Acta Neurol Belg DOI 10.1007/s13760-014-0301-3
ORIGINAL ARTICLE
Choroidal thickness changes in patients with migraine Mehmet O. Zengin • Zeynep Elmas Esat Cinar • Cem Kucukerdonmez
•
Received: 4 December 2013 / Accepted: 11 April 2014 Ó Belgian Neurological Society 2014
Abstract This observational study evaluated choroidal thickness using spectral domain optical coherence tomography (SD-OCT) in patients with migraine and compared the results with healthy controls. The study population consisted of 42 migraine patients (36 females and 6 males) who were referred from neurology clinics and 42 controls (36 female and 6 male) with no systemic or ocular disease and no headache of any type. All 84 patients underwent complete ophthalmic examination as well as determination of choroidal thickness using a high-speed, high-resolution SD-OCT device (k = 840 nm, 27.000 A-scans/s, 5-lm axial resolution). The migraine patients were classified into the migraine with aura group or the migraine without aura group, and a pain score from 1 to 10 was determined for each patient based on the Visual Analogue Scale (VAS). The mean choroidal thicknesses were 276.81 ± 37.76 lm in the migraine group and 300.44 ± 24.93 lm in controls. The difference in choroidal thickness between the migraine patients and the controls was significant (P = 0.001). Choroidal thickness measurements of five patients during an attack showed an acute decrease (mean 45.50 lm) in choroidal thickness from the values in the same patients during the attack-free period. There was no correlation between VAS score and the type of migraine with choroidal thickness (P [ 0.05). The decrease in mean choroidal thickness in patients with migraine compared to M. O. Zengin (&) E. Cinar C. Kucukerdonmez Department of Ophthalmology, Faculty of Medicine, Izmir University, Gursel Aksel Bulvarı, No. 14, Uckuyular, 35350 Izmir, Turkey e-mail: [email protected] Z. Elmas Department of Neurology, Faculty of Medicine, Izmir University, Izmir, Turkey
controls may be related to the vascular pathology of the migraine. The acute decrease in choroidal thickness during an attack also lends support to this hypothesis of reduced ocular blood flow in these patients. Keywords Choroidal thickness Migraine Optical coherence tomography
Introduction Migraine is a common neurological disorder characterised by recurrent moderate-to-severe headaches often in association with a number of autonomic nervous system symptoms. Associated symptoms may include vomiting, photophobia and phonophobia (increased sensitivity to sound), and the pain is generally aggravated by physical activity. Up to one-third of migraine headache sufferers perceive an aura, defined as a transient visual, sensory, language, or motor disturbance that signals that the headache will soon occur. There is no consensus on the pathophysiology of migraine, although a number of mechanisms have been postulated, including the vasogenic theory, neurogenic theory and cortical spreading depression [1]. The vasogenic theory is mainly dependent on the prolonged vasospasm followed by vasodilation [2]. Cerebral vasodilation and prolonged peripheral vasoconstriction were detected by transcranial Doppler ultrasound (USG) in migraine patients [3]. Therefore, ocular blood flow may also be affected by peripheral vasoconstriction in migraine. Ocular blood flow can be assessed by colour duplex imaging, laser speckle contrast imaging and Doppler flowmetry. Advances in optical coherence tomography (OCT) software have provided the means to evaluate the choroidal structure.
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Acta Neurol Belg
This study investigated the choroidal thickness in migraine patients, which was recently reported to change with the haemodynamic effects of chemicals, including sildenafil and cigarette smoking [4, 5].
Materials and methods This comparative study consisted of 42 newly diagnosed (at least 3 months) migraine patients (36 females and 6 males) that were referred from neurology clinics and 42 (36 females and 6 males) controls without systemic or ocular disease or any type of headache. The study protocol was approved by Izmir University Institutional Review Board and Ethics Committee (GOEK-010-2012). The research adhered to the tenets of the Declaration of Helsinki, and each subject provided written informed consent before participating in the study. Subjects were excluded if they had a history of ocular surface disorder, previous ocular surgery or ocular injury, or if they had a history of any chronic drug use, including analgesics, sildenafil, decongestants and antihistamines. Patients with any congenital or acquired retinal disorder, and high myopic and hyperopic refractive errors (greater than -6.0 or ?6.0 diopters) were also excluded due to the possible influence on choroidal thickness [6–9]. Migraine patients were divided into the migraine with aura group or the migraine without aura group. All patients were using nonsteroidal anti-inflammatory drugs (NSAIDS) for their migraine attacks. A pain score was determined for each patient based on the Visual Analogue Scale (VAS). The control group consisted of 42 patients who had been admitted to the ophthalmology outpatient department for routine ophthalmic examination and had a negative history for migraine headaches. The exclusion criteria for the migraine patients were the same as those for the controls. All of the patients and controls were non-smokers. All of the patients had undergone a detailed ophthalmic examination, including visual acuity testing, biomicroscopy, intraocular pressure measurement with non-contact tonometry, fundus examination, macular thickness and choroidal thickness measurements by OCT. Choroidal thickness measurements were performed by the same experienced technician using a spectral domainOCT device (k = 40 nm, 27,000 A-scans/s, 5 lm axial resolution), 3D OCT-2000 (Topcon Corp., Tokyo, Japan). The enhanced choroidal mode cross scan was performed centred on the fovea. This protocol consisted of 6 mm cross lines with 1024 A-scans/B-scans and overlapping 4 B-scans per image and direct B-scan observation. After the B-scan scale was adjusted to 1:1 and the size of the image was approximately doubled, the observer determined the subfoveal choroidal thickness perpendicular
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from the outer edge of the hyperreflective retinal pigment epithelium (RPE) to the inner sclera, centred on the fovea using a ‘‘calliper function’’, i.e. a built-in linear measuring tool. Scans with low quality and blinks were not included and were repeated. Choroidal thickness was measured perpendicularly from the outer edge of the RPE to the choroid–sclera boundary at the fovea and at five more points located 500 lm nasal to the fovea, 1000 lm nasal to the fovea, 500 lm temporal to the fovea, 1,000 lm temporal to the fovea and 1,500 lm temporal to the fovea as in the literature [5, 8, 10]. All OCT scans were performed at the same time of day (in the morning between 10:00 and 12:00) to avoid diurnal fluctuations. Choroidal thickness measurements were made by two physicians blinded to the groups (MOZ and CK), and the average of the two measurements was taken; the differences between readings of the two physicians were accepted when they were within 10 lm of the mean. If the measurements were not within this range, they were repeated, and if the inconsistency persisted, a third reader blinded to the groups (EC) also performed a measurement. The inter-examiner reproducibility of the choroidal thickness measurements was assessed by measuring the intraclass correlation coefficient (ICC). Statistical analyses were performed with SPSS for Windows 17.0 (SPSS Inc. Chicago, IL, USA). Data were analysed by independent samples t test, Mann–Whitney U test and Pearson’s correlation analysis. To quantify the reproducibility of manual repeated measurements of the choroidal thickness in cases of alignment errors, the ICC was calculated. In all analyses, P \ 0.05 was taken to indicate statistical significance.
Results The mean age of subjects in the migraine group (Group 1) was 34.1 ± 9.3 years (range 16–60 years), while that in the control group (Group 2) was 33.7 ± 10.6 years (range 17–62 years). There was no statistically significant difference in age between groups (P = 0.845). Among the 42 patients in the migraine group, 19 (45.2 %) had migraine with aura and 23 (54.8 %) had migraine without aura. A pain score from 1 to 10 was determined for all patients in Group 1 based on the VAS. Table 1 shows the demographic data of each group. The mean refractive error was –0.92 ± 0.59 D (range –1.5 to ?1.0 D) in Group 1 and –0.74 ± 0.53 D (range –1.25 to ?0.75 D) in Group 2. There was no significant difference with respect to mean refractive error between patients with migraine and controls (P = 0.583). The mean choroidal thickness was 276.81 ± 37.76 lm in Group 1 and as 300.44 ± 24.93 lm in Group 2
Acta Neurol Belg Table 1 Demographic data of patients and controls Group 1 (n = 42)
Group 2 (n = 42)
P value 0.845
Age (mean ± SD) (years)
34.1 ± 9.3
33.7 ± 10.6
Male/female (%)
6/36 (14/86 %)
6/36 (14/86 %)
NS
Refractive error (mean diopters)
-0.92 ± 0.59 D
-0.74 ± 0.53 D
0.583
NS statistically nonsignificant values
Table 2 The mean choroidal thickness measurements of migraine and controls Measurement pointsa
Migraine mean ± SD (lm)
Controls mean ± SD (lm)
P value
T3
273.3 ± 40.2
295.9 ± 30.2
0.005
T2
273.7 ± 42.9
296.2 ± 28.6
0.006
T1 F
283.3 ± 46.3 285.9 ± 38.3
307.1 ± 33.1 309.6 ± 33.4
0.008 0.003
N1
273.8 ± 41.9
297.8 ± 28.7
0.003
N2
270.8 ± 42.5
295.8 ± 34.9
0.004
a
F, choroidal thickness at fovea; N1, choroidal thickness at 500 lm nasal to the fovea; N2, choroidal thickness at 1,000 lm nasal to the fovea; T1, choroidal thickness at 500 lm temporal to the fovea; T2, choroidal thickness at 1,000 lm temporal to the fovea; T3, choroidal thickness at 1,500 lm temporal to the fovea
Table 3 Choroidal thickness measurements of patients during and after the cessation of migraine attack Case no.
Mean choroidal thickness in attack (lm)
Mean choroidal thickness post-attack (lm)
1
233.17
285.00
2
239.17
308.66
3
270.33
291.17
4
296.33
353.50
5
416.67
444.83
(P = 0.001). Choroidal thickness measurements in the migraine group revealed significant differences at all points compared to the control group (Table 2). Choroidal thickness measurements were obtained during an attack and after cessation of the attack in five migraine patients. As shown in Table 3 and Fig. 1, an average reduction in choroidal thickness of 45.50 lm was observed during an attack. There was no significant difference in choroidal thickness between migraine patients with and without aura (P = 0.230). The mean value of the pain score was 5.55 ± 2.93, and there were no correlations between choroidal thickness and VAS score in migraine patients (P = 0.304). The inter-examiner ICC for mean choroidal thickness was 0.926 (95 % CI, 0.905–0.966) and ICC was [0.90 for all measurement points.
Discussion In the present study, the mean choroidal thickness of migraine patients was significantly thinner than that of controls (300 vs. 277 lm, respectively; P \ 0.05). Furthermore, we were able to obtain measurements during an acute migraine attack in five patients, and these results also indicated an acute decrease in choroidal thickness. There have been many recent reports of ocular disorders associated with altered abnormal choroidal thickness. The choroid was reported to be of reduced thickness in high myopia, retinal dystrophy and age-related choroidal atrophy, while increased choroidal thickness was reported in central serous chorioretinopathy and Vogt–Koyanagi– Harada disease [6, 7, 11–15]. Moreover, peripapillary choroidal thickness was found to be lower in patients with normal-tension glaucoma compared to normal controls [16]. In addition, there have been a number of recent OCT studies regarding the haemodynamic effects of chemicals, i.e. sildenafil and cigarette smoke, on choroid [4, 5]. As a highly vascular ocular structure, the choroid is directly influenced by intraocular and perfusion pressures. Therefore, real-time high-definition images of the choroid are more likely to demonstrate the real-time vascular status of this tissue in vivo [17]. It has been suggested that even histology cannot demonstrate the thickness of the living choroid. Moreover, OCT is superior to histology in term of accuracy of measuring the choroidal thickness [18]. However, there is still debate regarding the relationship between choroidal thickness and choroidal blood flow. In an experimental study, increased choroidal blood flow measured by laser Doppler flowmetry was shown to precede the increase in choroidal thickness during recovery from deprivation myopia [19]. However, the same investigators also suggested that choroidal blood flow may not be correlated with choroidal thickness. In contrast, it has been reported that sildenafil citrate increases choroidal thickness due to a vasodilatory effect on choroidal circulation [4]. This relationship was further investigated in a study that used swept-scan high-frequency digital ultrasound to measure the ocular blood flow [20]. The results also suggested that increased choroidal circulation may be associated with increased choroidal thickness.
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Fig. 1 OCT images of a migraine patient showing acute decrease of choroidal thickness during an attack
In another recent study, subfoveal choroidal thickness, measured by enhanced depth imaging OCT (EDI-OCT), was not found to be significantly correlated with choroidal blood flow in young healthy eyes [21]. The authors speculated that there may be some relation between choroidal blood flow changes and choroidal thickness. However, evaluation of choroidal thickness may not be suited to assessing the choroidal circulation. The authors suggested that further prospective studies are required to determine the changes in choroidal thickness during the stimulation that can cause choroidal circulation changes. Recently, cigarette smoking was shown to be related to a decrease in choroidal thickness in otherwise healthy subjects [5]. To exclude the possible effects of systemic medications and smoking, only recently diagnosed migraine patients who were not using any medications and were non-smokers were included in the present study. This study had several limitations. First, the number of cases, including five patients during an attack, was limited. However, it is very difficult to obtain OCT images during a painful migraine attack. On the other hand, these five patients showed an acute decrease in choroidal thickness during the attack, which supports our suggestion of decreased blood flow according to the vasogenic theory of migraine. Another limitation was related to the effect of diurnal rhythm of choroidal thickness (a change of approximately 20–30 lm), which was demonstrated in previous studies [22, 23]. However, the OCT examinations in the present study were performed at the same time of day (10:00–12:00), even in the attack patients, and so it was unlikely to be a potential bias in our study. The last major limitation of this study was that the choroidal thickness measurements had to be performed manually, which remains a potential cause of interobserver bias. To overcome this limitation, two different observers performed measurements at six different points as described in previous reports. In addition, the thickness of the choroid was measured via manual segmentation by two independent operators. The ICCs between the two operators were strong (ICC [0.90 for all measurement points). Although the reproducibility of this method is high [24], manual measurements of the choroidal thickness took on average 5 min per scan. This relatively long duration may lead to observer
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fatigue, which in turn would increase the possibility of false measurements. Although this is still the most commonly used method for determining choroidal thickness, there is still a need to minimise the bias associated with this measurement method. Despite these limitations, the findings presented here may be useful in future studies regarding the effects of migraine on choroidal thickness. Conflict of interest The authors Mehmet O. Zengin, Zeynep Elmas, Esat Cinar, Cem Kucukerdonmez declare no conflict of interest.
References 1. Panconesi A, Bartolozzi ML, Guidi L (2009) Migraine pain: reflections against vasodilatation. J Headache Pain 10(5):317–325 2. Asghar MS, Hansen AE, Amin FM et al (2011) Ann Neurol 69(4):635–645 3. Thie A, Spitzer K, Lachenmayer L, Kunze K (1988) Prolonged vasospasm in migraine detected by noninvasive transcranial Doppler ultrasound. Headache J Head Face Pain 28(3):183–186 4. Vance SK, Imamura Y, Freund KB (2011) The effects of sildenafil citrate on choroidal thickness as determined by enhanced depth imaging optical coherence tomography. Retina 31(2): 332–335 5. Sizmaz S, Ku¨c¸u¨kerdo¨nmez C, Pinarci EY et al (2013) The effect of smoking on choroidal thickness measured by optical coherence tomography. Br J Ophthalmol 97(5):601–604 6. Fujiwara T, Imamura Y, Margolis R, Slakter JS, Spaide RF (2009) Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am J Ophthalmol 148(3): 445–450 7. Ikuno Y, Tano Y (2009) Retinal and choroidal biometry in highly myopic eyes with spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci 50(8):3876–3880 8. Flores-Moreno I, Lugo F, Duker JS, Ruiz-Moreno JM (2013) The relationship between axial length and choroidal thickness in eyes with high myopia. Am J Ophthalmol 155:314–319 9. Demircan A, Altan C, Osmanbasoglu OA, Celik U, Kara N, Demirok A (2014) Subfoveal choroidal thickness measurements with enhanced depth imaging optical coherence tomography in patients with nanophthalmos. Br J Ophthalmol 98:345–349 10. Zengin MO, Cinar E, Kucukerdonmez C (2014) The effect of nicotine on choroidal thickness. Br J Ophthalmol 98(2):233–237 11. Yeoh J, Rahman W, Chen F et al (2010) Choroidal imaging in inherited retinal disease using the technique of enhanced depth imaging optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 248(12):1719–1728 12. Spaide RF (2009) Age-related choroidal atrophy. Am J Ophthalmol 147(5):801–810
Acta Neurol Belg 13. Imamura Y, Fujiwara T, Margolis R, Spaide RF (2009) Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina 29(10):1469–1473 14. Maruko I, Iida T, Sugano Y, Ojima A, Ogasawara M, Spaide RF (2010) Subfoveal choroidal thickness after treatment of central serous chorioretinopathy. Ophthalmology 117(9):1792–1799 15. Maruko I, Iida T, Sugano Y et al (2011) Subfoveal choroidal thickness after treatment of Vogt-Koyanagi-Harada disease. Retina 31(3):510–517 16. Hirooka K, Tenkumo K, Fujiwara A, Baba T, Sato S, Shiraga F (2012) Evaluation of peripapillary choroidal thickness in patients with normal-tension glaucoma. BMC Ophthalmol 28(12):29. doi:10.1186/1471-2415-12-29 17. Manjunath V, Goren J, Fujimoto JG, Duker JS (2011) Analysis of choroidal thickness in age-related macular degeneration using spectral-domain optical coherence tomography. Am J Ophthalmol 152(4):663–668 18. Maul EA, Friedman DS, Chang DS et al (2011) Choroidal thickness measured by spectral domain optical coherence tomography: factors affecting thickness in glaucoma patients. Ophthalmology 118(8):1571–1579
19. Fitzgerald ME, Wildsoet CF, Reiner A (2002) Temporal relationship of choroidal blood flow and thickness changes during recovery from form deprivation myopia in chicks. Exp Eye Res 74(5):561–570 20. Kim DY, Silverman RH, Chan RV et al (2013) Measurement of choroidal perfusion and thickness following systemic sildenafil (Viagra). Acta Ophthalmol 91(2):183–188 21. Sogawa K, Nagaoka T, Takahashi A et al (2012) Relationship between choroidal thickness and choroidal circulation in healthy young subjects. Am J Ophthalmol 153(6):1129–1132 22. Tan CS, Ouyang Y, Ruiz H, Sadda SR (2012) Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 53(1):261–266 23. Usui S, Ikuno Y, Akiba M et al (2012) Circadian changes in subfoveal choroidal thickness and the relationship with circulatory factors in healthy subjects. Invest Ophthalmol Vis Sci 53(4):2300–2307 24. Karaca EE, Ozdek S, Yalc¸in NG et al (2014) Reproducibility of choroidal thickness measurements in healthy Turkish subjects. Eur J Ophthalmol 24:202–208
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ORIGINAL ARTICLE
Choroidal thickness changes in patients with migraine Mehmet O. Zengin • Zeynep Elmas Esat Cinar • Cem Kucukerdonmez
•
Received: 4 December 2013 / Accepted: 11 April 2014 Ó Belgian Neurological Society 2014
Abstract This observational study evaluated choroidal thickness using spectral domain optical coherence tomography (SD-OCT) in patients with migraine and compared the results with healthy controls. The study population consisted of 42 migraine patients (36 females and 6 males) who were referred from neurology clinics and 42 controls (36 female and 6 male) with no systemic or ocular disease and no headache of any type. All 84 patients underwent complete ophthalmic examination as well as determination of choroidal thickness using a high-speed, high-resolution SD-OCT device (k = 840 nm, 27.000 A-scans/s, 5-lm axial resolution). The migraine patients were classified into the migraine with aura group or the migraine without aura group, and a pain score from 1 to 10 was determined for each patient based on the Visual Analogue Scale (VAS). The mean choroidal thicknesses were 276.81 ± 37.76 lm in the migraine group and 300.44 ± 24.93 lm in controls. The difference in choroidal thickness between the migraine patients and the controls was significant (P = 0.001). Choroidal thickness measurements of five patients during an attack showed an acute decrease (mean 45.50 lm) in choroidal thickness from the values in the same patients during the attack-free period. There was no correlation between VAS score and the type of migraine with choroidal thickness (P [ 0.05). The decrease in mean choroidal thickness in patients with migraine compared to M. O. Zengin (&) E. Cinar C. Kucukerdonmez Department of Ophthalmology, Faculty of Medicine, Izmir University, Gursel Aksel Bulvarı, No. 14, Uckuyular, 35350 Izmir, Turkey e-mail: [email protected] Z. Elmas Department of Neurology, Faculty of Medicine, Izmir University, Izmir, Turkey
controls may be related to the vascular pathology of the migraine. The acute decrease in choroidal thickness during an attack also lends support to this hypothesis of reduced ocular blood flow in these patients. Keywords Choroidal thickness Migraine Optical coherence tomography
Introduction Migraine is a common neurological disorder characterised by recurrent moderate-to-severe headaches often in association with a number of autonomic nervous system symptoms. Associated symptoms may include vomiting, photophobia and phonophobia (increased sensitivity to sound), and the pain is generally aggravated by physical activity. Up to one-third of migraine headache sufferers perceive an aura, defined as a transient visual, sensory, language, or motor disturbance that signals that the headache will soon occur. There is no consensus on the pathophysiology of migraine, although a number of mechanisms have been postulated, including the vasogenic theory, neurogenic theory and cortical spreading depression [1]. The vasogenic theory is mainly dependent on the prolonged vasospasm followed by vasodilation [2]. Cerebral vasodilation and prolonged peripheral vasoconstriction were detected by transcranial Doppler ultrasound (USG) in migraine patients [3]. Therefore, ocular blood flow may also be affected by peripheral vasoconstriction in migraine. Ocular blood flow can be assessed by colour duplex imaging, laser speckle contrast imaging and Doppler flowmetry. Advances in optical coherence tomography (OCT) software have provided the means to evaluate the choroidal structure.
123
Acta Neurol Belg
This study investigated the choroidal thickness in migraine patients, which was recently reported to change with the haemodynamic effects of chemicals, including sildenafil and cigarette smoking [4, 5].
Materials and methods This comparative study consisted of 42 newly diagnosed (at least 3 months) migraine patients (36 females and 6 males) that were referred from neurology clinics and 42 (36 females and 6 males) controls without systemic or ocular disease or any type of headache. The study protocol was approved by Izmir University Institutional Review Board and Ethics Committee (GOEK-010-2012). The research adhered to the tenets of the Declaration of Helsinki, and each subject provided written informed consent before participating in the study. Subjects were excluded if they had a history of ocular surface disorder, previous ocular surgery or ocular injury, or if they had a history of any chronic drug use, including analgesics, sildenafil, decongestants and antihistamines. Patients with any congenital or acquired retinal disorder, and high myopic and hyperopic refractive errors (greater than -6.0 or ?6.0 diopters) were also excluded due to the possible influence on choroidal thickness [6–9]. Migraine patients were divided into the migraine with aura group or the migraine without aura group. All patients were using nonsteroidal anti-inflammatory drugs (NSAIDS) for their migraine attacks. A pain score was determined for each patient based on the Visual Analogue Scale (VAS). The control group consisted of 42 patients who had been admitted to the ophthalmology outpatient department for routine ophthalmic examination and had a negative history for migraine headaches. The exclusion criteria for the migraine patients were the same as those for the controls. All of the patients and controls were non-smokers. All of the patients had undergone a detailed ophthalmic examination, including visual acuity testing, biomicroscopy, intraocular pressure measurement with non-contact tonometry, fundus examination, macular thickness and choroidal thickness measurements by OCT. Choroidal thickness measurements were performed by the same experienced technician using a spectral domainOCT device (k = 40 nm, 27,000 A-scans/s, 5 lm axial resolution), 3D OCT-2000 (Topcon Corp., Tokyo, Japan). The enhanced choroidal mode cross scan was performed centred on the fovea. This protocol consisted of 6 mm cross lines with 1024 A-scans/B-scans and overlapping 4 B-scans per image and direct B-scan observation. After the B-scan scale was adjusted to 1:1 and the size of the image was approximately doubled, the observer determined the subfoveal choroidal thickness perpendicular
123
from the outer edge of the hyperreflective retinal pigment epithelium (RPE) to the inner sclera, centred on the fovea using a ‘‘calliper function’’, i.e. a built-in linear measuring tool. Scans with low quality and blinks were not included and were repeated. Choroidal thickness was measured perpendicularly from the outer edge of the RPE to the choroid–sclera boundary at the fovea and at five more points located 500 lm nasal to the fovea, 1000 lm nasal to the fovea, 500 lm temporal to the fovea, 1,000 lm temporal to the fovea and 1,500 lm temporal to the fovea as in the literature [5, 8, 10]. All OCT scans were performed at the same time of day (in the morning between 10:00 and 12:00) to avoid diurnal fluctuations. Choroidal thickness measurements were made by two physicians blinded to the groups (MOZ and CK), and the average of the two measurements was taken; the differences between readings of the two physicians were accepted when they were within 10 lm of the mean. If the measurements were not within this range, they were repeated, and if the inconsistency persisted, a third reader blinded to the groups (EC) also performed a measurement. The inter-examiner reproducibility of the choroidal thickness measurements was assessed by measuring the intraclass correlation coefficient (ICC). Statistical analyses were performed with SPSS for Windows 17.0 (SPSS Inc. Chicago, IL, USA). Data were analysed by independent samples t test, Mann–Whitney U test and Pearson’s correlation analysis. To quantify the reproducibility of manual repeated measurements of the choroidal thickness in cases of alignment errors, the ICC was calculated. In all analyses, P \ 0.05 was taken to indicate statistical significance.
Results The mean age of subjects in the migraine group (Group 1) was 34.1 ± 9.3 years (range 16–60 years), while that in the control group (Group 2) was 33.7 ± 10.6 years (range 17–62 years). There was no statistically significant difference in age between groups (P = 0.845). Among the 42 patients in the migraine group, 19 (45.2 %) had migraine with aura and 23 (54.8 %) had migraine without aura. A pain score from 1 to 10 was determined for all patients in Group 1 based on the VAS. Table 1 shows the demographic data of each group. The mean refractive error was –0.92 ± 0.59 D (range –1.5 to ?1.0 D) in Group 1 and –0.74 ± 0.53 D (range –1.25 to ?0.75 D) in Group 2. There was no significant difference with respect to mean refractive error between patients with migraine and controls (P = 0.583). The mean choroidal thickness was 276.81 ± 37.76 lm in Group 1 and as 300.44 ± 24.93 lm in Group 2
Acta Neurol Belg Table 1 Demographic data of patients and controls Group 1 (n = 42)
Group 2 (n = 42)
P value 0.845
Age (mean ± SD) (years)
34.1 ± 9.3
33.7 ± 10.6
Male/female (%)
6/36 (14/86 %)
6/36 (14/86 %)
NS
Refractive error (mean diopters)
-0.92 ± 0.59 D
-0.74 ± 0.53 D
0.583
NS statistically nonsignificant values
Table 2 The mean choroidal thickness measurements of migraine and controls Measurement pointsa
Migraine mean ± SD (lm)
Controls mean ± SD (lm)
P value
T3
273.3 ± 40.2
295.9 ± 30.2
0.005
T2
273.7 ± 42.9
296.2 ± 28.6
0.006
T1 F
283.3 ± 46.3 285.9 ± 38.3
307.1 ± 33.1 309.6 ± 33.4
0.008 0.003
N1
273.8 ± 41.9
297.8 ± 28.7
0.003
N2
270.8 ± 42.5
295.8 ± 34.9
0.004
a
F, choroidal thickness at fovea; N1, choroidal thickness at 500 lm nasal to the fovea; N2, choroidal thickness at 1,000 lm nasal to the fovea; T1, choroidal thickness at 500 lm temporal to the fovea; T2, choroidal thickness at 1,000 lm temporal to the fovea; T3, choroidal thickness at 1,500 lm temporal to the fovea
Table 3 Choroidal thickness measurements of patients during and after the cessation of migraine attack Case no.
Mean choroidal thickness in attack (lm)
Mean choroidal thickness post-attack (lm)
1
233.17
285.00
2
239.17
308.66
3
270.33
291.17
4
296.33
353.50
5
416.67
444.83
(P = 0.001). Choroidal thickness measurements in the migraine group revealed significant differences at all points compared to the control group (Table 2). Choroidal thickness measurements were obtained during an attack and after cessation of the attack in five migraine patients. As shown in Table 3 and Fig. 1, an average reduction in choroidal thickness of 45.50 lm was observed during an attack. There was no significant difference in choroidal thickness between migraine patients with and without aura (P = 0.230). The mean value of the pain score was 5.55 ± 2.93, and there were no correlations between choroidal thickness and VAS score in migraine patients (P = 0.304). The inter-examiner ICC for mean choroidal thickness was 0.926 (95 % CI, 0.905–0.966) and ICC was [0.90 for all measurement points.
Discussion In the present study, the mean choroidal thickness of migraine patients was significantly thinner than that of controls (300 vs. 277 lm, respectively; P \ 0.05). Furthermore, we were able to obtain measurements during an acute migraine attack in five patients, and these results also indicated an acute decrease in choroidal thickness. There have been many recent reports of ocular disorders associated with altered abnormal choroidal thickness. The choroid was reported to be of reduced thickness in high myopia, retinal dystrophy and age-related choroidal atrophy, while increased choroidal thickness was reported in central serous chorioretinopathy and Vogt–Koyanagi– Harada disease [6, 7, 11–15]. Moreover, peripapillary choroidal thickness was found to be lower in patients with normal-tension glaucoma compared to normal controls [16]. In addition, there have been a number of recent OCT studies regarding the haemodynamic effects of chemicals, i.e. sildenafil and cigarette smoke, on choroid [4, 5]. As a highly vascular ocular structure, the choroid is directly influenced by intraocular and perfusion pressures. Therefore, real-time high-definition images of the choroid are more likely to demonstrate the real-time vascular status of this tissue in vivo [17]. It has been suggested that even histology cannot demonstrate the thickness of the living choroid. Moreover, OCT is superior to histology in term of accuracy of measuring the choroidal thickness [18]. However, there is still debate regarding the relationship between choroidal thickness and choroidal blood flow. In an experimental study, increased choroidal blood flow measured by laser Doppler flowmetry was shown to precede the increase in choroidal thickness during recovery from deprivation myopia [19]. However, the same investigators also suggested that choroidal blood flow may not be correlated with choroidal thickness. In contrast, it has been reported that sildenafil citrate increases choroidal thickness due to a vasodilatory effect on choroidal circulation [4]. This relationship was further investigated in a study that used swept-scan high-frequency digital ultrasound to measure the ocular blood flow [20]. The results also suggested that increased choroidal circulation may be associated with increased choroidal thickness.
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Fig. 1 OCT images of a migraine patient showing acute decrease of choroidal thickness during an attack
In another recent study, subfoveal choroidal thickness, measured by enhanced depth imaging OCT (EDI-OCT), was not found to be significantly correlated with choroidal blood flow in young healthy eyes [21]. The authors speculated that there may be some relation between choroidal blood flow changes and choroidal thickness. However, evaluation of choroidal thickness may not be suited to assessing the choroidal circulation. The authors suggested that further prospective studies are required to determine the changes in choroidal thickness during the stimulation that can cause choroidal circulation changes. Recently, cigarette smoking was shown to be related to a decrease in choroidal thickness in otherwise healthy subjects [5]. To exclude the possible effects of systemic medications and smoking, only recently diagnosed migraine patients who were not using any medications and were non-smokers were included in the present study. This study had several limitations. First, the number of cases, including five patients during an attack, was limited. However, it is very difficult to obtain OCT images during a painful migraine attack. On the other hand, these five patients showed an acute decrease in choroidal thickness during the attack, which supports our suggestion of decreased blood flow according to the vasogenic theory of migraine. Another limitation was related to the effect of diurnal rhythm of choroidal thickness (a change of approximately 20–30 lm), which was demonstrated in previous studies [22, 23]. However, the OCT examinations in the present study were performed at the same time of day (10:00–12:00), even in the attack patients, and so it was unlikely to be a potential bias in our study. The last major limitation of this study was that the choroidal thickness measurements had to be performed manually, which remains a potential cause of interobserver bias. To overcome this limitation, two different observers performed measurements at six different points as described in previous reports. In addition, the thickness of the choroid was measured via manual segmentation by two independent operators. The ICCs between the two operators were strong (ICC [0.90 for all measurement points). Although the reproducibility of this method is high [24], manual measurements of the choroidal thickness took on average 5 min per scan. This relatively long duration may lead to observer
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fatigue, which in turn would increase the possibility of false measurements. Although this is still the most commonly used method for determining choroidal thickness, there is still a need to minimise the bias associated with this measurement method. Despite these limitations, the findings presented here may be useful in future studies regarding the effects of migraine on choroidal thickness. Conflict of interest The authors Mehmet O. Zengin, Zeynep Elmas, Esat Cinar, Cem Kucukerdonmez declare no conflict of interest.
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