From my own recently completed internal review (commissioned for a evidence-based New Zealand guidelines authority), the systematically reviewed and critically appraised evidence to date support the conclusion from multiple Class II RCTs ("probably effective" level) [2,3,4,7,8], cross-confirmed by Level I systematic reviews or meta-analyses [11-14], of the probable efficacy of magnesium in the prevention and clinical therapeutic management of migraine disorder, in agreement with recommendations to same effect from the latest just released (2013) AAN (American Academy of Neurology) and AHS (American Headache Society) Guidelines [1], in further agreement with Canadian and several other evidence-based guidelines and consensus statements, and without clinically relevant risk of harm and with manageable adverse events (diarrhea).

The AAN/AHS Guideline of NSAIDs and Other Complementary Treatments for Episodic Migraine Prevention in Adults (2013 Update) [1] reviewed 284 abstracts from which 49 Class I or Class II studies on migraine prevention were extracted, with a subset of 15 studies using nontraditional therapies, NSAIDs, or CAM (Complimentary and Alternative Medicine) interventions. Magnesium was originally (2000 Guideline) found to be probably effective for migraine prevention on the basis of 2 positive Class II (double-blind, placebo-controlled trials) studies [2,3], weighed against one negative Class III study [4] in which intravenous magnesium was effective as an abortive agent in patients with low ionized magnesium levels, but not in those with normal magnesium levels. I note here that the fact of the weight of the evidentiary support being for probably efficacy (Level II) should be placed in the wider context that the only natural agent with Level I ("effective") evidence of benefit in migraine is butterbur (standardized on petasin content).

Post the 2000 AAN/AHS Guideline, we also have the additional evidence of efficacy from the RMF (Riboflavin, Magnesium, Feverfew) RCT [5], a Class II trial, which evaluated the combination of magnesium (300 mg), riboflavin (400 mg), and the CO2 feverfew extract extract, MIG-99 (100 mg), against placebo (subtherapeutic dose of riboflavin (25 mg)), but this trial's positive findings are restricted only to the RMF combination and underpowered to determinate relative individual component efficacy, and so this study although cited in the AAN/AHS Guideline (2013) failed to meet the inclusion criteria of my review.

The first eligible prospective, multi-center RCT [2] was a therapeutic, not preventive, 12-week trial of magnesium citrate 600 mg versus placebo which found a significantly higher reduction in episode frequency in the final month of treatment relative to baseline in the intervention (magnesium) arm compared to the placebo group. We note in this connection that magnesium is the only preventive agent, traditional or alternative, to hold a Category-A pregnancy rating, making it an feasible choice for prophylaxis in women who are pregnant or actively attempting conception, with a recommendation of maximal dosing at 350 mg/daily in pregnant women suffering migraine (Health Canada [6]). And the RCT of magnesium prophylaxis for menstrual migraine [3] found an associated reduction of headache days for the magnesium (360 mg/d) intervention, and the examination of intracellular Mg++ levels suggested that magnesium deficiency may induce a lower migraine threshold.

In another recently (2012) reported clinical trial [7], 133 migrainous patients were randomly assigned into three intervention groups: M (magnesium oxide, 500 mg/day), C (l-carnitine, (500 mg/day), and MC (magnesium plus l-carnitine (500 mg/day each), and a control group, for 12 weeks, with magnesium supplementation showing manifest and significant reduction in all migraine indicators.

We also have the São Paulo University double-blind RCT of intravenous magnesium sulphate (1000 mg) [8] that concluded that IV magnesium was effective for the treatment of all symptoms in migraine with aura, as well as an adjuvant therapy for associated symptoms in patients with migraine without aura.

And although another RCT [9] failed to unequivocally demonstrate the superiority of oral magnesium oxide over placebo in preventing frequent migrainous headache in children, it nonetheless did lead to a significant reduction in headache days.

And although the Turkish RCT [10] of magnesium prophylaxis in non-aura migraine is often cited as a positive trial, it failed to meet my inclusion criteria due to serious methodological compromise due to highly unequal sized treatment groups (total n=40, but placebo group with only 10 patients).

As to systematic reviews, one recent German review [11] conducted a comparison of double-blind RCTs on the efficacy of propranolol, topimirate, feverfew, butterbur, riboflavin and magnesium, showing that natural preparations had comparable efficacy to the pharmaceuticals but with fewer adverse effects.

In another review of non-pharmacological interventions for migraine prophylaxis [12], it was concluded that "The prophylactic efficacy of magnesium, particularly for children and menstrually related migraine, has recently been substantiated".

In addition, the CHS (Canadian Headache Society) Prophylactic Guidelines Development Group Systematic Review of Medications for Migraine Prophylaxis [13] concluded with respect to magnesium: "We recommend that clinicians offer magnesium to eligible patients for migraine prophylaxis. There is some evidence for benefit and side effects are minimal. Due to the contrary evidence presented in these trials, we recommend that 24 mmol (600 mg) of elemental magnesium daily as magnesium citrate be used for migraine prophylaxis, since a positive result was only obtained with this compound".

Furthermore, the CCF (Cleveland Clinic Foundation) Review [14] concluded that the data extracted suggests that magnesium may be effective in treating all symptoms in patients experiencing migraine with aura across all migraine patients.

Finally, as the negative AEs or interactions: (1) one RCT [15] cautions that the addition of magnesium to another not uncommon migraine intervention, metoclopramide (Reglan), may negatively attenuate the effectiveness of metoclopramide in relieving migraine, likely but not decisively from countertherapeutic cerebral vasodilatation caused by magnesium; (2) in migraine-therapeutic range (~300 - 600 mg/daily), the principle adverse event of diarrhea remains mild to moderate in most users and manageable (one field trick is to consume the divided magnesium doses concurrent with daily calcium, since most supplement with 1500 mg calcium/daily for bone health (in divided dosing of 500 mg) which appears to help counteract the side effect).

As to plausible etiology related to magnesium, it will be more appropriate to discuss this in a separate posting (forthcoming), a complex and emerging - and fascinating I might add - understanding beginning to take shape with recent pathopysiological, molecular and genetic data, all furthermore with subtle intersections with copper, melatonin and CoQ10 metabolic activities, and magnesium at the spider-center of it all.

References

1. Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E, Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2013 Feb 26; 80(9):868-9.

2. Peikert A, Wilimzig C, Köhne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996;16(4):257–263.

3. Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache. 1991;31(5):298–301.

4. Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate relieves migraine attacks in patients with low serum ionized magnesium levels: a pilot study. Clin Sci (Lond). 1995;89(6):633–636.

5. Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache 2004; 44: 885– 890.

6. Health Canada. Magnesium [Monograph]. Ottawa (ON): The Department; 2007. Available: http://webprod.hc-sc.gc.ca/nhpid-bdipsn/monoReq.do?id=135&lang=eng (Accessed 1 march 2013).

7. Tarighat Esfanjani A, Mahdavi R, Ebrahimi Mameghani M, Talebi M, Nikniaz Z, Safaiyan A. The effects of magnesium, L-carnitine, and concurrent magnesium-L-carnitine supplementation in migraine prophylaxis. Biol Trace Elem Res 2012; 150(1-3):42-8.

8. Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia 2002; 22(5):345-53.

9. Wang F, Van Den Eeden SK, Ackerson LM, Salk SE, Reince RH, Elin RJ. Oral magnesium oxide prophylaxis of frequent migrainous headache in children: a randomized, double-blind, placebo-controlled trial. Headache 2003; 43(6):601-10.

10. Köseoglu E, Talaslioglu A, Gönül AS, Kula M. The effects of magnesium prophylaxis in migraine without aura. Magnes Res. 2008 Jun;21(2):101-8.

11. Diener, H. C.; Danesch, U. Vergleich mit etablierten synthetischen Wirkstoffen Wie wirksam sind pflanzliche und diätetische Migräneprophylaktika. [Effectiveness of chemical, herbal and dietetic migraine prophylaxis. An overview of randomized controlled double-blind studies]. MMW Fortschritte der Medizin 2009;151(24):42-45.

12. Schiapparelli P, Allais G, Castagnoli Gabellari I, Rolando S, Terzi MG, Benedetto C. Non-pharmacological approach to migraine prophylaxis: part II. Neurol Sci 2010; 31 Suppl 1:S137-9.

13. Pringsheim T, Davenport WJ, Mackie G, et al. Systematic Review: Medications for Migraine Prophylaxis - Section II. Can J Neurol Sci. 2012;39(Suppl. 2):S8-S28.

14. Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 1: triptans, dihydroergotamine, and magnesium. Headache 2012; 52(1):114-28.

15. Corbo J, Esses D, Bijur PE, Iannaccone R, Gallagher EJ. Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache. Ann Emerg Med. December 2001;38:621-627.

16. Sun-Edelstein, C. & Mauskop, A. (2009). Role of magnesium in the pathogenesis and treatment of migraine. Expert Rev Neurother, Vol.9, No.3, pp.369-379.

17. Sun-Edelstein, C. & Mauskop, A. (2011). Alternative Headache Treatments: Nutraceuticals, Behavioral and Physical Treatments. Headache, Vol., No., pp.469-483.

Constantine Kaniklidis

Director of Medical Research,

No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer Research (EACR)

Migraine is not "caused" by genetic factors. The genetic disposition makes migraine attacks possible, but it requires certain dysfunctions in the brain to create the seizure-like activity in the midbrain during an attack. We already know that it is deficits in the prefrontal cortex that allow the limbic system to gradually kindle the attacks.

"Biochemical" reactions are the result of "electrical" reactions in the brain. Whilst the liver is first and foremost a biochemical organ, the brain is first and foremost electrical in nature. Excessive, unproductive neuronal activity (= "seizure") during an attack as well as an increased CO2 reactivity commands increased blood flow as a consequence of a migraine attack, not as the "essence" or the "reason" or the "cause" or the "source" of any symptoms whatsoever.

Magnesium supplementation is not migraine medication. It can help when magnesium levels are low, but it is not a treatment for migraine. At best, it is a treatment for magnesium deficiency. How much scientific evidence would you need to justify magnesium supplementation to make up for an increased demand due to excessive calcium intake, water fluoridation, emotional distress or industrial agriculture? In cases of severe deficiency magnesium sulfate infusions are highly effective for attack abortion (same as in epileptic seizures). I hope this helps. Cheers, Martin Brink, Author of "The Migraine Revolution: We can End the Tyranny!" (www.TheMigraineRevolution.com).

that question really has caused many a headache... :)

Migraine headache as such has no age barriers it can occur at any age but less after 40, might be due to hormonal regression as age progresses and mainly due to environmental factors,diet factors,life style related events,genetic factors and stress causing events .inciting factors are sight,smell,sound excess of this causes migraine .migraine is due to sudden vasodilatation and vasoconstriction of cerebral blood vessels causes severe headache associated with vomiting,giddiness,

The crucial question is Where does the attack start? I think it is in the vestibular part of the inner ear. Brain dysfunction does not cause many of the associated symptoms like giddiness, ear pressure and audiosensitivity. Visual hallucinations can be generated from the vestibular as well as the visual system.

Sinusitis frontalis, ethmoidalis et sphenoidalis

Migraine is a heterogeneous genetic disorder characterized

by headaches in addition to many other neurological symptoms. Several rare monogenetic subtypes have been identified.

Linkage analysis has identified a number of chromosomal

loci in common forms of migraine, but no specific genes

have been found.

But for example Familial hemiplegic migraine (FHM) is a rare autosomal

dominant subtype of migraine with aura in which, in the

context of otherwise typical migraine attacks, patients experience hemiplegia

There is evidence to support the presence of both systemic and brain magnesium deficiency in migraineurs, particularly in the occipital lobes ( We lch e t al., 1995). Magnesium normally maintains a st rongly coupled state of mitochondrial oxidative phosphorylation. Magnesium also plays

an important role in “gating” N -methyl- d -aspartate (NMDA)

receptors. A magnesium deficit can therefore result in an

abnormality of mitochondrial oxidative phosphorylation and

lead to a gain in NMDA receptor function, there by causing

instability of neuronal polarization because of a loss of ionic

homeostasis. This would then lead to a state of neuronal

hyper-excitability and a lower threshold for spontaneous

depolarization, but yet there is no clear evidence that treatment with Mg will abort or give prophylactic effects for Migraineurs

The changes in blood vessel caliber and blood flow may be due to a primary neuronal event triggered by enhanced neuronal excitability and

susceptibility to spontaneous depolarization, resulting in

prolonged hypo-metabolism because of impaired energ y

metabolism caused by mitochondrial dysfunction.

Ayman, you wrote that migraine is a "genetic disorder". Would you also say that prostate cancer or period pain are genetic disorders? Female genes are protective against prostate cancer and male genes make period pain unlikely. What about obesity? The heritability of obesity is 65%, so it's a "genetic disorder", is it not? For more about this topic: "Studies prove: Migraine is not genetic" http://www.themigrainerevolution.com/migraine-is-not-genetic/

Dear Martin, It is clear that I was talking about specific types of migraine, as I said rare types such as Familial hemiplegic Migraine

In 1993, FHM was mapped to

chromosome 19p13 in linkage studies that were inspired by

the clinical association with migraine and cerebral autosomal

dominant arteriopathy with subcortical infarcts and leuko -encephalopathy (CADASIL). Ab out 50% of tested families have mutations in CACNA1A, a gene locate d on chromosome 19p13 that codes for the α1 -subunit of a brain specific

voltage-g ate d P/Q-t y p e calcium channel (Ophoff e t al., 1996)

Gardner e t al. (1997) reported another locus for FHM on chromosome 1q31 in a 39-member four generation pedigree showing a clear FHM phenotype.

Recent reports ( Terwindt e t al., 2001) not only implicate CACNA1A in FHM, but it may be over represented in patients with migraine without hemiplegia

However, studies testing the 19p13 region for linkage to typical migraine have produced conflicting results

Published association sites include 1p13.3

(Kusumi e t al., 2003), 4q31.2 ( Tzour io e t al., 2001), 9q34 (Lea

e t al., 2000), 11p15 (Mochi e t al., 2003), 11q23 (Del Zompo

e t al., 1998; Peroutka e t al., 1997, 1998), 17 q11.1-q12 (Ogilvie

e t al., 1998), 19p13.3/2 (McCarthy e t al., 2001), and 22q11.2

(Emin Erdal e t al., 2001)

A recent study based on a genome-wide screen of 50

multigenerational clinically well-defined Finnish families

showing inter-generational transmission of migraine with

visual aura yielded significant evidence of linkage between

the migraine w ith aur a phenotype and marker D4S1647

located on chromosome 4q24 ( Wessman e t al., 2002).

Thank u for giving wonderful information about fhm

From my own recently completed internal review (commissioned for a evidence-based New Zealand guidelines authority), the systematically reviewed and critically appraised evidence to date support the conclusion from multiple Class II RCTs ("probably effective" level) [2,3,4,7,8], cross-confirmed by Level I systematic reviews or meta-analyses [11-14], of the probable efficacy of magnesium in the prevention and clinical therapeutic management of migraine disorder, in agreement with recommendations to same effect from the latest just released (2013) AAN (American Academy of Neurology) and AHS (American Headache Society) Guidelines [1], in further agreement with Canadian and several other evidence-based guidelines and consensus statements, and without clinically relevant risk of harm and with manageable adverse events (diarrhea).

The AAN/AHS Guideline of NSAIDs and Other Complementary Treatments for Episodic Migraine Prevention in Adults (2013 Update) [1] reviewed 284 abstracts from which 49 Class I or Class II studies on migraine prevention were extracted, with a subset of 15 studies using nontraditional therapies, NSAIDs, or CAM (Complimentary and Alternative Medicine) interventions. Magnesium was originally (2000 Guideline) found to be probably effective for migraine prevention on the basis of 2 positive Class II (double-blind, placebo-controlled trials) studies [2,3], weighed against one negative Class III study [4] in which intravenous magnesium was effective as an abortive agent in patients with low ionized magnesium levels, but not in those with normal magnesium levels. I note here that the fact of the weight of the evidentiary support being for probably efficacy (Level II) should be placed in the wider context that the only natural agent with Level I ("effective") evidence of benefit in migraine is butterbur (standardized on petasin content).

Post the 2000 AAN/AHS Guideline, we also have the additional evidence of efficacy from the RMF (Riboflavin, Magnesium, Feverfew) RCT [5], a Class II trial, which evaluated the combination of magnesium (300 mg), riboflavin (400 mg), and the CO2 feverfew extract extract, MIG-99 (100 mg), against placebo (subtherapeutic dose of riboflavin (25 mg)), but this trial's positive findings are restricted only to the RMF combination and underpowered to determinate relative individual component efficacy, and so this study although cited in the AAN/AHS Guideline (2013) failed to meet the inclusion criteria of my review.

The first eligible prospective, multi-center RCT [2] was a therapeutic, not preventive, 12-week trial of magnesium citrate 600 mg versus placebo which found a significantly higher reduction in episode frequency in the final month of treatment relative to baseline in the intervention (magnesium) arm compared to the placebo group. We note in this connection that magnesium is the only preventive agent, traditional or alternative, to hold a Category-A pregnancy rating, making it an feasible choice for prophylaxis in women who are pregnant or actively attempting conception, with a recommendation of maximal dosing at 350 mg/daily in pregnant women suffering migraine (Health Canada [6]). And the RCT of magnesium prophylaxis for menstrual migraine [3] found an associated reduction of headache days for the magnesium (360 mg/d) intervention, and the examination of intracellular Mg++ levels suggested that magnesium deficiency may induce a lower migraine threshold.

In another recently (2012) reported clinical trial [7], 133 migrainous patients were randomly assigned into three intervention groups: M (magnesium oxide, 500 mg/day), C (l-carnitine, (500 mg/day), and MC (magnesium plus l-carnitine (500 mg/day each), and a control group, for 12 weeks, with magnesium supplementation showing manifest and significant reduction in all migraine indicators.

We also have the São Paulo University double-blind RCT of intravenous magnesium sulphate (1000 mg) [8] that concluded that IV magnesium was effective for the treatment of all symptoms in migraine with aura, as well as an adjuvant therapy for associated symptoms in patients with migraine without aura.

And although another RCT [9] failed to unequivocally demonstrate the superiority of oral magnesium oxide over placebo in preventing frequent migrainous headache in children, it nonetheless did lead to a significant reduction in headache days.

And although the Turkish RCT [10] of magnesium prophylaxis in non-aura migraine is often cited as a positive trial, it failed to meet my inclusion criteria due to serious methodological compromise due to highly unequal sized treatment groups (total n=40, but placebo group with only 10 patients).

As to systematic reviews, one recent German review [11] conducted a comparison of double-blind RCTs on the efficacy of propranolol, topimirate, feverfew, butterbur, riboflavin and magnesium, showing that natural preparations had comparable efficacy to the pharmaceuticals but with fewer adverse effects.

In another review of non-pharmacological interventions for migraine prophylaxis [12], it was concluded that "The prophylactic efficacy of magnesium, particularly for children and menstrually related migraine, has recently been substantiated".

In addition, the CHS (Canadian Headache Society) Prophylactic Guidelines Development Group Systematic Review of Medications for Migraine Prophylaxis [13] concluded with respect to magnesium: "We recommend that clinicians offer magnesium to eligible patients for migraine prophylaxis. There is some evidence for benefit and side effects are minimal. Due to the contrary evidence presented in these trials, we recommend that 24 mmol (600 mg) of elemental magnesium daily as magnesium citrate be used for migraine prophylaxis, since a positive result was only obtained with this compound".

Furthermore, the CCF (Cleveland Clinic Foundation) Review [14] concluded that the data extracted suggests that magnesium may be effective in treating all symptoms in patients experiencing migraine with aura across all migraine patients.

Finally, as the negative AEs or interactions: (1) one RCT [15] cautions that the addition of magnesium to another not uncommon migraine intervention, metoclopramide (Reglan), may negatively attenuate the effectiveness of metoclopramide in relieving migraine, likely but not decisively from countertherapeutic cerebral vasodilatation caused by magnesium; (2) in migraine-therapeutic range (~300 - 600 mg/daily), the principle adverse event of diarrhea remains mild to moderate in most users and manageable (one field trick is to consume the divided magnesium doses concurrent with daily calcium, since most supplement with 1500 mg calcium/daily for bone health (in divided dosing of 500 mg) which appears to help counteract the side effect).

As to plausible etiology related to magnesium, it will be more appropriate to discuss this in a separate posting (forthcoming), a complex and emerging - and fascinating I might add - understanding beginning to take shape with recent pathopysiological, molecular and genetic data, all furthermore with subtle intersections with copper, melatonin and CoQ10 metabolic activities, and magnesium at the spider-center of it all.

References

1. Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E, Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2013 Feb 26; 80(9):868-9.

2. Peikert A, Wilimzig C, Köhne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996;16(4):257–263.

3. Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache. 1991;31(5):298–301.

4. Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate relieves migraine attacks in patients with low serum ionized magnesium levels: a pilot study. Clin Sci (Lond). 1995;89(6):633–636.

5. Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache 2004; 44: 885– 890.

6. Health Canada. Magnesium [Monograph]. Ottawa (ON): The Department; 2007. Available: http://webprod.hc-sc.gc.ca/nhpid-bdipsn/monoReq.do?id=135&lang=eng (Accessed 1 march 2013).

7. Tarighat Esfanjani A, Mahdavi R, Ebrahimi Mameghani M, Talebi M, Nikniaz Z, Safaiyan A. The effects of magnesium, L-carnitine, and concurrent magnesium-L-carnitine supplementation in migraine prophylaxis. Biol Trace Elem Res 2012; 150(1-3):42-8.

8. Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia 2002; 22(5):345-53.

9. Wang F, Van Den Eeden SK, Ackerson LM, Salk SE, Reince RH, Elin RJ. Oral magnesium oxide prophylaxis of frequent migrainous headache in children: a randomized, double-blind, placebo-controlled trial. Headache 2003; 43(6):601-10.

10. Köseoglu E, Talaslioglu A, Gönül AS, Kula M. The effects of magnesium prophylaxis in migraine without aura. Magnes Res. 2008 Jun;21(2):101-8.

11. Diener, H. C.; Danesch, U. Vergleich mit etablierten synthetischen Wirkstoffen Wie wirksam sind pflanzliche und diätetische Migräneprophylaktika. [Effectiveness of chemical, herbal and dietetic migraine prophylaxis. An overview of randomized controlled double-blind studies]. MMW Fortschritte der Medizin 2009;151(24):42-45.

12. Schiapparelli P, Allais G, Castagnoli Gabellari I, Rolando S, Terzi MG, Benedetto C. Non-pharmacological approach to migraine prophylaxis: part II. Neurol Sci 2010; 31 Suppl 1:S137-9.

13. Pringsheim T, Davenport WJ, Mackie G, et al. Systematic Review: Medications for Migraine Prophylaxis - Section II. Can J Neurol Sci. 2012;39(Suppl. 2):S8-S28.

14. Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 1: triptans, dihydroergotamine, and magnesium. Headache 2012; 52(1):114-28.

15. Corbo J, Esses D, Bijur PE, Iannaccone R, Gallagher EJ. Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache. Ann Emerg Med. December 2001;38:621-627.

16. Sun-Edelstein, C. & Mauskop, A. (2009). Role of magnesium in the pathogenesis and treatment of migraine. Expert Rev Neurother, Vol.9, No.3, pp.369-379.

17. Sun-Edelstein, C. & Mauskop, A. (2011). Alternative Headache Treatments: Nutraceuticals, Behavioral and Physical Treatments. Headache, Vol., No., pp.469-483.

Constantine Kaniklidis

Director of Medical Research,

No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer Research (EACR)

Etiology and Pathophysiology of Migraine: The New "Classical" View - A Brief Summary

I will first sketch a brief account of the current evidence-based model of the etiology, pathophysiology, and genetics of migraine, and in a later posting look at some emerging directions, so the below represents the closest we have to a "classical" model (simplified of course for purposes of this discussion):

Given accumulated evidence to date, the headache phase of migraine is seen as consequent to the activation and sensitization of trigeminal nociceptors that innervate the meningeal large blood vessels, and these processes in turn trigger the sequential activation - and patient-variable sensitization - of later staged central trigeminovascular neurons, themselves activating differential brain stem and forebrain areas that result in pain perception and the many other components of migrainous symptomology [1-6].

However, the vascular theory of migraine via vasodilation has now been effectively challenged [7], as it appears that meningeal and/or extracranial artery vasodilation is neither necessary nor sufficient to induce migraine pain. Rather, one key mechanism that may underlie the sustained activation and sensitization of perivascular meningeal nociceptors appears to be a sterile meningeal inflammation [8-12], although this inflammatory process requires further elucidation. Nonetheless, calcitonin gene–related peptide (CGRP) occupies a pivotal role in migraine, with hypersensitivity of migraineurs to CGRP-mediated modulation of nociceptive pathways [13-17], and it is known that magnesium can influence circulating levels of CGRP [18].

In addition, preclinical in vivo data confirms that cortical spreading depression (CSD) (the underlying mechanism of migraine aura) is a central mechanism of headache initiation and can cause sustained activation of both (1) meningeal nociceptors and (2) central trigeminovascular neurons and can thus initiate the headache mechanisms, and in this context, low magnesium can effect the opening of calcium channels, with increased intracellular calcium, glutamate release, and increased extracellular potassium [19], processes that may in turn trigger cortical spreading depression (CSD), and these low levels of brain magnesium may augment N-methyl-D-aspartate (NMDA) receptor activity, to ultimately lowering the threshold for CSD [20], with magnesium playing a regulatory role on the uptake of glutamate into astrocytes to interfere with NMDA receptor function [21]. Furthermore, explorations on the between-attack period finds abnormal processing of sensory data consequent to a dysfunctional regulation of cortical excitability in migraineurs [22,23].

But besides these CNS-based pathophysiologies, it is now widely accepted that migraine is a complex genetic disorder with associated polygenic multifactorial inheritance, based on intensive studies of the rare monogenic form, familial hemiplegic migraine (FHM) [a theme nicely covered by Ayman Alboudi, see his posting above], with three causative genes now well-identified, namely CACNA1A, ATP1A2 and SCN1A, all involved in cerebral ion translocation and which cause a disturbed cerebral glutamate homeostasis that increases susceptibility to cortical spreading depression (CSD) [24-27]. And new data find a critical genetic role stemming from methylenetetrahydrofolate reductase gene (MTHFR), especially in migraine with aura susceptibility [28]. The monogenic FHM form of migraine also delivers another set of insights: from FHM knockin mouse models, functional analysis supports the brain excitability hypothesis of migraine, characterized by deficient regulation of the cortical excitatory/inhibitory balance, and adds additional confirmation to CSD as a key migraine trigger, with disturbances in magnesium ion homeostasis seen to be contributory to brain cortex hyperexcitability as suggested in the results of a clinical trial exploring differences in corticol magnesium across different migraine syndromes [29]. These ingenuous FHM mouse models show enhanced cortical excitatory synaptic transmission (although inhibitory synaptic transmission remains unaltered), along with the facilitation of induction and propagation of CSD from enhanced glutamatergic neurotransmission [30], with magnesium potentially modulating mitochondrial oxidative phosphorylation, 5-HT neurotransmission and the NO system [21].

References

1. Moskowitz MA. The neurobiology of vascular head pain. Ann. Neurol. 16:157–68; Pietrobon D, Striessnig J. 2003. Neurobiology of migraine. Nat. Rev. Neurosci. 1984;4:386–98.

2. Olesen J, Burstein R, Ashina M, Tfelt-Hansen P. Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol. 2009;8:679–90.

3. Levy D. Migraine pain and nociceptor activation—where do we stand? Headache 2010;50:909–16.

4. Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain 1994;117(Pt. 1):199–210.

5. Ayata C. Cortical spreading depression triggers migraine attack: pro. Headache 2010;50:725–30.

6. Charles A. Does cortical spreading depression initiate a migraine attack? Maybe not. Headache 2010;50:731–33.

7. Brennan KC, Charles A. An update on the blood vessel in migraine. Curr. Opin. Neurol. 2010;23:266–74.

8. Kruuse C, Thomsen LL, Birk S, Olesen J. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 2003;126:241–47.

9. Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD. Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study. Brain 2008;131:2192–200.

10. Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia 2008;28:226–36.

11. Asghar MS, Hansen AE, Amin FM, van der Geest RJ, Koning P, et al. Evidence for a vascular factor in migraine. Ann. Neurol. 2011;69:635–45.

12. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat. Med. 2002;8:136–42.

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Constantine Kaniklidis

Director of Medical Research,

No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer Research (EACR)

Those who have marked down my previous post might like to check the migraine literature on differences between those with and without aurae. Many studies now show that there is a higher incidence of peripheral vestibular anomalies in those with aurae, the simplest explanation for which is that aurae, especially the visual components, are being generated or triggered from the inner ear (as is the "phonophobia").

Nice article

new researches add coffee , chocolate, perfumes to migraine triggers

Lack of sleep and heavy cloudy day can also trigger mig in some

Lack of sleep, too brighty day,too sound such as overcrowding places,functions,spicy diet,diet not taken on correct time,stress factors,smell too much,too much on television, too much study,,travelling,skipping breakfast,eating srotonin rich foods such as chocolates, dosa, idly,bread and dairy products all can trigger migraine

To all those who throw so-called "triggers"into the discussion: Can you cite any evidence that migraine attacks are typically "triggered" at all? Or are you merely regurgitating the common beliefs which migraineurs develop by identifying their "triggers" in hindsight after an attack? I'm really looking forward to an explanation as to how a cloudy day "triggers" a migraine attack that otherwise wouldn't have occurred. Alternatively, what about renaming this platform to MythGate or RumourGate?

Meniere spectrum disorder and migraine overlap to such an extent that I think they have a common origin. In MSD the inner ear is in a hyperexcitable state, such that it becomes exquisitively sensitive to motion (travel sickness), sound ("phonophobia") and a wide range of drugs. MSD is also an extremely variable conditon, and may completely clear up in a few hours. Hence, it is very hard to experimentally test the effect of various compounds in triggering migraine. First, the person may have to have the necessary predisposition (eg MSD), then this has to be still present at the time the test was done. There is an overall consisency in patients' reports of triggers.

I am going to tell something as a general practioner. I know two patients since years, who sufferd from migraine with severe aurae. As I deal with vitamin B12 problems I control methyl-malon-acid (mma)in the urine as a functional test for Vitamin B12-deficiency. Both of the patients were positive, so I gave them the advice to take B12-injections. Both of them are free from migraine since about 4 years,

With one patient I failed. There seems to be a special problem because the body needs adenosylcobalamin for the proper functioning of the citrat-cycle may be because of a lack of a converting enzyme. The sign of the malfunctioning is the elevated release of mma. I am trying now to treat with adenosylcobalamin and I will do a folow-up.

You,yourself,relax,you dont have to be hard and authoritative on yourself,let your brains cool down,be aware of your harness,you dont really need it, be aware of the warmth and aliveness underneath,stop looking at yourself through the eyes of others,we are only limited by our own thoughts you are good enough and so is everybody else,live play experience,just be...you

The real mechanism of migraine has not been clear. The aura of migraine might be relative to cortex spreading depression of brain and headache might be result from hyperactivity of trigeminavascular reflex.

New researches show that migraines are not caused with cerebral arterial spasmus! And that classical antimigraine drugs has no effect on this type of cephalea.

"regulate blood flow to the brain"; I would say that this is at least controversial. In terms of causality, it is as well to keep in mind the Bradfor-Hill criteria. For a thorough discussion of various proposed mechanisms see here: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3452275/)

Magnesium is an inexpensive treatment with good evidence of efficacy and almost no adverse effects for most patients. As it modulates activity of the NMDAR, it's efficacy lends support to a disorder of electrical activity as being fundamental to pathogenesis. Likewise the efficacy of antiepileptics.

Migraines occur when our forefathers have been frequently hit on the head with fishing poles. The pain provoked is therefore forcefully nestled in our DNA and similar in nature to chronic open head syndrome.

Well we all know about the various etiopathologies that precipitate (and not build) migraine, or factors that cause them we have serotonin, dopamine, autonomic, ganglia theory n all. We're still long way to go though what I suspect is that it is a type of psychophysiological disorder that needs a vey different kind of approach which is not aken when the patient is treated empirically. Migraine afflicts a certain kind of personalities who are normal perse but have certain peculiar traits which could be wored about so it is very much probable that they usually subconsciously though, initiate the precipitation and many times the scapegoat is the one before the eyes. Although the symptoms are very much there and so is the discomfort. It is local autonomic response that may be exemplified in vascular changes and local neural structures like dura and trigem ganglia etc.

We find that most migraines are misdiagnosed dry sinus coupled with inflammatory states. Amazingly, when we were investigating keratoses obturans of the ear (see attached) we found nearly every individual complained of what they and their physicians called "migraines". Keratosis obturans does not happen in a vacuum (most often misdiagnosed as impacted earwax in the ear canal, when in fact they are deadly septic collections within many layers of keratin wrapped around itself). The connection, we believe is that there is a septic infection developing in the jaw or teeth (the most common co-occuring problem), in the gut (second most common), around a prosthesis, such as an artificial knee, hip, or other implanted item, or the foot (in-grown toe nail or developing neuropathy of the lower limbs).

But in everyday practice, as mentioned above these are ignored by most health professionals who encounter them-they take a lot of time to remove, and in a typical case when encountered we will ask, "How many doctors have looked in your ears over the past several years? The answer is usually, "oh, 5 or 6---they just said it was nothing, just 'some earwax'. I am attaching my monograph here for you to see what these are all about. These anomalies, of course, are not the only cause or even a major cause of migraines, but we find them co-occuring so often it is just one more piece of the puzzle connecting inflammatory states from unresolved infections in the body to proliferation of proinflammatory cytokines, making migraines a secondary response to inflammation. Medicating for the headache without addressing the primary cause, to me, is a shortcut in healthcare, in my opinion.

Christopher, one of our practitioners swears by the magnesium connection, and has success adding it to the patient's treatment plan.

Anthony, one of my areas of expertise is Meniere's--and I, too, see commonality and co-occurrence between Meniere's and Migraines. My findings of individual cases have been that they are both subject to the same inflammatory states which cause the pressure (on the delicate structures of the cochlear and vestibular organs in cases of Menieres, and on portions of the brain in cases of migraines). Resolve the underlying cause and both seem to clear immediately. Cover them up with powerful drugs and the Meniere's stays while the headache only experiences, at best, temporary relief and comes roaring back when effects wear off.

Thanks Sydney for your description of your scotoma. One of the beauties of RG is that it contains such useful descriptions that never find their way into modern journals. I agree this could not have been ocular, nor some local brain or systemic disorder. As I think such visual phenomena (and migraine aurae) can be generated from the vestibular system, it is hardly coincidental that this happened when you removed one of your hearing aids. I recall other patients reporting problems with their balance when wearing or removing their aids. I do not think vestibular infection at all likely in your case, in fact I think it may be more a psychological adjustment problem, the brain taking a while to adjust to differing auditory/vestibular inputs from the two sides. Balance is maintained by 3 main sensory systems. The importance of vision was shown by E Darwin (don't try this at home). Take one toddler, get it to fixate on a strong visual pattern, suddenly move pattern, toddler falls over. Someone with impaired but constant vestibular disorder may be able to stand OK with eyes open, but wobbles with eyes shut. I do not think there is any reason to suppose your proprioceptive system was affected, as your problems are all consistent with vestibular disorder, especially if it is fluctuant and hence uncompensatable, at least not immediately.

Thanks Max for your comments, though I think the link between migraine and Meniere's is simpler than you implied. First, I think the link is with Meniere spectrum disorder, a far commoner and more general disorder than its small subtype diagnosed as Meniere's disease in ENT clinics. Second, I think there is only one primary locus for migraine symptoms, the inner ear. Sensory areas of the brain may be secondarily involved, by reflexes for example. Sydney has just given a perfect example of how visual phenomena can arise from the labyrinth.

Studies have repeatedly shown that up to 50 percent of migraine patients have lowered levels of ionized magnesium during an attack, and an infusion of the mineral can provide rapid and sustained relief. Additionally, routine oral use of magnesium can reduce both the frequency and severity of such attacks. Though the exact role played by magnesium supplementation in migraines yet remains to be dicovered, a link between magnesium supplementation and serotonin and NMDA receptors has been found.

Read more: http://www.drdavidwilliams.com/magnsium-to-prevent-migraines#ixzz2VjMaYopl

Furthermore, one more finding suggests that Migraine sufferers may develop magnesium deficiency due to genetic inability to absorb magnesium, inherited renal magnesium wasting, excretion of excessive amounts of magnesium due to stress, low nutritional intake, and several other reasons.

http://www.ncbi.nlm.nih.gov/pubmed/22426836

Excellent observations, Harita. We find a nutritional component in all cases of migraine, sometimes an added heavy metal component, and often an osteophyte component in the neck from past unhealed injuries (causing slowed resorption of cerebral spinal fluid), and increasingly, polypharmacy components causing increased inflammatory cytokines and inflammation in the brain region. To us, investigating underlying causes and addressing these before resorting to the migraine class of drugs, is the proper say to go. Of course, there will be differing perspectives on discovering each factor depending upon the practice setting.

Just realized I had not responded to your comment on the Meniere's connection, Anthony. I agree and find most Meniere's cases with underlying issues as varied as the factors I mention above in my comment to Harita. In other words, our quest in behavioral medicine is finding root causes relative to each individual case history--admittedly a laborious approach to healthcare practice, but remarkably effective nonetheless. I mentioned the keratosis connection because it is rising quickly in the US population, because (in our opinion) of falling cellular pH levels in the general population, fewer natural chelates idn the food supply to control for heavy metals in the environment (fewer nutrients, too, of course), and medical practice's propensity to rely srictly on pharmaceuticals and surgery for nearly ALL treatment regimens today.

On the nutritional side, I just gave a lecture on the increasing pervasiveness of digestive disorders in the US (92 million now) due to a diet almost totally comprised of microwaved, irradiated, genetically modified, synthethically fortified, chemically preserved, and over processed diet. Aspertame, bromulated vegetable oil, caffeine, red/yellow sythetic dyes and GMO high fructose highlight the typical American diet, especially for the young where learning disorders and developmental delays are virtually skyrocketing. All so avoidable if we would have an honest converation as a healthcare community.

So, in the milieu of increasing chronic conditions in a population that should be exhibiting superior health we find the most medicated and highest per capita expenditure on healthcare in the world. Meniere's, migraine, tinnitus, learning/behavioral-cognitive disorders, and digestive and metabolic disease--symptomatic syndromes all-are adjuncts to the larger societal trends. Our biggest mistake it appears is getting lost in the mire of overmedicalized symptoms, rendering treatments that bring big dollars to vested interests but fail to get to root causes where healing can occur, as we lose sight of the larger forest of society's dietary trends. Ever learning but never coming to grips with what is actually occurring.

Thanks for your kind comments--they were well taken and agreeable from this end.

For the treatment of migraine we use intraosseous blockade with a pronounced therapeutic effect. www.pain-clinic.ru

I do mathematical modeling on spreading depression after ischemia. I have been told spreading depression is also the physiological substrate of the migraine aura, and that this phenomenon does not occur in all forms of migraine.

I am curious therefore, what the definition is of / what is usually meant with the term migraine in clinical practice? The headaches, disregulation of blood flow or the aura? Is there such a thing as the origin of migraine, or are there multiple types with (possibly) different treatments?

I was involved in research on facial pain in the 1980s and we stumbled across interesting findings related to common migraines in 1984. This resulted in our eventually theorizing that "migraine" cases without aura (classical) are qualitatively different from those without (common). The basic idea for common migraine was that structural imbalance in the TMJ in combination with parafunctional oral habits resulted in hyperactivation of portions of the temporalis muscle and unilateral headache pain. The last article I did on headaches was in 1989. I have posted those that I still have in RG if you have an interest. I left my academic positon and pusued the applications of a columnar brain model to psychotherapy and have not followed the headache/facial pain field. Thus, I am unsure as to whether anyone picked up on this line of research or it simply died. We also found some association with excessive sleep duration and headaches and speculated this may be related to serotonin depletion and lowered pain threshold. The references on the articles are:

Moss, R.A., Ruff, M.H., & Sturgis, E.T. (1984). Oral behavioral patterns in facial pain, headache and non-headache populations. Behavior Research and Therapy, 22, 683-687.

Villarosa, G.A., & Moss, R.A. (1985). Oral behavioral patterns as factors contributing to the development of head and facial pain. Journal of Prosthetic Dentistry, 54, 427-430.

Ruff, G., Moss, R.A., & Lombardo, T.W. (1986). Common Migraine: a review and proposal for a nonvascular etiology. Journal of Oral Rehabilitation, 13, 499-508.

Moss, R.A. (1987). A structural imbalance/muscular hyperactivity interactional theory of common migraine pain. Journal of Craniomandibular Practice, 5, 87-89.

Moss, R.A. (1987). Oral behavioral patterns in common migraine. Journal of Craniomandibular Practice, 5, 196-202.

Moss, R.A., McClure, J.R., Jackson, M.C., & Lombardo, T.W. (1987). The effect of sleep duration on headache pain and frontalis EMG. Journal of Oral Rehabilitation, 14, 331-335.

Moss, R.A., Lombardo, T.E., Cooley, J.E., Villarosa, G.A. & Gramling, S.E. (1987). Effects of sleep duration on classic migraine and depression headache pain: Case reports. Journal of Cardiomandibular Practice, 5, 87-95.

Moss, R.A., Villarosa, G.A., Cooley, J.E., & Lombardo, T.W. (1987). Masticatory muscle activity as a function of parafunctional, active and passive oral behavioral patterns. Journal of Oral Rehabilitation, 14, 361-370.

Moss, R.A. (1988). New approaches to the assessment and treatment of chronic headaches. Journal of Pain Management Practice, 1, 64-71.

Moss, R.A., Lombardo, T.W., Villarosa, G.A., Hodgson, J.M., O'Carroll, K., Cooley, J.E., & Smith, P. (1989). Ongoing assessment of oral habits in common migraine and non-headache populations. Journal of Craniomandibular Practice,6, 352-354.

Moss, R.A., Lombardo, T.W., Hodgson, J.M., & O'Carroll, K. (1989). Oral habits in common migraine, tension headaches, and non-headache populations. Journal of Oral Rehabilitation, 16, 71-74.

"Is migraine a genetic illness?

This question was previously controversial, but today the answer yes is generally accepted. The scientific evidence is the significantly increased familial risk of migraine, and the significantly higher concordance rate of migraine in monozygotic than dizygotic twin pairs. Finally, the three identified ion-channel genes that can cause familial hemiplegic migraine provide very strong evidence of genetics. Mutations in these genes can also cause sporadic hemiplegic migraine.

The next question is whether the different types of migraine, i.e. migraine without aura, migraine with aura, sporadic hemiplegic migraine and familial hemiplegic migraine share a common genetic cause.

This question is at present controversial. However, the fact that all types of migraine are paroxystic in nature suggest that a common genetic cause could be mutations in ion channels, although a common mutation has not yet been identified in the more common types of migraine: migraine without aura and migraine with aura."

Quoted from:

Russell MB. Is migraine a genetic illness? The various forms of migraine share a common genetic cause. Neurol Sci 2008; 29 (Suppl 1): S52-4.

For the benefit of those who downvoted my comment on Mar 21 2013, here is evidence for the extensive overlap of brain circuits for pain, migraine and vestibular processing:

Cephalalgia. 2014 Nov;34(13):1053-61. doi: 10.1177/0333102414527650. Epub 2014 Mar 24.

Central vestibular system modulation in vestibular migraine.

Obermann M1, Wurthmann S2, Steinberg BS2, Theysohn N3, Diener HC2, Naegel S2.

Abstract

BACKGROUND:

Vestibular migraine affects 1% of the general population, and 30%-50% of all migraine patients describe occasionally associated vertigo or dizziness. We aimed to identify brain regions altered in vestibular migraine in order to evaluate the connection between migraine and the vestibular system.

METHODS:

Seventeen patients with definite vestibular migraine were compared to 17 controls using magnetic resonance imaging-based voxel-based morphometry.

RESULTS:

We found grey matter (GM) volume reduction in the superior, inferior and middle (MT/V5) temporal gyrus as well as in the mid. cingulate, dorsolateral prefontal, insula, parietal and occipital cortex. A negative correlation of disease duration and GM volume was observed in areas associated with pain and vestibular processing. Moreover, there was a negative correlation between headache severity and prefrontal cortex volume.

CONCLUSION:

Alterations identified in vestibular migraine resemble those previously described for migraine, but also extend to areas involved in multisensory vestibular control and central vestibular compensation possibly representing the pathoanatomic connection between migraine and the vestibular system.

As per A. Gordon's reply, you may also wish to look for "labyrinthine concussion" and "postconcussion syndrome" as a search term. We review some aspects relevant to that in: Lawson, B.D., and Rupert, A.H. (2010). Vestibular aspects of head injury and recommendations for evaluation and rehabilitation following exposure to severe changes in head velocity or ambient pressure. In Turan, O., Bos, J., Stark, J., and Colwell, J., (Eds.), Proceedings of the International Conference on Human Performance at Sea (HPAS). (pp. 367-380). Glasgow, U.K. 

That may be on my ResearchGate list of publications or you can open my Recent Publications document there to get my email if you want me to send it to you.

Finally, there is some work by Jonathan Clark, I think published in (what was then called) Aviation, Space, and Environmental Medicine.

A study conducted by researchers in Brazil shows patients with chronic migraine are three times as likely to suffer from severe temporomandibular disorder.

http://www.jmptonline.org/article/S0161-4754(17)30045-3/fulltext