Evaluation of macular and peripapillary structure and microvasculature with optical coherence tomography angiography in migraine in the Indian population

Abstract

BACKGROUND

Migraine has been proposed as a potential contributing factor to ischemic complications involving the retina and optic nerve. Ophthalmic disorders connected with migraine encompass occlusions of the branch and central retinal arteries and veins, alongside anterior and posterior ischemic optic neuropathy. With the advent of optical coherence tomography angiography (OCTA), it is easy to identify these macular subclinical microvascular and structural changes.

AIM

To evaluate macular and peripapillary structural and microvasculature changes in patients with migraine with aura (MA), migraine without aura (MW), and healthy control (HC) participants using OCTA.

METHODS

In this observational cross-sectional study, we studied a total of 100 eyes: (1) 32 eyes of 16 patients with MA; (2) 36 eyes of 18 patients with MW, recruited based on the International Classification of Headache Disorders; and (3) 32 eyes of 16 age and sex-matched healthy participants. Foveal flux, foveal avascular zone (FAZ), peripapillary flux obtained from OCTA, and foveal and peripapillary ganglion cell layer (GCL) thickness calculated via optical coherence tomography were compared among the groups.

RESULTS

The mean FAZ area measured in patients with MA and MW was significantly larger than that in the control participants (P = 0.002). However, there was no significant difference between the FAZ of the MA and MW groups. Macular perfusion in the superficial capillary plexus in patients with MA was significantly lower compared to MW (P = 0.0018) and HCs (P = 0.002). There was also significant thinning of the GCL in patients with MA and MW (P = 0.001) compared to HCs. However, there was no significant difference in temporal GCL thickness between the MA and MW groups.

CONCLUSION

Significant changes have been found in structural and microvascular parameters in patients with migraines compared with HCs. OCTA can serve as a valuable non-invasive imaging technique for identifying microcirculatory disturbances, aiding in better understanding the pathogenesis of different types of migraine and establishing their link with other ischemic retinal and systemic pathologies.

Key Words: Migraine; Aura; Optical coherence tomography angiography; Foveal microvasculature; Macular perfusion

Core Tip: Our observational study shows that there are microvascular and structural changes seen on optical coherence tomography angiography in migraine, and these changes could serve as a valuable non-invasive biomarker in its diagnosis.

INTRODUCTION

Migraine, ranked as the third most prevalent disease worldwide, has an overall prevalence of 14.7% (18.8% in females and 10.7% in males)[1]. The term 'migraine' originates from the Latin word 'hemicrania,' signifying 'half skull.' This designation was initially used by the Greek physician Galenus of Pergamon[2]. Migraine auras refer to sensory symptoms (neurologic, gastrointestinal, and autonomic) that may manifest before or during a migraine attack. These symptoms include phenomena such as light flashes, blind spots, or tingling in the hands or face[2]. Their usual duration spans from 4 hours to 72 hours, and often cause significant incapacitation. These manifestations can occur episodically (fewer than 15 days per month) or chronically (more than 15 days per month). Among migraine headache sufferers, 70% experience migraine without aura (MW)[2]. While the complete pathophysiology of migraine remains elusive, there appears to be a complex interplay between neural and vascular factors that play a pivotal role[3].

For years, migraine has been proposed as a potential contributing factor to ischemic complications involving the retina and optic nerve[4]. Ophthalmic disorders associated with migraine include occlusions of the branch and central retinal arteries and veins, as well as anterior and posterior ischemic optic neuropathy[5]. Furthermore, there is evidence suggesting that migraine could increase the risk of onset or progression of normal tension glaucoma[6,7]. These disorders have been observed during both acute migraine attacks and the periods between attacks[8]. Consequently, both immediate and sustained alterations in ocular perfusion among patients with migraine might make them more susceptible to the aforementioned ocular complications[8,9].

There have been studies from Turkey and the United States describing optical coherence tomography (OCT) and OCT angiography (OCTA) parameters among patients with migraine[10], revealing numerous vascular differences compared to the healthy population[11-15]. Nonetheless, there is little literature available on the structural and microvascular parameters of the macula and peripapillary area among the Indian population.

In this study, we investigated the following parameters: (1) Foveal flux as a measure of foveal vasculature (flux is a novel metric that approximates the number of red blood cells moving through vessel segments per unit area); and (2) Foveal avascular zone (FAZ), peripapillary flux in the superior, inferior, nasal, and temporal quadrants through OCTA, and ganglion cell layer thickness (GCL) at the macula and in the superior, inferior, nasal, and temporal peripapillary quadrants as structural parameters through OCT. This study aimed to better understand the differences among three groups: patients with migraine with aura (MA), without aura (MW), and healthy controls (HCs).

MATERIALS AND METHODS

After approval from the Institutional Ethics Committee of our institute (Project No. RES2023067CLI), we prospectively studied a total of 100 eyes: (1) 32 eyes from 16 patients with MA; (2) 36 eyes from 18 patients with MW; and (3) 32 eyes from 16 HCs. We assessed distant and near visual acuity, refractive error, slit-lamp anterior segment evaluation, posterior segment evaluation by indirect ophthalmoscopy, intraocular pressure by applanation tonometry, and OCT and OCTA parameters, as previously discussed. Patients were selected from the outpatient clinic of the neuro-ophthalmology department of our institute and those referred by neurologists, with inclusion based on the International Classification of Headache Disorders, 3^rd edition[14]. Exclusion criteria for all groups included any neurologic disorder other than migraine (including neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease); any optic nerve disorders such as glaucoma, ischemic optic neuropathy, or retinal diseases; a history of intraocular surgery other than cataract extraction; systemic conditions affecting the microvasculature such as diabetes mellitus, hypertension, vasculitis, or renal disease; and ocular media opacity precluding high-quality imaging. HCs were also excluded if taking vasoactive medications, such as calcium channel blockers. The demographic parameters of participants are described in Table 1.

Table 1 Demographic parameters of participants, n (%).

Group	Mean age in years	Male	Female	Mean refraction (spherical)	Mean refraction (cylinder)	Mean intraocular pressure
Migraine with aura (n = 16)	28.18 ± 7.23	6 (37.5)	10 (62.5)	0.71 ± 0.67	0.31 ± 0.36	15.25 ± 2.87
Migraine without aura (n = 18)	28.94 ± 5.95	8 (44.44)	10 (55.55)	0.47 ± 0.48	0.20 ± 0.24	15.18 ± 2.58
Healthy controls (n = 16)	27.875 ± 6.97	7 (43.75)	9 (56.25)	0.27 ± 0.36	0.18 ± 0.26	15.82 ± 2.88

"Male" and "female" show the count and percentage of participants in each sex category for each group.

OCTA images were acquired using the AngioPlex matrix software on the CIRRUS HD-OCT Model 6000^© 2021 (Carl Zeiss Meditec, Inc., Dublin, CA, United States). The scanning area captured consisted of a 6 mm × 6 mm section centered on the fovea, a 4.5 mm × 4.5 mm section centered on the optic nerve head (ONH), and a 200 µm × 200 µm optic disc cube. The superficial retinal capillary plexus (SCP) was segmented with an inner boundary 3 µm posterior to the internal limiting membrane (ILM) and an outer boundary 15 µm posterior to the outer aspect of the inner plexiform layer. Optic nerve scans were segmented into ONH and radial peripapillary capillary (RPC) slabs. The ONH slab was segmented with an inner boundary at the anterior border of the ILM and an outer boundary 150 µm posterior to the ILM. The software automatically assigned two concentric circles centered at the fovea and ONH. The radii of the inner and outer circles were 1 mm and 2 mm, respectively, providing a ring width of 1 mm. The flux, as a measure of vascularity, of the macular and RPC was evaluated between these rings in the peripapillary region and in four sectors (superior, inferior, nasal, and temporal) around the ONH. The segmentation was between the ILM and the posterior limit of the retinal nerve fiber layer (RNFL). Color-encoded slabs representing different layers were generated. The FAZ area was directly measured with AngioPlex software using a slab from the ILM to 75 µm above the retinal pigment epithelium. CIRRUS 6000 automatically centers and optimizes B-scan settings. The device also automatically corrects for the patient’s refractive error and balances fundus brightness and contrast. Eye tracking was done using FastTrac™.

The macular and peripapillary GCL thickness was also evaluated in the peripapillary region and in four sectors using the same ONH analysis software. OCTA scans with low-quality or inadequate signal strength index (less than 6 on a 10-point scale) were excluded. Scans with blink artifacts, motion artifacts, media opacities interfering with the vessel signals, or segmentation errors were not included in the study.

Statistical analyses

Age, sex, intraocular pressure, refractive errors, and OCT and OCTA parameters were compared among the three groups: (1) MA; (2) MW; and (3) HCs. An independent t-test was used to test the significant difference between the means of two independent groups. Analysis of variance was used to determine whether the difference between group means (more than two groups) was statistically significant. P < 0.05 was considered statistically significant.

RESULTS

A total of 32 eyes from 16 patients in the MA group, 36 eyes from 18 patients in the MW group, and 32 eyes from 16 healthy participants were enrolled. The mean ages for the three groups were as follows. (1) The MA group had a mean age of 28.18 years ± 7.23 years; (2) The MW group had a mean age of 28.94 years ± 5.95 years; and (3) The HC group had a mean age of 27.87 years ± 6.97 years. Across the three groups, the distribution of sexes was similar. In the MA group, 37.5% were male and 62.5% were female; in the MW group, 44.44% were male and 55.56% were female; and in the HC group, 43.75% were male and 56.25% were female. The age (P = 0.89) and sex (P = 0.92) differences were not significant among the groups. Additionally, the intraocular pressure (P = 0.92) and mean refractive errors (0.55) were not significantly different among the groups, as described in Table 1.

All patients enrolled in the study had a best-corrected visual acuity of 6/6 by distance Snellen's chart and near acuity of N6 by the Jaeger chart. Representative OCTA scans of the MA, MW, and HC participants are shown in Figure 1A (macula) and Figure 1B (optic nerve). Quantitative analysis of macular OCTA findings in the patients with MA and MW, and HCs is shown in Table 2. The mean FAZ area measured 0.34 mm² ± 0.12 mm² in the patients with MA, which was significantly larger than that in the control participants (0.201 mm² ± 0.007 mm²; P = 0.002). The FAZ of patients with MW (0.29 mm² ± 0.14 mm²) was also significantly larger than that in the HCs (P = 0.007). However, there was no significant difference between the FAZ areas of the MA and MW groups.

Figure 1 Representative optical coherence tomography angiography scans of migraine with aura, migraine without aura, and healthy control participants. A: Optical coherence tomography angiography (OCTA) images at superficial retinal capillary plexus of fovea of migraine with aura (MA), migraine without aura (MW) and healthy controls (HCs) from left to right with their corresponding B scan below; B: OCTA scans at optic nerve head in the MA, MW, HC groups from left to right, respectively. ILM: Internal limiting membrane; IPL: Inner plexiform layer.

Table 2 Average ± standard deviation values of optical coherence tomography angiography parameters.

Optical coherence tomography angiography parameters	Migraine with aura	Migraine without aura	Healthy controls
Foveal flux	4.16 ± 1.47	6.21 ± 3.10	6.18 ± 2.12
Foveal avascular zone	0.34 ± 0.12	0.29 ± 0.14	0.20 ± 0.07
Superior peripapillary flux	18.57 ± 4.70	19.03 ± 0.93	18.69 ± 3.46
Inferior peripapillary flux	18.22 ± 1.84	18.49 ± 1.12	18.65 ± 1.25
Nasal peripapillary flux	17.88 ± 1.69	17.14 ± 3.96	17.76 ± 2.08
Temporal peripapillary flux	17.55 ± 1.81	22.51 ± 1.83	18.71 ± 1.42

Macular perfusion in the SCP was significantly lower in patients with MA (4.16 ± 1.47) compared to those with MW (6.21 ± 3.10; P = 0.0018) and HCs (6.18 ± 2.12; P = 0.002). There was no difference in foveal perfusion between the MW and HC groups. There were no significant differences in peripapillary perfusion in the superior, inferior, nasal, and temporal quadrants among the MA, MW, and HC groups, as shown in Table 2.

When comparing structural parameters obtained from OCT, no statistical differences were found in GCL thickness among the MA, MW, and HC groups in the foveal, superior, inferior, and nasal peripapillary regions. However, there was significant thinning of the GCL in patients with MA (29.43 ± 4.01; P = 0.001) compared to HC participants (30.59 ± 3.44). Additionally, the temporal GCL thickness in patients with MW (27.38 ± 3.76; P = 0.009) was significantly reduced compared to HC participants. However, there was no significant difference in temporal GCL thickness between the MA and MW groups.

DISCUSSION

After analyzing a total of 100 eyes divided into three groups (MA, MW, and HCs), we concluded that the FAZ was enlarged in patients with migraine, both with and without aura, compared to HCs. Microvascular ischemic events or capillary remodeling of near-normal FAZ may be the cause of FAZ enlargement. The FAZ area is reportedly associated with the severity of systemic diseases, such as diabetes, and some studies have indicated that screening for FAZ might help detect early microvascular abnormalities. OCT parameters of MA, MW, and HC are shown in Table 3.

Table 3 Optical coherence tomography parameters of migraine with aura, migraine without aura, and healthy controls.

Optical coherence tomography parameters	Migraine with aura	Migraine without aura	Healthy controls
Macular GCL thickness	9.46 ± 2.25	9.25 ± 2.27	10.15 ± 3.44
Superior GCL	29.43 ± 3.76	28.58 ± 3.78	30.68 ± 3.16
Inferior GCL	29.40 ± 4.22	29.30 ± 4.02	29.06 ± 3.59
Nasal GCL	29.43 ± 4.01	28.11 ± 3.59	28.75 ± 3.75
Temporal GCL	29.43 ± 4.01	27.38 ± 3.76	30.59 ± 3.44

GCL: Ganglion cell layer.

Enlarged FAZ has also been observed in several studies conducted in Turkey and the United States[13,15]. Our finding of an enlarged FAZ in patients with MW compared to HCs was supported by the results of Hamurcu et al[16] and Taşlı and Ersoy[17].

Another important conclusion of our study was the reduced foveal vascularity in the SCP in patients with MA compared to patients with MW and HCs. Similar findings have been reported by various studies[13,15,18,19]. The decreased foveal vessel density in the SCP in patients with MA is supportive of retinal microvascular disease. The chronic retinovascular alterations demonstrated by OCTA in patients with MA may be related to the increased risk of ocular complications in patients with migraine, even in the absence of an acute attack[13]. Since the advent of modern techniques, many studies have used various parameters to assess retinal vasculature to establish a link between migraine and other ischemic ocular and systemic diseases. Acer et al[20] reported that ocular pulse amplitude did not significantly differ between patients with migraine without aura and control cases. We employed foveal flux, a novel metric that approximates the number of red blood cells moving through vessel segments per unit area. In vitro and in vivo studies demonstrated that foveal flux is not only a complementary parameter to conventional vessel density but also a potentially useful measure of retinal perfusion, in addition to other OCTA-derived parameters.

We did not find any significant difference in peripapillary vasculature among the three groups. However, the temporal GCL thickness in patients with MA and MW was found to be significantly reduced compared to the HC group. Similar thinning of the GCC and RNFL has been documented in various studies[11,12]. Compromised choroidal blood flow can lead to focal ischemic damage in the optic disc[21]. These structural changes might provide insights into the association of migraine with optic nerve diseases such as anterior and posterior ischemic optic neuropathy, normal tension glaucoma, and others[5,6]. Amaurosis fugax in migraineurs has been proposed as a sign of affected choroidal blood flow[22].

Although most studies have shown more structural and microvascular changes in patients with aura compared to those with MW, we found in our study that FAZ enlargement and temporal GCL thinning were equally significant in patients with MW. Thus, we conclude that all patients with migraine, including those with and without aura, exhibit vascular and structural abnormalities compared to healthy eyes. Although the exact pathogenesis of migraine is still unknown, it is believed to be triggered by specific vessels and nerves in the brain. As the eye is an extension of the brain, these features could be reflected in the retinal blood vessels and nerves as observed by OCTA. Enlargement of the FAZ and loss of GCL could be early changes in migraine cases and may serve as potential biomarkers in the future.

To the best of our knowledge, our study is the first to employ OCT and OCTA parameters in three groups—MA, MW, and HC—to study structural and vascular changes in migraine within the Indian population.

This study had several limitations. First, the sample size was small, which might have contributed to the lack of significant results for some parameters. Additionally, most participants were in the interictal period, so vascular findings during an acute migraine attack could not be assessed. We also failed to include vascularity measures in the deep capillary plexus at the fovea and ONH, thus limiting access to important information. A possible confounding factor could have been the duration of migraine symptoms, as structural changes are chronic phenomena that we did not consider. Finally, migraine is a heterogeneous disorder, making it difficult to categorize patients into distinct groups.

CONCLUSION

In conclusion, we found significant FAZ enlargement in patients with migraine, both with and without aura, compared to HCs. Additionally, we observed reduced foveal vascularity in patients with aura compared to patients without aura and HCs. These microvascular changes can help establish a link between migraines and other retinal and choroidal ischemic diseases, providing a better understanding of migraine’s lesser-established pathophysiology. We also found temporal GCL thinning in both groups of patients with migraine compared to HC. Repeated insults due to reduced blood supply during attacks may explain these structural changes even during attack-free periods.

Having conducted a study involving 100 eyes across three groups—MA, MW, and HC—we can now consider the future prospects of our research. Building on this pilot study, there is potential to conduct extensive longitudinal investigations. This broader research could encompass factors such as the duration of migraine episodes, acquiring scans during the attack phase, and incorporating a more comprehensive array of parameters.