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Common Mechanisms in Migraine and Epilepsy: A Comment—Reply

Common Mechanisms in Migraine and Epilepsy: A Comment—Reply In reply I am grateful to Dr Schürks for his comments, which provide an opportunity to further elaborate on the commonalities between migraine and epilepsy. Current theories of migraine recognize that activation and sensitization of the trigeminovascular system are responsible for the throbbing pain in a migraine attack.1 However, in migraine with aura and perhaps also migraine without aura, cortical phenomena are believed to underlie episodic activation of the trigeminovascular system. The pivotal role of cortical mechanisms is an aspect of the pathophysiology of migraine shared with epilepsy. Nevertheless, new information has challenged the current dogma that presupposes neural events always precede trigeminovascular system activation.2,3 There is emerging recognition that vascular phenomena could in some circumstances be the primary trigger in a migraine attack, although in migraine with aura (and presumably also migraine without aura) neural mechanisms must necessarily come into play. The experimental literature investigating cortical responsivity in migraine is controversial. This is not surprising given the indirect nature of the diverse methodological approaches that have been applied and the heterogeneity and fluctuating course of migraine. Nevertheless, there are indications of global cortical hypersensitivity to external stimuli in patients with migraine during and between attacks. For example, most but not all studies have shown reduced phosphene thresholds in the visual cortex with transcranial magnetic stimulation. Interestingly, the preponderance of transcranial magnetic stimulation data supports the view that untreated patients with generalized epilepsy syndromes also have enhanced cortical excitability.4,5 Dr Schürks notes that variants in ion channel genes have not been linked to ordinary sporadic migraine. The same situation applies to epilepsy. Most rare mendelian idiopathic epilepsies have been associated with ion channel mutations. Nevertheless, despite the recognition since antiquity of the familial aggregation of epilepsy, genetic variants that influence the susceptibility of an individual to the common sporadic epilepsies have not yet been identified. It has been predicted that large-scale whole-genome association and candidate gene resequencing studies currently under way will provide insights into the genetic bases of common epilepsies.6 It would not be surprising if variation in ion channel (or more generally ion transport) genes or genes that regulate ion channel function are associated with susceptibility to ordinary forms of epilepsy. As in epilepsy, rare mendelian migraine syndromes have been associated with mutations in genes encoding ion transport proteins, and variation in such genes may one day be associated with migraine susceptibility. Finally, Dr Schürks proposes that the underlying pathophysiological mechanisms in migraine are heterogeneous and that this accounts for the unfortunate clinical reality that a proportion of patients with migraine are treatment resistant.7 Interestingly, there is a parallel in epilepsy, where it is well recognized that 20% to 40% of patients are drug refractory.8 Epilepsy and migraine have distinct clinical manifestations. However, the two types of disorders are similar in many respects. Better understanding of the common neurobiological mechanisms may lead to improved therapies for these episodic disorders as a class. Correspondence: Dr Rogawski, Department of Neurology, School of Medicine, University of California, Davis, 4860 Y St, Ste 3700, Sacramento, CA 95817 (rogawski@ucdavis.edu). Financial Disclosure: None reported. References 1. Pietrobon DStriessnig J Neurobiology of migraine. Nat Rev Neurosci 2003;4 (5) 386- 398PubMedGoogle ScholarCrossref 2. Dreier JPKleeberg JPetzold G et al. Endothelin-1 potently induces Leão's cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura? Brain 2002;125 (pt 1) 102- 112PubMedGoogle ScholarCrossref 3. Brennan KCBeltrán-Parrazal LLópez-Valdés HETheriot JToga AWCharles AC Distinct vascular conduction with cortical spreading depression. J Neurophysiol 2007;97 (6) 4143- 4151PubMedGoogle ScholarCrossref 4. Reutens DCBerkovic SFMacdonell RABladin PF Magnetic stimulation of the brain in generalized epilepsy: reversal of cortical hyperexcitability by anticonvulsants. Ann Neurol 1993;34 (3) 351- 355PubMedGoogle ScholarCrossref 5. Theodore WH Transcranial magnetic stimulation in epilepsy. Epilepsy Curr 2003;3 (6) 191- 197PubMedGoogle ScholarCrossref 6. Helbig IScheffer IEMulley JCBerkovic SF Navigating the channels and beyond: unravelling the genetics of the epilepsies. Lancet Neurol 2008;7 (3) 231- 245PubMedGoogle ScholarCrossref 7. Lipton RBBigal ME Toward an epidemiology of refractory migraine: current knowledge and issues for future research. Headache 2008;48 (6) 791- 798PubMedGoogle ScholarCrossref 8. French JA Refractory epilepsy: clinical overview. Epilepsia 2007;48 ((suppl 1)) 3- 7PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

Common Mechanisms in Migraine and Epilepsy: A Comment—Reply

Archives of Neurology , Volume 65 (11) – Nov 10, 2008

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Publisher
American Medical Association
Copyright
Copyright © 2008 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneur.65.11.1546-c
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Abstract

In reply I am grateful to Dr Schürks for his comments, which provide an opportunity to further elaborate on the commonalities between migraine and epilepsy. Current theories of migraine recognize that activation and sensitization of the trigeminovascular system are responsible for the throbbing pain in a migraine attack.1 However, in migraine with aura and perhaps also migraine without aura, cortical phenomena are believed to underlie episodic activation of the trigeminovascular system. The pivotal role of cortical mechanisms is an aspect of the pathophysiology of migraine shared with epilepsy. Nevertheless, new information has challenged the current dogma that presupposes neural events always precede trigeminovascular system activation.2,3 There is emerging recognition that vascular phenomena could in some circumstances be the primary trigger in a migraine attack, although in migraine with aura (and presumably also migraine without aura) neural mechanisms must necessarily come into play. The experimental literature investigating cortical responsivity in migraine is controversial. This is not surprising given the indirect nature of the diverse methodological approaches that have been applied and the heterogeneity and fluctuating course of migraine. Nevertheless, there are indications of global cortical hypersensitivity to external stimuli in patients with migraine during and between attacks. For example, most but not all studies have shown reduced phosphene thresholds in the visual cortex with transcranial magnetic stimulation. Interestingly, the preponderance of transcranial magnetic stimulation data supports the view that untreated patients with generalized epilepsy syndromes also have enhanced cortical excitability.4,5 Dr Schürks notes that variants in ion channel genes have not been linked to ordinary sporadic migraine. The same situation applies to epilepsy. Most rare mendelian idiopathic epilepsies have been associated with ion channel mutations. Nevertheless, despite the recognition since antiquity of the familial aggregation of epilepsy, genetic variants that influence the susceptibility of an individual to the common sporadic epilepsies have not yet been identified. It has been predicted that large-scale whole-genome association and candidate gene resequencing studies currently under way will provide insights into the genetic bases of common epilepsies.6 It would not be surprising if variation in ion channel (or more generally ion transport) genes or genes that regulate ion channel function are associated with susceptibility to ordinary forms of epilepsy. As in epilepsy, rare mendelian migraine syndromes have been associated with mutations in genes encoding ion transport proteins, and variation in such genes may one day be associated with migraine susceptibility. Finally, Dr Schürks proposes that the underlying pathophysiological mechanisms in migraine are heterogeneous and that this accounts for the unfortunate clinical reality that a proportion of patients with migraine are treatment resistant.7 Interestingly, there is a parallel in epilepsy, where it is well recognized that 20% to 40% of patients are drug refractory.8 Epilepsy and migraine have distinct clinical manifestations. However, the two types of disorders are similar in many respects. Better understanding of the common neurobiological mechanisms may lead to improved therapies for these episodic disorders as a class. Correspondence: Dr Rogawski, Department of Neurology, School of Medicine, University of California, Davis, 4860 Y St, Ste 3700, Sacramento, CA 95817 (rogawski@ucdavis.edu). Financial Disclosure: None reported. References 1. Pietrobon DStriessnig J Neurobiology of migraine. Nat Rev Neurosci 2003;4 (5) 386- 398PubMedGoogle ScholarCrossref 2. Dreier JPKleeberg JPetzold G et al. Endothelin-1 potently induces Leão's cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura? Brain 2002;125 (pt 1) 102- 112PubMedGoogle ScholarCrossref 3. Brennan KCBeltrán-Parrazal LLópez-Valdés HETheriot JToga AWCharles AC Distinct vascular conduction with cortical spreading depression. J Neurophysiol 2007;97 (6) 4143- 4151PubMedGoogle ScholarCrossref 4. Reutens DCBerkovic SFMacdonell RABladin PF Magnetic stimulation of the brain in generalized epilepsy: reversal of cortical hyperexcitability by anticonvulsants. Ann Neurol 1993;34 (3) 351- 355PubMedGoogle ScholarCrossref 5. Theodore WH Transcranial magnetic stimulation in epilepsy. Epilepsy Curr 2003;3 (6) 191- 197PubMedGoogle ScholarCrossref 6. Helbig IScheffer IEMulley JCBerkovic SF Navigating the channels and beyond: unravelling the genetics of the epilepsies. Lancet Neurol 2008;7 (3) 231- 245PubMedGoogle ScholarCrossref 7. Lipton RBBigal ME Toward an epidemiology of refractory migraine: current knowledge and issues for future research. Headache 2008;48 (6) 791- 798PubMedGoogle ScholarCrossref 8. French JA Refractory epilepsy: clinical overview. Epilepsia 2007;48 ((suppl 1)) 3- 7PubMedGoogle ScholarCrossref

Journal

Archives of NeurologyAmerican Medical Association

Published: Nov 10, 2008

Keywords: epilepsy,migraine disorders

References