title: Chronic migraine is associated with reduced corneal nerve fiber density and symptoms of dry eye.
abstract: BACKGROUND
  We used in vivo corneal confocal microscopy to investigate structural differences in the sub-basal corneal nerve plexus in chronic migraine patients and a normal population. We used a validated questionnaire and tests of lacrimal function to determine the prevalence of dry eye in the same group of chronic migraine patients. Activation of the trigeminal system is involved in migraine. Corneal nociceptive sensation is mediated by trigeminal axons that synapse in the gasserian ganglion and the brainstem, and serve nociceptive, protective, and trophic functions. Noninvasive imaging of the corneal sub-basal nerve plexus is possible with in vivo corneal confocal microscopy.
  
  
  METHODS
  For this case-control study, we recruited chronic migraine patients and compared them with a sex- and age-similar group of control subjects. Patients with peripheral neuropathy, a disease known to be associated with a peripheral neuropathy, or prior corneal or intraocular surgery were excluded. Participants underwent in vivo corneal confocal microscopy using a Heidelberg Retinal Tomography III confocal microscope with a Rostock Cornea Module. Nerve fiber length, nerve branch density, nerve fiber density, and tortuosity coefficient were measured using established methodologies. Migraine participants underwent testing of basal tear production with proparacaine, corneal sensitivity assessment with a cotton-tip applicator, measurement of tear break-up time, and completion of a validated dry eye questionnaire.
  
  
  RESULTS
  A total of 19 chronic migraine patients and 30 control participants completed the study. There were no significant differences in age or sex. Nerve fiber density was significantly lower in migraine patients compared with controls (48.4 ± 23.5 vs. 71.0 ± 15.0 fibers/mm2 , P < .001). Nerve fiber length was decreased in the chronic migraine group compared with the control group, but this difference was not statistically significant (21.5 ± 11.8 vs. 26.8 ± 5.9 mm/mm2, P < .084). Nerve branch density was similar in the two groups (114.0 ± 92.4 vs. 118.1 ± 55.9 branches/mm2 , P < .864). Tortuosity coefficient and log tortuosity coefficient also were similar in the chronic migraine and control groups. All migraine subjects had symptoms consistent with a diagnosis of dry eye syndrome.
  
  
  CONCLUSIONS
  We found that in the sample used in this study, the presence of structural changes in nociceptive corneal axons lends further support to the hypothesis that the trigeminal system plays a critical role in the pathogenesis of migraine. In vivo corneal confocal microscopy holds promise as a biomarker for future migraine research as well as for studies examining alterations of corneal innervation. Dry eye symptoms appear to be extremely prevalent in this population. The interrelationships between migraine, corneal nerve architecture, and dry eye will be the subject of future investigations.
authors.affiliation: Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT, USA.
authors.forename: Krista I
authors.initials: KI
authors.lastname: Kinard
authors.forename: A Gordon
authors.initials: AG
authors.lastname: Smith
authors.forename: J Robinson
authors.initials: JR
authors.lastname: Singleton
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Lessard
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Katz
authors.forename: Judith E A
authors.initials: JE
authors.lastname: Warner
authors.forename: Alison V
authors.initials: AV
authors.lastname: Crum
authors.forename: Mark D
authors.initials: MD
authors.lastname: Mifflin
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Brennan
authors.forename: Kathleen B
authors.initials: KB
authors.lastname: Digre
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002908:Chronic Disease; D003315:Cornea / Q000294:innervation*; D015352:Dry Eye Syndromes / Q000175:diagnosis* / Q000453:epidemiology*; D005260:Female; D006801:Humans; D008297:Male; D008881:Migraine Disorders / Q000175:diagnosis* / Q000453:epidemiology*; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D011446:Prospective Studies
keywords: corneal nerves; dry eye syndrome; in vivo corneal confocal microscopy; migraine
references.citation: Semin Ophthalmol. 2010 Sep-Nov;25(5-6):171-7
references.pmid: 21090996
references.citation: Cornea. 2013 Oct;32(10):1331-8
references.pmid: 23974884
references.citation: Diabetes Care. 2010 Aug;33(8):1792-7
references.pmid: 20435796
references.citation: Diabetes Care. 2015 May;38(5):838-43
references.pmid: 25633665
references.citation: Cephalalgia. 2006 Jun;26(6):742-6
references.pmid: 16686915
references.citation: J Peripher Nerv Syst. 2013 Mar;18(1):54-8
references.pmid: 23521645
references.citation: Invest Ophthalmol Vis Sci. 2008 Jul;49(7):2971-6
references.pmid: 18390645
references.citation: Diabetes Care. 2013 Sep;36(9):2748-55
references.pmid: 23579181
references.citation: Cornea. 2012 Dec;31(12):1376-80
references.pmid: 22257862
references.citation: Clin Exp Ophthalmol. 2007 Jan-Feb;35(1):71-88
references.pmid: 17300580
references.citation: Invest Ophthalmol Vis Sci. 2013 Aug 01;54(8):5144-50
references.pmid: 23833066
references.citation: Ocul Surf. 2007 Apr;5(2):93-107
references.pmid: 17508117
references.citation: Am J Ophthalmol. 2011 Dec;152(6):900-909.e1
references.pmid: 22019306
references.citation: J Diabetes Sci Technol. 2013 Sep 01;7(5):1179-89
references.pmid: 24124944
references.citation: PLoS One. 2013;8(1):e52157
references.pmid: 23341892
references.citation: N Engl J Med. 2002 Jan 24;346(4):257-70
references.pmid: 11807151
references.citation: Cont Lens Anterior Eye. 2010 Apr;33(2):55-60
references.pmid: 20093066