REVISING THE ROLE OF MAGNESIUM IN EPILEPSY RESEARCH AND MANAGEMENT
Abstract
Magnesium is a bioessential mineral with multiple neuroactive effects. The Mg2+ ion stabilizes excitable membranes. Epilepsy is the third most frequent chronic neurological condition characterized by spontaneous reappearance of unprovoked epileptic seizures, whose underlying mechanisms are not yet completely understood. A literature review of the role of magnesium in basic and clinical epileptology has been performed in order to elucidate the importance of magnesium deficiency in the mechanisms of epileptic brain hyperexcitability, as well as the significance of including magnesium into the management of epilepsy patients.
Neuronal magnesium requirements are high. The concentration of magnesium in cerebrospinal fluid (CSF) is even higher than in the blood. In experimental epilepsy research, perfusing hippocampal slices with artificial cerebrospinal fluid containing a low concentration of extracellular Mg2+ ions is a frequently used animal model of spontaneously induced epileptiform activity. Magnesium deficiency is the most frequent clinically unrecognized electrolyte disbalance, often overlooked in epilepsy patients. Serum and CSF Mg2+ concentrations are lower in patients with epilepsy, as compared to healthy controls. Hypomagnesaemia increases seizure frequency and the risk of sudden unexpected death in pharmacoresistant epilepsy. Oral magnesium supplements help achieve better seizure control. Parenterally administered Mg2+ ions efficiently control seizures in certain epileptic encephalopathies, in adults and children (in eclampsia, uremia, porphyria, febrile seizures, infantile spasms), and also helps control status epilepticus.
Subclinical magnesium deficiency, which is very frequent in the general population, acts as a factor contributing to seizure generation in epilepsy. It is recommended to assess magnesium status in epilepsy patients. This literature review reveals the therapeutic potential of magnesium as a simple antiepileptic agent, which exceeds its current clinical use.
References
1. Pešić B. Epilepsija. U: Nešović Ostojić J, Radosavljević T, Pešić B, urednici. Patofiziologija. Mehanizmi poremećaja zdravlja (drugi deo). Beograd: Medicinski fakultet Univerziteta u Beogradu; 2020. 705-12.
2. Кostić V, Vojvodić N, Petrović I. Neurologija. Drugo izdanje. Medicinski fakultet, Beograd; 2018. 161-78.
3. Stanojević M, Lopičić S, Spasić S, Nedeljkov V, Prostran M. Antiepileptičko dejstvo magnezijuma. Medicinska istraživanja. 2017;51(3):20-8. doi: 10.5937/MedIst1703020S.
4. Classen HG, von Ehrlich B, Kisters K, Kraus A, Vormann J. Magnesium: Nature’s physiological mood stabilizer. Trace Elements and Electrolytes. 2021;38:33-43. doi: 10.5414/TEX01645.
5. Somjen GG. The regulation of ions in the brain: normal function, seizures and stroke. New York: Oxford University Press; 2004.
6. Stanojević M, Lopicic S, Spasic S, Aleksic I, Nedeljkov V, Prostran M. Effects of high extracellular magnesium on electrophysiological properties of membranes of Retzius neurons in leech Haemopis sanguisuga. J Elem. 2016;21(1):221-30. doi:10.5601/jelem.2015.20.1.887.
7. Pusch M. Open-channel block of Na+ channels by intracellular Mg2+. Eur Biophys J. 1990;18(6):317-26. doi: 10.1007/BF00196922.
8. Shi J, Cui J. Intracellular Mg2+ enhances the function of BK-type Ca2+-activated K+ channels. J Gen Physiol. 2001;118(5):589-606. doi: 10.1085/jgp.118.5.589.
9. Skou JC. The Na,K-pump. Methods Enzymol. 1988;156:1-25. doi: 10.1016/0076-6879(88)56004-4.
10. Wilkinson S, Stuedemann J, Grunes D, Devine O. Relation of soil and plant magnesium to nutrition of animals and man. Magnesium. 1987;6(2):74-90.
11. Nardone R, Brigo F, Trinka E. Acute Symptomatic Seizures Caused by Electrolyte Disturbances. J Clin Neurol. 2016; 12(1):21-33. doi: 10.3988/jcn.2016.12.1.21.
12. Maier JA, Pickering G, Giacomoni E, Cazzaniga A, Pellegrino P. Headaches and Magnesium: Mechanisms, Bioavailability, Therapeutic Efficacy and Potential Advantage of Magnesium Pidolate. Nutrients. 2020;12(9):2660. doi: 10.3390/nu1209.
13. Kirkland AE, Sarlo GL, Holton KF. The Role of Magnesium in Neurological Disorders. Nutrients. 2018 Jun 6;10(6):730. doi: 10.3390/nu10060730.
14. Djokic G, Vojvodić P, Korcok D, Agic A, Rankovic A, Djordjevic V, et al. The Effects of Magnesium – Melatonin - Vit B Complex Supplementation in Treatment of Insomnia. Open Access Maced J Med Sci. 2019;7(18):3101-5. doi: 10.3889/oamjms.2019.771.
15. Кažić T. Lekovi za epilepsiju. U: Кažić T, Farmakologija. Кlinička farmakologija. Drugo izdanje. Beograd: Integra; 2002. 147-54.
16. Stanojević M. Magnezijum kao potencijalni antiepileptički agens u nesinaptičkoj epileptogenezi / Magnesium as a potential antiepileptic agent in nonsynaptic epileptogenesis. Zadužbina Andrejević, Beograd, 2017.
17. Lopičić S, Stanojević M. Poremećaji nervnog sistema. Poremećaji podražljivosti i sprovodljivosti u nervnom sistemu. U: Nešović Ostojić J, Radosavljević T, Pešić B, urednici. Patofiziologija. Mehanizmi poremećaja zdravlja (drugi deo). Beograd: Medicinski fakultet Univerziteta u Beogradu; 2020. 635-39.
18. Pathak D, Lopicic S, Stanojevic M, Nedeljkov A, Pavlovic D, Cemerikic D, et al. Ethanol and magnesium suppress nickel-induced bursting activity in leech Retzius nerve cells. Gen Physiol Biophys. 2009;28:9-17.
19. Stanojević M, Lopicic S, Jovanovic Z, Pathak D, Pavlovic DV, Spasic S, et al. Magnesium effects on nonsynaptic epileptiform activity in leech Retzius neurons. Folia Biol (Krakow). 2015;63(4):301-6. doi: 10.3409/fb63_4.301.
20. Derchansky M, Shahar E, Wennberg RA, Samoilova M, Jahromi SS, Abdelmalik PA, et al. Model of frequent, recurrent, and spontaneous seizures in the intact mouse hippocampus. Hippocampus. 2004;14(8):935-47. doi: 10.1002/hipo.20007.
21. Borges LF, Gücer G. Effect of magnesium on epileptic foci. Epilepsia. 1978;19(1):81-91. doi: 10.1111/j.1528-1157.1978.tb05015.x.
22. Leaver DD, Parkinson GB, Schneider KM. Neurological consequences of magnesium deficiency: correlations with epilepsy. Clin Exp Pharmacol Physiol. 1987;14(5):361-70. doi: 10.1111/j.1440-1681.1987.tb00985.x.
23. Spasov AA, Iezhitsa IN, Kharitonova MV, Kravchenko MS. Effect of magnesium chloride and magnesium L-aspartate on seizure threshold in rats under conditions of dietary magnesium deficiency. Bull Exp Biol Med. 2007;144(2):214-6. doi: 10.1007/s10517-007-0292-7.
24. Dhande PP, Ranade RS, Ghongane BB. Effect of magnesium oxide on the activity of standard anti-epileptic drugs against experimental seizures in rats. Indian J Pharmacol 2009;41(6):268-72. doi: 10.4103/0253-7613.59926.
25. Abdullahi I, Waitila MM, Shahi N, Nyandaiti YW, Bwala SA. Serum magnesium in adult patients with idiophatic and symptomatic epilepsy in Maiduguri, Northeast Nigeria. Niger J Clin Pract. 2019;22(2):186-93. doi: 10.4103/njcp.njcp_252_18.
26. Baek SJ, Byeon JH, Eun SH, Eun BL, Kim GH. Risk of low serum levels of ionized magnesium in children with febrile seizure. BMC Pediatr. 2018 Sep 7;18(1):297. doi: 10.1186/s12887-018-1271-z.
27. Yuen AWC, Sander JW. Can magnesium supplementation reduce seizures in people with epilepsy? A hypothesis. Epilepsy Res. 2012;100(1-2):152-6. doi: 10.1016/j.eplepsyres.2012.02.004.
28. Scorza FA, Cysneiros RM, Arida RM. Serum magnesium and sudden unexpected death in epilepsy: A curious clinical sign or a necessity of life. Epilepsy Res. 2012;101(3):293-4. doi: 10.1016/j.eplepsyres.2012.04.010.
29. Prousky JE. The Adjunctive Treatment of Epilepsy with Orthomolecular Substances. J Ortho Med. 2014;29(4):167-75.
30. Osborn KE, Shytle RD, Frontera AT, Soble JR, Schoenberg MR. Addressing Potential Role of Magnesium Dyshomeostasis to Improve Treatment Efficacy for Epilepsy: A Reexamination of the Literature. J Clin Pharmacol. 2016;56(3):260-5. doi: 10.1002/jcph.626.
31. Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol. 2005;105(2):402-10. doi: 10.1097/01.AOG.0000152351.13671.99.
32. Gröber U, Schmidt J, Kisters K. Magnesium in prevention and therapy. Nutrients. 2015;7(9):8199-226. doi: 10.3390/nu7095388.
33. Akhtar MI, Ullah H, Hamid M. Magnesium, a drug of diverse use. J Pak Med Assoc. 2011;61(12):1220-5.
34. Mohamed ZA, Tang C, Thokerunga E, Jimale AO, Fan J. Serum hypomagnesemia is associated with febrile seizures in young children. AIMS Neurosci. 2022;9(4):551-8. doi: 10.3934/ Neuroscience.2022032.
35. Yadav VK, Amrita A, Yadav S, Kumar R, Yadav KK. Role of Magnesium Supplementation in Children with West Syndrome: A Randomized Controlled Clinical Trial. Iran J Child Neurol. 2022;16(1):65-75. doi: 10.22037/ijcn.v16i1.30480.
36. Lazard EM. A preliminary report on the intravenous use of magnesium sulphate in puerperal eclampsia. Am J Obs Gynecol. 1925;9(2):178-88.
37. Storccheim F. Status epilepticus treated by magnesium sulphate, injected intravenously. JAMA 1933;101(17):1313-4. doi:10.1001/jama.1933.27430420001009.
38. Abdelmalik PA, Politzer N, Carlen PL. Magnesium as an effective adjunct therapy for drug resistant seizures. Can J Neurol Sci. 2012;39(3):323-7. doi: 10.1017/s0317167100013457.
39. Visser NA, Braun KP, Leijten FS, van Nieuwenhuizen O, Wokke JH, van den Bergh WM. Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations. J Neurol. 2011;258(2):218-22. doi: 10.1007/s00415-010-5721-2.
40. Pandey M, Gupta A, Baduni N, Vijfdar H, Sinha S, Jain A. Refractory status epilepticus – magnesium as rescue therapy. Anaesth Intensive Care. 2010;38(5):962.
41. Tan WW, Chan DWS, Lee JH, Thomas T, Menon AP, Chan YH. Use of Magnesium Sulfate Infusion for the Management of Febrile Illness-Related Epilepsy Syndrome: A Case Series. Child Neurol Open 2015;2(1): 2329048X14550067. doi: 10.1177/2329048X14550067.
42. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain. 2011;134(Pt 10):2802-18. doi: 10.1093/brain/awr215.
Normal
0
false
false
false
EN-GB
X-NONE
X-NONE
DefSemiHidden="true" DefQFormat="false" DefPriority="99"
LatentStyleCount="267">
UnhideWhenUsed="false" QFormat="true" Name="Normal"/>
UnhideWhenUsed="false" QFormat="true" Name="heading 1"/>
UnhideWhenUsed="false" QFormat="true" Name="Title"/>
UnhideWhenUsed="false" QFormat="true" Name="Subtitle"/>
UnhideWhenUsed="false" QFormat="true" Name="Strong"/>
UnhideWhenUsed="false" QFormat="true" Name="Emphasis"/>
UnhideWhenUsed="false" Name="Table Grid"/>
UnhideWhenUsed="false" QFormat="true" Name="No Spacing"/>
UnhideWhenUsed="false" Name="Light Shading"/>
UnhideWhenUsed="false" Name="Light List"/>
UnhideWhenUsed="false" Name="Light Grid"/>
UnhideWhenUsed="false" Name="Medium Shading 1"/>
UnhideWhenUsed="false" Name="Medium Shading 2"/>
UnhideWhenUsed="false" Name="Medium List 1"/>
UnhideWhenUsed="false" Name="Medium List 2"/>
UnhideWhenUsed="false" Name="Medium Grid 1"/>
UnhideWhenUsed="false" Name="Medium Grid 2"/>
UnhideWhenUsed="false" Name="Medium Grid 3"/>
UnhideWhenUsed="false" Name="Dark List"/>
UnhideWhenUsed="false" Name="Colorful Shading"/>
UnhideWhenUsed="false" Name="Colorful List"/>
UnhideWhenUsed="false" Name="Colorful Grid"/>
UnhideWhenUsed="false" Name="Light Shading Accent 1"/>
UnhideWhenUsed="false" Name="Light List Accent 1"/>
UnhideWhenUsed="false" Name="Light Grid Accent 1"/>
UnhideWhenUsed="false" Name="Medium Shading 1 Accent 1"/>
UnhideWhenUsed="false" Name="Medium Shading 2 Accent 1"/>
UnhideWhenUsed="false" Name="Medium List 1 Accent 1"/>
UnhideWhenUsed="false" QFormat="true" Name="List Paragraph"/>
UnhideWhenUsed="false" QFormat="true" Name="Quote"/>
UnhideWhenUsed="false" QFormat="true" Name="Intense Quote"/>
UnhideWhenUsed="false" Name="Medium List 2 Accent 1"/>
UnhideWhenUsed="false" Name="Medium Grid 1 Accent 1"/>
UnhideWhenUsed="false" Name="Medium Grid 2 Accent 1"/>
UnhideWhenUsed="false" Name="Medium Grid 3 Accent 1"/>
UnhideWhenUsed="false" Name="Dark List Accent 1"/>
UnhideWhenUsed="false" Name="Colorful Shading Accent 1"/>
UnhideWhenUsed="false" Name="Colorful List Accent 1"/>
UnhideWhenUsed="false" Name="Colorful Grid Accent 1"/>
UnhideWhenUsed="false" Name="Light Shading Accent 2"/>
UnhideWhenUsed="false" Name="Light List Accent 2"/>
UnhideWhenUsed="false" Name="Light Grid Accent 2"/>
UnhideWhenUsed="false" Name="Medium Shading 1 Accent 2"/>
UnhideWhenUsed="false" Name="Medium Shading 2 Accent 2"/>
UnhideWhenUsed="false" Name="Medium List 1 Accent 2"/>
UnhideWhenUsed="false" Name="Medium List 2 Accent 2"/>
UnhideWhenUsed="false" Name="Medium Grid 1 Accent 2"/>
UnhideWhenUsed="false" Name="Medium Grid 2 Accent 2"/>
UnhideWhenUsed="false" Name="Medium Grid 3 Accent 2"/>
UnhideWhenUsed="false" Name="Dark List Accent 2"/>
UnhideWhenUsed="false" Name="Colorful Shading Accent 2"/>
UnhideWhenUsed="false" Name="Colorful List Accent 2"/>
UnhideWhenUsed="false" Name="Colorful Grid Accent 2"/>
UnhideWhenUsed="false" Name="Light Shading Accent 3"/>
UnhideWhenUsed="false" Name="Light List Accent 3"/>
UnhideWhenUsed="false" Name="Light Grid Accent 3"/>
UnhideWhenUsed="false" Name="Medium Shading 1 Accent 3"/>
UnhideWhenUsed="false" Name="Medium Shading 2 Accent 3"/>
UnhideWhenUsed="false" Name="Medium List 1 Accent 3"/>
UnhideWhenUsed="false" Name="Medium List 2 Accent 3"/>
UnhideWhenUsed="false" Name="Medium Grid 1 Accent 3"/>
UnhideWhenUsed="false" Name="Medium Grid 2 Accent 3"/>
UnhideWhenUsed="false" Name="Medium Grid 3 Accent 3"/>
UnhideWhenUsed="false" Name="Dark List Accent 3"/>
UnhideWhenUsed="false" Name="Colorful Shading Accent 3"/>
UnhideWhenUsed="false" Name="Colorful List Accent 3"/>
UnhideWhenUsed="false" Name="Colorful Grid Accent 3"/>
UnhideWhenUsed="false" Name="Light Shading Accent 4"/>
UnhideWhenUsed="false" Name="Light List Accent 4"/>
UnhideWhenUsed="false" Name="Light Grid Accent 4"/>
UnhideWhenUsed="false" Name="Medium Shading 1 Accent 4"/>
UnhideWhenUsed="false" Name="Medium Shading 2 Accent 4"/>
UnhideWhenUsed="false" Name="Medium List 1 Accent 4"/>
UnhideWhenUsed="false" Name="Medium List 2 Accent 4"/>
UnhideWhenUsed="false" Name="Medium Grid 1 Accent 4"/>
UnhideWhenUsed="false" Name="Medium Grid 2 Accent 4"/>
UnhideWhenUsed="false" Name="Medium Grid 3 Accent 4"/>
UnhideWhenUsed="false" Name="Dark List Accent 4"/>
UnhideWhenUsed="false" Name="Colorful Shading Accent 4"/>
UnhideWhenUsed="false" Name="Colorful List Accent 4"/>
UnhideWhenUsed="false" Name="Colorful Grid Accent 4"/>
UnhideWhenUsed="false" Name="Light Shading Accent 5"/>
UnhideWhenUsed="false" Name="Light List Accent 5"/>
UnhideWhenUsed="false" Name="Light Grid Accent 5"/>
UnhideWhenUsed="false" Name="Medium Shading 1 Accent 5"/>
UnhideWhenUsed="false" Name="Medium Shading 2 Accent 5"/>
UnhideWhenUsed="false" Name="Medium List 1 Accent 5"/>
UnhideWhenUsed="false" Name="Medium List 2 Accent 5"/>
UnhideWhenUsed="false" Name="Medium Grid 1 Accent 5"/>
UnhideWhenUsed="false" Name="Medium Grid 2 Accent 5"/>
UnhideWhenUsed="false" Name="Medium Grid 3 Accent 5"/>
UnhideWhenUsed="false" Name="Dark List Accent 5"/>
UnhideWhenUsed="false" Name="Colorful Shading Accent 5"/>
UnhideWhenUsed="false" Name="Colorful List Accent 5"/>
UnhideWhenUsed="false" Name="Colorful Grid Accent 5"/>
UnhideWhenUsed="false" Name="Light Shading Accent 6"/>
UnhideWhenUsed="false" Name="Light List Accent 6"/>
UnhideWhenUsed="false" Name="Light Grid Accent 6"/>
UnhideWhenUsed="false" Name="Medium Shading 1 Accent 6"/>
UnhideWhenUsed="false" Name="Medium Shading 2 Accent 6"/>
UnhideWhenUsed="false" Name="Medium List 1 Accent 6"/>
UnhideWhenUsed="false" Name="Medium List 2 Accent 6"/>
UnhideWhenUsed="false" Name="Medium Grid 1 Accent 6"/>
UnhideWhenUsed="false" Name="Medium Grid 2 Accent 6"/>
UnhideWhenUsed="false" Name="Medium Grid 3 Accent 6"/>
UnhideWhenUsed="false" Name="Dark List Accent 6"/>
UnhideWhenUsed="false" Name="Colorful Shading Accent 6"/>
UnhideWhenUsed="false" Name="Colorful List Accent 6"/>
UnhideWhenUsed="false" Name="Colorful Grid Accent 6"/>
UnhideWhenUsed="false" QFormat="true" Name="Subtle Emphasis"/>
UnhideWhenUsed="false" QFormat="true" Name="Intense Emphasis"/>
UnhideWhenUsed="false" QFormat="true" Name="Subtle Reference"/>
UnhideWhenUsed="false" QFormat="true" Name="Intense Reference"/>
UnhideWhenUsed="false" QFormat="true" Name="Book Title"/>
/* Style Definitions */
table.MsoNormalTable
{mso-style-name:"Table Normal";
mso-tstyle-rowband-size:0;
mso-tstyle-colband-size:0;
mso-style-noshow:yes;
mso-style-priority:99;
mso-style-qformat:yes;
mso-style-parent:"";
mso-padding-alt:0cm 5.4pt 0cm 5.4pt;
mso-para-margin-top:0cm;
mso-para-margin-right:0cm;
mso-para-margin-bottom:10.0pt;
mso-para-margin-left:0cm;
line-height:115%;
mso-pagination:widow-orphan;
font-size:11.0pt;
font-family:"Calibri","sans-serif";
mso-ascii-font-family:Calibri;
mso-ascii-theme-font:minor-latin;
mso-fareast-font-family:"Times New Roman";
mso-fareast-theme-font:minor-fareast;
mso-hansi-font-family:Calibri;
mso-hansi-theme-font:minor-latin;
mso-bidi-font-family:"Times New Roman";
mso-bidi-theme-font:minor-bidi;}