Dr. Nikhil Kandurwar, K15719, Dr. Chaitra Jayadev, Dr. AbdulRawoof, Dr. Rohit Shetty
Migraine is a multifactorial disorder characterized by severe throbbing pain or a pulsing sensation, usually on just one side of the head and it is often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. Etiopathology of migraine is not completely understood. The global burden of disability due to migraine ranks between most disabling disorders attributing to almost 3% disability due to any disease.1 Prevalence of migraine has been reported from 1.2% to as high as 26.1% .2 Thirty eight percent of migraineurs experience aura. Visual aura is the most common are seen in up to 92% of migraineurs. Visual phenomena are present in 92.1% of patients with aura and often being present as the only aura symptom.3
Migraine pain is primarily mediated through trigeminovascular network which is a complex neurovascular phenomenon.4 The corneal nerves that are terminal branches of ophthalmic division of trigeminal nerve forms a sub-basal nerve plexus which runs parallel to ocular surface. The axons from these corneal nerve terminal serve nociceptive, trophic and protective functions conducting signals from nociceptive, thermo and mechanoreceptors.5 In vivo confocal microscopy (IVCM) is non-invasive imaging modality to image sub-basal nerve plexus and dendritic cell morphology. Kinard et al reported pathological alterations in corneal nerves in chronic migraine patients on in vivo confocal microscopy. The abnormal visual stimuli exacerbating attacks of migraine and concurrent presence altered corneal nerves indicated possible correlation.6
Several studies support the role of inflammation in the pathogenesis of migraine in which the attacks are associated with neurovascular inflammation of the cerebral and extracerebral vessels.7 The inflammatory aspect of migraine pathogenesis has further been supported by increased serum levels of inflammatory cytokines in the various phases of migraine.8 Tear analysis of migraine patients showed raised inflammatory biomolecules adding further to the strength to the possible association between inflammation and migraine.9 Dry eye disease is multifactorial with the key etiologies of tear film instability and ocular surface inflammation. In the light of new data, neurosensory abnormalities were also included in the definition.10 Tear film disturbances with cause more optical aberrations in the eye which leads to more aberrated visual stimuli. Therefore, we proposed this study to establish an axis of various ocular factors which can be potential triggers for migraine attacks.
The study was approved by the hospital’s institutional review board and was in agreement with the tenets of the Declaration of Helsinki. This was an observational cross-sectional study. All patients after having been given a full explanation of the procedure provided a written informed consent. Subjects aged 18-35 years, mean refractive spherical equivalent (MRSE) within +/- 0.75D without systemic diseases associated with dry eye (e.g. rheumatoid arthritis), any pre-existing ocular disorder or history of ocular surgery served as controls. Patients with a confirmed diagnosis of migraine after neurological consult were included in the study. The patients with contact lens usage, drug allergy, meibomian gland dysfunction and patients with ocular manifestations of systemic diseases involving ocular surface like Sjogren syndrome, rheumatoid arthritis, Stevens-Johnson syndrome and diabetes mellitus were excluded from the study
Clinical examination and optical analysis
After a thorough clinical history to rule out ocular and systemic co-morbidities, visual acuity assessment, refraction, detailed slit-lamp examination and fundus evaluation were performed. Ocular wavefront aberrations in root mean square (RMS) were measured using Optical Path Difference (OPDIII,Nidek,Japan) and intraocular light scattering quantified with objective scatter index(OSI) of the optical quality analysis system(OQAS;Visiometrics,Terrassa,Spain) based on the principle of double pass using a laser diode wavelength of 780 nm. The OSI was measured after 4–5 blinks and then at 0.5-second intervals over 20 s without the subject blinking in between.
In vivo confocal microscopy
IVCM imaging was performed using Rostock Corneal Module/Heidelberg Retina Tomograph ll with a 670nm diode laser (RCM/HRT ll,Heidelberg Engineering GmBH, Dossenheim, Germany). 0.5% proparacaine drops were used to anaesthetize the cornea before the procedure. Study subjects were asked to fixate on a distant target and the central cornea was scanned in a single area at a desired depth. A drop of 0.5% moxifloxacin was instilled after the procedure. None of the subjects experienced any visual symptoms or corneal complications as a result of this examination. The central corneal nerves were analyzed using a 400×400µ frame followed by quantitation (CCMetrics,UK software ver 1). Nerve parameters analyzed were corneal nerve fibre density(CNFD),corneal nerve fibre length(CNFL),corneal nerve branch density(CNBD),corneal total branch density(CTBD),corneal nerve fibre width(CNFW) and corneal nerve fibre area(CNFA). Also additional analysis was done for corneal dendritic cell density and types of dendrites.
Tears were collected using sterile Schirmer’s strips – Whatman filter paper measuring 5 × 35-mm2 (Contacare Opthalmics and Diagnostics, India) and proteins extracted for cytokine analysis. The levels of various inflammatory proteins in the tears were measured using cytometric bead array (BD CBA Human Soluble Protein Flex Set System, BD Biosciences, Haryana, India) on a flow cytometer (BD FACSCalibur, BD Biosciences).
Shapiro-Wilk normality test was used tocheck distribution of the data set. ANOVA with Tukey’s multiple comparisons, and independent sample t-test were used to analyse normally distributed data. Kruskal-Wallis, and Mann-Whitney U test were used to analyze data sets that were not normally distributed. Statistical analysis was performed using commercial software (Stata ver. 12.1; StataCorp, College Station, TX). A p-value of ≤ 0.05 was considered statistically significant.
Sixty eyes of 30 subjects with migraine (Group 1) and 60 eyes of 30 normal patients (Group 2) were enrolled in this study. There were 19 females and 11 males in each group. The mean age of subjects in Group 1 was (24.93±4.54) years and that in Group 2 was (26.8±6.16) years. The independent T-test between the study groups showed significantly higher total aberrations (p = 0.049), higher order aberrations (p = 0.009), coma (p = 0.03), spherical aberrations (p = 0.018) and OSI (p < 0.001) were significantly higher in migraine group as compared to controls. However, Trefoil (p = 0.26), TBUT (p = 0.398) and Schirmer’s test with anaesthesia (p =0.78) were not significantly different between both group.
Analysis of the SBNP features using independent t-test revealed significantly low CNFL, CNBD, CTBD, and CNFA in migraine patients compared with controls. However CNFD and CNFW did not differ significantly between the study groups.
On tear cytometric analysis , IL- 2,4,6,10,17A,17F, IFN α,γ FasL,ICAM-1, VCAM, P,L-selectin and VEGF were found to be significantly raised in migraine group as compared to controls whereas, IL-1α,8,9 RANTES, Eotaxin and b-FGF did not show significant difference between study groups.
Migraine patients often present to ophthalmologists first with complains of glare photophobia and visual aura which are not necessarily followed by headaches.3 Migraine headaches and dry eye syndrome are both life‐disabling diseases. Dry eye being an inflammatory disease and increased prevalence in migraine patients was similar between our study group and other studies.11 Increased dry eyes and altered tear film causes more aberration in these patients which were statistically higher in our migraine patient group. The presence of high aberrations (higher spherical aberration, coma and total aberrations) and dysfunctional tear film degrade retinal image quality induced by more scatter (high OSI). Higher scattering of the retinal image will possibly cause aura and possible trigger migraine attack.
This study showed a significant reduction in CNFL, CNBD, CTBD and CNFA in migraine patients. Diabetic neuropathy patients show decreased nerve density and increased tortuosity as well as a correlative decrease in corneal sensitivity. Corneal nerve changes are manifestation of chronic disease process and sign of neuropathy.12 Structural nerve changes reported similarly in other studies, supports the role of changes in nociceptive corneal axons of the trigeminal pathway which is common for migraine aura and pain pathway and therefore the possible correlation.6 Migraineurs with increased level of dryness, subsequent tear film alterations inducing higher aberrations in the optical system and altered nerve parameters can trigger visual aura and migraine.
Dry eyes and migraine share common inflammatory pathophysiology. Increased levels of inflammatory cytokines in dry eye patients 13 and in migraine patients14 (also in our study group) further supports the possible increased ocular inflammation in migraineurs similar to dry eye patients. Migraineurs having more dry eyes with increased tear levels of inflammatory cytokines and altered neuropathic nerve morphologies would stimulate more visual phenomenon.
In conclusion, interrelationship between inflammation, dry eyes, aberrations, increased tear cytokines and nerve changes gives us a clue of plausible correlation between the migraine and TONE variables. Further large scale studies are required to establish the TONE axis. This will give insight into treatment of dry eyes and inflammation to reduce migraine attacks. IVCM can be a potential ancillary imaging tool for diagnosis of migraine.
- Ethics approval and consent to participate – taken from the institute’s ethics committee.
- Consent for publication – consent was obtained from all enrolled patients.
- Availability of data and material – all data generated or analysed during this study are included in this published article
- Competing interests – the authors declare that they have no competing interests
- Funding – none
- Authors’ contributions – all authors contributed equally to the manuscript
- Acknowledgements – none
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