Cegielska J, Szmidt-Sałkowska E, Domitrz W, Gaweł M, Radziwoń-Zaleska M, Domitrz I. Migraine and its association with hyperactivity of cell membranes in the course of latent magnesium deficiency-preliminary study of the importance of the latent tetany presence in the migraine pathogenesis. Nutrients. 2021;13(8):2701.
To determine whether there is a relationship between presumed latent magnesium deficiency and migraine through correlation of electrophysiological latent tetany test
The study involved 35 consecutive patients from the Headache Outpatient Clinic diagnosed with migraine (29 women and 6 men; aged 22–57 years). Eight patients had migraine with aura (ie, classical migraine), and 27 had migraine without aura (ie, common migraine). All patients had normal serum levels of magnesium, potassium, and parathyroid hormone concentrations. A control group of 24 healthy volunteers (17 women and 7 men; aged 23–61 years) was also assessed for comparison.
Patients with the following were excluded from the study:
- medical history of metabolic or hormonal disorders including thyroid and parathyroid disease
- cardiovascular diseases
- cancer or other serious diseases (dementia, depression)
- participation in elimination diets
- use of drugs affecting electrolyte concentration or over-the-counter supplements
Study Parameters Assessed
Investigators assessed latent tetany in migraine patients and control patients through electrophysiological measurements using modified testing for Trousseau sign.
Primary Outcome Measures
Investigators calculated correlation between spasmophilia (positive result of electrophysiological latent tetany) and migraine status.
Overall, no significant difference was found between occurrence of spasmophilia in migraine and control groups (P=0.13). In subgroup analysis, a statistical difference was seen in patients who experience migraine with aura compared to controls (P=0.04).
This study provides multiple insights for the practitioner that may not be apparent from initial reading. While providing insight, it does not definitively answer whether magnesium is a valuable intervention in migraine headaches, nor does it provide insight as to the best type of magnesium to be trialed as an intervention. However, it does provide some provocative information about the assessment of latent magnesium insufficiency, which may be useful for patient selection criteria in future studies of magnesium interventions in migraine patients.
It is important to recognize that this is not an interventional study and as such does not support or fail to support causation. Rather, investigators relied on self-reports of migraine patients through diaries and correlated that with the response to a tetany test. If this study had been extended to supplement magnesium in those with spasmophilia with primary outcomes of migraine frequency and intensity, stronger implications would be apparent.
The pathogenesis of migraine headaches has been under investigation for decades. Theories include neuronal disorders, ion channel disturbances of receptors including NMDA, AMPA, mGluR, cannabinoid, vanilloid, and PAR.1-3 However, the leading theory is that migraine onset is due to changes in cerebral blood flow and reactivity of cerebral vessels.4
Simplifying the metabolic steps of the pathophysiology results in the following:
Magnesium is known to block the calcium channel of the NMDA receptor. The NMDA receptor allows glutamate release. Without sufficient magnesium, the neuroexcitatory glutamate is enhanced and increases oxidative stress. Increased perfusion occurs. Imaging (magnetic resonance spectroscopy) also shows changes in the occipital cortex during migraine with aura. Moderate perfusion, especially to the occipital cortex, may cause a phenomenon known as cortical spreading depression (CSD), causing a self-propagating wave to other areas of the brain and the experience of headache pain. Worth noting is that magnesium insufficiency may lower the threshold for nociception, and aberrant glutamate release is associated with migraine as well as other neurologic conditions.5-8 Genetic and/or acquired mitochondrial dysfunction may contribute to this cascade of events as well.8
In frank nutrient deficiency, this pathogenesis is relatively straightforward, but in the absence of known insufficiency, it may be more complex.
Thus, an individual with normal serum magnesium may have low concentrations in platelets, erythrocytes, neurons, and/or myocytes.
All patients in this study had normal serum magnesium levels as well as potassium and parathyroid hormone levels. While serum magnesium levels were normal, it is important to remember serum levels do not mirror intracellular magnesium status. Thus, an individual with normal serum magnesium may have low concentrations in platelets, erythrocytes, neurons and/or myocytes.9 Red blood cell (RBC) magnesium may be a better marker for intracellular magnesium status.
Patients presenting with low levels of serum magnesium and/or low magnesium intake assessed via dietary intake assessment should continue to be supplemented as required, independent of migraine status.
Clinicians may be familiar with the Trousseau test for tetany, which, when positive, is most commonly indicative of hypocalcemia.10 This test is performed by occluding the brachial artery with a sphygmomanometer for 3 minutes at a pressure of 10 to 20 mm Hg above normal systolic measurements for the individual. A test is positive if spontaneous flexion of the affected hand’s wrist occurs, often accompanied by flexion of the metacarpophalangeal (MCP) joints and modest extension of the distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints and digital adduction due to neuromuscular excitability.
Investigators in this study modified the procedure by applying the sphygmomanometer for 10 minutes with the last 2 minutes being accompanied by hyperventilation. The modifications ensured vascular occlusion and induced respiratory alkalosis and can be used as an indirect marker for latent tetany caused by low magnesium status according to these authors. Rather than evaluating observed positional changes, the investigators used needle electromyography to measure neuromuscular excitability. The procedures used in this study are not likely to be used in clinical practice.
When an assessment is not easily used in practice, other signs or symptoms may be used to give context to the clinical picture. In this study, no statistically significant result was found between tetany and other symptoms also common in patients with migraine. These included arrhythmia, sleep disturbances, anxiety attacks, mouth paresthesia, hand paresthesia, foot paresthesia, hand cramps, foot cramps, calf cramps, laryngospasms, fasciculations of the eyelids, or fainting. Dizziness did have a statistically significant correlation. The researchers indicated this correlation was not clinically relevant, but it’s unclear how they came to that conclusion. Presence or absence of these symptoms may not be good indicators of intracellular magnesium. Demographic factors also did not contribute, as neither age nor gender was a statistically significant correlation for any factor.