Abstracts

Migraine is a neurological disorder that frequently involves cortical paroxysmal dysfunction expressed as aura¹1 Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75(1):365-91. http://dx.doi.org/10.1146/annurev-physiol-030212-183717
https://doi.org/10.1146/annurev-physiol-... . The most frequent aura type is visual, sometimes experienced as fortification spectra, known as teichopsia. This typical zigzag, horseshoe-shaped expanding bright perception, usually perceived as complex interlacing lines named “chevaux de frises” by Gowers followed by a bean-shaped loss of visual acuity strongly suggests involvement of visual processing areas. Clinical, experimental and neuroimaging evidence demonstrate that cortical spreading depression (CSD) is the phenomenon underlying the pathophysiology of bizarre visual perceptions among migraineurs. Computerized models simulating a CSD wave passing through cortical area V1 convincingly reproduce the teichopsia pattern²2 Dahlem MA, Engelmann R, Lowel S, Muller SC. Does the migraine aura reflect cortical organization? Eur J Neurosci. 2000;12(2):767-70. http://dx.doi.org/10.1046/j.1460-9568.2000.00995.x
https://doi.org/10.1046/j.1460-9568.2000... .

The cortical function is deeply dependent on neuronal input. Depriving the cortex of its natural input might influence the cerebral function and change the cortical maps both locally and distantly³3 Kujala T, Alho K, Naatanen R. Cross-modal reorganization of human cortical functions. Trends Neurosci. 2000;23(3):115-20.. In blind individuals, the occipital cortex is critical for tactile Braille reading⁴4 Hamilton RH, Pascual-Leone A. Cortical plasticity associated with Braille learning. Trends Cogn Sci. 1998;2:168-74. http://dx.doi.org/10.1016/s0166-2236(99)01504-0
https://doi.org/10.1016/s0166-2236(99)01... . Since the visual cortex is pivotal in the pathophysiology of the migraine aura, the objective of the present study was to investigate whether the phenotype of migraine-related visual phenomena would change in amaurotic patients.

Method

Two hundred visually impaired adult subjects (VIS) were randomly recruited at the Instituto Benjamin Constant (IBC), a Brazilian reference treatment and education centre for the unsighted located in Rio de Janeiro. One of the authors (GCCS), a fully trained neurologist, personally interviewed and examined all the VIS from October 2010 to May 2011, and March to July 2012. Study procedures included the headache and visual impairment history recording, neurological examination, and IBC medical records review for access to full ophthalmological and clinical data. This descriptive, observational study was approved by the Hospital Naval Marcílio Dias (HNMD) ethics committee (56/2010) and authorized by the IBC board in 10 August 2010. All VIS who volunteered to participate signed or fingerprinted an informed consent.

A standardized interview was used to espy migraine patients among the VIS. The International Classification of Headache Disorders version II (ICHD-II)⁵5 Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd ed. Cephalalgia. 2004;24(Suppl 1):S9-160. was applied to distinguish migraineurs fulfilling the criteria for the following disorders: migraine without aura, typical aura with migrainous headache, typical aura with non migrainous headache, typical aura without headache, probable migraine without aura and probable migraine with aura, present for at least one year prior to the interview. Visual phenomena not necessarily meeting the ICHD-II criteria for typical aura, either atypical in form, colour and/or duration; occurring without, before or during the headache, being migrainous or not, were also considered. VIS had to suffer from acquired or congenital amaurosis according to the 10^th revision of the International Classification of Diseases (ICD-10) code H54, corresponding to vision impairment categories 3, 4 or 5 (WHO Study Group on the Prevention of Blindness, Geneva, 6-10 November 1972, WHO Technical Report Series no. 518, 1973).

Exclusion criteria comprise ICHD-II familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, retinal migraine, migraine complications, chronic migraine, migrainous status, persistent aura without infarction, migrainous infarction, seizure triggered by migraine and probable chronic migraine, migraine onset after the age of 50, comorbidities ‒ systemic or not ‒ potentially causing or manifesting as a migraine-like disorder.

Results

From the 200 individuals initially interviewed, 9 were excluded: three refused to participate, four because of cognitive impairment, one because of a brain tumour and one due to marijuana addiction. Among the 191 remaining VIS, 63 fulfilled criteria for amaurosis. In this subgroup, 35 (55.5%) referred recurrent headaches, mostly of the migrainous type (23-37.0%), as opposed to 12 (19%) with other headache disorders and 28 (44%) headache free subjects. Eight (12.7%, 6 females, 40.00±13.06 y-o, range 25-56) migraine with aura patients were selected and studied in further detail (Table), of which seven presented with visual aura not necessarily fulfilling.

Internacional Headache Society (IHS) diagnostic criteria⁵5 Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd ed. Cephalalgia. 2004;24(Suppl 1):S9-160. (in four, the aura lasts less than 5 min), and one referred auditory aura (uncharacteristic noise). In the majority of our population the headache started before the visual impairment.

Among the seven amaurotic patients with visual aura, five failed to present aura following the sightlessness onset. In patient 1, diagnosed as typical aura with headache not fulfilling migraine criteria, and patient 7, with atypical aura – auditory – the migraine with aura started after the visual impairment. Patient 4 used to perceive scintillations in some headache attacks prior to blindness, changing to perceptions in colour and forms after vision loss. Regardless of the headache type, visual aura symptoms were atypical because of length (too short) colour (blue, silver or fire-like); and/or shape (round shapes).

Photophobia, referred by all patients in whom the headache preceded the blindness in time (n=6), disappeared after the visual impairment. The remaining two subjects denied this symptom.

Discussion

In this study, we looked for the lifetime prevalence of migraine in a population of visually impaired subjects in order to address the disease phenotype in this particular population. After blindness, only one patient continued to express aura as before. This suggests that normal visual input and processing is crucial for aura expression in migraine. Besides, in one patient who became blind years before the migraine attacks, auditory rather than visual phenomena emerged, possibly reflecting an aura-like symptom. Photophobia is clearly dependent on vision, as it is not present concomitantly with total blindness.

Kowacs et al. looked for migraine among visually impaired and found a 6 months prevalence ratio of 14.28% (37% in our material). In their series, four subjects had aura: one totally blind patient presented auditory aura and two subnormal vision individuals referred atypical visual aura lasting 2-4 min. In the last patient aura symptoms disappeared as the vision impairment progressed⁶6 Kowacs PA, Piovesan EJ, Lange MC, Weneck LC, Tatsio CE, Ribas LC et al. Prevalence and clinical features of migraine in a population of visually impaired subjects in Curitiba, Brazil. Cephalalgia. 2001;21(9):900-5. http://dx.doi.org/10.1046/j.1468-2982.2001.00286.x
https://doi.org/10.1046/j.1468-2982.2001... . Noseda et al. reported on 6 (2 with aura) totally blind and 14 (5 with aura) visually impaired (light perception) migraineurs, but aura details were not provided⁷7 Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K et al. A neural mechanism for exacerbation of headache by light. Nat Neurosci. 2010;13(2):239-45. http://dx.doi.org/10.1038/nn.2475 
https://doi.org/10.1038/nn.2475... .

Aura is supposed to be the clinical counterpart of CSD, a neurophysiological wave of excitation followed by depression of cortical activity⁸8 Leão AAP. Spreading depression of activity in cerebral cortex. J Neurophysiol. 1944;7:359-90.. Migraine has been related with cortical hyperexcitability⁹9 Welch KM, D'Andrea G, Tepley N, Barkley G, Ramadan NM. The concept of migraine as a state of central neuronal hyperexcitability. Neurol Clin. 1990;8(4):817-28., and the migrainous occipital cortex is particularly responsive to interictal visual stimulation¹⁰10 Vincent M, Pedra E, Mourao-Miranda J, Bramati IE, Henrique AR, Moll J. Enhanced interictal responsiveness of the migraineous visual cortex to incongruent bar stimulation: a functional MRI visual activation study. Cephalalgia. 2003;23(9):860-8. http://dx.doi.org/10.1046/j.1468-2982.2003.00609.x
https://doi.org/10.1046/j.1468-2982.2003... . There are limited data on CSD provoked by stimuli either then seizure induction or direct chemical/mechanical stimulation, but it is well known that migraine attacks may be triggered by visual stimuli such as sunlight¹¹11 Bekkelund SI, Hindberg K, Bashari H, Godtliebsen F, Alstadhaug KB. Sun-induced migraine attacks in an Arctic population. Cephalalgia. 2011;31(9):992-8. http://dx.doi.org/10.1177/0333102411409071
https://doi.org/10.1177/0333102411409071... , red-green flickering¹²12 Cao Y, Welch KM, Aurora S, Vikingstad EM. Functional MRI-BOLD of visually triggered headache in patients with migraine. Arch Neurol. 1999;56(5):548-54. http://dx.doi.org/10.1001/archneur.56.5.548
https://doi.org/10.1001/archneur.56.5.54... or particular striped patterns¹³13 Harle DE, Shepherd AJ, Evans BJ. Visual stimuli are common triggers of migraine and are associated with pattern glare. Headache. 2006;46(9):1431-40. http://dx.doi.org/10.1111/j.1526-4610.2006.00585.x
https://doi.org/10.1111/j.1526-4610.2006... . Exercise was used to induce a migraine aura during which a CSD-like wave was detected in the brain¹⁴14 Hadjikhani N, Sanchez del Rio M, Wu O, Schwartz D, Bakker D, Fischi B et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98(8):4687-92. http://dx.doi.org/10.1073/pnas.071582498
https://doi.org/10.1073/pnas.071582498 ... . In rats, darkness seems to reduce the CSD propagation¹⁵15 Batinga H, Barbosa PP, Ximenes-da-Silva A. Daytime modulation of cortical spreading depression according to blood glucose levels. Neurosci Lett. 2011;491(1):58-62. http://dx.doi.org/10.1016/j.neulet.2011.01.008
https://doi.org/10.1016/j.neulet.2011.01... . Sound may trigger CSD in rats¹⁶16 Vinogradova LV, Kuznetsova GD, Coenen AM. Unilateral cortical spreading depression induced by sound in rats. Brain Res. 2009;1286:201-7. http://dx.doi.org/10.1016/j.brainres.2009.06.047
https://doi.org/10.1016/j.brainres.2009.... and light was also reported to precipitate CSD in rabbits hyperexcited by subconvulsive doses of pentylenetetrazol¹⁷17 Van Harreveld A, Stamm JS. Cortical responses to metrazol and sensory stimulation in the rabbit. Electroencephalogr Clin Neurophysiol. 1955;7(3):363-70. http://dx.doi.org/10.1016/0013-4694(55)90005-5
https://doi.org/10.1016/0013-4694(55)900... . Thus, there is clinical and experimental evidence that increased neuronal excitability renders the migrainous cortex more vulnerable to CSD.

Plasticity is an intrinsic endowment of the brain¹⁸18 Pascual-Leone A, Amedi A, Fregni F, Merabet LB. The plastic human brain cortex. Annu Rev Neurosci. 2005;28:377-401. http://dx.doi.org/10.1146/annurev.neuro.27.070203.144216
https://doi.org/10.1146/annurev.neuro.27... and blindness induces substantial cerebral reorganization¹⁹19 Collignon O, Dormal G, Albouy G, Vandewall G, Voss P, Phillips C et al. Impact of blindness onset on the functional organization and the connectivity of the occipital cortex. Brain. 2013;136(9):2769-83. http://dx.doi.org/10.1093/brain/awt176
https://doi.org/10.1093/brain/awt176 ... . Blind individuals may compensate the lack of sight by developing hyper-effective non-visual senses. Although tactile input activates the visual cortex in sighted individuals²⁰20 Sathian K. Visual cortical activity during tactile perception in the sighted and the visually deprived. Dev Psychobiol. 2005;46(3):279-86. http://dx.doi.org/10.1002/dev.20056
https://doi.org/10.1002/dev.20056... , blinds activate their primary visual areas V1 and V2 during Braille reading as a compensatory cross-modal strategy⁴4 Hamilton RH, Pascual-Leone A. Cortical plasticity associated with Braille learning. Trends Cogn Sci. 1998;2:168-74. http://dx.doi.org/10.1016/s0166-2236(99)01504-0
https://doi.org/10.1016/s0166-2236(99)01... . Blind subjects develop auditory abilities beyond controls²¹21 Morgan M. Sensory perception: supernormal hearing in the blind? Curr Biol. 1999;9(2):R53-4. http://dx.doi.org/10.1016/S0960-9822(99)80009-8
https://doi.org/10.1016/S0960-9822(99)80... and absolute pitch is more prevalent in blind musicians²²22 Hamilton RH, Pascual-Leone A, Schlaug G. Absolute pitch in blind musicians. Neuroreport. 2004;15(5):803-6. http://dx.doi.org/10.1097/00001756-200404090-00012
https://doi.org/10.1097/00001756-2004040... . Sightless people detect much more efficiently moving sounds²³23 Lewald J. Exceptional ability of blind humans to hear sound motion: implications for the emergence of auditory space. Neuropsychologia. 2013;51(1):181-6. http://dx.doi.org/10.1016/j.neuropsychologia.2012.11.017
https://doi.org/10.1016/j.neuropsycholog... .

Therefore, in theory, non-cortical blindness should not preclude CSD from occurring in a migraineous brain, as the cortex remains functional and is activated by various inputs. Since the occipital cortex may change from processing visual information to processing other sensory modalities in sightlessness, we hypothesized that the lack of visual input would render the visual cortex less susceptible to CSD, leading to the cessation of the visual auras. Likewise, as sight deteriorates before blindness subnormal vision would partially reduce CSD susceptibility, possibly explaining the atypical visual auras, mostly too short or expressing colour changes not commonly seen in ordinary migraine. Alternatively, the cortical reorganization induced by the lack of vision could still allow CSD but change just its clinical expression, leading to the discontinuation of visual phenomena. If this hypothesis is correct, the auditory aura referred by patient 7 could be the result of an aberrant activation as a result of blindness.

It is noteworthy that visual phenomena were significantly shorter in many VIS. According to the ICHD-II, aura should develop gradually over 5-20 minutes and last for less than 60 minutes. Each aura symptom lasts, by definition, ≥5 and ≤60 minutes⁵5 Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd ed. Cephalalgia. 2004;24(Suppl 1):S9-160.. These time restrictions are maintained in the present ICHD-3 beta version²⁴24 Headache Classification Committee of the International Headache S. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629-808. http://dx.doi.org/10.1177/0333102413485658
https://doi.org/10.1177/0333102413485658... . In half of our cases the visual symptoms possibly reflecting aura were shorter than 5 minutes. Based in these results, we suggest that the 5-60 minutes aura limit should not encompass VIS. More subnormal vision subjects must be studied to confirm this finding. The reason as why aura is shorter the VIS is not known, my may be the result of cortical plasticity and/or lack of visual input to the visual cortex.

Auditory aura is rarely seen in migraine, but auditory hallucination has been reported as a type of acoustic aura²⁵25 Feltz-Cornelis CM, Biemans H, Timmer J. Hearing voices: does it give your patient a headache? A case of auditory hallucinations as acoustic aura in migraine. Neuropsychiatr Dis Treat. 2012;8:105-11. http://dx.doi.org/10.2147/NDT.S29300
https://doi.org/10.2147/NDT.S29300... . Our case and the one described by Kowacs et al.⁶6 Kowacs PA, Piovesan EJ, Lange MC, Weneck LC, Tatsio CE, Ribas LC et al. Prevalence and clinical features of migraine in a population of visually impaired subjects in Curitiba, Brazil. Cephalalgia. 2001;21(9):900-5. http://dx.doi.org/10.1046/j.1468-2982.2001.00286.x
https://doi.org/10.1046/j.1468-2982.2001... in small sightless populations contrast with the rarity of this phenomenon in ordinary migraine, indicating that acoustic aura might be significantly more common among blind subjects. Speculatively, if the lack of vision result in overactivation of cortical areas related to hearing, this could favour auditory aura in this population.

Photophobia is present in >80% of migraine patients²⁶26 Rasmussen BK, Jensen R, Olesen J. A population-based analysis of the diagnostic criteria of the International Headache Society. Cephalalgia. 1991;11(3):129-34. http://dx.doi.org/10.1046/j.1468-2982.1991.1103129.x
https://doi.org/10.1046/j.1468-2982.1991... and seems to be closely inter-related with trigeminal pain. Painful²⁷27 Drummond PD, Woodhouse A. Painful stimulation of the forehead increases photophobia in migraine sufferers. Cephalalgia. 1993;13(5):321-4. http://dx.doi.org/10.1046/j.1468-2982.1993.1305321.x
https://doi.org/10.1046/j.1468-2982.1993... and optokinetic simuli²⁸28 Drummond PD. Motion sickness and migraine: optokinetic stimulation increases scalp tenderness, pain sensitivity in the fingers and photophobia. Cephalalgia. 2002;22(2):117-24. http://dx.doi.org/10.1046/j.1468-2982.2002.00332.x
https://doi.org/10.1046/j.1468-2982.2002... increase light discomfort in migraineurs. In controls, luminous stimulation at certain intensities did not produce activation of the visual cortex without concomitant pain as detected by positron emisson tomography, but in migraineurs cortical activation occurred at the same luminous stimulation levels without simultaneous pain, which in turn potentiated the light activation even further²⁹29 Boulloche N, Denuelle M, Payoux P, Fabre N, Trotter Y, Geraud G. Photophobia in migraine: an interictal PET study of cortical hyperexcitability and its modulation by pain. J Neurol Neurosurg Psychiatr. 2010;81(9):978-84. http://dx.doi.org/10.1136/jnnp.2009.190223
https://doi.org/10.1136/jnnp.2009.190223... .

The pathophysiology of photophobia is largely unknown and may involve non-image formation visual pathways. The fact that mice lacking rods and cones showed normal suppression of pineal melatonin in response to monochromatic light was the first evidence of an additional ocular photoreception in mammals. Melanopsin, an opsin/vitamin A-based photopigment sensitive to blue stimuli present in some retinal ganglion cells³⁰30 Hankins MW, Peirson SN, Foster RG. Melanopsin: an exciting photopigment. Trends Neurosci. 2008;31(1):27-36. http://dx.doi.org/10.1016/j.tins.2007.11.002
https://doi.org/10.1016/j.tins.2007.11.0... may play a key role in migraine photophobia. In contrast with the present findings, sensitivity to light was referred by blind migraineurs who had preservation of pupillary light response and circadian photoentrainment, but in patients with bilateral enucleation or damage to the optic nerves photophobia was absent⁷7 Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K et al. A neural mechanism for exacerbation of headache by light. Nat Neurosci. 2010;13(2):239-45. http://dx.doi.org/10.1038/nn.2475 
https://doi.org/10.1038/nn.2475... , indicating that image formation input is not obligatory for photophobia. As shown in rats, it is possible that retina originated fibres projecting to the thalamus induce retinal photoactivation in a discrete area at the posterior thalamus where dura-sensitive fibres converge⁷7 Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K et al. A neural mechanism for exacerbation of headache by light. Nat Neurosci. 2010;13(2):239-45. http://dx.doi.org/10.1038/nn.2475 
https://doi.org/10.1038/nn.2475... . In our cases, no blind patient admitted pain exacerbation or discomfort by light. This is probably due to the fact that rod, cone and melanopsin perceptions were all damaged in our cases.

The small number of subjects and the lack of congenitally blind subjects are limitations of this study. We are fully aware that memory biases could have interfered with our results somehow. Reviewing the medical records was the possible way to minimize this drawback. However, we are confident that the cases reported herein do suggest that visual function is crucial for both the expression of migraine aura and photophobia, regardless of the visual cortex integrity.

Acknowledgment

We are indebted to Instituto Benjamin Constant for their cooperation with this study.

References

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