02), steroid use (OR: 5.5 [1.1–26.2]; and type A personality10 with narcissistic traits11 P [ .03), and recent psychological stress (OR: have also been identified as contributing factors. 15.3 [4.1–54.5]; P < .001) were found to be indepen- Additional associations have been reported with hyper- dently associated with CSCR. tension, coronary heart disease, peptic ulcer disease, CONCLUSION: The outcomes of this study suggest that antihistamines, antibiotics, and psychopharmacologic shift work is an independent risk factor of CSCR. Further medications.6,12 studies are required to confirm these results and to ‘‘Shift work’’ includes work hours that fall outside the examine if work reconversion would be beneficial in the standard daylight hours (7 AM to 6/7 PM),13 including treatment of patients with chronic/recurrent evening, night, morning, rotating, and irregular shifts.14 Ó CSCR. (Am J Ophthalmol 2016;165:23–28. 2016 In industrialized countries, 15%–20% of the work force Elsevier Inc. All rights reserved.) have regular shift work.13–15 It leads to circadian misalignment and sleep disturbances that have been associated with increased risk of obesity, diabetes, ENTRAL SEROUS CHORIORETINOPATHY (CSCR) IS A cardiovascular disease, depression, and cancer.16,17 chorioretinal disease that most often affects Mechanisms underlying these health problems are not middle-aged men.1 It is characterized by posterior C fully elucidated but are thought to be related to sleep and circadian disruption.14 Indeed, sleep disturbances have Supplemental Material available at AJO.com. been associated with increased activities of the Accepted for publication Feb 15, 2016. hypothalamic-pituitary adrenal axis and the autonomic From the Department of Ophthalmology (E.B., M.D., M.L., P.-R.R., sympathoadrenal system, characterized by altered secretion T.B.) and Sleep and Vigilance Center (V.B., D.L.), Hoˆtel-Dieu of Paris, 18 Assistance Publique-Hoˆpitaux de Paris, AP-HP, Paris, France, of cortisol and catecholamine hormones. Universite´ Sorbonne Paris Cite´, Paris, France; Inserm U1138, Team 17, Since CSCR patients have higher levels of urine and Universite´ Sorbonne Paris Cite´, Universite´ Pierre et Marie Curie, plasma cortisol compared with the control group19,20 Centre de Recherche des Cordeliers, Paris, France (E.B., P.-R.R., F.B.- 21 C.); and Department of Ophthalmology University of Lausanne, Jules and increased levels of plasma catecholamines, we Gonin Ophthalmic Hospital, Fondation Asile des Aveugles, Lausanne, questioned whether shift work and/or sleep disturbance Switzerland (C.B., A.D., F.B.-C.). Inquiries to Elodie Bousquet, Hoˆpital Hoˆtel Dieu, 1 Parvis Notre Dame, evaluated by the Insomnia Severity Index (ISI) could 75004 Paris, France; e-mail: [email protected] be risk factors for CSCR.

0002-9394/$36.00 Ó 2016 ELSEVIER INC.ALL RIGHTS RESERVED. 23 http://dx.doi.org/10.1016/j.ajo.2016.02.012 METHODS TABLE 1. Univariate Risk Factors for Central Serous STUDY PATIENTS: Patients were prospectively included Chorioretinopathy between November 4, 2013 and December 31, 2014 at Control 95% the Department of Ophthalmology in the Hoˆtel Dieu Hos- Patients With Patients Odds Conﬁdence pital, Paris, France. The Ethics Committee of the French Exposure CSCR (n ¼ 40) (n ¼ 40) Ratio Interval P Value

Society of Ophthalmology approved this study. Informed Age, years 44.1 6 8.6 43 6 10.1 - - .6 signed consent was obtained from all subjects in compli- (mean 6 SD) ance with the tenets of the Helsinki agreement. Male (%) 85 85 - - 1 Patients of working age between 20 and 60 years and Sleep disorders 23 (57.5%) 6 (15%) 7.6 2.7–21.7 <.001 presenting symptoms of CSCR were enrolled. Active (ISI >10), n (%) CSCR was defined as a localized serous retinal detachment Shift work, n (%) 17 (42.5%) 6 (15%) 4.6 1.5–11.9 .007 on optical coherence tomography associated with angio- Steroid use, 15 (37.5%) 4 (10%) 5.4 1.7–17.3 .007 graphic leakage on fluorescein angiography without signs n (%) < of choroidal neovascularization, polypoidal choroidal Stress, n (%) 27 (67.5%) 5 (12.5%) 14.5 4.8–44.1 .001 vasculopathy, or inflammation. Chronic CSCR was defined Hypertension, 9 (22.5%) 3 (7.5%) 3.6 0.96–13.3 .06 n (%) by the persistence of serous retinal detachment (SRD) for Depression, n (%) 7 (17.5%) 9 (22.5%) 0.7 0.2–2.1 .6 more than 6 months and/or with recurrent SRD associated Allergic disease, 13 (32.5%) 14 (35%) 0.9 0.4–2.2 .8 with widespread decompensation of the retinal pigment n (%) 22 epithelium. Tobacco use, 17 (42.5%) 12 (30%) 1.7 0.7–4.3 .2 Control patients were matched for age and sex at a ratio n (%) of 1:1 and recruited at the emergency consultation with Alcohol use, 6 (15%) 4 (10%) 1.6 0.4–5.8 .5 ocular complaint but with no previous or ongoing retinal n (%) pathology. The frequency of diseases including conjuncti- ¼ ¼ vitis, blepharitis, chalazion, dry eye, keratitis, anterior CSCR central serous chorioretinopathy; ISI insomnia severity index. uveitis, refractive disorders, vitreous floaters, eye contu- sion, endophthalmitis, and migraine could not exceed 10% of the whole sample. off score of 10 has been previously selected to detect insomnia (86.1% sensitivity and 87.7% specificity).17 STUDY PROTOCOL: All patients were asked to complete study questionnaires, which included an ISI questionnaire STATISTICAL ANALYSIS: The data obtained were in addition to questions addressing previously identified analyzed with independent t test or Mann-Whitney test for risk factors such as history of systemic diseases (hyperten- continuous variables. Categorical variables were compared sion, depression, allergic disease), current medication (cur- using x2 or Fisher exact test. Risk factors were initially rent or recent [<3 months] corticosteroid intake [oral, analyzed using univariate linear regression analysis. Those intranasal, inhalational, topical skin application, intrave- with statistical significance on univariate analysis were nous, intramuscular, eye drop]), and degree of alcohol or included in multivariate analysis using logistic regression tobacco use. Recent psychological stresses including life with forward stepwise selection (stepAIC, MASS package). changes (death, divorce, familial strife, layoff) and stress Statistical analyses were performed with R version 3.1.3 (R at work were also assessed. Participants provided informa- foundation of Statistical Computing, Vienna, Austria). A tion on present and past (<1 year) working hours. Shift P value of less than .05 was considered significant. work was defined as work starting before 7:00 AM or finish- ing after 7:00 PM, and thus included evening, night, or early morning working within this broader schema. RESULTS

INSOMNIA SEVERITY INDEX: Sleep disturbances were PATIENT CHARACTERISTICS: A total of 40 CSCR evaluated using the ISI, which is a widely used instrument patients were compared with 40 sex- and age-matched con- for evaluating insomnia symptoms and severity.23 The ISI trol patients (Table 1). The mean age (6 standard devia- is a 7-item self-report questionnaire assessing the severity tion [SD]) of the CSCR group was 44.1 6 8.6 years, of sleep onset, sleep maintenance, early-morning awak- whereas the mean age of the control group was 43 6 10.1 ening problems, sleep dissatisfaction, interference of sleep years (P ¼ .6). Both the CSCR and the control groups difﬁculties with daytime functioning, noticeability of sleep were composed of 34 male (85%) and 6 female patients problems by others, and distress caused by the sleep difﬁ- (15%), with a male-to-female ratio of 5.6:1. culties, with a total score ranging from 0 to 28 In the CSCR group, 26 patients (65%) had an acute form (Supplementary Material, available at AJO.com).17 A cut- of the disease and 14 patients (35%) had a chronic CSCR,

24 AMERICAN JOURNAL OF OPHTHALMOLOGY MAY 2016 FIGURE. Insomnia Severity Index (ISI) score obtained in central serous chorioretinopathy (CRSC) and control group. (Left) The mean of the ISI score was significantly higher in the CSCR group (9.6 ± 6.2) than in the control group (4.1 ± 4.5; P < .001). (Right) ISI score was higher in the CSCR group than in the control group for ISI 1A, ISI 1B, ISI 1C, ISI 2, ISI 3, and ISI 5. The ISI score comprises 7 items assessing the severity of sleep onset (ISI 1A), sleep maintenance (ISI 1B), early-morning awakening problems (ISI 1C), sleep dissatisfaction (ISI 2), interference of sleep difficulties with daytime functioning (ISI 3), noticeability of sleep problems by others (ISI 4), and distress caused by the sleep difficulties (ISI 5).

defined by the persistence of the SRD for more than Recent psychological stress was reported in 27 CSCR 6 months and/or with recurrent SRD associated with bilat- patients (67.5%) and in 5 control patients (12.5%; eral widespread retinal pigment epithelium alterations.22 P < .001; OR: 14.5 [4.8–44.1], Table 1). Among the 27 CSCR patients, 14 patients reported stressful life changes UNIVARIATE ANALYSIS: Previously reported risk factors, (death, disease, divorce, familial strife, layoff) and 13 sleep disturbance, and shift work were first analyzed with patients reported stress at work. The 5 control patients univariate analysis (Table 1). reported work-related stress. Sleep disturbances evaluated with the ISI questionnaire Other previously reported risk factors, such as hyperten- occurred more frequently in patients with CSCR (57.5% sion, depression, allergy, and tobacco or alcohol use, were had ISI score >10) than it did in the control group not statistically significantly different in CSCR and control (15%; P < .001; odds ratio [OR] [95% confidence interval]: groups (Table 1). 7.6 [2.7–21.7]; Table 1). Moreover, the mean of the ISI score (6 SD) was significantly higher in the CSCR group MULTIVARIATE LOGISTIC REGRESSION (9.6 6 6.2) than in the control group (4.1 6 4.5; ANALYSIS: A stepwise logistic regression confirmed the P < .001; Figure). We also examined the relationship following risk factors (Table 2): shift work (P ¼ .02; OR: between CSCR type and sleep disorders, which were 5 [1.2–20.4]), corticosteroid use (P ¼ .03; OR: 5.5 more frequently observed in cases of chronic CSCR [1.1–26.2]), and recent psychological stress (P < .001; (78.6% had ISI score >10) than in acute CSCR (46.1%; OR: 15.3 [4.1–54.5]). P < .05). Seventeen CSCR patients (42.5%) had performed shift work, vs 6 patients (15%) in the control group (P ¼ .007; OR: 4.6 [1.5–11.9], Table 1). Shift workers had a higher ISI score than day workers (ISI mean 6 SD, shift workers: DISCUSSION 10.9 6 5.5 vs day workers: 5.2 6 5.5; P < .001). Previously reported risk factors were also analyzed. IN THIS STUDY, SHIFT WORK AND SLEEP DISTURBANCE WERE Corticosteroid use was present or reported in the reported significantly more frequently in CSCR patients 3 months before the first CSCR symptoms in 15 patients than in matched control individuals. Shift work was re- (37.5%)oftheCSCRgroupand4patients(10%)inthe ported by 15% of individuals in the control group, consis- control group (P ¼ .007; OR: 5.4 [1.7–17.3], Table 1). tent with the percentage of shift workers in the Among the 15 CSCR patients, use of corticosteroids industrialized countries.14 However, in the CRSC patients was topical skin application in 5 patients (33.3%), intra- this was elevated to 42.5%. We can speculate that shift nasal administration in 4 patients (26.7%), oral medica- work could affect the course and the severity of CSCR. tion in 4 patients (26.7%), intravenous injection in Indeed, sleep disturbances were found more frequently in 1 patient (6.7%), and intramuscular injection in 1 pa- chronic CSCR than in the acute form. In our study data, tient (6.7%). In the control group, among the 4 patients shift workers had a higher ISI score than day workers; reporting corticosteroid use, 2 reported eye drop, this agrees well with previous studies, which reported a 1 topical skin application, and 1 oral corticosteroid strong association between shift work and sleep distur- administration. bance.15,24,25

VOL. 165 SHIFT WORK AND CENTRAL SEROUS CHORIORETINOPATHY 25 29% of patients had elevated single morning plasma cate- TABLE 2. Multivariate Adjusted Risk Factors for Central cholamine levels. These observations support the potential Serous Chorioretinopathy involvement of corticosteroid and possibly cathecholamine metabolism deregulation in the pathogenesis of CSCR. P Exposure Odds Ratio 95% Confidence Interval Value Melatonin, a major marker of biological-clock activity,32 Shift work, n (%) 5 1.2–20.4 .02 is secreted by the pineal gland with a marked circadian Steroid use, n (%) 5.5 1.1–26.2 .03 rhythm, peaking at night for a duration directly related to Stress, n (%) 15.3 4.1–54.5 <.001 the length of the night.33 Melatonin production is suppressed by light through melanopsin ganglion cell acti- In large epidemiologic studies, shift work has been recog- vation in the retina during daylight, explaining the lower nized as a risk factor for cardiovascular diseases, diabetes, level of melatonin detected in shift workers exposed to obesity, depression, and certain types of cancers, raising light during night time.13,34 Melatonin rhythm and levels public health concerns.13 Circadian disruption resulting have not been explored in CSCR patients. But a recent from shift work may act as a pathogenic factor,14 enhancing study, although in a limited number of patients, showed the activity of neuroendocrine and pro-oxidative systems potential beneficial effect of oral melatonin in patients and reducing immune defenses. Several studies have with nonresolving CSCR.35 assessed the impact of shift work schedules on stress Although prospective and controlled, this study still has hormone rhythms and levels. In particular, cortisol and cat- limitations. Sleep disturbance, evaluated by the ISI ques- echolamines are controlled by circadian regulation, the tionnaire, was significantly more frequent in CSCR sleep/wake cycle,26 light exposure conditions,27 and the patients, and even more so in patients with chronic pattern of activity.28 Cortisol follows a strict diurnal CSCR, than in matched control subjects. While shift rhythm, with peak levels in the early morning and lower work is a recognized cause of sleep disturbance, a full anal- levels in the evening and night periods. Plasma epineph- ysis of sleep disturbance mechanisms was not undertaken in rine and norepinephrine levels, markers of sympathetic this study. Other reasons for sleep disturbance were previ- nervous activity, exhibit endogenous circadian rhyth- ously identified in CSCR patients, such as anxiety36 and micity, with a maximum release during the middle of the obstructive sleep apnea (with contradictory results day and minimum release during the night.16 Both cortisol reported).37,38 Sleep disturbance is multifactorial and and catecholamine rhythms can thus be deregulated in impossible to separate fully from the other contributing shift workers and therefore may contribute to the CSCR factors. Another weakness is the subjective assessment of pathophysiology. sleep with a questionnaire scoring as compared to the Indeed, the role of corticosteroid and possibly catechol- objectivity of polysomnography. However, the ISI amines has previously been recognized in the pathophysi- questionnaire has been shown to correlate well with ology of CSCR.3 Many of the described risk factors, such polysomnography, indicating that ISI is a useful and a as therapeutic corticosteroid use, psychological stress, simple tool to quantify perceived insomnia severity.39 type A personality, and pregnancy, are conditions associ- The sample size, although relatively small, allowed ated with alteration of glucocorticoid metabolism.29 recognition of the 2 main identified risk factors: corticoste- CSCR develops in up to 5% of patients with endogenous roid intake and stress. Importantly, a significant association Cushing syndrome.30,31 The metabolism of systemic and was identified between shift work and CSCR. Shift work ocular corticosteroids in CSCR patients as compared to may be an independent risk factor for CSCR patients, matched controls has not yet been fully analyzed. But and further research should be undertaken to confirm these several studies have documented that 8 AM and 11 PM preliminary results. Workday reconfiguration should be serum cortisol levels and total 24-hour urine cortisol levels considered as part of the therapeutic scheme of patients were significantly higher in acute CSCR patients than in with chronic and/or recurrent CSCR. If confirmed, controls.19 Another study29 demonstrated that 50% of CSCR could be added to the long list of shift work–associ- CSCR patients had elevated 24-hour urine cortisol and ated diseases.

FUNDING/SUPPORT: THIS WORK WAS SUPPORTED BY GRANTS FROM THE FONDATION VISIO. FINANCIAL DISCLOSURES: THE following authors have no ﬁnancial disclosures: Elodie Bousquet, Myriam Dhundass, Mathieu Lehmann, Pierre-Raphae¨l Rothschild, Virginie Bayon, Damien Leger, Ciara Bergin, Ali Dirani, Talal Beydoun, and Francine Behar-Cohen. All authors attest that they meet the current ICMJE criteria for authorship.

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