Genetics and biology of migraine: how far are we from the truth?
Vinod Gupta, Dubai Police Medical Services, P.O. Box 12005, Dubai, United Arab Emirates
4 April 2006
Curtain et al. found no evidence of length variations of the second polyglutamine array in the N-terminus of the KCNN3 channel between Caucasian migraine patients and controls. [1]
Migraine research efforts are based on a long, extremely tenuous chain of poorly-linked assumptions about the related basic sciences. [2,3,4,5] The assumption that KCNN3 plays a critical role in migraine pathogenesis by determining the firing pattern of brain neurons is, in the first instance, another such research premise.
To make sense of genetic analyses in any medical entity, a certain minimum quantum of biological comprehension of the illness is mandatory. The biology of any illness is not what is recorded in the laboratory – pathological or radiological – but the elucidation of physiological events that push patients towards or away from that disease. [6] In primary headache research, every aberration recorded in the laboratory has been somehow knitted into a vague pathogenetic matrix without any thought for physiological processes that (i) significantly delay the onset of migraine attacks in a wide variety of clinical circumstances and situations; (ii) maintain protracted and characteristic periods of remissions in most migraine patients; and (iii) prevent onset of migraine in the majority of the general population that is, in general, equally exposed to stresses of life.[6] In this context, the biology of migraine is in its infancy. For around fifty years, since propranolol -- the prototypic non-selective beta-blocker -- was found serendipitously to prevent migraine, it has been maintained that sympathetic hyperactivation can precipitate migraine. This thinking found expression as the bio-behavioral model of migraine that has served as the research bedrock since two decades. [7] Such a pathogenetic assumption does not permit rationalization of key clinical and pharmacotherapeutic features including: (i) occurrence of post-stress headache [6]; (ii) prophylactic activity of both atenolol or nadolol (that do not freely cross the intact blood-brain barrier (BBB) or critically influence any neuronal or neural function in humans) and amitriptyline (a pro-convulsive or potentially convulsive agent that clearly stimulates the brain monoaminergic -- adrenergic as well as serotonergic – systems; and (iii) precipitation of migraine attacks by caffeine and cocaine withdrawal rather than consumption, both substances unequivocally stimulating brain noradrenergic function. [8-10] Paradoxically, a large body of pharmacological absolutes has been completely relegated by contemporary research efforts in primary headache. The first major theoretical effort in elucidation of secondary or adaptive mechanisms in migraine was the proposal that the vasopressin-serotonergic-noradrenergic system has a prominent role in delaying onset of migraine headache as well as maintaining significant periods of remission.[11]
That migraine might involve central nervous system ionic channels is a carefully constructed research extrapolation from the key speculative assumption that brain neuronal dysfunction is triggered by intrinsic noradrenergic activation in migraine patients. Verapamil is the drug of choice in prevention of familial hemiplegic migraine [12] but this drug does not cross the BBB or critically influence any brain neuronal function. Conversely, the role of neuronal ion channel inhibitors in the management of migraine is controversial. [5,13] Also, acetazolamide neither has a direct action on the P/Q type calcium channel nor does it alter penetration of sodium ions into the parietal cortex. [14,15]. There is but little evidence to support the theoretical assumption that migraine, including the familial variety, is predominantly related to neuronal ion channel anomalies. In addition, the evidences that support a selective ophthalmic nerve – rather than a pan-trigeminal – involvement and challenge the pathogenetic role of cortical spreading depression in pathogenesis of migraine indicate how far we have digressed from reason and logic. [16,17]
The negative findings of Curtain et al. [1] are important in that they challenge extant dogma. Biological advancement of migraine, however, requires a considerably different approach. Till the time a defensible over-arching theory of migraine has not been evolved, genetic analyses will carry little meaning. In analyzing evidences for or against genetic findings in migraine, recourse has necessarily to be taken to a series of assumptions between autonomic nervous system dysfunction, brain neuronal activation, or neurotransmitter release.
References
1. Curtain R, Sundholm J, Lea R et al.: Association analysis of a highly polymorphic CAG Repeat in the human potassium channel gene KCNN3 and migraine susceptibility. BMC Med Genetics 2005, 6:32.
2. Gupta VK. Classification of primary headaches: pathophysiology versus nosology? BMJ 2004. Available at: http://bmj.bmjjournals.com/cgi/eletters/328/7432/119.
3. Gupta VK. Sleep remits and precipitates migraine: role of the monoaminergic-vasopressin system. J Neurol Neurosurg Psychiatry (10 November 2005). Available at: http://jnnp.bmjjournals.com/cgi/eletters/76/10/1467.
4. Gupta V. Migraine, cortical excitability and evoked potentials: a clinico-pharmacological perspective. Brain 2005, 128:E36.
5. Gupta VK. Lamotrigine, migraine aura and headache: tightening the Gordian knot of primary headache? (28 November 2005). Available at: http://jnnp.bmjjournals.com/cgi/eletters/76/12/1730#764
6. 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
10. Dhuna A, Pascual –Leone, Belgrade M. Cocaine-related vascular headaches. J Neurol Neurosurg Psychiatry 1991, 54:847-8.
11. Gupta VK. A clinical review of the adaptive potential of vasopressin in migraine. Cephalalgia 1997, 17:561-69.
12. Silberstein SD, Young WB. Migraine aura and prodrome. Semin Neurol 1995,15:175-82.
13. Gupta VK. Topiramate for migraine prophylaxis: addressing the blood-brain barrier related pharmacokinetic-pathophysiological disconnect. IJCP (In press).
14. De Simone R, Marano E, Di Stasio E, Bonuso S, Fiorillo C, Bonavita V. Acetazolamide efficacy and tolerability in migraine with aura: a pilot study. Headache 2005,45:385-6.
15. Spacey SD, Hildebrand ME, Materek LA, Bird TD, Snutch TP. Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. Ann Neurol 2004, 56:213-20.
16. Gupta VK. Migraine, cortical excitability and evoked potentials: a clinico-pharmacological perspective. Brain 2005;128:E36.
17. Gupta VK. Migrainous scintillating scotoma and headache is ocular in origin: a new hypothesis. Med Hypotheses 2005 (In press).
Genetics and biology of migraine: how far are we from the truth?
4 April 2006
Curtain et al. found no evidence of length variations of the second polyglutamine array in the N-terminus of the KCNN3 channel between Caucasian migraine patients and controls. [1]
Migraine research efforts are based on a long, extremely tenuous chain of poorly-linked assumptions about the related basic sciences. [2,3,4,5] The assumption that KCNN3 plays a critical role in migraine pathogenesis by determining the firing pattern of brain neurons is, in the first instance, another such research premise.
To make sense of genetic analyses in any medical entity, a certain minimum quantum of biological comprehension of the illness is mandatory. The biology of any illness is not what is recorded in the laboratory – pathological or radiological – but the elucidation of physiological events that push patients towards or away from that disease. [6] In primary headache research, every aberration recorded in the laboratory has been somehow knitted into a vague pathogenetic matrix without any thought for physiological processes that (i) significantly delay the onset of migraine attacks in a wide variety of clinical circumstances and situations; (ii) maintain protracted and characteristic periods of remissions in most migraine patients; and (iii) prevent onset of migraine in the majority of the general population that is, in general, equally exposed to stresses of life.[6] In this context, the biology of migraine is in its infancy. For around fifty years, since propranolol -- the prototypic non-selective beta-blocker -- was found serendipitously to prevent migraine, it has been maintained that sympathetic hyperactivation can precipitate migraine. This thinking found expression as the bio-behavioral model of migraine that has served as the research bedrock since two decades. [7] Such a pathogenetic assumption does not permit rationalization of key clinical and pharmacotherapeutic features including: (i) occurrence of post-stress headache [6]; (ii) prophylactic activity of both atenolol or nadolol (that do not freely cross the intact blood-brain barrier (BBB) or critically influence any neuronal or neural function in humans) and amitriptyline (a pro-convulsive or potentially convulsive agent that clearly stimulates the brain monoaminergic -- adrenergic as well as serotonergic – systems; and (iii) precipitation of migraine attacks by caffeine and cocaine withdrawal rather than consumption, both substances unequivocally stimulating brain noradrenergic function. [8-10] Paradoxically, a large body of pharmacological absolutes has been completely relegated by contemporary research efforts in primary headache. The first major theoretical effort in elucidation of secondary or adaptive mechanisms in migraine was the proposal that the vasopressin-serotonergic-noradrenergic system has a prominent role in delaying onset of migraine headache as well as maintaining significant periods of remission.[11]
That migraine might involve central nervous system ionic channels is a carefully constructed research extrapolation from the key speculative assumption that brain neuronal dysfunction is triggered by intrinsic noradrenergic activation in migraine patients. Verapamil is the drug of choice in prevention of familial hemiplegic migraine [12] but this drug does not cross the BBB or critically influence any brain neuronal function. Conversely, the role of neuronal ion channel inhibitors in the management of migraine is controversial. [5,13] Also, acetazolamide neither has a direct action on the P/Q type calcium channel nor does it alter penetration of sodium ions into the parietal cortex. [14,15]. There is but little evidence to support the theoretical assumption that migraine, including the familial variety, is predominantly related to neuronal ion channel anomalies. In addition, the evidences that support a selective ophthalmic nerve – rather than a pan-trigeminal – involvement and challenge the pathogenetic role of cortical spreading depression in pathogenesis of migraine indicate how far we have digressed from reason and logic. [16,17]
The negative findings of Curtain et al. [1] are important in that they challenge extant dogma. Biological advancement of migraine, however, requires a considerably different approach. Till the time a defensible over-arching theory of migraine has not been evolved, genetic analyses will carry little meaning. In analyzing evidences for or against genetic findings in migraine, recourse has necessarily to be taken to a series of assumptions between autonomic nervous system dysfunction, brain neuronal activation, or neurotransmitter release.
References
1. Curtain R, Sundholm J, Lea R et al.: Association analysis of a highly polymorphic CAG Repeat in the human potassium channel gene KCNN3 and migraine susceptibility. BMC Med Genetics 2005, 6:32.
2. Gupta VK. Classification of primary headaches: pathophysiology versus nosology? BMJ 2004. Available at: http://bmj.bmjjournals.com/cgi/eletters/328/7432/119.
3. Gupta VK. Sleep remits and precipitates migraine: role of the monoaminergic-vasopressin system. J Neurol Neurosurg Psychiatry (10 November 2005). Available at: http://jnnp.bmjjournals.com/cgi/eletters/76/10/1467.
4. Gupta V. Migraine, cortical excitability and evoked potentials: a clinico-pharmacological perspective. Brain 2005, 128:E36.
5. Gupta VK. Lamotrigine, migraine aura and headache: tightening the Gordian knot of primary headache? (28 November 2005). Available at: http://jnnp.bmjjournals.com/cgi/eletters/76/12/1730#764
6. 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
7. Welch KMA. Migraine. A biobehavioral disorder. Arch Neurol 1987, 44:323-7.
8. Gupta VK. Caffeine and migraine: analgesia and intrinsic brain noradrenergic activation. Headache (In press).
9. Satel SL, Gawin FH. Migrainelike headache and cocaine use. JAMA 1989, 261:2995-6.
10. Dhuna A, Pascual –Leone, Belgrade M. Cocaine-related vascular headaches. J Neurol Neurosurg Psychiatry 1991, 54:847-8.
11. Gupta VK. A clinical review of the adaptive potential of vasopressin in migraine. Cephalalgia 1997, 17:561-69.
12. Silberstein SD, Young WB. Migraine aura and prodrome. Semin Neurol 1995,15:175-82.
13. Gupta VK. Topiramate for migraine prophylaxis: addressing the blood-brain barrier related pharmacokinetic-pathophysiological disconnect. IJCP (In press).
14. De Simone R, Marano E, Di Stasio E, Bonuso S, Fiorillo C, Bonavita V. Acetazolamide efficacy and tolerability in migraine with aura: a pilot study. Headache 2005,45:385-6.
15. Spacey SD, Hildebrand ME, Materek LA, Bird TD, Snutch TP. Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. Ann Neurol 2004, 56:213-20.
16. Gupta VK. Migraine, cortical excitability and evoked potentials: a clinico-pharmacological perspective. Brain 2005;128:E36.
17. Gupta VK. Migrainous scintillating scotoma and headache is ocular in origin: a new hypothesis. Med Hypotheses 2005 (In press).
Competing interests
Nil