Seminars in Ophthalmology, Early Online, 1–5, 2013 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2013.833270
ORIGINAL ARTICLE
Macula and Retinal Nerve Fiber Layer in Migraine Patients: Analysis By Spectral Domain Optic Coherence Tomography
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Fatma Yu¨lek1, Ebru Bilge Dirik2, Yasemin Eren2, Hu¨seyin Simavlı3,4, Nagihan ¸ ag˘ ıl1, and S ¸ aban S ¸ ims ek5 Ug˘urlu1, Nurullah C 1
Department of Ophthalmology and 2Department of Neurology, Medical Faculty, Ankara Atatu¨rk Education and Training Hospital, Yıldırım Beyazıt University, Ankara, Turkey, 3Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA, 4Department of Ophthalmology, Izzet Baysal Bolu State Hospital, Bolu, Turkey, and 5Department of Ophthalmology, Medical Faculty, Maltepe University, Istanbul, Turkey
ABSTRACT Aim: Investigating the retinal nerve fiber layer (RNFL), macular and ganglion cell complex thickness in eyes of migraine patients using optical coherence tomography. Methods: The study was designed as an observational cross-sectional study. 50 patients with migraine (30 patients with aura and 20 patients without aura) and 50 healthy volunteers were included. Optical coherence tomography was performed with Optovue technology. The fast RNFL thickness (3.4) scan, MM5, and GCC acquisition protocols were used. Results: There was no statistically significant difference in retinal thickness in any of the quadrants between the control group and the migraine patients (p40.05). The average RNFL thickness (110.50 vs 102.84 microns, p = 0.03) was significantly thinner in migrainers as compared to the control. The ANOVA did not reveal any significant difference between migrainers with aura, migrainers without aura, and the control group. The VAS (visual analogue scale) score of migraine patients was not statistically significantly correlated with any of the parameters, while the length of migraine history was negatively correlated with the average RNFL thickness (r = 0.32, p = 0.03). Conclusıon: The average RNFL thickness in the migraine patients was found to be thinner than that in the control group. In addition, we found a negative weak correlation between length of migraine history and the average RNFL thickness, supporting the possible association between these pathologies. Keywords: Ganglion cell complex thickness, macular thickness, migraine, nerve fiber layer thickness, spectral domain optical coherence tomography
INTRODUCTION
Mountain study. Patients with pressure-independent glaucoma have reported migraine headaches3 two to three times more often than the control subjects or patients with open-angle glaucoma. On the other hand, some other studies that investigated a possible relationship between migraine and glaucoma failed to find a significant association4,5 between the two conditions. The investigation of the retinal nerve fiber layer and the macula of patients with migraine may reveal
Migraine and glaucoma have been found to be associated events by several studies. Elderly patients with pressure-independent glaucoma reported the presence of general headaches with or without the classic signs of migraine at a higher rate than control subjects.1 A moderate association between migraine and open-angle glaucoma has been revealed2 in patients between the ages of 70 and 79 by the Blue
Received 24 July 2013; accepted 6 August 2013; published online 20 September 2013 Correspondence: Huseyin Simavlı, Massachusetts Eye and Ear Infirmary, 243 Charles Street, 8th floor, 02114, Boston, MA, USA. E-mail: [email protected]
1
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2
F. Yu¨lek et al.
the possible association of these two conditions. The optical coherence tomography is a non-invasive technique that provides cross-sectional images of tissue morphology in vivo and quantitative information6 about the retinal nerve fiber layer and the retinal thickness. Previously, the RNFL has been assessed by time domain (td) OCT,7 with the result that temporal RNFL was thinner in migraine patients. Spectral domain (sd) OCT technology with better scan resolution than td OCT8,9 also provides repeatable10 measurements. Evaluation of macular thickness and ganglion cell complex thickness may reflect possible problems of retinal circulation that may be affected by vasomotor problems in migraine. The purpose of this study was to identify any structural differences in the nerve fiber layer, the macular thickness and ganglion cell complex that may exist between patients with migraine and age-matched control subjects by spectral domain optical coherence tomography (sd-OCT).
MATERIALS AND METHODS The study group was comprised of 50 subjects who had been medically diagnosed with migraine headache (mean age 35.16 10.02 years, range 18 to 60 years, 39 females and 11 males) according to the criteria of the Headache International Society. The non-headache control group consisted of 50 healthy volunteers (mean age 38.54 7.80 years, range 19 to 54 years, 32 females and 18 male) that reported no migraine history and had never received medication for migraine syndrome. The research subjects were recruited consecutively from the neurology and ophthalmology clinics. Ethics approval for the project was provided by the institutional review board and the research followed the tenets of the Declaration of Helsinki. Subjects gave written informed consent before participation in the study. Exclusion criteria included known optic nerve diseases or anomalies (glaucoma or glaucoma suspects, optic disc drusen, optic neuropathy, optic pit, or coloboma), known other retinal diseases (diabetic retinopathy, hypertensive retinopathy), uveitis, intraocular pressure (IOP) higher than 20 mm Hg or a previous history of ocular hypertension, refractive error of more than 6 diopters (D) sphere or 3 D cylinder, previous intraocular or refractive surgery, a diagnosis of diabetes mellitus, and inability to hold reasonable fixation, or media opacity that precluded a high-quality OCT examination. The VAS score, which is an easy and reliable indicator of pain level and thus the severity of migraine,11,12 was used to evaluate the severity of migraine attacks of patients. Sd-OCT scanning was performed on all subjects using Optovue technology (RTVue Model-RT100 version 3.5; Optovue Inc, Fremont, California, USA).
The RNFL 3,45 protocol was used for peripapillary RNFL analysis. Peripapillary RNFL thickness was measured at a diameter of 3.45 mm around the center of the optic disc with a total of 2225 A scans. The results were displayed in a color map using customized software with normative data adjusted for age and optic disc size. A peripapillary RNFL thickness map was shown as a numerical value and the color code in each of 16 segments for the four quadrants: superior (46 to 135 degrees), nasal (316 to 45 degrees for the right and 136 to 225 degrees for the left), inferior (226 to 315 degrees), and temporal (136 to 225 degrees for the right and 316 to 45 degrees for the left). Ganglion cell complex thickness was measured using the GCC protocol. This protocol is composed of 15 vertically oriented B-scans of 7.0 mm in length (800 A-scans each), each separated by 0.50 mm, and a single horizontally oriented B-scan of 7.0 mm in length (12 934 A-scans), all centered (roughly) on the macula by the operator (the center of the GCC scan is shifted 1.0 mm temporally to better sample the temporal peripheral macula that is associated with the nasal visual field). This scan configuration provides a total of 24 934 A-scans in 1.0 s. Areas between A-scans are interpolated. Additional macular scans also were performed using the MM5 protocol, which is presented as 5-mm macular thickness maps with results compared with color codes based on age-similar customized normative data. The scan acquisition time required for each of the MM5 scans was 0.78 seconds. Macular thickness measurements reported are GCC thickness (software-defined region bound by the presumed internal-limiting membrane and inner plexiform layers) and macular thickness (softwaredefined region bound by the presumed internallimiting membrane and bottom of the RPE).
Data Analysis Peripapillary RNFL and macular thickness in each quadrant and ganglion cell complex in each hemisphere were analyzed. Measurements from both eyes of patients were provided and the two eyes of each patient were compared by bivariate correlation. There was high correlation (r value more than 0.5) between two eyes for the measurements. Therefore only the left eye of each patient was involved in statistical analysis in order to prevent the repetition of data. The thickness measurements from our patients with migraine were analyzed compared with those of the normal subjects using an unpaired Student t test. The migraine patients were further divided into two according to the presence of aura, and these three groups were analyzed by ANOVA. Probability values less than 0.05 were considered to be statistically significant. Seminars in Ophthalmology
Macula and RNFL Thickness in Migraine by SD-OCT
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RESULTS The study included 50 patients with migraine (30 patients with aura and 20 patients without aura) and 50 control subjects. The three groups were not significant in terms of distribution of sex (p = 0.28) and age (p = 0.17). The mean duration of migraine and the VAS scores of the migraine patients are observed in Table 1. The length of duration of migraine (p = 0,18) and VAS scores (p = 0,83) were not significantly different between two groups: migraine with aura, and migraine without aura. The average retinal thicknesses in different quadrants of the macula of the migranieners and the control group were not statistically different (Table 2). The average RNFL thickness was significantly thinner in migrainers compared to the control group (p = 0.03). The RNFL thickness in the other quadrants and GCC thickness were not statistically significantly different in migrainers (Table 3). The comparison of migraine patients with aura, those patients without aura, and the control group by ANOVA did not reveal a statistically significant difference. The correlation of VAS score with the retinal thickness and the RNFL thickness in all of the regions
analyzed was not statistically significant. The negative weak correlation between length of migraine history and the thickness of retina in perifoveal superior hemisphere (p = 0.02) and perifoveal nasal (p = 0.04) quadrants were statistically significant (Table 4). The negative weak correlation between the length of migraine history and thickness of the RNFL was statistically significant in all of the quadrants except temporal and nasal ones (Table 5). The GCC thickness had also weak correlation with length of migraine history, which was not statistically siginificant (Table 5). The VAS score had weak correlation with all of the parameters stuided by sd OCT that was not also statistically significant.
DISCUSSION Migraine is a chronic, recurrent neurological condition resulting in periodic attacks of head pain. Its etiology is unknown but several theories have been presented to explain the pathophysiology. The clinical TABLE 3. The mean thickness of RNFL (retinal nerve fiber layer) in different quadrants and ganglion cell complex layer (GCC) in superior and inferior hemispheres in microns (*: statistically significant). Migrainers
TABLE 1. The duration of migraine and the VAS (visual analogue scale) scores in migraine patients with aura and those without aura (SEM: Standard error of mean). Migraine with aura
Duration of migraine (years) VAS score
Migraine without aura
Mean
SEM
Mean
SEM
6.02
1.20
3.86
0.69
7.57
0.31
7.47
0.27
TABLE 2. The mean retinal thickness in different quadrants of the control group and the migrainers in microns. Migrainers
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249.22 320.62 322.14 320.28 310.90 325.86 324.08 321.76 295.24 294.02 295.46 286.04 287.18 312.10 291.64
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3.36 2.92 3.04 3.29 2.92 3.23 3.09 3.02 2.74 3.42 2.82 2.85 6.35 3.05 3.18
Average RNFL Superior hemisphere RNFL Inferior hemisphere RNFL Temporal RNFL Superior RNFL Nasal RNFL Inferior RNFL GCC in superior hemisphere GCC in inferior hemisphere
102.84 104.76 101.10 81.74 128.08 75.36 127.58 99.07 100.65
3.47 2.04 2.24 1.96 2.00 2.30 2.58 1.90 2.18 2.18 2.27 2.15 2.34 2.57 2.36
0.34 0.50 0.54 0.79 0.50 0.57 0.56 0.55 0.24 0.20 0.24 0.16 0.18 0.37 0.45
2.91 3.07 2.86 2.74 4.02 2.57 4.04 1.30 1.25
110.50 112.26 106.04 84.34 137.46 79.62 135.90 102.26 103.49
2.01 2.12 2.16 1.81 3.04 1.630 3.40 0.93 0.84
0.03* 0.05 0.17 0.43 0.07 0.16 0.12 0.05 0.06
TABLE 4. The pearson correlation coefficient and significance values for the correlation between retinal thickness in different quadrants and length of migraine history (*: statistically significant).
Control
253.80 323.02 324.48 321.32 313.30 328.14 326.42 323.90 299.41 299.29 299.78 291.12 296.31 315.67 294.63
Control
Mean SEM Mean SEM p Value
r Value
Mean SEM Mean SEM p Value Central fovea Parafoveal center Parafoveal superior hemisphere Parafoveal inferior hemisphere Parafoveal temporal Parafoveal superior Parafoveal nasal Parafoveal inferior Perifoveal center Perifoveal superior hemisphere Perifoval inferior hemisphere Perifoveal temporal Perifoveal superior Perifoveal nasal Perifoveal inferior
3
Central fovea Parafoveal center Parafoveal superior hemisphere Parafoveal inferior hemisphere Parafoveal temporal Parafoveal superior Parafoveal nasal Parafoveal inferior Perifoveal center Perifoveal superior hemisphere Perifoval inferior hemisphere Perifoveal temporal Perifoveal superior Perifoveal nasal Perifoveal inferior
0.03 0.21 0.20 0.20 0.27 0.15 0.22 0.17 0.20 0.33 0.21 0.15 0.18 0.30 0.19
p 0.84 0.15 0.17 0.17 0.06 0.30 0.13 0.25 0.14 0.02* 0.16 0.32 0.23 0.04* 0.20
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TABLE 5. The pearson correlation coefficient and significance values for the correlation between RNFL thickness in different quadrants and length of migraine history (*: statistically significant). r Value
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Average RNFL Superior hemisphere RNFL Inferior hemisphere RNFL Temporal RNFL Superior RNFL Nasal RNFL Inferior RNFL GCC in superior hemisphere GCC in inferior hemisphere
0.32 0.29 0.33 0.23 0.33 0.11 0.38 0.18 0.12
p 0.03 0.04 0.02 0.11 0.02 0.44 0.01 0.24 0.43
concept of vasospasm, which was first described in the late 1850s by Gull13 and later supported by several laboratory studies14,15 and by angiography,16 has evolved into neurovascular theory by other studies.17,18 The vascular link to the development of glaucoma, first proposed by Gasser and Flammer, highlighted the generalized vascular dysfunction as a component of glaucoma.19,20 The increased frequency of headache reported in normotensive glaucoma patients1 further supports a link between migraine and glaucoma. To test the hypothesis that there may be RNFL problems in migraine patients due to the possible role of vascular dysfunctions, new technologies have been used. Tan et al. have used scanning laser polarimetry for measurement of RNFL thickness and concluded that the RNFL thickness was not affected in migraine.21 Their study did not provide any information about the frequency of migraine attacks or the severity of migraine. Martinez et al. have found that the temporal RNFL is thin in migrainers compared to control patients by td-OCT.7 Additionally, they have noted that the RNFL thickness showed a significant correlation with the MIDAS score and duration of migraine history. Several earlier studies have shown that td-OCT measurements are reproducible, with RNFL thickness in glaucomatous eyes being slightly more variable than in normal eyes.22–24 However, sd-OCT measurements were similarly repeatable in both healthy and patient eyes.10 Therefore, we planned to study the RNFL, macular, and GCC thickness by sd-OCT. The macular thickness may reflect changes in the inner retinal layers due to changes in the central retinal artery circulation. In our study, the migraine patients had significant differences in overall average RNFL thickness as compared to the control group. Retinal thickness analysis did not yield a significant difference in any of the quadrants. We have not observed a study comparing GCC and macular thickness in migraine patients before. The central foveal thickness was
thinner in migraine patients, though not statistically significant (249.22 vs 253.80 microns). Clinically, the significance is debatable. On the other hand, higher resistivity indices in the central retinal artery (CRA) and posterior ciliary arteries (PCA) have been reported in migrainers during the headache-free periods compared to the control subjects by using color Doppler imaging.25 This effect on central retinal vessels may be responsible for the decreased central foveal thickness. However, this interesting finding should be studied further. Martinez et al. had found only temporal RNFL thickness significantly thin in migrainers.7 However, in our study we have found overall average RNFL thickness significantly thin. The length of migraine history, VAS scores, and the sd OCT parameters were not significantly different between migraine patients with aura and those without aura. The severity of migraine was measured by VAS (visual analogue scale) score in our study. The Midas score was also calculated, but it was relatively unreliable in a great proportion of our patients with lower education level. The VAS score is an easy and reliable indicator of pain level and thus the severity of migraine.11,12 The VAS score was not correlated with any of the parameters we studied by OCT. In contrast, Martinez et al. have found that the Midas scoring system that they had used for scoring severity of migraine was signicantly correlated with the RNFL.7 This may be attributed to the different scoring systems used and also the heterogenity and the severity of the migraine headache in the study groups. The duration of migraine history was significantly correlated with the overall RNFL thickness in our study, in accordance with other studies.7 We may conclude that this is an important factor for the effect on retinal structures. An important limitation of our study is the small patient group studied. In fact, multicenter studies with different populations may be more valuable in this aspect. Also, increasing the number of patients in addition to taking patients with different severity of scores and length of duration of migraine may be important to evaluate the effect of severity of migraine on RNFL. We conclude that sd OCT is a useful method for the evaluation of migraine patients and the association of this pathology with glaucoma.
ACKNOWLEDGEMENTS This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors. Each author has contributed to the paper for authorship. Seminars in Ophthalmology
Macula and RNFL Thickness in Migraine by SD-OCT
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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REFERENCES 1. Phelps CD, Corbett JJ. Migraine and low-tension glaucoma: A case-control study. Invest Ophthalmol Vis Sci 1985; 26:1105–1108. 2. Wang JJ, Mitchell P, Smith W. Is there an association between migraine headache and open-angle glaucoma? Findings from the Blue Mountains Eye Study. Ophthalmology 1997;104:1714–1719. 3. Cursiefen C, Wisse M, Cursiefen S, et al. Migraine and tension headache in high-pressure and normal-pressure glaucoma. Am J Ophthalmol 2000;129:102–104. 4. Usui T, Iwata K, Shirakashi M, Abe H. Prevalence of migraine in low-tension glaucoma and primary openangle glaucoma in Japanese. Br J Ophthalmol 1991;75: 224–226. 5. Klein BE, Klein R, Meuer SM, Goetz LA. Migraine headache and its association with open-angle glaucoma: The Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 1993; 34:3024–3027. 6. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991;254:1178–1181. 7. Martinez A, Proupim N, Sanchez M. Retinal nerve fibre layer thickness measurements using optical coherence tomography in migraine patients. Br J Ophthalmol 2008; 92:1069–1075. 8. van Velthoven ME, Faber DJ, Verbraak FD, et al. Recent developments in optical coherence tomography for imaging the retina. Prog Retin Eye Res 2007;26: 57–77. 9. Chen TC, Cense B, Pierce MC, et al. Spectral domain optical coherence tomography: Ultra-high speed, ultrahigh resolution ophthalmic imaging. Arch Ophthalmol 2005; 123:1715–1720. 10. Vizzeri G, Weinreb RN, Gonzalez-Garcia AO, et al. Agreement between spectral-domain and time-domain OCT for measuring RNFL thickness. Br J Ophthalmol 2009;93:775–781.
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2013 Informa Healthcare USA, Inc.
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11. Downie WW, Leatham PA, Rhind VM, Wright V, Branco JA, Anderson JA. Studies with pain rating scales. Ann Rheum Dis 1978;37:378–381. 12. Wewers ME, Lowe NK. A critical review of visual analogue scales in the measurement of clinical phenomena. Res Nurs Health 1990;13:227–236. 13. Gull WM. Cases of aneurism of the cerebral vessels. Guys Hosp Rep 1859;5:281–304. 14. Florey H. Microscopical observations on the circulation of the blood in the cerebral cortex. Brain 1925;48: 43–64. 15. Zucker MB. A study of substances in blood serum and platelets which stimulate smooth muscle. Am J Physiol 1944;142:12–26. 16. Ecker A, Riemenschneider PA. Arteriographic demonstration of spasm of the intracranial arteries, with special reference to saccular arterial aneurysms. J Neurosurg 1951; 8:660–667. 17. Hadjikhani N, Sanchez Del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA 2001;98: 4687–4692. 18. Moskowitz MA. Trigeminovascular system. Cephalalgia 1992;12:127. 19. Gasser P. Ocular vasospasm: A risk factor in the pathogenesis of low-tension glaucoma. Int Ophthalmol 1989;13: 281–290. 20. Gasser P, Flammer J. Influence of vasospasm on visual function. Doc Ophthalmol 1987;66:3–18. 21. Tan FU, Akarsu C, Gullu R. Retinal nerve fiber layer thickness is unaffected in migraine patients. Acta Neurol Scand 2005;112:19–23. 22. Budenz DL, Fredette MJ, Feuer WJ, Anderson DR. Reproducibility of peripapillary retinal nerve fiber thickness measurements with stratus OCT in glaucomatous eyes. Ophthalmology 2008;115:661–666. 23. Paunescu LA, Schuman JS, Price LL, et al. Reproducibility of nerve fiber thickness, macular thickness, and optic nerve head measurements using Stratus OCT. Invest Ophthalmol Vis Sci 2004;45:1716–1724. 24. Schuman JS, Pedut-Kloizman T, Hertzmark E, et al. Reproducibility of nerve fiber layer thickness measurements using optical coherence tomography. Ophthalmology 1996;103:1889–1898. 25. Kara SA, Erdemoglu AK, Karadeniz MY, Altinok D. Color Doppler sonography of orbital and vertebral arteries in migraineurs without aura. J Clin Ultrasound 2003;31: 308–314.
ORIGINAL ARTICLE
Macula and Retinal Nerve Fiber Layer in Migraine Patients: Analysis By Spectral Domain Optic Coherence Tomography
Semin Ophthalmol Downloaded from informahealthcare.com by Dalhousie University on 06/30/14 For personal use only.
Fatma Yu¨lek1, Ebru Bilge Dirik2, Yasemin Eren2, Hu¨seyin Simavlı3,4, Nagihan ¸ ag˘ ıl1, and S ¸ aban S ¸ ims ek5 Ug˘urlu1, Nurullah C 1
Department of Ophthalmology and 2Department of Neurology, Medical Faculty, Ankara Atatu¨rk Education and Training Hospital, Yıldırım Beyazıt University, Ankara, Turkey, 3Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA, 4Department of Ophthalmology, Izzet Baysal Bolu State Hospital, Bolu, Turkey, and 5Department of Ophthalmology, Medical Faculty, Maltepe University, Istanbul, Turkey
ABSTRACT Aim: Investigating the retinal nerve fiber layer (RNFL), macular and ganglion cell complex thickness in eyes of migraine patients using optical coherence tomography. Methods: The study was designed as an observational cross-sectional study. 50 patients with migraine (30 patients with aura and 20 patients without aura) and 50 healthy volunteers were included. Optical coherence tomography was performed with Optovue technology. The fast RNFL thickness (3.4) scan, MM5, and GCC acquisition protocols were used. Results: There was no statistically significant difference in retinal thickness in any of the quadrants between the control group and the migraine patients (p40.05). The average RNFL thickness (110.50 vs 102.84 microns, p = 0.03) was significantly thinner in migrainers as compared to the control. The ANOVA did not reveal any significant difference between migrainers with aura, migrainers without aura, and the control group. The VAS (visual analogue scale) score of migraine patients was not statistically significantly correlated with any of the parameters, while the length of migraine history was negatively correlated with the average RNFL thickness (r = 0.32, p = 0.03). Conclusıon: The average RNFL thickness in the migraine patients was found to be thinner than that in the control group. In addition, we found a negative weak correlation between length of migraine history and the average RNFL thickness, supporting the possible association between these pathologies. Keywords: Ganglion cell complex thickness, macular thickness, migraine, nerve fiber layer thickness, spectral domain optical coherence tomography
INTRODUCTION
Mountain study. Patients with pressure-independent glaucoma have reported migraine headaches3 two to three times more often than the control subjects or patients with open-angle glaucoma. On the other hand, some other studies that investigated a possible relationship between migraine and glaucoma failed to find a significant association4,5 between the two conditions. The investigation of the retinal nerve fiber layer and the macula of patients with migraine may reveal
Migraine and glaucoma have been found to be associated events by several studies. Elderly patients with pressure-independent glaucoma reported the presence of general headaches with or without the classic signs of migraine at a higher rate than control subjects.1 A moderate association between migraine and open-angle glaucoma has been revealed2 in patients between the ages of 70 and 79 by the Blue
Received 24 July 2013; accepted 6 August 2013; published online 20 September 2013 Correspondence: Huseyin Simavlı, Massachusetts Eye and Ear Infirmary, 243 Charles Street, 8th floor, 02114, Boston, MA, USA. E-mail: [email protected]
1
Semin Ophthalmol Downloaded from informahealthcare.com by Dalhousie University on 06/30/14 For personal use only.
2
F. Yu¨lek et al.
the possible association of these two conditions. The optical coherence tomography is a non-invasive technique that provides cross-sectional images of tissue morphology in vivo and quantitative information6 about the retinal nerve fiber layer and the retinal thickness. Previously, the RNFL has been assessed by time domain (td) OCT,7 with the result that temporal RNFL was thinner in migraine patients. Spectral domain (sd) OCT technology with better scan resolution than td OCT8,9 also provides repeatable10 measurements. Evaluation of macular thickness and ganglion cell complex thickness may reflect possible problems of retinal circulation that may be affected by vasomotor problems in migraine. The purpose of this study was to identify any structural differences in the nerve fiber layer, the macular thickness and ganglion cell complex that may exist between patients with migraine and age-matched control subjects by spectral domain optical coherence tomography (sd-OCT).
MATERIALS AND METHODS The study group was comprised of 50 subjects who had been medically diagnosed with migraine headache (mean age 35.16 10.02 years, range 18 to 60 years, 39 females and 11 males) according to the criteria of the Headache International Society. The non-headache control group consisted of 50 healthy volunteers (mean age 38.54 7.80 years, range 19 to 54 years, 32 females and 18 male) that reported no migraine history and had never received medication for migraine syndrome. The research subjects were recruited consecutively from the neurology and ophthalmology clinics. Ethics approval for the project was provided by the institutional review board and the research followed the tenets of the Declaration of Helsinki. Subjects gave written informed consent before participation in the study. Exclusion criteria included known optic nerve diseases or anomalies (glaucoma or glaucoma suspects, optic disc drusen, optic neuropathy, optic pit, or coloboma), known other retinal diseases (diabetic retinopathy, hypertensive retinopathy), uveitis, intraocular pressure (IOP) higher than 20 mm Hg or a previous history of ocular hypertension, refractive error of more than 6 diopters (D) sphere or 3 D cylinder, previous intraocular or refractive surgery, a diagnosis of diabetes mellitus, and inability to hold reasonable fixation, or media opacity that precluded a high-quality OCT examination. The VAS score, which is an easy and reliable indicator of pain level and thus the severity of migraine,11,12 was used to evaluate the severity of migraine attacks of patients. Sd-OCT scanning was performed on all subjects using Optovue technology (RTVue Model-RT100 version 3.5; Optovue Inc, Fremont, California, USA).
The RNFL 3,45 protocol was used for peripapillary RNFL analysis. Peripapillary RNFL thickness was measured at a diameter of 3.45 mm around the center of the optic disc with a total of 2225 A scans. The results were displayed in a color map using customized software with normative data adjusted for age and optic disc size. A peripapillary RNFL thickness map was shown as a numerical value and the color code in each of 16 segments for the four quadrants: superior (46 to 135 degrees), nasal (316 to 45 degrees for the right and 136 to 225 degrees for the left), inferior (226 to 315 degrees), and temporal (136 to 225 degrees for the right and 316 to 45 degrees for the left). Ganglion cell complex thickness was measured using the GCC protocol. This protocol is composed of 15 vertically oriented B-scans of 7.0 mm in length (800 A-scans each), each separated by 0.50 mm, and a single horizontally oriented B-scan of 7.0 mm in length (12 934 A-scans), all centered (roughly) on the macula by the operator (the center of the GCC scan is shifted 1.0 mm temporally to better sample the temporal peripheral macula that is associated with the nasal visual field). This scan configuration provides a total of 24 934 A-scans in 1.0 s. Areas between A-scans are interpolated. Additional macular scans also were performed using the MM5 protocol, which is presented as 5-mm macular thickness maps with results compared with color codes based on age-similar customized normative data. The scan acquisition time required for each of the MM5 scans was 0.78 seconds. Macular thickness measurements reported are GCC thickness (software-defined region bound by the presumed internal-limiting membrane and inner plexiform layers) and macular thickness (softwaredefined region bound by the presumed internallimiting membrane and bottom of the RPE).
Data Analysis Peripapillary RNFL and macular thickness in each quadrant and ganglion cell complex in each hemisphere were analyzed. Measurements from both eyes of patients were provided and the two eyes of each patient were compared by bivariate correlation. There was high correlation (r value more than 0.5) between two eyes for the measurements. Therefore only the left eye of each patient was involved in statistical analysis in order to prevent the repetition of data. The thickness measurements from our patients with migraine were analyzed compared with those of the normal subjects using an unpaired Student t test. The migraine patients were further divided into two according to the presence of aura, and these three groups were analyzed by ANOVA. Probability values less than 0.05 were considered to be statistically significant. Seminars in Ophthalmology
Macula and RNFL Thickness in Migraine by SD-OCT
Semin Ophthalmol Downloaded from informahealthcare.com by Dalhousie University on 06/30/14 For personal use only.
RESULTS The study included 50 patients with migraine (30 patients with aura and 20 patients without aura) and 50 control subjects. The three groups were not significant in terms of distribution of sex (p = 0.28) and age (p = 0.17). The mean duration of migraine and the VAS scores of the migraine patients are observed in Table 1. The length of duration of migraine (p = 0,18) and VAS scores (p = 0,83) were not significantly different between two groups: migraine with aura, and migraine without aura. The average retinal thicknesses in different quadrants of the macula of the migranieners and the control group were not statistically different (Table 2). The average RNFL thickness was significantly thinner in migrainers compared to the control group (p = 0.03). The RNFL thickness in the other quadrants and GCC thickness were not statistically significantly different in migrainers (Table 3). The comparison of migraine patients with aura, those patients without aura, and the control group by ANOVA did not reveal a statistically significant difference. The correlation of VAS score with the retinal thickness and the RNFL thickness in all of the regions
analyzed was not statistically significant. The negative weak correlation between length of migraine history and the thickness of retina in perifoveal superior hemisphere (p = 0.02) and perifoveal nasal (p = 0.04) quadrants were statistically significant (Table 4). The negative weak correlation between the length of migraine history and thickness of the RNFL was statistically significant in all of the quadrants except temporal and nasal ones (Table 5). The GCC thickness had also weak correlation with length of migraine history, which was not statistically siginificant (Table 5). The VAS score had weak correlation with all of the parameters stuided by sd OCT that was not also statistically significant.
DISCUSSION Migraine is a chronic, recurrent neurological condition resulting in periodic attacks of head pain. Its etiology is unknown but several theories have been presented to explain the pathophysiology. The clinical TABLE 3. The mean thickness of RNFL (retinal nerve fiber layer) in different quadrants and ganglion cell complex layer (GCC) in superior and inferior hemispheres in microns (*: statistically significant). Migrainers
TABLE 1. The duration of migraine and the VAS (visual analogue scale) scores in migraine patients with aura and those without aura (SEM: Standard error of mean). Migraine with aura
Duration of migraine (years) VAS score
Migraine without aura
Mean
SEM
Mean
SEM
6.02
1.20
3.86
0.69
7.57
0.31
7.47
0.27
TABLE 2. The mean retinal thickness in different quadrants of the control group and the migrainers in microns. Migrainers
!
249.22 320.62 322.14 320.28 310.90 325.86 324.08 321.76 295.24 294.02 295.46 286.04 287.18 312.10 291.64
2013 Informa Healthcare USA, Inc.
3.36 2.92 3.04 3.29 2.92 3.23 3.09 3.02 2.74 3.42 2.82 2.85 6.35 3.05 3.18
Average RNFL Superior hemisphere RNFL Inferior hemisphere RNFL Temporal RNFL Superior RNFL Nasal RNFL Inferior RNFL GCC in superior hemisphere GCC in inferior hemisphere
102.84 104.76 101.10 81.74 128.08 75.36 127.58 99.07 100.65
3.47 2.04 2.24 1.96 2.00 2.30 2.58 1.90 2.18 2.18 2.27 2.15 2.34 2.57 2.36
0.34 0.50 0.54 0.79 0.50 0.57 0.56 0.55 0.24 0.20 0.24 0.16 0.18 0.37 0.45
2.91 3.07 2.86 2.74 4.02 2.57 4.04 1.30 1.25
110.50 112.26 106.04 84.34 137.46 79.62 135.90 102.26 103.49
2.01 2.12 2.16 1.81 3.04 1.630 3.40 0.93 0.84
0.03* 0.05 0.17 0.43 0.07 0.16 0.12 0.05 0.06
TABLE 4. The pearson correlation coefficient and significance values for the correlation between retinal thickness in different quadrants and length of migraine history (*: statistically significant).
Control
253.80 323.02 324.48 321.32 313.30 328.14 326.42 323.90 299.41 299.29 299.78 291.12 296.31 315.67 294.63
Control
Mean SEM Mean SEM p Value
r Value
Mean SEM Mean SEM p Value Central fovea Parafoveal center Parafoveal superior hemisphere Parafoveal inferior hemisphere Parafoveal temporal Parafoveal superior Parafoveal nasal Parafoveal inferior Perifoveal center Perifoveal superior hemisphere Perifoval inferior hemisphere Perifoveal temporal Perifoveal superior Perifoveal nasal Perifoveal inferior
3
Central fovea Parafoveal center Parafoveal superior hemisphere Parafoveal inferior hemisphere Parafoveal temporal Parafoveal superior Parafoveal nasal Parafoveal inferior Perifoveal center Perifoveal superior hemisphere Perifoval inferior hemisphere Perifoveal temporal Perifoveal superior Perifoveal nasal Perifoveal inferior
0.03 0.21 0.20 0.20 0.27 0.15 0.22 0.17 0.20 0.33 0.21 0.15 0.18 0.30 0.19
p 0.84 0.15 0.17 0.17 0.06 0.30 0.13 0.25 0.14 0.02* 0.16 0.32 0.23 0.04* 0.20
4
F. Yu¨lek et al.
TABLE 5. The pearson correlation coefficient and significance values for the correlation between RNFL thickness in different quadrants and length of migraine history (*: statistically significant). r Value
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Average RNFL Superior hemisphere RNFL Inferior hemisphere RNFL Temporal RNFL Superior RNFL Nasal RNFL Inferior RNFL GCC in superior hemisphere GCC in inferior hemisphere
0.32 0.29 0.33 0.23 0.33 0.11 0.38 0.18 0.12
p 0.03 0.04 0.02 0.11 0.02 0.44 0.01 0.24 0.43
concept of vasospasm, which was first described in the late 1850s by Gull13 and later supported by several laboratory studies14,15 and by angiography,16 has evolved into neurovascular theory by other studies.17,18 The vascular link to the development of glaucoma, first proposed by Gasser and Flammer, highlighted the generalized vascular dysfunction as a component of glaucoma.19,20 The increased frequency of headache reported in normotensive glaucoma patients1 further supports a link between migraine and glaucoma. To test the hypothesis that there may be RNFL problems in migraine patients due to the possible role of vascular dysfunctions, new technologies have been used. Tan et al. have used scanning laser polarimetry for measurement of RNFL thickness and concluded that the RNFL thickness was not affected in migraine.21 Their study did not provide any information about the frequency of migraine attacks or the severity of migraine. Martinez et al. have found that the temporal RNFL is thin in migrainers compared to control patients by td-OCT.7 Additionally, they have noted that the RNFL thickness showed a significant correlation with the MIDAS score and duration of migraine history. Several earlier studies have shown that td-OCT measurements are reproducible, with RNFL thickness in glaucomatous eyes being slightly more variable than in normal eyes.22–24 However, sd-OCT measurements were similarly repeatable in both healthy and patient eyes.10 Therefore, we planned to study the RNFL, macular, and GCC thickness by sd-OCT. The macular thickness may reflect changes in the inner retinal layers due to changes in the central retinal artery circulation. In our study, the migraine patients had significant differences in overall average RNFL thickness as compared to the control group. Retinal thickness analysis did not yield a significant difference in any of the quadrants. We have not observed a study comparing GCC and macular thickness in migraine patients before. The central foveal thickness was
thinner in migraine patients, though not statistically significant (249.22 vs 253.80 microns). Clinically, the significance is debatable. On the other hand, higher resistivity indices in the central retinal artery (CRA) and posterior ciliary arteries (PCA) have been reported in migrainers during the headache-free periods compared to the control subjects by using color Doppler imaging.25 This effect on central retinal vessels may be responsible for the decreased central foveal thickness. However, this interesting finding should be studied further. Martinez et al. had found only temporal RNFL thickness significantly thin in migrainers.7 However, in our study we have found overall average RNFL thickness significantly thin. The length of migraine history, VAS scores, and the sd OCT parameters were not significantly different between migraine patients with aura and those without aura. The severity of migraine was measured by VAS (visual analogue scale) score in our study. The Midas score was also calculated, but it was relatively unreliable in a great proportion of our patients with lower education level. The VAS score is an easy and reliable indicator of pain level and thus the severity of migraine.11,12 The VAS score was not correlated with any of the parameters we studied by OCT. In contrast, Martinez et al. have found that the Midas scoring system that they had used for scoring severity of migraine was signicantly correlated with the RNFL.7 This may be attributed to the different scoring systems used and also the heterogenity and the severity of the migraine headache in the study groups. The duration of migraine history was significantly correlated with the overall RNFL thickness in our study, in accordance with other studies.7 We may conclude that this is an important factor for the effect on retinal structures. An important limitation of our study is the small patient group studied. In fact, multicenter studies with different populations may be more valuable in this aspect. Also, increasing the number of patients in addition to taking patients with different severity of scores and length of duration of migraine may be important to evaluate the effect of severity of migraine on RNFL. We conclude that sd OCT is a useful method for the evaluation of migraine patients and the association of this pathology with glaucoma.
ACKNOWLEDGEMENTS This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors. Each author has contributed to the paper for authorship. Seminars in Ophthalmology
Macula and RNFL Thickness in Migraine by SD-OCT
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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REFERENCES 1. Phelps CD, Corbett JJ. Migraine and low-tension glaucoma: A case-control study. Invest Ophthalmol Vis Sci 1985; 26:1105–1108. 2. Wang JJ, Mitchell P, Smith W. Is there an association between migraine headache and open-angle glaucoma? Findings from the Blue Mountains Eye Study. Ophthalmology 1997;104:1714–1719. 3. Cursiefen C, Wisse M, Cursiefen S, et al. Migraine and tension headache in high-pressure and normal-pressure glaucoma. Am J Ophthalmol 2000;129:102–104. 4. Usui T, Iwata K, Shirakashi M, Abe H. Prevalence of migraine in low-tension glaucoma and primary openangle glaucoma in Japanese. Br J Ophthalmol 1991;75: 224–226. 5. Klein BE, Klein R, Meuer SM, Goetz LA. Migraine headache and its association with open-angle glaucoma: The Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 1993; 34:3024–3027. 6. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991;254:1178–1181. 7. Martinez A, Proupim N, Sanchez M. Retinal nerve fibre layer thickness measurements using optical coherence tomography in migraine patients. Br J Ophthalmol 2008; 92:1069–1075. 8. van Velthoven ME, Faber DJ, Verbraak FD, et al. Recent developments in optical coherence tomography for imaging the retina. Prog Retin Eye Res 2007;26: 57–77. 9. Chen TC, Cense B, Pierce MC, et al. Spectral domain optical coherence tomography: Ultra-high speed, ultrahigh resolution ophthalmic imaging. Arch Ophthalmol 2005; 123:1715–1720. 10. Vizzeri G, Weinreb RN, Gonzalez-Garcia AO, et al. Agreement between spectral-domain and time-domain OCT for measuring RNFL thickness. Br J Ophthalmol 2009;93:775–781.
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2013 Informa Healthcare USA, Inc.
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11. Downie WW, Leatham PA, Rhind VM, Wright V, Branco JA, Anderson JA. Studies with pain rating scales. Ann Rheum Dis 1978;37:378–381. 12. Wewers ME, Lowe NK. A critical review of visual analogue scales in the measurement of clinical phenomena. Res Nurs Health 1990;13:227–236. 13. Gull WM. Cases of aneurism of the cerebral vessels. Guys Hosp Rep 1859;5:281–304. 14. Florey H. Microscopical observations on the circulation of the blood in the cerebral cortex. Brain 1925;48: 43–64. 15. Zucker MB. A study of substances in blood serum and platelets which stimulate smooth muscle. Am J Physiol 1944;142:12–26. 16. Ecker A, Riemenschneider PA. Arteriographic demonstration of spasm of the intracranial arteries, with special reference to saccular arterial aneurysms. J Neurosurg 1951; 8:660–667. 17. Hadjikhani N, Sanchez Del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA 2001;98: 4687–4692. 18. Moskowitz MA. Trigeminovascular system. Cephalalgia 1992;12:127. 19. Gasser P. Ocular vasospasm: A risk factor in the pathogenesis of low-tension glaucoma. Int Ophthalmol 1989;13: 281–290. 20. Gasser P, Flammer J. Influence of vasospasm on visual function. Doc Ophthalmol 1987;66:3–18. 21. Tan FU, Akarsu C, Gullu R. Retinal nerve fiber layer thickness is unaffected in migraine patients. Acta Neurol Scand 2005;112:19–23. 22. Budenz DL, Fredette MJ, Feuer WJ, Anderson DR. Reproducibility of peripapillary retinal nerve fiber thickness measurements with stratus OCT in glaucomatous eyes. Ophthalmology 2008;115:661–666. 23. Paunescu LA, Schuman JS, Price LL, et al. Reproducibility of nerve fiber thickness, macular thickness, and optic nerve head measurements using Stratus OCT. Invest Ophthalmol Vis Sci 2004;45:1716–1724. 24. Schuman JS, Pedut-Kloizman T, Hertzmark E, et al. Reproducibility of nerve fiber layer thickness measurements using optical coherence tomography. Ophthalmology 1996;103:1889–1898. 25. Kara SA, Erdemoglu AK, Karadeniz MY, Altinok D. Color Doppler sonography of orbital and vertebral arteries in migraineurs without aura. J Clin Ultrasound 2003;31: 308–314.
