HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH REGISTER		Author Keyword(s) Vol Page [Advanced]

To: Journal of PRACTICAL NEUROLOGY Letters

Electronic Letters to:

Short reports: C Lampl, Z Katsarava, H-C Diener, and V Limmroth Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura J Neurol Neurosurg Psychiatry 2005; 76: 1730-1732 [Abstract] [Full text] [PDF]

eLetters: Submit a response to this article

Electronic letters published:

Lamotrigine, migraine aura and headache: tightening the Gordian knot of primary headache?

Vinod K Gupta   (28 November 2005)

Lamotrigine, migraine aura and headache: tightening the Gordian knot of primary headache? 28 November 2005
Vinod K Gupta, Physician Dubai Police Medical Services, P.O. Box 12005, Dubai, United Arab Emirates Send letter to journal: Re: Lamotrigine, migraine aura and headache: tightening the Gordian knot of primary headache? dr_vkgupta{at}yahoo.com Vinod K Gupta	Dear Editor, With widely divergent therapeutic options and uncertain, largely indefensible underlying theoretical premises varying widely from closure of patent foramen ovale[1] to use of biological toxins like scalp injection of botulinum toxin[2,3], untrammeled but vigorous research efforts have converted migraine into a giant, virtually insoluble puzzle. A miniscule fraction of the effort spent in the elaboration of newer versions of an unwieldy and purely phenomenological system of classification of primary headache would have been sufficient to appropriately underscore the importance of atenolol, a first-line migraine prophylactic agent that does not cross the blood-brain barrier (BBB) or alter any brain or peripheral neural function[4], or the ability of both serotonergic agonists (like amitriptyline) and serotonergic antagonists (like cyproheptadine) to prevent migraine[5], or the prophylactic role of agents that might increase (amitriptyline) or decrease (anti-convulsants) brain cortical excitability[4], or the fact that caffeine or cocaine withdrawal rather than consumption predictably precipitates migraine headache.[6,7] While shifting stance between vascular and neuronal theories of migraine or rigidly espousing either theory, researchers have paid scant attention to the characteristic phenomeon of post-stress headache in migraine that clearly signposts the primary involvement of a cranial physiological system that enjoys a significant but variable protection from dysfunction during stress.[8] Claiming significant biological advances in migraine research on the basis of genetic research and a limited link to ion channelopathies, migraine researchers have not felt the need to define the biology of migraine into physiological processes that push patients towards attacks or keep them in remission[8]; this critical need has been substituted by elaborating upon precipitating and remitting clinical features. The first major theoretical effort in this direction was the elaboration of the possible role vasopressin in delaying onset of migraine headache as well as maintaining significant periods of remission.[9] The psyche of the migraine researcher is (?irretrievably) buried deep in the mystery of cortical spreading depression (CSD). To neurologists, it is nothing short of gospel truth that the migraine aura originates at the level of the brain cortex. Maintenance of this belief in the face of evidence that drugs that do not readily or freely cross the intact BBB -- like nifedipine or isoproterenol -- can instantaneously abort migraine aura[10] is a tribute to a peculiar human trait to steadfastly preserve a preconception in the face of contrary evidences. Use of advanced neuroimaging to record activation of the brain / brainstem as a surrogate for CSD / brain activation is a classic example of the reductionist nature of laboratory findings – equating and elevating, as such efforts do, the laboratory to biology. The primary pathogenetic aberrations in migraine are buried in the completely inaccessible “pre-prodromal” phase and to a lesser extent in the largely inaccessible prodrome.[4] Recording of physiological changes in brain after onset of headache or of aura and extrapolating it to signify primary pathogenetic alterations is a faulty research premise; equating spreading oligaemia in migraine patients to CSD in animals is intrinsically incorrect.[11,12] Second, the neuroprotective effect of CSD is increasingly being recognized[13-15], indicating a wide and irreconcilable contemporary diversion of scientific beliefs. Finally, the peculiar neuroanatomical distribution in humans of ophthalmic pain and temperature fibres only to the first cervical spinal segment, occurrence of photophobia, and absence of migraine in cohorts of patients having undergone enucleation or evisceration of the eye reflect a selective involvement of the ophthalmic division in migraine.[16] Migraine is not, in direct contrast to the general impression, a pan-trigeminal nerve disorder; CSD cannot explain selective involvement of the ophthalmic nerve.[16] There is a crucial difference between scintillating scotoma and other varieties of migraine aura. Ophthalmologically, it is accepted that the scintillating scotoma is monocular[17] but migraine researchers have unquestioningly accepted it as a binocular phenomenon akin to homonymous hemianopia.[8] If the migrainous scintillating scotoma is indeed monocular in distribution, it cannot arise at the visual cortex. In headache research, a most well guarded secret – besides the BBB-related pharmacokinetics of atenolol -- is that Lećo also recorded spreading cortical silence / depression after retinal stimulation.[19] The basis for retinal origin of the migrainous scintillating scotoma has been presented recently.[16] In a placebo-controlled trial, lamotrigine was not found effective for migraine prophylaxis.[20] Topiramate is also not effective in preventing aura in migraine patients.[21] To maintain that lamotrigine is highly effective for prophylaxis of migraine aura while topiramate is not does not appear to theoretically impregnable. The limitations for a migraine prophylactic role for topiramate and other neuronal ion-channel inhibitors has been discussed.[22] In a highly variable condition such as migraine, the value of statistical significance in uncontrolled studies is severely limited. Stratification of results by frequency of headache is also important. Long neglected basic science issues require to be knitted into our perception of migraine. References 1. Gupta VK. PFO / ASD closure and migraine: searching the rationale for the procedure. J Am Coll Cardiol 2005, 46: 737-738. 2. Gupta VK. Botulinum toxin type A therapy for chronic tension-type headache: fact versus fiction. Pain 2005, 116: 166-167. 3. Gupta VK. Botulinum toxin: a treatment for migraine? A critical review. Pain Med 2005 (In press). 4. Gupta VK. Migraine, cortical excitability and evoked potentials: a clinico-pharmacological perspective. Brain 2005; 128: E36. 5. Gupta VK. Amitriptyline versus cyproheptadine: opposite influences on brain 5-HT function. Headache 2005 (In press). 6. Gupta VK. Caffeine and migraine: analgesia and intrinsic brain noradrenergic activation. Headache 2005 (In press). 7. Gupta VK. Amphetamine, migraine, and brain noradrenergic activation: contradictions in headache research. Headache (In press). 8. Gupta VK. Stress, adaptation, and traumatic-event headaches: pathophysiologic and pharmacotherapeutic insights. BMC Neurology 2004: 4: 17. Available at: http://www.biomedcentral.com/1471-2377/4/17/comments#106454 9. Gupta VK. A clinical review of the adaptive role of vasopressin in migraine. Cephalalgia 1997; 17: 561-569. 10. Gupta VK. Management of migraine aura: basic theoretical and clinical reconsiderations. Headache 2005 (In press). 11. Gupta VK. Non-lateralizing brain PET changes in migraine: phenomenology versus pharmacology? Brain 2004, 127:E12. 12. Gupta VK. MRI in primary headaches. Radiology (In press). 13. Gupta VK. Cortical spreading depression is neuroprotective: the challenge of basic sciences. Headache 2005, 45:177-178. 14. Thompson CS, Hakim AM. Cortical spreading depression modifies components of the inflammatory cascade. Mol Neurobiol 2005, 32:51-58. 16. 15. Yanamoto H, Miyamoto S, Tohnai N, Nagata I, Xue JH, Nakano Y, Nakajo Y, Kikuchi H. Induced spreading depression activates persistent neurogenesis in the subventricular zone, generating cells with markers for divided and early committed neurons in the caudate putamen and cortex. Stroke 2005, 36:1544-1550. 16. Gupta VK. Migrainous scintillating scotoma and headache is ocular in origin: a new hypothesis. Med Hypotheses 2005 (In press). 17. Hupp SL, Kline LB, Corbett JJ. Visual disturbances of migraine. Surv Ophthalmol 1989, 33:221-236. 18. Campbell JK. Manifestations of migraine. Neurol Clin 1990, 8:841- 855. 19. Lećo AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol. 1944;7:359-390. 20. Steiner TJ, Findley LJ, Yuen AWC. Lamotrigine versus placebo in the prophylaxis of migraine with and without aura. Cephalalgia 1997;17:109-12. 21. Lampl C, Bonelli S, Ransmayr G. Efficacy of topiramate in migraine aura prophylaxis: preliminary results of 12 patients. Headache 2004;44:174-6. 22. Gupta VK. Topiramate for migraine prophylaxis: addressing the blood-brain barrier related pharmacokinetic-pathophysiological disconnect. IJCP (In press).