Ocular Immunology & Inflammation, Early Online, 1–5, 2014 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2014.916309
ORIGINAL ARTICLE
Retinal and Choroidal Thickness in Children with Familial Mediterranean Fever Mesut Erdurmu¸s, MD1, Mervan Bekda¸s, MD2, Fatih Demirciog˘lu, MD2, Adem Soydan, MD1, Sevil Bilir Go¨ksu¨gu¨r, MD2, and Erol Kısmet, MD2
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Cornell University on 06/11/14 For personal use only.
1
Department of Ophthalmology and 2Department of Pediatrics, Abant Izzet Baysal University Medical School, Bolu, Turkey
ABSTRACT Purpose: The aim of the present study was to evaluate retinal and choroidal thicknesses in children with familial Mediterranean fever (FMF). Methods: Thirty patients with FMF and 28 healthy controls were included in the study. The thicknesses of the retina and choroid of each subject’s right eye were measured at the fovea and horizontal nasal and temporal quadrants at 500-mm intervals to 1500 mm from the foveal center using spectral-domain optic coherence tomography. Results: Retinal and choroidal thicknesses at the fovea did not differ between groups (p = 0.32 and p = 0.39, respectively). Horizontal nasal and temporal retinal and choroidal thickness measurements at 500-mm intervals to a distance of 1500 mm from the foveal center were also similar between the groups (all p40.05). Conclusions: The retinal and choroidal thicknesses of children with FMF do not differ from those of age- and sex-matched healthy controls. Keywords: Childhood, choroidal thickness, enhanced depth imaging, familial Mediterranean fever, optical coherence tomography
Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder characterized by recurrent acute attacks of fever and polyserositis. People of Mediterranean ancestry, most commonly Sephardic Jews, Turks, Armenians, and Arabs, are more susceptible to the disease than are individuals of other ethnicities.1 Most patients develop symptoms in childhood, although in 10% of cases, the disease is not diagnosed until after age 20. FMF is the most common cause of renal failure due to amyloidosis in children.2 Amyloidosis in FMF results from extracellular accumulation of the acute-phase reactant serum amyloid A (SAA) protein; SAA levels increase after inflammatory stimulation.3 FMF is generally
treated with colchicine, which may prevent acute febrile attacks and fatal complications of the disease. FMF is caused by missense mutations in the MEditerranean FeVer (MEFV) gene, which alter the structure and function of the pyrin protein.4 These alterations interfere with pyrin’s ability to regulate inflammatory pathways, resulting in prolonged or augmented inflammation and predisposing FMF patients and carriers of the MEFV mutation to a proinflammatory state. This increased inflammation may increase susceptibility to vascular comorbidities in FMF patients. Systemic vasculitides affecting small and medium vessels, including Henoch– Schonlein purpura, polyarteritis nodosa, and Behc¸et
Received 17 January 2014; revised 2 March 2014; accepted 14 April 2014; published online 5 June 2014 Correspondence: Mesut Erdurmus, MD, Associate Professor, Department of Ophthalmology, Abant Izzet Baysal University Medical School, 14280, Bolu, Turkey. E-mail: [email protected]
1
2
M. Erdurmu¸s et al.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Cornell University on 06/11/14 For personal use only.
FIGURE 1. Representative spectral-domain optical coherence tomographic image with retinal and choroidal thickness measurements. The œ symbols indicate predefined measurement points.
disease, are more common in patients with FMF than in the general population.5–9 The vascular layer of the eye, the choroid, along with the ciliary body and iris form the uveal tract, which lies between the retina and the sclera and contains choroidal vessels, connective tissue, and melanin. Larger-diameter vessels are located in the outermost layer of the choroid, and medium-sized vessels lie between the larger-diameter vessels and choriocapillaris. The choroid plays an important role in supplying nutrients to and removing waste products from the outer region of the retina. The choroid is more vulnerable to the effects of inflammatory and vascular systemic diseases than are other eye tissues. Recent developments have improved choroidal imaging by optical coherence tomography (OCT).10 In the present study, we aimed to compare the thicknesses of the retina and choroid in patients with FMF with those of age- and sex-matched healthy children using spectral-domain OCT.
MATERIALS AND METHODS All participants received a detailed explanation of the study and signed an informed consent form in accordance with the principles embodied in the Declaration of Helsinki. This study was approved by the local institutional ethics committee. Subjects included children with FMF who were already being treated by the pediatrics department of our institution and age- and sex-matched healthy volunteers (controls). Exclusion criteria included previous eye trauma, previous ocular surgery, congenital malformations of the eye, amblyopia, refractive error greater than ±1 diopters, and inability to cooperate during a screening OCT examination. The diagnosis of FMF was based on Tel–Hashomer criteria.11 All subjects underwent a thorough ophthalmic evaluation, which included slit-lamp biomicroscopy, intraocular pressure (IOP) measurement, and fundus examination. Demographic data, such as age, gender, duration of FMF, and systemic
medication(s), were collected from a computerized patient database. Only the right eye of each study participant was assessed. All procedures were performed in one session in the morning to eliminate the contribution of diurnal fluctuations in choroidal thickness.12 One experienced examiner (AS) measured the retinal and choroidal thicknesses in all participants. All subjects were examined with undilated pupils using an enhanced depth imaging (EDI) system with multimodal capabilities (wavelength: 870 nm; scan pattern: EDI; Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany). Images were constructed from an average of 100 scans using the automatic averaging and eye-tracking features of the supplied Heidelberg Eye Explorer software (version 1.5.12.0; Heidelberg Engineering), which was also used for image analysis. Choroidal thickness was measured manually from the outer portion of the hyperreflective line corresponding to the retinal pigment epithelium (RPE) to the inner surface of the sclera. Retinal thickness (from the RPE to the internal limiting membrane) was measured using the same technique. Each thickness was measured at the foveal center and within the horizontal nasal and temporal quadrants at 500-mm intervals to a distance of 1500 mm from the foveal center. The central and total macular volumes were calculated by estimating the distance between the inner limiting membrane and Bruch’s membrane in 1- and 6-mm-diameter cylinders, respectively, using the OCT software’s segmentation algorithm. Figure 1 summarizes retinal and choroidal thickness measurements using spectral-domain optical coherence tomography and identifies the above-mentioned measurement points.
Statistical Analysis All analyses were performed using the SPSS for Windows V.15.0 software package. Continuous variables are presented as means ± SD. Categorical variables are presented as frequencies accompanied by percentages. Differences in measured parameters Ocular Immunology & Inflammation
Retinal and Choroidal Thickness in Childhood FMF 3 between the two groups were analyzed by independent-samples t tests or Mann–Whitney U tests, as appropriate. Correlations between variables were analyzed by Pearson’s or Spearman’s correlation coefficients. Differences were considered significant when the p value was less than 0.05.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Cornell University on 06/11/14 For personal use only.
RESULTS The mean ages of FMF patients (n = 30, 14 female, 16 male) and controls (n = 28, 17 female, 11 male) were 11.7 ± 5.1 years and 13.5 ± 4.7 years, respectively. There was no difference between the groups in terms of age or sex (p = 0.16 and p = 0.28, respectively). Demographic data and disease characteristics of the FMF patients are summarized in Table 1. Retinal and choroidal thicknesses at the foveal center were 213 ± 17.3 mm and 336.1 ± 78 mm in FMF patients and 217 ± 12.1 mm and 352.1 ± 60 mm in controls, respectively. Retinal and choroidal thicknesses at the fovea did not differ between groups (p = 0.32 and p = 0.39, respectively). Retinal and choroidal thicknesses at each point within the horizontal nasal and temporal quadrants were also similar between FMF patients and controls (all p40.05). Table 2 provides retinal and choroidal thicknesses at each point for both groups and the significance values of each comparison. The central macular volume was 0.205 ± 0.015 mm3 in FMF patients and 0.203 ± 0.013 mm3 in controls. TABLE 1. Demographic data and disease characteristics of the familial Mediterranean fever (FMF) patients. Data/characteristics
Mean or frequency
Age (years) Gender (female/male) Family history of FMF Duration of FMF (years) Drug usage (months) Temperature Abdominal pain Chest pain Arthritis
11.7 ± 5.1 (9.8–13.6) 14/16 17 of 30 4.7 ± 2.8 (3.6–5.7) 28.1 ± 25.6 (18.6–37.6) 22 of 30 (73.3%) 27 of 30 (90%) 13 of 30 (43.3%) 16 of 30 (53.3%)
The total macular volume was 8.75 ± 0.53 mm3 in FMF patients and 8.6 ± 0.52 mm3 in controls. There was no statistically significant difference between the groups in terms of central macular volume (p = 0.65) or total macular volume (p = 0.38). There was no association between the demographic or disease characteristics (age, gender, family history of FMF, duration of disease, drug usage, temperature, abdominal pain, arthritis, and chest pain) and any of the measured parameters.
DISCUSSION Since the introduction of in vivo choroidal imaging using spectral-domain OCT, associations between the anatomy of the choroid and pathologic conditions have become better studied. FMF is an autoinflammatory disease that affects almost all organs. The present study was designed to examine for the first time in the literature whether retinal and choroidal thicknesses in children with FMF differed from those of age- and sex-matched healthy controls; no differences were observed. Moreover, central and total macular volume in FMF patients did not differ from controls, and no clinical characteristics of the disease were correlated with individual retinal or choroidal thickness. The choroid is a vascularized and pigmented tissue that extends from the ora serrata anteriorly to the optic nerve posteriorly. Histopathologic evaluations of choroid tissue have been performed since the 17th century and have determined that it is 0.22 mm thick posteriorly and 0.10–0.15 mm thick anteriorly.13 Until recently, the choroid could only be evaluated by indocyanine green angiography, laser Doppler flowmetry, and ultrasound.14,15 Although these techniques are useful for determining vessel abnormalities or changes in the choroidal blood flow, they do not provide three-dimensional anatomical information about the choroid. The development of OCT, which is analogous to ultrasonography but with greater resolution, enables high-quality cross-sectional imaging of the macula or ONH.
TABLE 2. Retinal and choroidal thicknesses in predefined reference points in the groups. FMF group (n = 30) Location Foveal center Nasal (500 mm) Temporal (500 mm) Nasal (1000 mm) Temporal (1000 mm) Nasal (1500 mm) Temporal (1500 mm) !
p Value
Control group (n = 28)
Retinal thickness (mm)
Choroidal thickness (mm)
Retinal thickness (mm)
Choroidal thickness (mm)
Retinal thickness
Choroidal thickness
212.97 ± 17.27 296.63 ± 19.49 293.23 ± 20,30 347.16 ± 15.80 332.47 ± 14.28 352.63 ± 16.47 325.20 ± 17.32
336.07 ± 78.03 324.23 ± 76.83 318.60 ± 73.18 314.50 ± 75.92 307.17 ± 71.90 287.17 ± 78.55 297.83 ± 74.72
216.93 ± 12.11 291.35 ± 19.87 295.36 ± 21.13 342.64 ± 14.70 332 ± 15.17 350.57 ± 15.13 323.10 ± 15.99
352.14 ± 59.95 329.50 ± 57.49 345.89 ± 68.12 312.93 ± 54.19 339.75 ± 62.32 285.11 ± 49.96 322.39 ± 66.27
0.32 0.31 0.70 0.27 0.91 0.62 0.64
0.39 0.77 0.15 0.93 0.07 0.9 0.19
2014 Informa Healthcare USA, Inc.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Cornell University on 06/11/14 For personal use only.
4
M. Erdurmu¸s et al.
However, adequate morphologic examination of the choroid using OCT has not been possible until recently owing to its posterior location and the presence of pigmented cells in the RPE that attenuate incident light. Recent reports have demonstrated successful examination and measurement of choroidal thickness in normal and pathologic states using spectral-domain OCT instruments16–20 and good reproducibility and repeatability of choroidal thickness measurements using the Heidelberg Spectralis OCT device.21 Globally, familial Mediterranean fever (FMF) is the most common autoinflammatory disease, affecting 1 of every 250–1,000 the inhabitants of the Eastern Mediterranean region, where it is most prevalent.22,23 The most commonly encountered ocular findings of FMF included episcleritis,24 posterior uveitis,25 retinal abnormalities,25 amaurosis fugax,26 optic nerve edema,27 and ocular surface and tear-film abnormalities.28 A literature search identified no studies of changes in retinal and choroidal thicknesses in patients with FMF, particularly in children. Therefore, the present study sought to compare the thicknesses of the retina and choroid of FMF patients with those of healthy controls using EDI OCT. We found that neither the retinal nor choroidal thickness of FMF patients differed from that of controls, nor were demographic variables or disease characteristics associated with retinal or choroidal thickness. The measured choroidal thickness values in our sample were consistent with those of previous studies in children of similar age.29–31 However, unlike previous studies, we found no correlation between age or sex and choroidal measurements. This difference may be due to either our small sample size and strict exclusion criteria or other unknown factors that could affect the measurements. In the present study, the choice to have all measurements performed by a single experienced OCT operator was based on previous reports that interobserver variability may reach 32 mm.32 However, some degree of intraobserver variability is an unavoidable problem in caliper-assisted manual choroidal thickness measurement. There are several limitations of the present study. First, this was a single-center study, and thus the data may not be representative of all FMF patients. Another limitation was the relatively small sample size. Retinal and choroidal thickness may change during FMF attacks, but only five of our measurements were taken during acute attacks. In conclusion, retinal and choroidal thicknesses of children with FMF were not significantly different from those of controls. Further studies are warranted to evaluate choroidal thickness in FMF patients in a larger sample, particularly during acute attacks.
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. Gershoni-Baruch R, Shinawi M, Leah K, et al. Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet. 2001;9:634–637. 2. Bilginer Y, Akpolat T, Ozen S. Renal amyloidosis in children. Pediatr Nephrol. 2011;26:1215–1227. 3. Lachmann HJ, Goodman HJB, Gilbertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356:2361–2371. 4. Ozc¸akar ZB, Yalc¸ ınkaya F. Vascular comorbidities in familial Mediterranean fever. Rheumatol Int. 2011;31: 1275–1281. 5. Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever (FMF) in Turkey: results of nationwide multicenter study. Medicine. 2005;84:1–11. 6. Ozdogan H, Arisoy N, Kasapcopur O, et al. Vasculitis in familial Mediterranean fever. J Rheumatol. 1997;24:323–327. 7. Touitou I, Magne X, Molinari N, et al. MEFV mutation in Behcet’s disease. Hum Mutat. 2000;16:271–272. 8. Atagunduz P, Ergun T, Direskeneli H. MEFV mutations are increased in Behcet’s disease (BD) and are associated with vascular involvement. Clin Exp Rheumatol. 2003;21:35–37. 9. Rabinovich E, Shinar Y, Leiba M, et al. Common FMF alleles may predispose to development of Behcet’s disease with increased risk for venous thrombosis. Scand J Rheumatol. 2007;36:48–52. 10. Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol. 2009;147:811–815. 11. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40:1879–1885. 12. Zengin MO, Cinar E, Kucukerdonmez C. The effect of nicotine on choroidal thickness. Br J Ophthalmol. 2014;98: 233–237. 13. Ryan SJ. Retina, vol. 1, 4th ed. Philadelphia, PA: Elsevier Mosby; 2006:33–34. 14. Inoue R, Sawa M, Tsujikawa M, et al. Association between the efficacy of photodynamic therapy and indocyanine gren angiography findings for central serous chorioretinopathy. Am J Ophthalmol. 2010;149:441–44.e1-2. 15. Nagaoka T, Kitaya N, Sugawara R, et al. Alteration of choroidal circulation in the foveal region in patients with type 2 diabetes. Br J Ophthalmol. 2004;88:1060–1063. 16. Branchini L, Regatieri CV, Flores-Moreno I, et al. Reproducibility of choroidal thickness measurements across three spectral domain optical coherence tomography systems. Ophthalmology. 2012;119:119–123. 17. Coskun E, Gurler B, Pehlivan Y, et al. Enhanced depth imaging optical coherence tomography findings in Behc¸et disease. Ocul Immunol Inflamm. 2013;21:440–445. 18. Fujiwara T, Imamura Y, Margolis R, et al. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am J Ophthalmol. 2009;148:445–450. 19. Imamura Y, Fujiwara T, Margolis R, et al. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina. 2009;29:1469–1473. 20. Manjunath V, Taha M, Fujimoto JG, et al. Choroidal thickness in normal eyes measured using Cirrus HD Ocular Immunology & Inflammation
Retinal and Choroidal Thickness in Childhood FMF 5
21.
22. 23.
24.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Cornell University on 06/11/14 For personal use only.
25.
26.
!
optical coherence tomography. Am J Ophthalmol. 2010;150: 325–329.e1. Matsuo Y, Sakamoto T, Yamashita T, et al. Comparisons of choroidal thickness of normal eyes obtained by two different spectral-domain OCT instruments and one sweptsource OCT Instrument. Invest Ophthalmol Vis Sci. 2013;54: 7630–7636. Ben-Chetrit E, Touitou I. Familial Mediterranean fever in the world. Arthritis Rheum. 2009;61:1447–1453. Samuels J, Aksentijevich I, Torosyan Y, et al. Familial Mediterranean fever at the millennium: clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore). 1998;77:268–297. Scharf J, Meyer E, Zonis S. Episcleritis associated with familial Mediterranean fever. Am J Ophthalmol. 1985;100: 337–339. Hirsh A, Hura R, Ashkenazi I, et al. Recurrent bilateral panuveitis and rhegmatogenous retinal detachment in a patient with familial Mediterranean fever. Am J Ophthalmol. 1990;110:702–703. Wonneberger W, Friman V, Zetterberg M. Unilateral anterior uveitis and amaurosis fugax in a patient with familial Mediterranean fever. J Clin Exp Ophthalmol. 2011;2: 1000168.
2014 Informa Healthcare USA, Inc.
27. Kumar S. Bilateral disc edema in familial Mediterranean fever. J Clin Diagnostic Res. 2007;1:521–524. 28. Karalezli A, Borazan M, Yilmaz S, et al. Conjunctival impression cytology and tear-film changes in patients with familial Mediterranean fever. Acta Ophthalmol. 2009;87: 39–43. 29. Bidaut-Garnier M, Schwartz C, Puyraveau M, et al. Choroidal thickness measurement in children using optical coherence tomography. Retina. 2014;34:768–774. 30. Li XQ, Jeppesen P, Larsen M, Munch IC. Subfoveal choroidal thickness in 1323 children aged 11 to 12 years and association with puberty: the Copenhagen Child Cohort 2000 Eye Study. Invest Ophthalmol Vis Sci. 2014;55: 550–555. 31. Read SA, Collins MJ, Vincent SJ, Alonso-Caneiro D. Choroidal thickness in myopic and nonmyopic children assessed with enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54: 7578–7586. 32. Rahman W, Chen FK, Yeoh J, et al. Repeatability of manual subfoveal choroidal thickness measurements in healthy subjects using the technique of enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52:2267–2271.
ORIGINAL ARTICLE
Retinal and Choroidal Thickness in Children with Familial Mediterranean Fever Mesut Erdurmu¸s, MD1, Mervan Bekda¸s, MD2, Fatih Demirciog˘lu, MD2, Adem Soydan, MD1, Sevil Bilir Go¨ksu¨gu¨r, MD2, and Erol Kısmet, MD2
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Cornell University on 06/11/14 For personal use only.
1
Department of Ophthalmology and 2Department of Pediatrics, Abant Izzet Baysal University Medical School, Bolu, Turkey
ABSTRACT Purpose: The aim of the present study was to evaluate retinal and choroidal thicknesses in children with familial Mediterranean fever (FMF). Methods: Thirty patients with FMF and 28 healthy controls were included in the study. The thicknesses of the retina and choroid of each subject’s right eye were measured at the fovea and horizontal nasal and temporal quadrants at 500-mm intervals to 1500 mm from the foveal center using spectral-domain optic coherence tomography. Results: Retinal and choroidal thicknesses at the fovea did not differ between groups (p = 0.32 and p = 0.39, respectively). Horizontal nasal and temporal retinal and choroidal thickness measurements at 500-mm intervals to a distance of 1500 mm from the foveal center were also similar between the groups (all p40.05). Conclusions: The retinal and choroidal thicknesses of children with FMF do not differ from those of age- and sex-matched healthy controls. Keywords: Childhood, choroidal thickness, enhanced depth imaging, familial Mediterranean fever, optical coherence tomography
Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder characterized by recurrent acute attacks of fever and polyserositis. People of Mediterranean ancestry, most commonly Sephardic Jews, Turks, Armenians, and Arabs, are more susceptible to the disease than are individuals of other ethnicities.1 Most patients develop symptoms in childhood, although in 10% of cases, the disease is not diagnosed until after age 20. FMF is the most common cause of renal failure due to amyloidosis in children.2 Amyloidosis in FMF results from extracellular accumulation of the acute-phase reactant serum amyloid A (SAA) protein; SAA levels increase after inflammatory stimulation.3 FMF is generally
treated with colchicine, which may prevent acute febrile attacks and fatal complications of the disease. FMF is caused by missense mutations in the MEditerranean FeVer (MEFV) gene, which alter the structure and function of the pyrin protein.4 These alterations interfere with pyrin’s ability to regulate inflammatory pathways, resulting in prolonged or augmented inflammation and predisposing FMF patients and carriers of the MEFV mutation to a proinflammatory state. This increased inflammation may increase susceptibility to vascular comorbidities in FMF patients. Systemic vasculitides affecting small and medium vessels, including Henoch– Schonlein purpura, polyarteritis nodosa, and Behc¸et
Received 17 January 2014; revised 2 March 2014; accepted 14 April 2014; published online 5 June 2014 Correspondence: Mesut Erdurmus, MD, Associate Professor, Department of Ophthalmology, Abant Izzet Baysal University Medical School, 14280, Bolu, Turkey. E-mail: [email protected]
1
2
M. Erdurmu¸s et al.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Cornell University on 06/11/14 For personal use only.
FIGURE 1. Representative spectral-domain optical coherence tomographic image with retinal and choroidal thickness measurements. The œ symbols indicate predefined measurement points.
disease, are more common in patients with FMF than in the general population.5–9 The vascular layer of the eye, the choroid, along with the ciliary body and iris form the uveal tract, which lies between the retina and the sclera and contains choroidal vessels, connective tissue, and melanin. Larger-diameter vessels are located in the outermost layer of the choroid, and medium-sized vessels lie between the larger-diameter vessels and choriocapillaris. The choroid plays an important role in supplying nutrients to and removing waste products from the outer region of the retina. The choroid is more vulnerable to the effects of inflammatory and vascular systemic diseases than are other eye tissues. Recent developments have improved choroidal imaging by optical coherence tomography (OCT).10 In the present study, we aimed to compare the thicknesses of the retina and choroid in patients with FMF with those of age- and sex-matched healthy children using spectral-domain OCT.
MATERIALS AND METHODS All participants received a detailed explanation of the study and signed an informed consent form in accordance with the principles embodied in the Declaration of Helsinki. This study was approved by the local institutional ethics committee. Subjects included children with FMF who were already being treated by the pediatrics department of our institution and age- and sex-matched healthy volunteers (controls). Exclusion criteria included previous eye trauma, previous ocular surgery, congenital malformations of the eye, amblyopia, refractive error greater than ±1 diopters, and inability to cooperate during a screening OCT examination. The diagnosis of FMF was based on Tel–Hashomer criteria.11 All subjects underwent a thorough ophthalmic evaluation, which included slit-lamp biomicroscopy, intraocular pressure (IOP) measurement, and fundus examination. Demographic data, such as age, gender, duration of FMF, and systemic
medication(s), were collected from a computerized patient database. Only the right eye of each study participant was assessed. All procedures were performed in one session in the morning to eliminate the contribution of diurnal fluctuations in choroidal thickness.12 One experienced examiner (AS) measured the retinal and choroidal thicknesses in all participants. All subjects were examined with undilated pupils using an enhanced depth imaging (EDI) system with multimodal capabilities (wavelength: 870 nm; scan pattern: EDI; Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany). Images were constructed from an average of 100 scans using the automatic averaging and eye-tracking features of the supplied Heidelberg Eye Explorer software (version 1.5.12.0; Heidelberg Engineering), which was also used for image analysis. Choroidal thickness was measured manually from the outer portion of the hyperreflective line corresponding to the retinal pigment epithelium (RPE) to the inner surface of the sclera. Retinal thickness (from the RPE to the internal limiting membrane) was measured using the same technique. Each thickness was measured at the foveal center and within the horizontal nasal and temporal quadrants at 500-mm intervals to a distance of 1500 mm from the foveal center. The central and total macular volumes were calculated by estimating the distance between the inner limiting membrane and Bruch’s membrane in 1- and 6-mm-diameter cylinders, respectively, using the OCT software’s segmentation algorithm. Figure 1 summarizes retinal and choroidal thickness measurements using spectral-domain optical coherence tomography and identifies the above-mentioned measurement points.
Statistical Analysis All analyses were performed using the SPSS for Windows V.15.0 software package. Continuous variables are presented as means ± SD. Categorical variables are presented as frequencies accompanied by percentages. Differences in measured parameters Ocular Immunology & Inflammation
Retinal and Choroidal Thickness in Childhood FMF 3 between the two groups were analyzed by independent-samples t tests or Mann–Whitney U tests, as appropriate. Correlations between variables were analyzed by Pearson’s or Spearman’s correlation coefficients. Differences were considered significant when the p value was less than 0.05.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Cornell University on 06/11/14 For personal use only.
RESULTS The mean ages of FMF patients (n = 30, 14 female, 16 male) and controls (n = 28, 17 female, 11 male) were 11.7 ± 5.1 years and 13.5 ± 4.7 years, respectively. There was no difference between the groups in terms of age or sex (p = 0.16 and p = 0.28, respectively). Demographic data and disease characteristics of the FMF patients are summarized in Table 1. Retinal and choroidal thicknesses at the foveal center were 213 ± 17.3 mm and 336.1 ± 78 mm in FMF patients and 217 ± 12.1 mm and 352.1 ± 60 mm in controls, respectively. Retinal and choroidal thicknesses at the fovea did not differ between groups (p = 0.32 and p = 0.39, respectively). Retinal and choroidal thicknesses at each point within the horizontal nasal and temporal quadrants were also similar between FMF patients and controls (all p40.05). Table 2 provides retinal and choroidal thicknesses at each point for both groups and the significance values of each comparison. The central macular volume was 0.205 ± 0.015 mm3 in FMF patients and 0.203 ± 0.013 mm3 in controls. TABLE 1. Demographic data and disease characteristics of the familial Mediterranean fever (FMF) patients. Data/characteristics
Mean or frequency
Age (years) Gender (female/male) Family history of FMF Duration of FMF (years) Drug usage (months) Temperature Abdominal pain Chest pain Arthritis
11.7 ± 5.1 (9.8–13.6) 14/16 17 of 30 4.7 ± 2.8 (3.6–5.7) 28.1 ± 25.6 (18.6–37.6) 22 of 30 (73.3%) 27 of 30 (90%) 13 of 30 (43.3%) 16 of 30 (53.3%)
The total macular volume was 8.75 ± 0.53 mm3 in FMF patients and 8.6 ± 0.52 mm3 in controls. There was no statistically significant difference between the groups in terms of central macular volume (p = 0.65) or total macular volume (p = 0.38). There was no association between the demographic or disease characteristics (age, gender, family history of FMF, duration of disease, drug usage, temperature, abdominal pain, arthritis, and chest pain) and any of the measured parameters.
DISCUSSION Since the introduction of in vivo choroidal imaging using spectral-domain OCT, associations between the anatomy of the choroid and pathologic conditions have become better studied. FMF is an autoinflammatory disease that affects almost all organs. The present study was designed to examine for the first time in the literature whether retinal and choroidal thicknesses in children with FMF differed from those of age- and sex-matched healthy controls; no differences were observed. Moreover, central and total macular volume in FMF patients did not differ from controls, and no clinical characteristics of the disease were correlated with individual retinal or choroidal thickness. The choroid is a vascularized and pigmented tissue that extends from the ora serrata anteriorly to the optic nerve posteriorly. Histopathologic evaluations of choroid tissue have been performed since the 17th century and have determined that it is 0.22 mm thick posteriorly and 0.10–0.15 mm thick anteriorly.13 Until recently, the choroid could only be evaluated by indocyanine green angiography, laser Doppler flowmetry, and ultrasound.14,15 Although these techniques are useful for determining vessel abnormalities or changes in the choroidal blood flow, they do not provide three-dimensional anatomical information about the choroid. The development of OCT, which is analogous to ultrasonography but with greater resolution, enables high-quality cross-sectional imaging of the macula or ONH.
TABLE 2. Retinal and choroidal thicknesses in predefined reference points in the groups. FMF group (n = 30) Location Foveal center Nasal (500 mm) Temporal (500 mm) Nasal (1000 mm) Temporal (1000 mm) Nasal (1500 mm) Temporal (1500 mm) !
p Value
Control group (n = 28)
Retinal thickness (mm)
Choroidal thickness (mm)
Retinal thickness (mm)
Choroidal thickness (mm)
Retinal thickness
Choroidal thickness
212.97 ± 17.27 296.63 ± 19.49 293.23 ± 20,30 347.16 ± 15.80 332.47 ± 14.28 352.63 ± 16.47 325.20 ± 17.32
336.07 ± 78.03 324.23 ± 76.83 318.60 ± 73.18 314.50 ± 75.92 307.17 ± 71.90 287.17 ± 78.55 297.83 ± 74.72
216.93 ± 12.11 291.35 ± 19.87 295.36 ± 21.13 342.64 ± 14.70 332 ± 15.17 350.57 ± 15.13 323.10 ± 15.99
352.14 ± 59.95 329.50 ± 57.49 345.89 ± 68.12 312.93 ± 54.19 339.75 ± 62.32 285.11 ± 49.96 322.39 ± 66.27
0.32 0.31 0.70 0.27 0.91 0.62 0.64
0.39 0.77 0.15 0.93 0.07 0.9 0.19
2014 Informa Healthcare USA, Inc.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Cornell University on 06/11/14 For personal use only.
4
M. Erdurmu¸s et al.
However, adequate morphologic examination of the choroid using OCT has not been possible until recently owing to its posterior location and the presence of pigmented cells in the RPE that attenuate incident light. Recent reports have demonstrated successful examination and measurement of choroidal thickness in normal and pathologic states using spectral-domain OCT instruments16–20 and good reproducibility and repeatability of choroidal thickness measurements using the Heidelberg Spectralis OCT device.21 Globally, familial Mediterranean fever (FMF) is the most common autoinflammatory disease, affecting 1 of every 250–1,000 the inhabitants of the Eastern Mediterranean region, where it is most prevalent.22,23 The most commonly encountered ocular findings of FMF included episcleritis,24 posterior uveitis,25 retinal abnormalities,25 amaurosis fugax,26 optic nerve edema,27 and ocular surface and tear-film abnormalities.28 A literature search identified no studies of changes in retinal and choroidal thicknesses in patients with FMF, particularly in children. Therefore, the present study sought to compare the thicknesses of the retina and choroid of FMF patients with those of healthy controls using EDI OCT. We found that neither the retinal nor choroidal thickness of FMF patients differed from that of controls, nor were demographic variables or disease characteristics associated with retinal or choroidal thickness. The measured choroidal thickness values in our sample were consistent with those of previous studies in children of similar age.29–31 However, unlike previous studies, we found no correlation between age or sex and choroidal measurements. This difference may be due to either our small sample size and strict exclusion criteria or other unknown factors that could affect the measurements. In the present study, the choice to have all measurements performed by a single experienced OCT operator was based on previous reports that interobserver variability may reach 32 mm.32 However, some degree of intraobserver variability is an unavoidable problem in caliper-assisted manual choroidal thickness measurement. There are several limitations of the present study. First, this was a single-center study, and thus the data may not be representative of all FMF patients. Another limitation was the relatively small sample size. Retinal and choroidal thickness may change during FMF attacks, but only five of our measurements were taken during acute attacks. In conclusion, retinal and choroidal thicknesses of children with FMF were not significantly different from those of controls. Further studies are warranted to evaluate choroidal thickness in FMF patients in a larger sample, particularly during acute attacks.
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. Gershoni-Baruch R, Shinawi M, Leah K, et al. Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet. 2001;9:634–637. 2. Bilginer Y, Akpolat T, Ozen S. Renal amyloidosis in children. Pediatr Nephrol. 2011;26:1215–1227. 3. Lachmann HJ, Goodman HJB, Gilbertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356:2361–2371. 4. Ozc¸akar ZB, Yalc¸ ınkaya F. Vascular comorbidities in familial Mediterranean fever. Rheumatol Int. 2011;31: 1275–1281. 5. Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever (FMF) in Turkey: results of nationwide multicenter study. Medicine. 2005;84:1–11. 6. Ozdogan H, Arisoy N, Kasapcopur O, et al. Vasculitis in familial Mediterranean fever. J Rheumatol. 1997;24:323–327. 7. Touitou I, Magne X, Molinari N, et al. MEFV mutation in Behcet’s disease. Hum Mutat. 2000;16:271–272. 8. Atagunduz P, Ergun T, Direskeneli H. MEFV mutations are increased in Behcet’s disease (BD) and are associated with vascular involvement. Clin Exp Rheumatol. 2003;21:35–37. 9. Rabinovich E, Shinar Y, Leiba M, et al. Common FMF alleles may predispose to development of Behcet’s disease with increased risk for venous thrombosis. Scand J Rheumatol. 2007;36:48–52. 10. Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol. 2009;147:811–815. 11. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40:1879–1885. 12. Zengin MO, Cinar E, Kucukerdonmez C. The effect of nicotine on choroidal thickness. Br J Ophthalmol. 2014;98: 233–237. 13. Ryan SJ. Retina, vol. 1, 4th ed. Philadelphia, PA: Elsevier Mosby; 2006:33–34. 14. Inoue R, Sawa M, Tsujikawa M, et al. Association between the efficacy of photodynamic therapy and indocyanine gren angiography findings for central serous chorioretinopathy. Am J Ophthalmol. 2010;149:441–44.e1-2. 15. Nagaoka T, Kitaya N, Sugawara R, et al. Alteration of choroidal circulation in the foveal region in patients with type 2 diabetes. Br J Ophthalmol. 2004;88:1060–1063. 16. Branchini L, Regatieri CV, Flores-Moreno I, et al. Reproducibility of choroidal thickness measurements across three spectral domain optical coherence tomography systems. Ophthalmology. 2012;119:119–123. 17. Coskun E, Gurler B, Pehlivan Y, et al. Enhanced depth imaging optical coherence tomography findings in Behc¸et disease. Ocul Immunol Inflamm. 2013;21:440–445. 18. Fujiwara T, Imamura Y, Margolis R, et al. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am J Ophthalmol. 2009;148:445–450. 19. Imamura Y, Fujiwara T, Margolis R, et al. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina. 2009;29:1469–1473. 20. Manjunath V, Taha M, Fujimoto JG, et al. Choroidal thickness in normal eyes measured using Cirrus HD Ocular Immunology & Inflammation
Retinal and Choroidal Thickness in Childhood FMF 5
21.
22. 23.
24.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Cornell University on 06/11/14 For personal use only.
25.
26.
!
optical coherence tomography. Am J Ophthalmol. 2010;150: 325–329.e1. Matsuo Y, Sakamoto T, Yamashita T, et al. Comparisons of choroidal thickness of normal eyes obtained by two different spectral-domain OCT instruments and one sweptsource OCT Instrument. Invest Ophthalmol Vis Sci. 2013;54: 7630–7636. Ben-Chetrit E, Touitou I. Familial Mediterranean fever in the world. Arthritis Rheum. 2009;61:1447–1453. Samuels J, Aksentijevich I, Torosyan Y, et al. Familial Mediterranean fever at the millennium: clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore). 1998;77:268–297. Scharf J, Meyer E, Zonis S. Episcleritis associated with familial Mediterranean fever. Am J Ophthalmol. 1985;100: 337–339. Hirsh A, Hura R, Ashkenazi I, et al. Recurrent bilateral panuveitis and rhegmatogenous retinal detachment in a patient with familial Mediterranean fever. Am J Ophthalmol. 1990;110:702–703. Wonneberger W, Friman V, Zetterberg M. Unilateral anterior uveitis and amaurosis fugax in a patient with familial Mediterranean fever. J Clin Exp Ophthalmol. 2011;2: 1000168.
2014 Informa Healthcare USA, Inc.
27. Kumar S. Bilateral disc edema in familial Mediterranean fever. J Clin Diagnostic Res. 2007;1:521–524. 28. Karalezli A, Borazan M, Yilmaz S, et al. Conjunctival impression cytology and tear-film changes in patients with familial Mediterranean fever. Acta Ophthalmol. 2009;87: 39–43. 29. Bidaut-Garnier M, Schwartz C, Puyraveau M, et al. Choroidal thickness measurement in children using optical coherence tomography. Retina. 2014;34:768–774. 30. Li XQ, Jeppesen P, Larsen M, Munch IC. Subfoveal choroidal thickness in 1323 children aged 11 to 12 years and association with puberty: the Copenhagen Child Cohort 2000 Eye Study. Invest Ophthalmol Vis Sci. 2014;55: 550–555. 31. Read SA, Collins MJ, Vincent SJ, Alonso-Caneiro D. Choroidal thickness in myopic and nonmyopic children assessed with enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54: 7578–7586. 32. Rahman W, Chen FK, Yeoh J, et al. Repeatability of manual subfoveal choroidal thickness measurements in healthy subjects using the technique of enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52:2267–2271.
