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Short reports: S Afridi, H Kaube, and P J Goadsby Occipital activation in glyceryl trinitrate induced migraine with visual aura J Neurol Neurosurg Psychiatry 2005; 76: 1158-1160 [Abstract] [Full text] [PDF]

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Glyceryl trinitrate and migraine: nitric oxide donor precipitating and aborting migrainous aura

Vinod K Gupta   (24 October 2005)

Glyceryl trinitrate and migraine: nitric oxide donor precipitating and aborting migrainous aura 24 October 2005
Vinod K Gupta, Physician Dubai Police Medical Services, P.O. Box 12005, Dubai, United Arab Emirates Send letter to journal: Re: Glyceryl trinitrate and migraine: nitric oxide donor precipitating and aborting migrainous aura dr_vkgupta{at}yahoo.com Vinod K Gupta	Dear Editor, Afridi and colleagues present a case of migraine with aura precipitated by challenge with glyceryl trinitrate; these authors have shown activation in the primary visual area of the occipital cortex during the aura.[1] Several issues merit attention: 1. Activation of primary visual area in the occipital cortex does not confirm that glyceryl trinitrate itself induced visual cortical neuronal activation. Any stimulus that can activate the retina will also activate the primary visual cortex. 2. In humans, glyceryl trinitrate is not known to influence any neuronal function, whether central (brain) or peripheral. 3. Glyceryl trinitrate is used experimentally to induce migraine attacks in humans. The same investigators have reported development of migraine without aura in 32 of 44 migraine patients.[2] Occurrence of premonitory symptoms in 12 of 44 patients following glyceryl trinitrate infusion[2] does not offer support for primary pathogenesis at the level of the brain. Premonitory symptoms are arousal-related symptoms that are probably secondary or adaptive in nature. The earliest pathophysiological disturbances at the onset of migraine develop in the interim between exposure to the headache-provoking stimulus and the prodrome, i.e., in the “pre-prodromal” phase. We have also to begin to question the long-held view that the brain / brain stem is indeed the primary and exclusive source of origin of migraine.[3] 4. Since glyceryl trinitrate is commonly used as a therapy for migraine aura[4,5], it does not appear that visual cortex activation induced by it[1] is pathogenetic. 5. Other investigators have concluded that glyceryl trinitrate activates craniovascular sensory pathways at a site at, or peripheral to, the second-order neuron; such an action may account for at least the acute -onset headache induced by glyceryl trinitrate.[6] Central or brain neuronal activation is not a sine qua non for the generation of antidromic trigeminal nerve discharge. 6. The most pathognomonic form of migrainous aura is the scintillating scotoma.[4,5] Scintillating scotomata of migraine are almost always uniocular or monocular in distribution; the classical description is hemianopic[4] but has remained conceptually unchallenged in migraine research as a homonymous deficit. 7. Displaceable visual phenomena, positive or negative, are invariably retinal in origin.[4] There has been no systematic study of displaceability of scintillating scotomata of migraine.[4,7] 8. As a monocular positive functional phenomenon, the scintillating scotoma cannot arise from the occipital visual cortex. 9. The retina is the only other tissue that can manifest a spreading depression phenomenon like the cortical spreading depression of Lećo.[8-13] Retinal spreading depression has been suggested to underlie scintillating scotomata following internal carotid artery dissection.[14] 10. The ocular choroid possesses the greatest blood supply in the human body, with a circulation volume 10-20 times that of the cerebral cortex.[15] As a powerful vasodilator, glyceryl trinitrate can cause sudden ocular choroidal overperfusion or congestion, particularly in migraine patients who commonly have regional ocular sympathetic hypofunction, and trigger a mechanical activating wavefront in the retina that precipitates scintillating scotomata. 10. A similar mechanical distortion of the anterior segment of the eye can produce painful impulses in the ophthalmic component of the trigeminal nerve arising from compression of the cornea, iris and anterior chamber.[16,17] 11. Several first-line migraine prophylactic agents like propranolol and atenolol besides metoprolol, nadolol, verapamil, flunarizine, and clonidine lower the intraocular pressure[18-21] indicating that a pathogenetic link prevails between migraine and dysregulation of the intraocular pressure. Besides, bilateral glaucomatous retinal visual deficits consistent with non-ischaemic retinal damage have been demonstrated in 30% to 60% of migraine patients, confirming the results of previous studies.[22] 12. Nitric oxide (NO) directly inhibits propagation of retinal spreading depression in a concentration-and time-dependent manner; also, NO speeds up the recovery of the intrinsic optical signal after the Wavefront.[23] Despite being a powerful vasodilator and nitric oxide contributor, glyceryl trinitrate generally aborts the migraine aura instantaneously[4,5], the mechanism of which might involve suppression of retinal spreading depression. 13. A conceptual divide needs to be developed between migrainous scintillating scotoma that is usually hemianopic (monocular) and migrainous negative visual deficit such as homonymous hemianopia that is clearly binocular and probably vasospastic in origin. References 1. Afridi S, Kaube H, Goadsby PJ. Occipital activation in glyceryl trinitrate induced migraine with visual aura. J Neurol Neurosurg Psychiatry 2005; 2005; 76: 1158-1160. 2. Afridi SK, Kaube H, Goadsby PJ. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain 2004; 110: 675-680. 3. Gupta V. Migraine, cortical excitability and evoked potentials: a clinico-pharmacological perspective. Brain 2005;128: E36. 4. Hupp SL, Kline LB, Corbett JJ. Visual disturbances of migraine. Surv Ophthalmol 1989; 33: 221--236. 5. Silberstein SD, Young WB. Migraine aura and prodrome. Semin Neurol 1995; 15: 175--182. 6. Lambert GA, Boers PM, Hoskin KL, Donaldson C, Zagami AS. Suppression by eletriptan of the activation of trigeminovascular sensory neurons by glyceryl trinitrate. Brain Res 2002 ; 953: 181-188. 7. Gupta VK. Migraine following head injury: do all roads in migraine pathophysiology lead to cortical spreading depression? Headache (In press). 8. Weimer MS, Hanke W. Propagation velocity and triggering threshold of retinal spreading depression are not correlated. Exp Brain Res 2005; 164: 185--193. 9. Duarte MA, Almeida AC, Infantosi AF, Bassani JW. Functional imaging of the retinal layers by laser scattering: an approach for the study of Leao's spreading depression in intact tissue. J Neurosci Methods 2003; 123:139--151. 10. Brand S, Fernandes de Lima VM, Hanke W. Pharmacological modulation of the refractory period of retinal spreading depression. Naunyn Schmiedebergs Arch Pharmacol 1998;357:419--425. 11. Maranhao-Filho PA, Martins-Ferreira H, Vincent MB, Ribeiro LJ, Novis SA. Sumatriptan blocks spreading depression in isolated chick retina. Cephalalgia 1997; 17: 822--825. 12. Wiedemann M, de Lima VM, Hanke W. Effects of antimigraine drugs on retinal spreading depression. Naunyn Schmiedebergs Arch Pharmacol 1996; 353: 552--556. 13. Dahlem MA, Muller SC. Self-induced splitting of spiral-shaped spreading depression waves in chicken retina. Exp Brain Res 1997;115:319-- 324. 14. Ramadan NM, Tietjen G, Levine SR, Welch KMA. Scintillating scotomata with internal carotid artery dissection: report of three cases. Neurology 1991; 41: 1084--1087. 15. Bill A. Blood circulation and fluid dynamics in the eye. Physiol Rev 1975; 55: 383--417. 16. Duke-Elder S. System of Ophthalmology. The Physiology of the Eye and of Vision, vol 4, p. 276--7; 280--283. 17. Zuazo A, Ibanez J, Belmonte C. Sensory nerve responses elicited by experimental ocular hypertension. Exp Eye Res 1986; 43: 759--769. 18 Gupta VK. Visual function impairment in migraine: cerebral versus retinal deficit. Cephalalgia 1993;13:431--432. 19. Shields MB. Textbook of glaucoma. 2nd edition. Baltimore: Williams and Wilkins, 1987, pp 45-70. 20. Osborne NN, Wood JP, Cupido A, Melena J, Chidlow G. Topical flunarizine reduces IOP and protects the retina against ischemia- excitotoxicity. Invest Ophthalmol Vis Sci 2002; 43: 1456--1464. 21. Siegner SW, Netland PA, Schroeder A, Erickson KA. Effect of calcium channel blockers alone and in combination with antiglaucoma medications on intraocular pressure in the primate eye. J Glaucoma 2000;9:334--339. 22. McKendrick AM, Badcock DR. Decreased visual field sensitivity measured 1 day, then 1 week, after migraine. Invest Ophthalmol Vis Sci 2004; 45: 1061--1070. 23. Ulmer HJ, de Lima VM, Hanke W. Effects of nitric oxide on the retinal spreading depression. Brain Res 1995;691:239--242.