Frequency of fibromyalgia syndrome in patients with central serous chorioretinopathy

Purpose:
To ınvestigate frequency of fibromyalgia syndrome (FMS) among patients with central serous chorioretinopathy (CSCR).


Methods:
The study included 83 patients with CSCR and 201 age- and sex-matched healthy controls; the mean age was 47.5 ± 11.3 years in the CSCR group (18 women; 21.7%) and 47.2 ± 11.2 years in the control group (44 women; 21.9%). All participants were assessed for FMS based on 2010 American College of Rheumatology diagnostic criteria and for depression and anxiety with the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI).


Results:
FMS was diagnosed in 35 patients (42.2%) from the CSCR group and in 21 individuals (10.4%) from the control group (p<0.001). It was found in 77.77% of the women (14/18) and 32.3% of the men (21/65) in the CSCR group and in 22.7% of the women (10/44) and 7.0% of the men (11/157) in the control group. Familial stress, BDI and BAI scores were higher in the patients with FMS than in those without. When independent risk factors were evaluated by logistic regression analysis, it was found that only the presence of familial stress was a significant risk factor for FMS.


Conclusions:
Patients with CSCR should be assessed for the presence of FMS, and this should be taken into consideration when developing a treatment plan. Further studies with a larger sample size are needed to clarify the relationship between FMS and CSCR.

Descritores: Coriorretinopatia serosa central; Fibromialgia; Doenças da coroide; Epi télio pigmentado ocular/patologia; Doenças retinianas seen at 20-55 years (6) .A diagnosis of FMS is used for heterogeneous pathological conditions associated with pain, including anxiety disor der, depression, lethargy, sleep disorders, and gastrointestinal symptoms (3,6) .These may be due to the presence of psychological di sorders concomitant with FMS; indeed, psychiatric symptoms are rather common and affect the course of the disease (7) .It has been reported that patients with FMS experience an increase in comorbid diseases, such as depression, anxiety, and bipolar disorder (7) .Some studies have reported disorders in personality traits in patients with FMS, supporting the idea that personality and mood disorders may predispose an individual to FMS (8,9) .Stress is an important risk factor for FMS (10) .In summary, it is known that depression and psychiatric di sorders increase with FMS.
Typically, acute CSCR is a self-limiting process in which visual acuity recovers within 1 to 4 months after onset, with a few recognized visual sequelae coinciding with the reattachment of the neurosensory re tina (11) .However, its recurrence is common, with approximately Arq Bras Oftalmol.2017;80(1):4-8 30%-50% of patients experiencing recurrence within one year (12) .Retinal pigment epithelium atrophy and changes in the neurosensory retina may develop in patients with frequent recurrences, or there may be chronic detachment of the neurosensory retina, resulting in permanent loss of visual functions such as visual acuity, color vision, and contrast sensitivity (13)(14)(15) .It is therefore important to prevent recurrence to protect ocular functions.All patients diagnosed with CSCR should be assessed for triggering and precipitating factors, which should then be modified (13) .FMS can accompany CSCR as these entities have similarities in etiopathogenesis (such as personality trait, stress, depression, and cortisol level).FMS and FMS-related psychiatric disorders accompanying CSCR may be involved in the recurrence of CSCR.In addition, the presence of acute stress-anxiety after a diagnosis of CSCR may play a role in the development of FMS.The aim of this prospective study was to investigate the frequency of FMS among patients with CSCR.

ParticiPants
All patients with a diagnosis of CSCR that were being followed up in the ophthalmology department of Antalya Teaching Hospital, Turkey, were screened for the following inclusion and exclusion criteria: a definitive diagnosis of CSCR, volunteering their participation, no known depression disorder or any psychiatric disease, no known comorbid disease, the absence of known rheumatic disease, the absence of a FMS diagnosis before the CSCR diagnosis, and no medica tion, including steroids and antidepressants.Overall, 83 patients fulfilled these criteria and were included to the study.As a control group, 201 age-and sex-matched healthy individuals were recruited from among hospital employees.The mean age was 47.5 ± 11.3 years (18 women; 21.7%) in the CSCR group and 47.2 ± 11.2 years (44 women; 21.9%) in the control group.The study was explained to all participants, who gave their written informed consent.The study was approved by the Ethics Committee of Antalya Training and Research Hospital (#2015-177) and was conducted in line with the principles in the Declaration of Helsinki.
Using a data sheet developed by the researchers, the following data were obtained for the patients: age, sex, body mass index (BMI), edu cation level, smoking status, marital status, occupation, work stress, familial stress, disease type (acute or chronic), and the presence of gastroesophageal reflux disease (GERD), which was assessed clinically.The patients were questioned about burning sensations and regurgitation, the classic symptoms of GERD, and GERD was defined as the presence of one or both of these symptoms at least once a week (16) .To exclude asymptomatic CSCR, all controls underwent ocular examination by an ophthalmologist.

Ocular examinatiOn
All participants underwent a detailed ocular examination, including for best-corrected visual acuity, a slit-lamp evaluation, and a di lated fundus examination.CSCR was confirmed by using fundus fluorescein angiography (FFA, Visucam NM/FA, Carl Zeiss, Germany) and fundus autofluorescence (FAF).Neurosensory or retinal pigment epithelium detachment was also assessed by optical coherence tomography imaging (Cirrus HD-OCT Model 5000, Carl Zeiss Meditec Inc., Dublin, CA, USA).If results were inconclusive, indocyanine angiography (Visucam NM/FA, Carl Zeiss, Germany) was performed to make a definitive diagnosis.A single experienced retinal specialist performed choroidal thickness measurements by EDI OCT using the SD-OCT mode of the device (Cirrus HD-OCT Model 5000, Carl Zeiss Meditec Inc., Dublin, CA, USA) according to a previously described technique (17) .The choroidal thickness was measured perpendicularly from the outer edge of the retinal pigment epithelium to the choroidsclera boundary at the fovea using a single line of 6-mm length cen-tered horizontally on the fovea for visualization of the choroid.Only the central subfoveal choroidal thickness was measured.

Other assessments
A rheumatologist performed a comprehensive examination of all participants, including a detailed history and a physical examination.Potential comorbid rheumatic disorders (such as undiagnosed connective tissue disorders) were assessed in both patients and controls to rule out secondary FMS.A diagnosis of FMS was based on the 2010 American College of Rheumatology (ACR) diagnostic criteria (18) .The Revised Fibromyalgia Impact Questionnaire (FIQR) was administered to the patients and controls diagnosed with FMS.In addition, the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were administered to all of the patients in the CSCR group and to the controls diagnosed with FMS.The following paragraphs describe these instruments in more detail.
The 2010 ACR Diagnostic Criteria for FMS were a new set of crite ria that included a widespread pain index (WPI) and a symptom severity scale.However, the criteria did not include tender points, which can be used as an alternative method for assessing FMS in routine clinical practice (18) .The WPI results in an overall score of 0-19 points, given by the number of up to 19 specific areas where the patient experienced pain over the previous week, including the left shoulder girdle, right shoulder girdle, right upper arm, left upper arm, right lower arm, left lower arm, right hip (gluteal region), left hip (gluteal region), right upper leg, left upper leg, right lower leg, left lower leg, right jaw, left jaw, chest, abdomen, upper back, lower back, and neck.Symptom severity scale assesses fatigue, waking unrefreshed, cognitive functions, and somatic symptoms, which include muscle pain, tiredness, irritable bowel syndrome, thinking or remembering problems, headache, abdominal pain, numbness/tingling, dizziness, insomnia, depression, constipation, and a dry mouth.The four items were each rated as 0-3 (0, none; 1, mild; 2, moderate; 3, severe), resulting in an overall score of 0-12 points.
The FIQR was used to assess functional status, disease progression, and outcomes.The validity and reliability of the Turkish version was confirmed by Bennett et al. (19) .The questionnaire includes 20 items covering physical function, occupation, depression, anxiety, sleep, pain, stiffness, fatigue, and well-being.
The BAI was developed by Beck et al. in 1988.It assesses the severity of anxiety symptoms experienced by an individual, addressing both subjective and somatic symptoms.It is a self-reported assessment scale including 21 items rated on a 3-point Likert scale.Higher total scores indicate greater severity of anxiety.The validity and reliability of the Turkish version have been confirmed (20) .
The BDI was developed by Beck et al. in 1961.It assesses an in dividual's risk for depression as well as the level of depressive symptoms and changes in their severity.It is a self-reported assessment scale including 21 statements rated on a 4-point Likert scale.The validity and reliability of the Turkish version have been confirmed (21) .

statistical analysis
Descriptive statistics are presented as frequency and per centage, mean and standard deviation (SD), or median with range.Fisher's exact test and Pearson's chi-square test were used to assess relationship between categorical variables.Normality was tested with the Shapiro-Wilks test for groups with a sample size <50 and with the Kolmogorov-Smirnov test for groups larger than this.Normality was assessed using the Shapiro-Wilks test when analyzing differences between measurements in two groups.Differences were tested using Student's t test for variables with normal distribution and using the Mann-Whitney U test for variables with skewed data.Variables found to be significant in univariate analysis were included into logistic regression analysis, with results presented by Wald statistics, odds ratio, and 95% confidence interval (CI).A p value <0.05 was considered to be statistically significant.All analyses were performed using SPSS version 22.0.

RESULTS
The CSCR and control group were comparable regarding age, sex, and educational level (Table 1).The mean disease duration was 18.8 ± 16.6 months and the mean choroidal thickness was 400 ± 111 µm in the CSCR group, with 23 patients (28.4%) having acute CSCR.Table 2 presents the characteristics of the CSCR group.FMS was diagnosed in 35 patients (42.2%) from the CSCR group and in 21 individuals (10.4%) from the control group (p<0.001).In the CSCR group, 14 women (14/35, 40%) and 21 men (21/35, 60%) were diagnosed with FMS.The BDI and BAI scores, FMS criteria score, and FIQR scores were comparable between the patients and controls diagnosed with FMS (Table 3).Women constituted 40% of the patients with FMS and 8.3% of those without FMS.Familial stress and BDI and BAI scores were higher in the patients with FMS than in those without.Table 4 presents the characteristics of patients with or without FMS in the CSCR group.All of the controls with FMS and 94.3% of the patients FMS were older than 30 years.The duration of education was <8 years for 62.9% of the FMS patients in the CSCR group and 38.1% of the controls with FMS.
When independent risk factors for FMS prevalence were evaluated by logistic regression analysis, it was found that only the presence of familial stress was a significant risk factor for FMS, with an odds ratio of 11.553 (95% CI: 2.117-62.708,Table 5).

DISCUSSION
In this study, we found increased frequency of FMS in the patients with CSCR compared with the control group, as well as thicker subfoveal choroid.Although choroidal thickening in CSCR eyes has already been reported, to the best of our knowledge this is the first report to show that FMS frequency increased in both female and male patients with CSCR compared with the controls.In the CSCR group, familial stress and BDI and BAI scores were significantly higher in the patients with FMS than in those without, although logistic regression analysis showed the only significant factor associated with the presence of FMS was familial stress.disorders (8) .One hypothesis is that psychiatric disorders develop as a response to FMS.Conversely, another hypothesis advocates that psychiatric disorders can trigger FMS symptoms.A third hypothesis suggests shared mechanisms in the pathophysiology of FMS and the psychiatric disorders (22) .For instance, prolonged stress causes the release of pro-inflammatory cytokines in brain, which, in turn, can pre dispose an individual to both psychiatric disorders and pain perception (23) .In addition, it is possible that acute emotional alterations experienced after a diagnosis of CSCR could trigger FMS.In our study, BDI and BAI scores were higher in patients with CSCR with FMS than in those without.There is a need for further studies with a larger sample size to clarify the association between CSCR and FMS.However, our results indicate that patients with CSCR should be assessed for concomitant FMS.The recurrence of CSCR could be prevented by the treatment of concomitant FMS, which is important for the protection of ocular functions.FMS is more common among women.In the USA, the prevalence of FMS has been reported as 3.4% among women and 0.5% among men (24) .In our study, FMS was detected in 22.7% of women and 7.0% of men in the control group, which is a higher frequency than found in previous studies.This finding may be due to the selection of the control group from among hospital employees, who were all active workers and were at ages where peak FMS prevalence is observed.In the CSCR group, FMS was detected in 77.7% of the women and 32.3% of the men; this frequency was significantly higher than in the controls, and the difference between men and women was also statistically significant.
In previous studies, it has been reported that FMS prevalence increases with advancing age (25) , with the likelihood of FMS lower in young adults than in middle-aged individuals.In our study, we found that FMS frequency did not change with age.However, all of the controls with FMS and 94.3% of the patients with FMS were older than 30 years.
In previous studies, FMS prevalence has been reported to be lower in single individuals (5,24) .However, we found that marital status did not affect FMS frequency in our study.In addition, education level was lower in patients with FMS than in those without, although this difference did not reach statistical significance.All potential parameters that could be associated with FMS frequency were assessed in logistic regression analysis, but only the presence of familial stress was found to be significantly associated with FMS frequency.
It is well known that depression and psychiatric disorders are increased by FMS.Stress is one of the most important factors implied in the pathogenesis of CSCR.Several recent studies have reported increased psychological distress in patients with CSCR in comparison to healthy controls (26) .Conversely, stress may be experienced as a result of the CSCR symptoms, given that a sudden loss of visual acuity can  It has been shown that depression and anxiety disorders are increased in patients with FMS when compared with other conditions with chronic pain (7) .Several suggestions have been proposed to explain the frequent association of FMS with depression and anxiety cause a considerable degree of psychological distress (26) .Stress may therefore contribute to an undesirable vicious circle in patients with CSCR, counteracting therapeutic efforts.A higher incidence of critical life events has been proposed as an important trigger in these patients (27) .
FMS is important for both the identification of comorbid psychiatric conditions and for developing the CSCR treatment plan.It has been suggested that depression observed in patients with FMS has different characteristics from those in other individuals; for example, negative ideation, helplessness, and anxiety are more commonly seen in patients with FMS (28) .It has also been reported that patients with FMS experience difficulty in recognizing self-emotions and coping with these emotions (29) .A relationship between CSCR and the type A personality trait has also been identified.Individuals with this personality trait may have insufficient ability to cope with the distress.
The most common symptom in patients with FMS is pain, with fatigue, poorer quality of life, insomnia, cognitive problems, morning stiffness, depression, and anxiety also being common (10) .Pain is the most important of these for causing a poorer quality of life.Prolonged pain results in physical, psychosocial, and social problems; thus, psychosocial and behavioral interventions and education are as important as medical therapies (30) .The successful management of FMS requires a multidisciplinary approach.
In conclusion, this is the first study to evaluate the prevalence of FMS in patients with CSCR.We found that FMS was more prevalent among patients with CSCR than in controls.The management of classic CSCR usually involves careful observation with risk factor modification.In most cases, a three-month period is sufficient to allow subretinal fluid to resolve spontaneously.Visual acuity typically returns to normal after a first episode.However, recurrent attacks lead to a progression to chronic CSCR and disrupted visual functions.It is therefore important to correct modifiable risk factors and to prevent recurrence in patients with CSCR.These patients should be assessed for the presence of FMS, and FMS should be taken into consideration when making a treatment plan.We consider the treatment of FMS to be important for reducing stress factors that play a role in the pathogenesis of CSCR.However, further studies are needed to clarify the association between FMS and CSCR.

Table 1 . Characteristics of the central serous chorioretinopathy (CSCR) and control groups Parameter CSCR group N=83
a = Mann-Whitney U test; b = Student's t test; c = Pearson chi-square test.

Table 5 . Logistic regression analysis of factors that could influence fibromyalgia syndrome
OR= odds ratio; CI= confidence interval; GERD= gastroesophageal reflux disease; BDI= beck depression inventory; BAI= beck anxiety inventory.