Research Submissions

Serum Ionized Magnesium Levels and Serum Ionized Calcium/Ionized Magnesium Ratios in Women With Menstrual Migraine
Alexander Mauskop, MD; Bella T. Altura, PhD; Burton M. Altura, PhD

Objective.It has been suggested that magnesium deficiency may play an important role in menstrual migraine and that the serum ionized calcium (ICa2 )/ionized magnesium (IMg2 ) ratio is important in migraine headache. Studies were designed to test these hypotheses. Design.We prospectively evaluated 270 women seen at a headache clinic and in 61 women with menstrual migraine measured IMg2 , total magnesium, and ICa2 levels so as to calculate the ICa2 /IMg2 ratio. Results.The incidences of IMg2 deficiency were 45% during menstrual attacks, 15% during nonmenstrual attacks, 14% during menstruation without a migraine, and 15% between menstruations and between migraine attacks. The serum ICa2 levels were within our reference range, but the ICa 2 /IMg2 ratio was elevated (P .01) in menstrual migraine. Conclusions.The high incidence of IMg2 deficiency and the elevated ICa2 /IMg2 ratio during menstrual migraine confirm previous suggestions of a possible role for magnesium deficiency in the development of menstrual migraine. Key words: headache, migraine, menstruation, total Mg, ionized Mg 2 , ICa2 /IMg2 ratios, magnesium deficiency Abbreviations: Mg magnesium, TMg serum total magnesium, IMg 2 serum ionized magnesium, ICa2 serum ionized calcium
(Headache. 2002;42:242-248)

A recent, general population, epidemiological study indicated that among women with migraine, 24% reported menstruation to be a precipitating factor.1 In those 24%, 70% experienced more than half of their attacks in relation to menstruation. There is currently no agreement as to the precise definition of menstrual migraine, but the term often is applied to patients whose migraines consistently worsen in relation to menstruation.2 Silberstein and Merriam have

From The New York Headache Center (Dr. Mauskop); and The Center For Cardiovascular and Muscle Research and the Departments of Physiology and Pharmacology (Drs. B.T. Altura and B.M. Altura) and Medicine (Dr. B.M. Altura), SUNY Downstate Medical Center, Brooklyn, NY. Address all correspondence to Dr. Burton M. Altura, Box 31, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203. Accepted for publication January 12, 2002.

proposed that only those women who experience only migraine headaches perimenstrually (an ill-defined time period in itself) should be considered to have true menstrual migraine.2 Menstrual migraine attracts particular attention because it is frequently difficult to treat. The decline in the estrogen level occurring before menstruation has been implicated as the precipitating biologic event for menstrual migraine.2 How this decline triggers a migraine attack is unclear. Pregnancy often is followed by an improvement in these headaches, and the prevalence of migraine, in general, declines after the menopause.2 Anecdotal reports suggest that hormonal manipulation with drugs like danazol, tamoxifen, or leuprolide can be effective in some patients with menstrual migraine who do not respond to other therapies. Abnormal magnesium (Mg) metabolism has been proposed as a possible factor in the development of migraine headache.3 Low serum and tissue levels of 242

Headache total magnesium (TMg) have been reported in patients with migraine, including women with menstrual migraine.4-6 Some of the findings in these reports have been contradictory, as both normal and low levels of Mg were found in the same tissues of patients with migraine. We have suggested that these inconsistencies may be due to small sample size, different methodology, and, most importantly, the fact that TMg levels were measured rather than free ionized magnesium (IMg2 ).7 It is likely that only the biologically active, ionized portion of the TMg is truly reflective of disturbed Mg metabolism.8 In one small, but doubleblind and placebo-controlled study, Mg supplementation was reported to be effective in the treatment of menstrual migraines.4 In addition, Mg sulfate 1 to 2 g administered intravenously to patients with acute migraine who exhibit deficiency in serum IMg2 is effective for headache reduction in approximately 90% of the cases.9-11 Finally, it recently has been reported that the ratio of serum ionized calcium (ICa2 ) to IMg2 is elevated in almost 50% of all randomly tested patients with migraine.7,9,11 In the study described here, we evaluated women with menstrual migraine for possible deficiency of IMg2 or TMg and for elevation of the ICa2 /IMg2 ratio. We included the latter because it has remained unclear how the ratio and IMg2 levels correlate and which of these two indices may be the more important as related to the pathogenesis of migraine.7-11

243 We selected 61 women with migraine without aura whose headaches were more common or worsened during menstruation. Migraine was considered to be menstrual when it occurred within a week of onset of menstruation. A total of 67 serum samples were obtained. All clinical information was withheld from the laboratory staff (B.T.A. and B.M.A.). Severity of head pain was measured on a verbal 1 to 10 scale. Wherever appropriate, mean values SEM were calculated and compared for statistical significance by a nonpaired Student t test, analysis of variance (ANOVA), and the Scheffe contrast test.

METHODS Detailed clinical information was collected prospectively on 270 patients seen at a headache clinic. The International Headache Society (IHS) classification was used to establish a diagnosis of migraine. Serum IMg2 , ICa2 , and TMg levels were measured, and ICa2 /IMg2 ratios were calculated. We used ionselective electrodes for IMg2 , ICa2 , and pH with NOVA Biomedical Stat Profile 8 Analyzers; the accuracy of these electrodes is 97% to 100%.12,13 Serum total Mg was determined by atomic absorption spectroscopy and a Kodak DT-60 Ektachem Analyzer which yield identical results.12,13 The normal reference ranges for our laboratory are as follows: Ca2 , 1.09 to 1.33 mmol/L; Mg2 , 0.54 to 0.64 mmol/L; TMg, 0.74 to 0.96 mmol/L; and ICa2 /IMg2 ratios, 1.88 to 2.08.

RESULTS Ionized Mg levels were low in 45% of women experiencing menstrual migraine, while only 14% of women menstruating without migraine had low serum IMg2 levels (Table 1). Both women with acute migraine independent of menstruation and women between menstruations and without a headache had a 15% incidence of low IMg2 levels. All subjects had normal serum TMg and ICa2 levels. No correlation between IMg2 and severity of head pain (measured on a 1 to 10 verbal scale) was found. Mean serum IMg2 in women with menstrual migraine attacks and low serum IMg2 was 0.51 0.012 (mmol/L SEM). In healthy age-matched women with normal serum IMg2 , the mean IMg2 was 0.60 0.004 (P .01). Serum TMg levels in these two groups were 0.79 0.03 mmol/L and 0.88 0.06 mmol/L (P .05), respectively. Ionized calcium/IMg2 ratios were 2.38 0.11 and 2.03 0.18, respectively (P .01). Individual laboratory values and other details are listed in Tables 2 and 3. COMMENTS The role of Mg2 in the regulation of a large number of neurotransmitters and 325 enzyme systems is well established, and such wide involvement makes it difficult to establish a specific mechanism of action by which a lowered IMg2 concentration may contribute towards a particular disease process. Magnesium plays important roles in the regulation of cellular bioenergetics, cerebrovascular tone, Ca2 influx and its subcellular distribution, serotonin receptor activity, plate-

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Table 1.Results of Ionized Magnesium (IMg2 ), Ionized Calcium/(ICa2 )/IMg2 Ratios, and Total Magnesium (TMg) in Women With Menstrual Migraine During and Between Attacks and During Menstruation*

IMg2

ICa2 /IMg2

TMg

Controls (n 66) During menstrual attacks (n 20) Abnormal, % During nonmenstrual attacks (n 13) Abnormal, % During menses (n 14) Abnormal, % Between attacks and menses (n 20) Abnormal, %

0.600 0.004 0.559 0.012 45 0.578 0.012 15 0.571 0.009 14 0.579 0.009 15

1.95 0.006 2.19 0.052 50 2.12 0.037 31 2.11 0.03 36 2.09 0.038 25

0.843 0.842 0.888 0.874 0.876

0.008 0.015 0.022 0.019 0.014

*Values are mean (mmol/L SEM) unless otherwise indicated. Significantly different from controls (P .01). Significantly different from other values (P .01).

let aggregation, calcium and potassium currents in brain cells, biosynthesis and release of nitric oxide, fatty acid content and chain length within cerebrovascular muscle membranes, biosynthesis and release of sphingolipids (eg, ceramide), regulation of biosynthesis and release of inflammatory-pain mediators (eg, neuropeptides, substance P, cytokines), and nuclear transcription factors in brain cells.14-23 These actions of IMg2 combining vascular, bioenergetic, neuropeptide, and serotonergic effectsintersect nicely with the theories of migraine pathogenesis most popular today.3,24-26 Low Mg2 (extracellular and intracellular) is known to produce cerebrovascular constriction and increased vascular reactivity and membrane receptor activity (mediated by influx and release of Ca2 ) to mediators such as serotonin.3,14-17 In addition, low Mg2 decreases cellular bioenergetics (ie, lowers intracellular levels of Mg adenosine triphosphate [ATP], decreases brainmitochondrial free energy of ATP hydrolysis, as well as decreases the cytosolic phosphorylation potential).27 Further, low cellular levels of Mg2 are known to generate and release high levels of substance P; proinflammatory cytokines such as tumor necrosis factor, interleukin-1, interleukin-6; prostanoids; and free radicals.23,28 The high incidence of IMg2 deficiency we found in our patients during menstrual migraine attacks in-

dicates that Mg may have a role in the development of this disease in a subgroup of patients. It appears from our study that some women exhibit IMg2 deficiency between migraines and menstruations but that the incidence rises when these two events are combined. Total erythrocyte Mg concentration was found to be low in patients with symptoms of premenstrual syndrome.29 It is possible that IMg2 levels always drop just prior to or during menses, thus predisposing all women to migrainous headache, but that only those who are intrinsically susceptible to the condition have additional migraine-provoking factors, or those who have especially low levels of IMg2 actually develop a migraine. The highly significant difference in IMg2 between women with low and normal serum IMg2 levels suggests that this abnormality plays a key role only in a certain group of women and is not continuously distributed and exerting only an incremental effect. It has been suggested that the ICa2 /IMg2 ratio may be important in the regulation of certain neurotransmitter activities, cerebrovascular tone, and most of the other functions associated with Mg.30 We previously have reported a strong correlation between serum IMg2 levels and the ICa2 /IMg2 ratio in migraine and other headache types.7,9-11,30 If our findings in menstrual migraine are confirmed, only the measurement of IMg2 may be needed. Serum IMg2 is reflective

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Table 2.Results of Ionized Magnesium (IMg2 ), Ionized Calcium (ICa2 )/IMg2 Ratios, and Total Magnesium (TMg) in Women With Menstrual Migraine Versus Nonmenstrual Migraine

Patient*

Age, y

IMg2 , mmol/L

ICa2 /IMg2

TMg, mmol/L

Menstrual migraine attack 1 2 3 4 5 6 7 8 9 10a 11b 12c 13 14 15 16 17d 18d 19 20 Nonmenstrual migraine attack 1 2 3 4 5 6 7a 8 9 10 11 12 13

24 38 45 32 45 44 41 43 32 48 28 42 35 39 44 34 31 31 40 25 35 49 31 47 32 38 48 34 44 20 39 46 31

0.68 0.65 0.48 0.53 0.49 0.56 0.48 0.53 0.58 0.53 0.63 0.59 0.57 0.51 0.54 0.56 0.52 0.55 0.57 0.62 0.61 0.49 0.57 0.59 0.57 0.59 0.60 0.56 0.56 0.63 0.65 0.53 0.56

1.76 1.80 2.52 2.28 2.55 2.23 2.52 2.30 2.16 2.30 1.84 2.10 2.16 2.33 2.35 2.16 2.35 2.20 2.10 1.84 1.95 2.41 2.12 2.08 2.03 2.05 2.03 2.25 2.23 1.98 2.05 2.30 2.14

0.99 0.95 0.74 0.82 0.74 0.86 0.78 0.80 0.80 0.82 0.82 0.86 0.90 0.82 0.82 0.86 0.78 0.86 0.86 0.95 0.86 0.82 0.90 0.90 0.86 0.95 0.86 0.86 0.95 1.07 0.95 0.78 0.78

*Letters following patient numbers indicate that the patient had more than one serum sample drawn; same letter indicates same patient at different months.

of the level of Mg2 within cells and tissues, and its level varies according to the absence versus presence of menstrual migraine, whereas the ICa2 level does not.30 If our study is representative of the female population at large, then serum IMg2 deficiency may be quite common in women with menstrual migraine and may be a more reliable indicator of disturbed Mg metabolism than TMg. It also may help to explain why there often has been no correlation found between migraine and TMg levels in this syndrome. Some re-

cent evidence from our laboratory indicates that in young, healthy cycling women and on isolated, primary cerebrovascular muscle cells in culture, circulating levels of estrogen and progesterone play major roles in regulating levels of circulatory Mg2 and Ca2 (and, presumably, levels in brain neurons as well).31-33 In at least the proportion of patients with low serum IMg2 , hormonal actions on Mg2 may be responsible for the menstrual migraine syndrome and intravenous administration of Mg2 to those patients may be effective in terminating headache attacks.10,34

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Table 3.Results of Serum Ionized Magnesium (IMg2 ), Ionized Calcium (ICa2 )/IMg2 Ratios, and Total Magnesium (TMg) in Women During Menses Without Any Migraine Attack and in Women Between Migraines and Between Menses*

Patient*

Age, y

IMg2 , mmol/L

ICa2 /IMg2

TMg, mmol/L

During menses, no migraine 1 2 3e 4e 5 6 7 8c 9c 10 11 12 13 14 Between migraines and between menses 1 2 3 4 5 6 7 8 9 10 11 12 13 14a 15b 16 17 18 19 20

39 51 23 23 28 36 36 42 42 43 41 29 41 22 31 43 25 35 45 49 47 49 37 43 43 34 36 48 28 24 44 40 34 40

0.57 0.58 0.51 0.61 0.52 0.56 0.56 0.56 0.57 0.58 0.63 0.64 0.57 0.54 0.59 0.58 0.59 0.51 0.56 0.61 0.60 0.60 0.63 0.54 0.58 0.56 0.66 0.58 0.54 0.49 0.60 0.52 0.61 0.62

2.10 2.12 2.51 2.00 2.19 2.21 2.14 2.21 2.23 1.96 2.01 1.92 2.09 2.30 1.97 2.00 2.03 2.23 2.21 2.00 2.00 1.93 1.87 2.28 2.09 2.16 1.85 2.19 2.09 2.43 2.07 2.50 2.03 2.00

0.86 0.86 0.74 0.90 0.78 0.86 0.86 0.78 0.90 0.95 1.03 0.95 0.82 0.78 0.90 0.90 0.90 0.78 0.82 0.99 0.90 0.90 0.90 0.74 0.90 0.82 0.90 0.90 0.86 0.82 0.95 0.82 0.86 0.95

*Letters following patient numbers indicate that the patient had more than one serum sample drawn; same letter indicates same patient at different months.

Acknowledgment: Some of the laboratory measures performed were supported in part by NIH Research Grant AA-08674 (B.M.A.).

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