PREISPITIVANJE ULOGE MAGNEZIJUMA U ISTRAŽIVANJIMA

EPILEPSIJE I ZBRINJAVANJU PACIJENATA SA EPILEPSIJOM

PREGLEDNI RAD REVIEW ARTICLE

REVISING THE ROLE OF MAGNESIUM IN EPILEPSY

RESEARCH AND MANAGEMENT

Marija Stanojević1, Miro Parezanović1,2, Aneta Popović1, Svetolik Spasić1, Srđan Lopičić1,
Vladimir Nedeljkov1, Zorica Jovanović3, Sonja Vučković4
1
Univerzitet u Beogradu, Medicinski fakultet, Institut za patološku 1
University of Belgrade, Faculty of Medicine, Institute for
fiziologiju, Beograd, Srbija Pathological Physiology, Belgrade, Serbia
2
Institut za zdravstvenu zaštitu majke i deteta Srbije ,,Dr Vukan 2
Institute for Mother and Child Healthcare of Serbia Dr Vukan
Čupić“, Beograd, Srbija Čupić, Belgrade, Serbia
3
Univerzitet u Kragujevcu, Fakultet medicinskih nauka, Odeljenje 3
University of Kragujevac, Faculty of Medical Sciences, Department
za patološku fiziologiju, Kragujevac, Srbija of Pathological Physiology, Belgrade, Serbia
4
Univerzitet u Beogradu, Medicinski fakultet, Institut za 4
University of Belgrade, Faculty of Medicine, Institute of
farmakologiju, kliničku farmakologiju i toksikologiju, Beograd, Pharmacology, Clinical Pharmacology and Toxicology, Belgrade,
Srbija Serbia

SAŽETAK ABSTRACT
Magnezijum je mineral bioesencijalan za ekscitabilna tkiva, koji pokazuje višestruka ne- Magnesium is a bioessential mineral with multiple neuroactive effects. Mg2+ ion
uroaktivna dejstva. Jon Mg2+ stabilizuje ekscitabilne membrane. Epilepsija je jedna od stabilizes excitable membranes. Epilepsy is the third most frequent chronic neurological
najčešćih hroničnih neuroloških bolesti koju odlikuje spontano ponavljanje neprovocira- condition characterized by spontaneous reappearance of unprovoked epileptic seizures,
nih epileptičkih napada. Njihovi mehanizmi nastanka nisu potpuno rasvetljeni. Pregled whose underlying mechanisms are not completely understood yet. A literature review
literature o ulozi magnezijuma u bazičnim i kliničkim istraživanjima epilepsije napravljen on the role of magnesium in basic and clinical epileptology has been made in order to
je da bi se rasvetlio značaj nedostatka magnezijuma u nastanku epileptičke hipereksci- enlighten the importance of magnesium deficiency in the mechanisms of epileptic
tabilnosti mozga, kao i značaj primene preparata magnezijuma u zbrinjavanju pacijenata brain hyperexcitability, as well as the significance of including magnesium into the
sa epilepsijom. management of epilepsy patients.
Potrebe neurona za magnezijumom su velike. Njegova koncentracija u likvoru je veća Neuronal magnesium requirements are high. The concentration of magnesium in the
nego u serumu. U eksperimentalnim istraživanjima epilepsije perfuzija isečaka hipokam- cerebrospinal fluid (CSF) is even higher than in the blood. In experimental epilepsy
pusa veštačkim likvorom sa niskim sadržajem Mg2+ predstavlja često korišćen animalni research, perfusing hippocampal slices with artificial CSF containing low concentration
model spontano indukovane epileptiformne aktivnosti. Deficit Mg2+ kao elektrolitni of extracellular Mg2+ is a frequently used animal model of spontaneously induced
disbalans često ostaje klinički neprepoznat, i često se previdi kod bolesnika sa epilepsi- epileptiform activity. Magnesium deficiency is the most frequent clinically unrecognized
jom. Nivo Mg2+ u likvoru i serumu pacijenata sa epilepsijom niži je nego u zdravih kontro- electrolyte disbalance, often overlooked in epilepsy patients. Serum and CSF Mg2+
la. Кod njih hipomagnezijemija povećava učestalost epileptičkih napada, a u farmakorezi- concentrations are lower in patients with epilepsy, as compared to healthy controls.
stentnoj bolesti povećava rizik od naprasne, neočekivane smrti. Peroralna suplementacija Hypomagnesaemia increases seizure frequency and the risk of sudden unexpected death
magnezijumom pomaže u boljoj kontroli napada. Antikonvulzivno dejstvo parenteralnih in pharmacoresistant epilepsy. Oral magnesium supplements help achieve better seizure
preparata Mg2+ koristi se za suzbijanje napada u pojedinim epileptičkim encefalopatija- control. Parenterally administered Mg2+ efficiently controls seizures in several epileptic
ma kod odraslih i dece (u eklampsiji, uremiji, porfiriji, febrilnim napadima, infantilnim encephalopathies in adults and children (in eclampsia, uremia, porphyria, febrile
spazmima). Infuzije magnezijuma pomažu i u kontroli epileptičkog statusa. seizures, infantile spasms), and also helps control status epilepticus.
Subklinički deficit magnezijuma, veoma čest u opštoj populaciji, u epilepsiji može da Subclinical magnesium deficiency, very frequent in general population, acts as a factor
deluje kao faktor koji doprinosi pojavi epileptičkih napada. Stoga je kod bolesnika sa contributing to seizure generation in epilepsy. It is recommended to assess magnesium
epilepsijom potrebno proveriti magnezijumski status. Pregled literature pokazuje da status in epilepsy patients. This literature review reveals the therapeutic potential of
magnezijum predstavlja jednostavno antiepileptičko sredstvo čiji terapijski potencijal magnesium as a simple antiepileptic agent, which exceeds its current clinical use.
prevazilazi njegovu aktuelnu kliničku primenu za ovu indikaciju.
Key words: magnesium, epilepsy, basic epilepsy research, clinical epilepsy research
Ključne reči: magnezijum, epilepsija, bazična istraživanja epilepsije, klinička istraživa-
nja epilepsije

Autor za korespondenciju: Corresponding author:

Marija Stanojević Marija Stanojević
Institut za patološku fiziologiju ,,Ljubodrag Buba Mihailović“ Institute of Pathological Physiology Ljubodrag Buba Mihailović
Univerzitet u Beogradu, Medicinski fakultet University of Belgrade, Faculty of Medicine
Adresa: Dr Subotića 9, 11000 Beograd, Srbija Address: 9, Dr Subotića Street, 11000 Belgrade, Serbia
Elektronska adresa: [email protected] E-mail: [email protected]
Primljeno • Received: May 15, 2023; Revidirano • Revised: May 25, 2023; Prihvaćeno • Accepted: June 8, 2023; Online first: June 25, 2023
DOI: 10.5937/smclk4-44498

Serbian Journal of the Medical Chamber | Volume 4 / No. 2 | June 2023 175
 preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. i sar.
revising the role of magnesium in epilepsy research and management

UVOD INTRODUCTION
Epilepsija je hronična bolest centralnog nervnog siste- Epilepsy is a chronic disease of the central nervous sys-
ma koju odlikuju ponavljanja iznenadnih reverzibilnih tem characterized by repetitive, sudden and reversible
epizoda disfunkcije mozga, koje se odvijaju po stereo- episodes of brain dysfunction, which occur in a stereo-
tipnom obrascu. Ovakve epizode su označene kao epi- typed pattern. These episodes are termed as the epi-
leptički napadi, a nastaju spontano kao rezultat naglog leptic seizures, and they arise spontaneously as a result
i prekomernog generalizovanog ili fokalnog električ- of abrupt and excessive generalized or focal electrical
nog pražnjenja neurona u sivoj masi mozga. Epileptički discharge of neurons in the gray matter of the brain.
napadi se mogu prezentovati različitim kliničkim ispo- Epileptic seizures can present with different clinical
ljavanjima. Osim prvog epileptičkog napada koji pa- manifestations. Apart from the first epileptic attack
cijenti dožive, za dijagnozu epilepsije kao neurološke that patient experiences, to diagnose epilepsy as a
bolesti, važna je permanentna sklonost mozga ka po- neurological condition, a permanent tendency of the
navljanju napada. Iznenadnost, stereotipnost i ponav- brain to develop repeated seizures must be present.
ljanje su tri osnovne karakteristike napada u epilepsiji. Abruptness, stereotypy and repetition are the three
Epilepsija je jedno od najčešćih neuroloških obol- basic features of seizures in epilepsy.
jenja, od kojeg boluje u proseku svaka stota osoba u Epilepsy is one of the most common neurological
svetu. Epilepsija utiče na kvalitet života i životni vek diseases, affecting 1 out of a 100 people worldwide on
obolelog. Smrtnost obolelih od epilepsije je značajno average. Epilepsy affects the quality of life and the lifes-
povećana u odnosu na opštu populaciju. Smrtni isho- pan of the diseased. The mortality of people suffering
di su najčešće povezani sa osnovnim uzrokom bolesti, from epilepsy is significantly increased, as compared to
posledica su nesrećnih slučajeva i trauma, utapanja, the general population. Fatal outcomes are most often
naprasne neočekivane smrti u epilepsiji (engl. Sudden related to the underlying cause of the disease, the con-
Unexpected Death in Epilepsy – SUDEP), i dr. sequences of accidents and trauma, drowning, sudden
Prema etiologiji se razlikuju idiopatske, primarne unexpected death in epilepsy (SUDEP), etc.
i simptomatske epilepsije. Кod idiopatske epilepsije According to their etiology, epilepsies are classi-
pacijenti nemaju strukturno, metaboličko ili neko dru- fied as being idiopathic, primary or symptomatic. In
go poznato oboljenje ili oštećenje mozga. Primarne ep- idiopathic epilepsy, patients have no known structural,
ilepsije su uslovljene monogenskim defektima. Simp- metabolic or other brain disease or damage. Primary
tomatska epilepsija nastaje kao posledica oštećenja epilepsies are caused by monogenic defects. Symp-
mozga poznate etiologije. Epileptički napadi mogu da tomatic epilepsy occurs as a result of brain damage
se jave i kod osoba koje nemaju epilepsiju, kao simp- of known etiology. Epileptic seizures can also occur
tom neke druge bolesti ili oštećenja mozga, kao akutni in people who do not have epilepsy, as a symptom
simptomatski, odnosno provocirani epileptički napadi. of some other brain disease or damage, i.e. as acute
Osnovni patofiziološki mehanizmi nastanka napada symptomatic or provoked epileptic seizures. The basic
(iktogeneza) i nastanka epilepsije kao bolesti (epi- pathophysiological mechanisms of onset of epileptic
leptogeneza) još uvek nisu dovoljno razjašnjeni, ali je seizures (ictogenesis) and the development of epilepsy
poznato da im najviše doprinose sinaptički i nesinap- as a disease (epileptogenesis) are not sufficiently eluci-
tički procesi razvoja hiperekscitabilnosti neurona i hip- dated yet, but it is known that synaptic and non-syn-
ersinhronizacije njihovog električnog pražnjenja [1]. aptic processes of the development of neuronal hy-
U kliničkoj slici epileptičkih napada se mogu javi- perexcitability and the hypersynchronization of their
ti različite motorne, senzitivne, senzorne, vegeta- electrical discharge contribute the most [1].
tivne i psihičke manifestacije, poremećaji ponašanja, Various motor, sensitive, sensory, vegetative and
poremećaji svesti, i drugo. Glavni tipovi napada u epi- psychological manifestations, alterations of behavior,
lepsiji su fokalni i generalizovani napadi. Fokalni napa- disorders of consciousness and other abnormalities
di se javljaju kada su epileptička pražnjenja ograničena may occur as clinical presentation of epileptic seizures.
na određeni deo mozga. Epileptički status (Lat. Status Main types of seizures in epilepsy are focal and gener-
epilepticus – SE) jeste urgentno stanje u neurologiji i alized seizures. Focal seizures develop when epileptic
najteže stanje u epileptologiji, koje podrazumeva ep- discharges arise from a specific and limited region of
ileptičku aktivnost produženog trajanja ili ponavljane the brain. Status epilepticus (SE) is an emergency con-
epileptičke napade između kojih ne dolazi do oporav- dition in neurology and the most severe condition in
ka svesti [2]. epileptology, implying epileptic activity of prolonged
Dijagnoza epilepsije je elektro-klinička, zasnovana duration or repeated epileptic seizures between which
na semiologiji napada i nalazu u zapisu elektroence- the patient does not regain consciousness [2].

176 Jun 2023. | Volumen 4 / Broj 2 | Srpski medicinski časopis Lekarske komore
preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. et al.
revising the role of magnesium in epilepsy research and management

falograma (EEG). Epilepsiju odlikuju promene u EEG-u The diagnosis of epilepsy is electro-clinical, based on
koje mogu da se uoče u toku napada (iktalno) i između seizure semiology and the findings in recordings of the
napada (interiktalno). Prisustvo EEG promena van na- electroencephalogram (EEG). Epilepsy is characterized
pada govori u prilog abnormalnoj električnoj aktivno- by changes in the EEG trace that can be observed during
sti mozga i sklonosti da napadi spontano nastaju. Ipak, seizures (ictally) and between seizures (interictally). The
odsustvo promena u EEG-u, u klinički mirnom periodu, presence of EEG changes in between seizures suggests
ne isključuje dijagnozu epilepsije. abnormal electrical activity of the brain and a tendency
Terapija epilepsije je individualna – donosi se odlu- of spontaneous seizure occurrence. However, the ab-
ka o lečenju svakog bolesnika ponaosob, zbog različi- sence of EEG changes during a clinically asymptomatic
tih uzroka nastanka bolesti, različitih oblika bolesti, period, does not exclude the diagnosis of epilepsy.
razlika u efikasnosti i neželjenim dejstvima lekova, The treatment of epilepsy is tailored to the indi-
zbog eventualnog prisustva komorbiditeta, i drugih vidual patient, i.e. the decision on the therapy is made
faktora. Primena antiepileptičkih lekova (AEL) ima za for each patient separately, due to different causes of
cilj uspostavljanje stabilne kontrole napada, odnos- the disease, different forms of the disease, differences
no prekidanje započetih napada i suzbijanje njihovog in the effectiveness and side effects of drugs, possible
ponavljanja. Prednost ima monoterapija antiepileptici- presence of comorbidities, and other factors. The use
ma zbog manje toksičnosti, jednostavnije i redovnije of antiepileptic drugs (AEDs) aims to establish stable
primene, izbegavanja interakcija između lekova i slič- seizure control, that is to abort ongoing seizures and
no. Međutim, veliki je broj bolesnika koji ne reaguju za- suppress their future repetition. Monotherapy with an-
dovoljavajuće na medikamentozno lečenje epilepsije tiepileptics is advantageous, as it is less toxic, simple to
(farmakorezistentni ili refraktarni oblik bolesti). U ovim administer and achieves a more regular patient com-
slučajevima, epilepsija se može lečiti i metodama elek- pliance, whereas it avoids drug interactions, etc. How-
trostimulacije, hirurškim metodama (npr. operativna ever, there is a large number of patients who do not re-
resekcija epileptičkog žarišta), i drugim metodama [2]. spond appropriately to pharmacological treatment of
epilepsy (pharmacoresistant or refractory form of the
ZNAČAJ MAGNEZIJUMA ZA PRAVILNO disease). In these cases, epilepsy can be treated with
FUNKCIONISANJE NERVNOG SISTEMA electrostimulation methods, epilepsy surgery (e.g. op-
Magnezijum je veoma zastupljen mineral u organizmu erative resection of the epileptic focus), or other treat-
sisara. Jon Mg2+ zastupljeniji je u intracelularnoj tečno- ment approaches [2].
sti (drugi nakon К+), dok je ekstracelularno to četvrti
THE IMPORTANCE OF MAGNESIUM IN THE
najzastupljeniji katjon. Njegove intracelularne i ekstra-
celularne koncentracije su regulisane funkcijom jon-
PROPER FUNCTIONING OF THE NERVOUS
skih kanala ćelijske membrane, kao i kontrolnim me- SYSTEM
hanizmima za njegovo skladištenje u ćelijske ogranele. Magnesium is a mineral found in abundance in mam-
Održavanje homeostaze magnezijuma je veoma važno malian organisms. Mg2+ ion is present in higher con-
za očuvanje opšteg stanja zdravlja [3]. centration in the intracellular fluid (second to K+ ion),
Magnezijum ima mnoge metaboličke funkcije u than in the extracellular fluid (the fourth most abun-
organizmu (kofaktor brojnih enzima), ali takođe pred- dant cation). Its intracellular and extracellular concen-
stavlja i katjon koji je bioesencijalan za sve ekscitabilne trations are regulated by the function of cell membrane
ćelije i tkiva. Кao takav, magnezijum je posebno zna- ion channels, as well as by the control mechanisms
čajan za pravilnu funkciju centralnog nervnog sistema regulating its storage in cell organelles. Maintaining
(CNS). U tkivu mozga sisara sadržaj magnezijuma iznosi magnesium homeostasis is very important for preserv-
6 – 7 mmol/kg (prisutan pretežno u sivoj masi mozga). ing the general state of health [3].
U fiziološkim uslovima, krvna plazma i likvor, odnosno Magnesium has many metabolic functions in the
cerebrospinalna tečnost (CST), razlikuju se međusobno body (a cofactor of numerous enzymes), but it is also
u sadržaju pojedinih jona. Tako je nivo Cl- viši, nivo K+ a cation bio-essential for all excitable cells and tissues.
niži, nivoi Na+ i Ca2+ gotovo isti, dok je nivo Mg2+ znatno As such, magnesium is particularly important for the
viši u CST-i u odnosu na plazmu. Razlike u koncentraci- proper functioning of the central nervous system
jama jona u plazmi i likvoru postoje zbog aktivnosti ho- (CNS). In mammalian brain tissue, magnesium content
roidnog pleksusa [4]. Jon Mg2+ je jedini katjon aktivno is 6 – 7 mmol/kg (predominantly present in brain gray
sekretovan od strane epitela horoidnog spleta, čija je matter). Under physiological conditions, blood plasma
koncentracija veća u likvoru nego u krvi (ako se izuzme and cerebrospinal fluid (CSF) differ regarding the con-
H+ jon). Transport magnezijuma, odnosno njegovu ak- tent of individual ions. Thus, the level of Cl- is higher, the

Serbian Journal of the Medical Chamber | Volume 4 / No. 2 | June 2023 177
 preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. i sar.
revising the role of magnesium in epilepsy research and management

tivnu sekreciju, omogućavaju katjonski kanali permea- level of K+ is lower, levels of Na+ and Ca2+ are almost the
bilni za Mg2+ jone – članovi 6 i 7 melastatinske potfami- same, whereas the level of Mg2+ is significantly higher
lije kanala za prolazne receptorske potencijale: TRPM6 i in the CSF as compared to plasma. Differences in ionic
TRPM7 (engl. transient receptor potential melastatin) [5]. composition of plasma and CSF exist due to choroid
Magnezijum ispoljava višestruka neuroaktivna plexus activity [4]. Mg2+ ion is the only cation actively
dejstva na molekulskom, ćelijskom i sistemskom ni- secreted by the choroid plexus epithelium with a con-
vou. Dejstva magnezijuma na nervni sistem u celini centration higher in the CSF than in the blood (except
obuhvataju antidepresivno, anksiolitičko, anestetičko, for H+). Magnesium transport i.e. its active secretion oc-
analgetičko, antimigrenozno, antikonvulzivno, antie- curs through cation channels permeable to Mg2+ – the
pileptičko i neuroprotektivno dejstvo [3]. Na nivou će- transient receptor potential melastatin channels types
lijske membrane pojedinačnih neurona, magnezijum 6 and 7 (TRPM6 and TRPM7) [5].
ispoljava sveukupno stabilizujuće dejstvo. Elektrofizio- Magnesium exerts multiple neuroactive effects on
loška ispitivanja pokazuju da jon Mg2+ učestvuje u re- a molecular, cellular and systemic level. The effects of
gulaciji intrinsičkih svojstava membrane neurona (eks- magnesium on the nervous system as a whole include
citabilnost, provodljivost i otpornost) i vrši kompleksnu the antidepressant, anxiolytic, anesthetic, analgesic,
modulaciju električne aktivnosti neurona putem svojih antimigraine, anticonvulsant, antiepileptic and neu-
sinaptičkih i nesinaptičkih dejstava, odnosno efekata roprotective effects [3]. Magnesium exerts an overall
na jonske kanale, transportere i pumpe, te receptore u stabilizing effect on cell membranes of individual neu-
membrani [6]. Magnezijum suprimira hemijsku sinap- rons. Electrophysiological research shows that Mg2+ ion
tičku neurotransmisiju vezivanjem za voltažno zavisne contributes to the regulation of the intrinsic properties
Ca2+ kanale presinaptičkih nervnih završetaka, čime of the neuronal cell membrane (excitability, conduc-
suzbija oslobađanje neurotransmitera iz centralnih, tivity, and resistance), and performs complex modula-
kao i perifernih sinapsi (neuro-mišićna spojnica). Po- tion of neuronal electrical activity through its synaptic
red toga, vanćelijski Mg2+ blokira N-metil-D-aspartat and non-synaptic effects, i.e. Mg2+ effects on ion chan-
(NMDA) jonotropne receptore za glutamat na voltažno nels, transporters and pumps, and receptors in the
zavisan način. cell membrane [6]. Magnesium suppresses chemical
Od nesinaptičkih dejstava, između ostalog je po- synaptic neurotransmission by binding to voltage de-
znato, da sa intracelularne strane membrane, Mg2+ jon pendent Ca2+ channels of presynaptic nerve endings,
može da blokira voltažno zavisne Na+ kanale. Veliki hi- thereby suppressing the release of neurotransmitters
dratisani joni Mg2+ se kompetitivno vezuju za Na+ ka- from central as well as peripheral synapses (neuro-
nale u toku njihovog aktiviranog stanja, čime dovode muscular junction). In addition, extracellular Mg2+ ions
do sporijeg okidanja akcionih potencijala (AP) koji su i block N-methyl-D-aspartate (NMDA) ionotropic gluta-
manje amplitude [7]. Pojedine studije ukazuju i na ak- mate receptors in a voltage-dependent manner.
tivirajuće dejstvo jona Mg2+ na kalcijumom aktivirane Regarding the non-synaptic effects, it is known
K+ kanale (KCa) [8]. Najzad, jon Mg2+ neophodan je i za that intracellular Mg2+, among other things, can block
pravilnu funkciju pumpe za Na+ i K+ [9]. Svi ovi nalazi voltage-gated Na+ channels. Large hydrated Mg2+ ions
potvrđuju značajnu ulogu Mg2+ jona u regulaciji eks- competitively bind to Na+ channels in their activated
citabilnosti neurona, kao i velike potrebe neurona za state, thus leading to a decrease in action potential
magnezijumom. (AP) firing rate and AP amplitude [7]. Certain studies
S obzirom da blokira depolarišuće jonske struje also indicate the activating effect of Mg2+ ions on cal-
kroz voltažno zavisne Na+ i Ca2+ kanale i kanale gluta- cium-activated K+ channels (KCa) [8]. Finally, Mg2+ ion is
matergičkih NMDA receptora, kao i da potencira hiper- also necessary for the proper functioning of the Na+/K+
polarišuće jonske struje KCa kanala i pumpe za Na+ i K+, pump [9]. All of these findings confirm the significant
jon Mg2+ ispoljava snažan efekat stabilizacije električ- role of Mg2+ in the regulation of neuronal excitability,
nog potencijala i aktivnosti ćelijske membrane. Ovo as well as high neuronal requirements for magnesium.
istovremeno doprinosi važnom neuroprotektivnom Concerning that Mg2+ blocks the depolarizing ion
dejstvu magnezijuma, budući da se suprotstavlja pre- currents through voltage-gated Na+ and Ca2+ channels
komernoj depolarizaciji ćelije i razvoju patofiziološkog and channels of glutamatergic NMDA receptors, and
mehanizma ekscitotoksičnosti, koji posreduje u ošte- potentiates the hyperpolarizing ion currents through
ćenju i odumiranju neurona u brojnim patofiziološkim KCa channels and the Na+/K+ pump, Mg2+ ion exerts a
stanjima (neurodegenerativnim procesima, ishemij- strong effect of overall stabilization of cell membrane
skim lezijama mozga, kraniocerebralnim traumama, electrical potential and activity. This simultaneously
epileptičnim pražnjenjima, i dr.). Magnezijum dovodi contributes to the important neuroprotective effect of

178 Jun 2023. | Volumen 4 / Broj 2 | Srpski medicinski časopis Lekarske komore
preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. et al.
revising the role of magnesium in epilepsy research and management

i do povećanog stvaranja vazodilatatornih prostaglan- magnesium, since it counteracts the excessive mem-
dina u mozgu. Takođe je poznato da magnezijum po- brane depolarization and the development of the
većava neuroplastičnost i olakšava procese učenja i pathophysiological mechanism of excitotoxicity, which
pamćenja. mediates neuronal damage and death in numerous
Rutinski se nivo magnezijuma u krvi retko određu- pathophysiological conditions (neurodegenerative
je, a i kada se meri – obično se meri samo nivo uku- processes, ischemic brain lesions, craniocerebral trau-
pnog magnezijuma u krvnom serumu (opseg normal- ma, epileptic discharges etc). Magnesium also induces
nih vrednosti: 0,75 – 0,95 mmol/l). Uzorak treba da increased production of vasodilator prostaglandins in
bude serum, a ne krvna plazma, jer različiti dodati an- the brain. It is also known that magnesium increases
tikoagulansi (etilendiamin tetraacetat, citrat, oksalat) neuroplasticity and facilitates learning and memory.
mogu da vezuju jone Mg2+, usled čega nastaju greške u The level of magnesium in the blood is rarely test-
merenju njihove koncentracije. U cilju određivanja ma- ed routinely, and even when measured – it is usually
gnezijumskog statusa organizma i ispitivanja pacijenta the level of total magnesium in the blood serum that
na hipomagnezijemiju (kao potencijalni uzrok ili dopri- is measured (normal range: 0.75 – 0.95 mmol/l). The
noseći faktor za nastanak epileptičkih napada), senzi- sample should be the serum, and not blood plasma, be-
tivniji pokazatelj je merenje koncentracije slobodne, cause various anticoagulants added (ethylenediamine
jonizovane frakcije Mg2+, koja predstavlja biološki ak- tetraacetate, citrate, oxalate) can bind Mg2+ ions, result-
tivnu formu jona Mg2+. Normalan opseg vrednosti kon- ing in errors in the measurement of its concentration. In
centracije jonizovanog Mg2+ u serumu iznosi od 0,50 order to determine magnesium status of the organism
do 0,70 mmol/l [3]. and test the patient for hypomagnesemia (as a poten-
Hipomagnezijemija je stanje smanjene koncentra- tial cause or contributing factor for epileptic seizures),
cije magnezijuma u serumu. Nedostatak magnezijuma a more sensitive indicator should be used, i.e. the con-
kod ljudi može nastati iz nekoliko razloga: nedovoljno centration of the free, ionized fraction of Mg2+ should be
unošenje, nedostatak magnezijuma u zemljištu ali i measured, as it represents the biologically active form of
namirnicama biljnog i životinjskog porekla, zatim ma- Mg2+ ions. Normal range of the concentration of ionized
lapsorpcija i maldigestija, renalni gubici magnezijuma, Mg2+ in the serum is between 0.50 and 0.70 mmol/l [3].
redistribucija iz vanćelijskog u unutarćelijski prostor, i Hypomagnesemia is a condition of reduced serum
drugo [10]. Akutna deficijencija može proći nezapaže- magnesium concentration. Magnesium deficiency in
no, odnosno asimptomatski, ili se manifestuje mučni- humans can occur for several reasons: insufficient in-
nom, povraćanjem, letargijom i uznemirenošću. Hro- take, lack of magnesium in the soil, but also in foodstuff
nični deficit magnezijuma dovodi do težih patofizio- of herbal and animal origin, malabsorption and maldi-
loških stanja. Hipomagnezijemija je često neprepoznat gestion, renal loss of magnesium, redistribution from
elektrolitni disbalans. Njeni znaci se javljaju kada nivo the extracellular to the intracellular space, and other
serumskog magnezijuma opadne ispod 0,50 mmol/l. causes [10]. Acute deficiency may undergo unnoticed,
Tada se razvijaju i znaci nervne i neuromišićne iritabil- i.e. it may be asymptomatic, or it may manifest as nau-
nosti i moždane hiperekscitabilnosti: tetanički grčevi sea, vomiting, lethargy and agitation. Chronic magne-
mišića, srčane aritmije, anksioznost, konfuzija, a u teš- sium deficiency leads to more severe pathophysiologi-
koj hipomagnezemiji dolazi i do razvoja delirijuma i cal conditions. Hypomagnesemia as an electrolyte im-
konvulzija, čak i do pojave epileptičkog statusa [11]. balance is often unrecognized. Its signs appear when
U terapiji hipomagnezijemije se koriste MgO i soli serum magnesium levels drop below 0.50 mmol/l. This
magnezijuma neorganskog i organskog porekla. Razli- is when signs of nervous and neuromuscular irritabili-
čite soli magnezijuma imaju različitu bioiskoristljivost. ty and brain hyperexcitability develop: tetanic muscle
Tako, na primer, magnezijum pidolat ima veću bioisko- spasms, cardiac arrhythmias, anxiety, confusion, and
ristljivost i penetrantnost na celularnom nivou, i može in severe hypomagnesemia, delirium and convulsions
ubrzo nakon primene da reguliše deficijenciju magne- develop, leading even to status epilepticus [11].
zijuma koja je bila uzročnik glavobolja [12]. Neke od In the treatment of hypomagnesemia, MgO and
soli magnezijuma čiji se preparati koriste u terapiji su: magnesium salts of inorganic and organic origin are
sulfat, hlorid i karbonat, od neorganskih, i citrat, acetat, used. Different magnesium salts have different bio-
laktat, glicinat, aspartat, glukonat, pidolat i treonat, od availability. Thus, for example, magnesium pidolate
organskih soli magnezijuma. has a higher bioavailability and penetrability on a
Latentna i blaga hipomagnezijemija se mogu lečiti cellular level and can regulate the lack of magnesium
oralnom primenom preparata magnezijuma (npr. ma- causing headaches soon after its administration [12].
gnezijum glukonat). Manifestna i teška hipomagnezi- Some of the magnesium salts whose preparations are

Serbian Journal of the Medical Chamber | Volume 4 / No. 2 | June 2023 179
 preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. i sar.
revising the role of magnesium in epilepsy research and management

jemija, pogotovo uz prisutne srčane aritmije i epilep- used in therapy are the following: sulfate, chloride and
tičke napade, zahteva hitnu parenteralnu nadoknadu carbonate (inorganic salts) and citrate, acetate, lactate,
injekcijama i infuzijama MgSO4, sve do normalizacije glycinate, aspartate, gluconate, pidolate and threonate
srčanog ritma i obustave napada. Pri tom je potreban (organic magnesium salts).
oprez u slučaju bubrežne slabosti – ako pacijent ima Latent and mild hypomagnesemia can be treated
renalno oštećenje, doza magnezijuma se smanjuje. with oral magnesium preparations (e.g. magnesium
Magnezijum ima ulogu u prevenciji i terapiji većeg gluconate). Manifested and severe hypomagnesemia,
broja neuroloških i neuropsihijatrijskih poremećaja, especially with heart rhythm disorders and epileptic
kao što su anksioznost, depresija, migrenske i tenzi- seizures present, requires immediate parenteral com-
one glavobolje, hronična bolna stanja, ali i Alchajme- pensation with injections and infusions of MgSO4 un-
rova (Alzheimer) bolest, Parkinsonova bolest, moždani til heart rhythm normalizes and the seizures cease. In
udar i epilepsija [13]. Suplementacija magnezijumom doing so, caution is required in case of kidney failure
pomaže i u lečenju nesanice, koja predstavlja najčešći – if the patient has kidney damage, the dose of magne-
poremećaj spavanja [14]. Intracisternalna, intratekalna sium should be reduced.
i epiduralna aplikacija magnezijuma su se pokazale ko- Magnesium plays a role in the prevention and treat-
risnim za produženje efekata anestezije, u cilju posti- ment of a number of neurological and neuropsychiat-
zanja analgezije, kao i u terapiji arterijske hipertenzije. ric disorders, such as anxiety, depression, migraine and
Intranazalna aplikacija magnezijuma je alternativni put tension headaches, chronic pain conditions, but also
unosa leka, onda kada je potrebna njegova distribuci- Alzheimer’s disease, Parkinson’s disease, stroke and ep-
ja u mozak. Lek se tada transportuje putem vlakana ilepsy [13]. Magnesium supplementation also helps to
olfaktornog nerva direktno u CNS [4]. treat insomnia, the most common sleep disorder [14].
Intracisternal, intrathecal and epidural application of
MAGNEZIJUM U ISTRAŽIVANJIMA EPILEPSIJE magnesium have proven useful in prolonging the ef-
Epilepsija je hronična bolest nedovoljno poznate fects of anesthesia, in achieving analgesia, as well as
etiopatogeneze, kao i veoma različitih kliničkih is- the treatment of arterial hypertension. Intranasal ap-
poljavanja. Medikamentno lečenje epilepsije danas plication of magnesium is an alternative route of drug
dostupnim standardnim antiepileptičkim lekovima administration when its distribution in the brain is
povezano je sa brojnim poteškoćama, usled rizika od needed. The drug is then transported via the olfactory
dozno-zavisne toksičnosti lekova, te potrebe za praće- nerve fibers directly into the CNS [4].
njem koncentracije leka u plazmi, zbog dugog trajanja
terapije, kao i neželjenih interakcija u slučaju potrebe
MAGNESIUM IN EPILEPSY RESEARCH
za politerapijom [15]. Antiepileptici mogu da stupaju Epilepsy is a chronic disease of insufficiently known
i u interakcije sa drugim lekovima koje pacijent koristi. etiopathogenesis and of varying clinical manifestations.
Oni takođe mogu da dovedu i do deplecije pojedinih Medical treatment of epilepsy with standard antiepilep-
vitamina i minerala, i da na taj način utiču na pojavu tic drugs available today is associated with numerous
napada. Iz tih razloga, kao i zbog velikog ukupnog bro- difficulties, due to the risk of dose-dependent drug tox-
ja obolelih, mogućih ozbiljnih neželjenih efekata ovih icity, the need for monitoring drug concentration in the
lekova, te velikog broja slučajeva koji su farmakorezi- plasma, long duration of the therapy, as well as the un-
stentni na postojeću terapiju (oko 30 % bolesnika sa wanted drug interactions in case of need for polyther-
epilepsijom), i dalje se traga za novim antiepileptičkim apy [15]. Antiepileptic drugs can also interact with oth-
lekovima i novim modalitetima lečenja epilepsije, a u er drugs that the patient is using. They can also cause
cilju postizanja veće efikasnosti i bolje podnošljivosti depletion of certain vitamins and minerals, and thus
terapije za epilepsiju. Ovo uključuje i dodatne alterna- affect the occurrence of seizures. For all these reasons,
tivne i komplementarne pristupe lečenju, koji mogu da as well as the large total number of epilepsy patients,
doprinesu uspostavljanju bolje kontrole epileptičkih the possible serious side effects of AEDs, and the large
napada. number of pharmacoresistant epilepsy cases (about 30
Magnezijum, kao jednostavno antiepileptičko % of all epilepsy patients), the search for new antiepi-
sredstvo ima terapijski potencijal veći od njegove leptic drugs and new modalities of epilepsy treatment
trenutne kliničke primene za ovu indikaciju [16]. Кao still continues, for the purpose of achieving greater ef-
dodatak postojećem armamentarijumu korišćenih ficiency and better tolerability of epilepsy therapy. This
antiepileptičkih agenasa, mogao bi da doprinese po- also includes additional alternative and complementa-
boljšanju prognoze, toka i ishoda bolesti kod bar nekih ry treatment approaches, which can contribute to es-
pacijenata sa epilepsijom. Stoga je najpre potrebno sa- tablishing better control of epileptic seizures.

180 Jun 2023. | Volumen 4 / Broj 2 | Srpski medicinski časopis Lekarske komore
preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. et al.
revising the role of magnesium in epilepsy research and management

brati iskustva iz dosadašnje kliničke prakse, kao i nauč- Magnesium, as a simple antiepileptic agent, has
na saznanja iz objavljenih bazičnih i kliničkih studija o therapeutic potential which surpasses its current clin-
ulozi poremećaja homeostaze magnezijuma u nastan- ical application for this indication [16]. As an addition
ku epilepsije i značaju primene magnezijuma u lečenju to the existing armamentarium of applied antiepileptic
epilepsije. U tom smislu nam može pomoći pregled agents, it could contribute to improving the prognosis,
odgovarajuće literature. Ovaj pregledni rad nastojao course and outcome of the disease in at least some pa-
je da obuhvati pretklinička in vitro i in vivo istraživa- tients with epilepsy. Therefore, it is necessary first of all
nja, urađena sa zajedničkim ciljevima – da se otkrije to gather experiences from clinical practice to date, as
doprinos koji, nekad i skriveni deficit magnezijuma u well as scientific knowledge from published basic and
organizmu ima u procesima iktogeneze i epileptoge- clinical studies and trials, on the role of disorders of
neze, kao i da se utvrde mehanizmi antiepileptičkog i magnesium homeostasis in the onset of epilepsy and
antiepileptogenog dejstva magnezijuma. Najzad, obu- the importance of using magnesium in the treatment
hvaćene su i one kliničke studije i prikazi slučajeva koji of epilepsy. A review of relevant literature can be of use
se bave korišćenjem magnezijuma u terapiji pojedinih for this cause. This review attempts to include preclin-
tipova epileptičkih napada i epileptičkog stanja. ical in vitro and in vivo research, carried out with the
common goals to reveal the contribution that some-
MAGNEZIJUМ U PRETKLINIČKIM times latent magnesium deficiency in the body has in
ISTRAŽIVANJIMA EPILEPSIJE the processes of ictogenesis and epileptogenesis, as
U bazičnim neurofiziološkim istraživanjima, ogledi se well as to determine the mechanisms of antiepileptic
rade na različitim animalnim modelima bolesti, počev and antiepileptogenic magnesium effects. Finally, clin-
od nivoa organizma u in vivo eksperimentima, uključu- ical studies and case reports on the use of magnesium
jući i životinjske vrste beskičmenjaka (lat. invertebrata) in the therapy of certain types of epileptic seizures and
i sisara, preko in vitro eksperimenata na izolovanim or- epileptic state have also been included.
ganima, isečcima mozga, neuronima u kulturi, i slično,
MAGNESIUM IN PRECLINICAL EPILEPSY
pa sve do subćelijskog – molekulskog nivoa izolovanih
pojedinačnih jonskih kanala, kao i na kompjuterskim
RESEARCH
modelima sistema. Brojna fundamentalna istraživanja In basic neurophysiological research, experiments are
bazičnih mehanizama u epilepsiji pokazuju da nedo- performed on different animal models of disease –
statak Mg2+ u organizmu može da bude direktno pove- starting from the whole organism level in experiments
zan sa iktogenezom i epileptogenezom [16]. in vivo, including invertebrate and mammalian species,
Na membrane centralnih neurona sniženje vanće- over in vitro experiments on isolated organs, brain slic-
lijske koncentracije Mg2+ deluje da spusti nivo praga es, cell cultures etc, down to the subcellular - molecu-
nadražljivosti i povećava ekscitabilnost neurona [17]. lar level of isolated individual ion channels, as well as
Smanjenje sadržaja Mg2+ u cerebrospinalnoj tečnosti on computer model systems. Numerous fundamental
i u intersticijalnoj tečnosti tkiva mozga neuropila koji studies of the basic mechanisms in epilepsy show that
neurone neposredno okružuje može dovesti do spon- the defficiency of Mg2+ in the body may be directly
tanog razvoja epileptiformne aktivnosti. linked to ictogenesis and epileptogenesis [16].
Mehanizmi epileptogeneze nisu u potpunosti ra- A decrease in the extracellular Mg2+ concentration
svetljeni, tako da je i postojeće znanje o značaju Mg2+ acts on the membranes of central neurons to lower the
jona u epilepsiji – nepotpuno. Ipak, postoje mnoga excitation threshold level and increase neuronal excit-
saznanja o ulozi magnezijuma u eksperimentalnoj epi- ability [17]. A decrease in Mg2+ content in the CSF and
lepsiji. Za ovo postoje brojni primeri u bazičnim studi- the interstitial fluid of the brain tissue (neuropil imme-
jama epilepsije na modelima in vitro. Tako, na primer, diately surrounding the neurons), can lead to the spon-
nesinaptičko Na+–zavisno epileptiformno pražnjenje, taneous development of the epileptiform activity.
indukovano u Recijusovim neuronima pijavice prime- The mechanisms of epileptogenesis have not been
nom nikla, biva suprimirano dejstvom Mg2+ jona na fully elucidated, which is why the existing knowledge
dozno zavisni način [18,19]. on the importance of Mg2+ in epilepsy is also incom-
Sniženje koncentracije Mg2+ jona u ekstracelularnoj plete. However, there is a significant body of knowl-
tečnosti izaziva patofiziološku hiperekscitabilnost neu- edge regarding the role of magnesium in experimen-
rona sisara. Niska vanćelijska koncentracija Mg2+ jona, tal epilepsy. There are numerous examples of this in
ili potpuno uklanjanje Mg2+ jona iz rastvora za perfuzi- basic studies of epilepsy on in vitro models. For exam-
ju preparata, indukuje spontani razvoj epileptiformne ple, Mg2+ reversibly suppresses in a dose-dependent
aktivnosti piramidnih neurona na eksperimentalnim manner the non-synaptic Na+-dependent epileptiform

Serbian Journal of the Medical Chamber | Volume 4 / No. 2 | June 2023 181
 preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. i sar.
revising the role of magnesium in epilepsy research and management

modelima intaktnog hipokampusa miša i isečaka hipo- discharge induced in leech Retzius neurons by the ap-
kampusa pacova [20]. plication of nickel [18,19].
Nedostatak magnezijuma takođe ima epileptoge- A decrease in the concentration of Mg2+ in the ex-
no dejstvo kod oglednih životinja in vivo. Fokalna ek- tracellular fluid causes pathophysiological hyperexcit-
sperimentalna epileptička aktivnost akutno izazvana ability of mammalian neurons. Low extracellular Mg2+
topikalnom primenom penicilina na korteks ogledne concentration or complete removal of Mg2+ from the
životinje biva suprimirana intravenoznim (i.v.) dava- perfusion solution (zero Mg2+ artificial CSF) induces
njem Mg2+. Pri tom je stepen supresije izazvanog in- spontaneous development of epileptiform activity of
teriktalnog EEG pražnjenja direktno srazmeran posti- pyramidal neurons in experimental models of intact
gnutoj koncentraciji Mg2+ jona u serumu životinje. Ma- mouse hippocampus and rat hippocampal slices [20].
gnezijum ostvaruje centralno antikonvulzivno dejstvo Magnesium deficiency also has an epileptogenic
po dospevanju do epileptičkog fokusa prolaskom kroz effect in experimental animals in vivo. Focal experi-
oštećenu i propustljivu krvno-moždanu barijeru [21]. mental epileptic activity acutely induced by topical ap-
Deficit magnezijuma u ishrani ovaca direktno izazi- plication of penicillin to the cortex of an experimental
va pad nivoa Mg2+ u plazmi i nivoa Mg2+ u likvoru, kao animal is suppressed by intravenous (i.v.) administra-
i nastanak konvulzija koje se prekidaju intravenoznim tion of Mg2+, the degree of suppression of the induced
davanjem Mg2+ [22]. Slično tome, dijetna restrikcija ma- interictal EEG discharge being directly proportional to
gnezijumau ishrani snižava konvulzivni prag mozga pa- the achieved Mg2+ concentration in the serum of the
cova za izazivanje napada pentilen-tetrazolom, što se animal. Magnesium achieves a central anticonvulsive
koriguje peroralnom nadoknadom magnezijuma [23]. effect upon reaching the epileptic focus by passing the
Peroralno davanje MgO u niskim dozama pokazuje damaged and permeable blood-brain barrier [21].
protektivni efekat protiv razvoja epileptičkih napada, Magnesium deficiency in the diet of sheep direct-
izazvanih kod pacova primenom maksimalnog elek- ly causes a drop in both plasma and CSF Mg2+ levels,
trošoka, dok suplementacija magnezijum oksidom u as well as the onset of convulsions, which can be sup-
visokim dozama pojačava dejstvo standardnih AEL-a pressed by i.v. administration of Mg2+ [22]. Likewise,
fenitoina i karbamazepina na ovom eksperimentalnom a dietary magnesium restriction lowers the rat brain
modelu [24]. convulsive threshold for pentylene-tetrazole induced
seizures, the effect being corrected by oral magnesium
MAGNEZIJUM U KLINIČKIM ISTRAŽIVANJIMA supplementation [23].
EPILEPSIJE Oral administration of MgO in low doses shows a
Iako su poremećaji magnezijumskog statusa sa na- protective effect against the development of epileptic
stankom deficita Mg2+ često udruženi sa pojavom epi- seizures induced in rats by applying maximal electro-
leptičkih napada, u kliničkoj praksi se kod bolesnika shock, while supplementation with MgO in high doses
sa epilepsijom nivo Mg2+ jona u krvi, na žalost, i danas enhances the effect of standard AEDs phenytoin and
retko određuje i prati. Dok deficit magnezijuma deluje carbamazepine on this experimental model [24].
prokonvulzivno, njegova nadoknada pokazuje efika-
MAGNESIUM IN CLINICAL EPILEPSY RESEARCH
sno centralno antikonvulzivno dejstvo. Davanje infu-
zija soli Mg2+ je ranije imalo veću primenu u kliničkoj Although disorders of magnesium status resulting in
epileptologiji. Nakon kasnijeg razvoja i uvođenja novih Mg2+ deficiency are often associated with epileptic
AEL-a, magnezijum sulfat se održao do danas samo u seizures, in clinical practice today unfortunately the
lečenju pojedinih specifičnih tipova epileptičkih na- level of Mg2+ in the blood is still rarely tested and mon-
pada – MgSO4 je ostao antikonvulziv izbora uglavnom itored in patients with epilepsy. While magnesium
samo za konvulzije kod određenih hipertenzivnih i me- deficiency has a proconvulsant effect, magnesium
taboličkih epileptičkih encefalopatija. compensation shows an efficient central anticonvul-
Ipak, u novije vreme sve je veći broj kliničkih studija sant effect. Administering infusions of Mg2+ salts was
koje ponovo skreću pažnju na klinički značajan, a nedo- previously used more widely in clinical epileptology.
voljno iskorišćen potencijal antiepileptičkog dejstva pre- However, since the development and introduction of
parata magnezijuma za parenteralnu i peroralnu prime- new AEDs, magnesium sulfate continued to be ap-
nu. Mehanizmi antiepileptičkog dejstva magnezijuma su plied only in the treatment of certain specific types of
nedovoljno razjašnjeni, ali je verovatno da im doprinose epileptic seizures – MgSO4 has mainly remained the
ona sinaptička i nesinaptička dejstva kojima jon Mg2+ i anticonvulsant of choice only for the convulsions in
fiziološki ostvaruje stabilizujuće dejstvo na električni certain hypertensive and metabolic epileptic enceph-
potencijal i električnu aktivnost membrane neurona (u alopathies.

182 Jun 2023. | Volumen 4 / Broj 2 | Srpski medicinski časopis Lekarske komore
preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. et al.
revising the role of magnesium in epilepsy research and management

neepileptičnim uslovima), kao i mogućnost njegovog However, an increasing number of clinical studies
prelaska, po terapijskom davanju, iz krvi u CNS, u patofi- has recently once again drawn attention to the clini-
ziološkim uslovima oštećenja i povećanja propustljivosti cally significant, but underutilized potential of antiepi-
krvno-moždane barijere u ovim bolestima. leptic effect of magnesium preparations for parenteral
Značajno sniženje nivoa magnezijuma pronađe- and oral administration. The mechanisms of the antie-
no je u serumu kod osoba sa dijagnozom idiopatske pileptic action of magnesium are as yet insufficiently
epilepsije. Deficit magnezijuma je prepoznat, između elucidated, but they are likely to be mediated by those
ostalog, i kod odraslih sa generalizovanim konvulziv- synaptic and non-synaptic effects through which Mg2+
nim napadima, kao i dece sa febrilnim konvulzijama, ion physiologically exerts a stabilizing effect on the
u poređenju sa zdravom populacijom [25,26]. Najveći electrical potential and electrical activity of the neu-
deficit magnezijuma je ustanovljen u epileptičkom sta- ronal cell membrane (under non-epileptic conditions),
tusu i u teškim oblicima epilepsije [27]. U bolesnika sa as well as by the possibility of Mg2+ penetration, upon
farmakorezistentnom epilepsijom hipomagnezijemija therapeutic administration, from the blood to the
povećava učestalost napada, a time i rizik od pojave CNS tissue, under pathophysiological conditions of
SUDEP-a [28]. damage to and an increase in the permeability of the
Кada je primena magnezijuma u terapiji epilepsije blood-brain barrier in these diseases.
u pitanju, u kliničkim studijama i preglednim radovi- A significant decrease in Mg2+ concentration was
ma se u terapijskim protokolima navodi i magnezijum found in the serum of people diagnosed with idio-
kao sredstvo u lečenju pojedinih tipova epileptičkih pathic epilepsy. Magnesium deficiency has been rec-
napada. Ima studija koje pokazuju da se konvulzivni ognized among others, in adult patients with gener-
napadi bolje kontrolišu uz adekvatnu suplementaciju alized convulsive attacks and in children with febrile
magnezijumom [27]. Pokazano je da dnevna primena convulsions, compared to healthy population [25,26].
450 mg magnezijuma kod pacijenata sa konvulzijama The greatest deficit of magnesium was found in status
smanjuje potrebu za primenom AEL-a [29]. Oralna su- epilepticus and in severe forms of epilepsy [27]. In pa-
plementacija magnezijumom u epilepsiji pomaže i u tients with drug-resistant epilepsy, hypomagnesemia
smanjenju učestalosti napada kod bolesnika sa epi- increases the frequency of seizures, and thus the risk
lepsijom [30]. of SUDEP [28].
Regarding the use of magnesium in the treatment
TERAPIJSKE PRIMENE MAGNEZIJUMA U of epilepsy in clinical studies and review papers, in
EPILEPSIJI therapeutic protocols there are mentions of magne-
Nakon otkrića antiepileptičkih lekova, MgSO4 je ostao sium as means of treating certain types of epileptic
antikonvulziv izbora za manji broj indikacija u oblasti seizures. There are studies showing that convulsive
epilepsije kod odraslih. Magnezijum se daje za hitno seizures are controlled better with an adequate mag-
zbrinjavanje eklampsije i teške preeklampsije, hiper- nesium supplementation [27]. Daily administration of
tenzivnog sindroma koji se javlja tokom trudnoće, 450 mg of magnesium in patients with convulsions
porođaja ili babinja, i odlikuje se razvojem generalizo- has been shown to reduce the need for AEDs [29].
vanih konvulzija majke. Patogeneza eklamptičkih kon- Oral magnesium supplementation in epilepsy also
vulzija i dalje je nedovoljno ispitana. Eklampsija pred- helps to reduce the frequency of seizures in patients
stavlja urgentno stanje u porodiljstvu, životno ugroža- with epilepsy [30].
vajuće za majku i plod.
THERAPEUTIC APPLICATION OF MAGNESIUM
Primena magnezijuma se veoma dobro pokaza-
la u lečenju generalizovanih konvulzivnih napada u
IN EPILEPSY
eklampsiji. Magnezijum ima prednost u lečenju za ovu Since the discovery of antiepileptic drugs, MgSO4 has
indikaciju nad ostalim antiepilepticima, zbog svoje remained the anticonvulsant of choice for a very limited
visoke efikasnosti i dobrog bezbednosnog profila za number of indications in the field of epilepsy in adults.
majku i dete. Stoga i.v. infuzija MgSO4 i danas predstav- Magnesium is given for the emergency management
lja lek prvog izbora za prevenciju i kontrolu eklamptič- of eclampsia and severe preeclampsia, a hypertensive
kih konvulzija, koji značajno smanjuje maternalnu syndrome that occurs during pregnancy, labor or post-
smrtnost u eklampsiji [31]. partal confinement, characterized by the development
Antikonvulzivno dejstvo parenteralno datog of generalized convulsions of the mother. The patho-
MgSO4 takođe ima kliničku primenu u prevenciji i preki- genesis of eclamptic convulsions is still incompletely
danju ponovnih konvulzivnih napada u uremiji, porfiri- investigated. Eclampsia is an urgent condition in ob-
ji, hipomagnezijemiji i u eklamptičkom statusu [32,33]. stetrics, life-threatening for both mother and child.

Serbian Journal of the Medical Chamber | Volume 4 / No. 2 | June 2023 183
 preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. i sar.
revising the role of magnesium in epilepsy research and management

Magnezijum ima svoje mesto u kliničkoj primeni i The use of magnesium has proven to be very bene-
u pedijatrijskoj epileptologiji, pre svega u lečenju in- ficial in the treatment of generalized convulsive attacks
fantilnih epileptičkih encefalopatija. Veći broj kliničkih in eclampsia. For this indication magnesium has a ther-
studija nalazi da je nivo serumskog magnezijuma kod apeutic advantage over other antiepileptics due to its
dece sa febrilnim napadima niži u odnosu na kontrolu, high efficacy and a strong safety profile for the mother
i da se parenteralni MgSO4 može koristiti u njihovom and the child. Therefore, i.v. infusion of MgSO4 remains
lečenju [26, 33]. even today the drug of first choice for the prevention
Vestov (West) sindrom je oblik epilepsije ranog deč- and control of eclamptic convulsions, as it significantly
jeg uzrasta, koju odlikuje elektro-klinički trijas: infantilni reduces maternal mortality in eclampsia [31]. The anti-
spazmi, psihomotorna retardacija i nalaz hipsaritmije u convulsant effect of parenterally administered MgSO4
EEG-u. Кod dece sa epileptičkim spazmima i Vestovim also has its clinical application for the prevention and
sindromom lečenje adrenokortikotropnim hormonom termination of recurrent convulsive seizures in uremia,
(engl. adrenocorticotropic hormone – ACTH) u kombina- porphyria, hypomagnesemia and in eclamptic status
ciji sa i.v. magnezijum sulfatom daje bolje rezultate od [32,33].
hormonske monoterapije, naročito u pogledu normali- Magnesium has its place in clinical application in
zacije EEG zapisa kod deteta [35]. pediatric epileptology as well, primarily in the treat-
Status epilepticus (SE) jedno je od najčešćih urgen- ment of infantile epileptic encephalopathies. A num-
tnih stanja neurokritičnih pacijenata. Ubrzo nakon što ber of clinical studies have found that serum magne-
je Lazar (Lazard) objavio prvi, i to uspešni pokušaj le- sium levels in children with febrile seizures (convul-
čenja eklampsije, koji je sproveo 1925. godine intrave- sions) are lower as compared to controls, and that
noznim davanjem MgSO4 [36], Storhajm (Storchheim) parenterally administered MgSO4 can be used in their
je objavio svoje nalaze u vezi sa praćenjem i poređe- treatment [26,33].
njem ishoda lečenja epileptičkog statusa standardnom West syndrome is a form of early childhood epilep-
terapijom i lečenja i.v. magnezijum sulfatom. Pokazalo sy characterized by the electro-clinical triad: infantile
se da terapija magnezijumom omogućava stabilizaciju spasms, psychomotor retardation and hypsarrhythmia
stanja pacijenata posle terapije i njihovo dobro preživ- in the EEG trace. In children with epileptic spasms and
ljavanje [37]. Noviji podaci iz literature navode da se West syndrome, treatment with adrenocorticotropic
infuzije soli magnezijuma mogu davati pacijentima u hormone (ACTH) in combination with i.v. magnesium
SE-u sa ili bez hipomagnezijemije, u eklamptičnom i sulfate gives better results than the hormone mono-
neeklamptičnom epileptičkom statusu [11]. therapy alone, especially regarding the normalization
Ukoliko SE pokazuje produženo trajanje (> 60 min), of the EEG recording of the child [35].
usled rezistencije na uobičajenu terapiju benzodiaze- Status epilepticus (SE) is one of the most common
pinima i nesedirajućim antiepilepticima, označava se emergency conditions in neurocritical patients. Shortly
kao refraktarni status epilepticus (RSE). Magnezijum je after Lazard had published success of the first attempt
koristan i u lečenju refraktarne epilepsije [27,38] i re- to treat eclampsia giving i.v. magnesium sulfate, which
fraktarnog epileptičkog stanja [39,40]. Smatra se da he conducted in 1925 [36], Storchheim published his
se infuzije MgSO4 mogu koristiti i za pedijatrijski RSE findings concerning the follow-up and comparison of
[41]. U jednog broja bolesnika se RSE održava čak i the outcomes of status epilepticus treatment with stan-
duže od 24 h uprkos terapiji opštim anesteticima – tzv. dard therapy and with i.v. MgSO4. Magnesium treat-
super-refraktarni status epilepticus (SRSE). Ova tri enti- ment was shown to facilitate the stabilization of the pa-
teta: SE, RSE i SRSE prate visok morbiditet i mortalitet. tients’ condition after the given therapy, as well as their
Trenutno ne postoji jedinstveni terapijski algoritam za favorable survival [37]. Recent data from the literature
kontrolu SRSE-a. Među mnogo dostupnih terapijskih indicate that magnesium salt infusions can be given to
pristupa različite efikasnosti, davanje infuzija MgSO4 patients in SE with or without hypomagnesemia, in ec-
se može razmotriti za kontrolu SRSE-a, premda je malo lamptic and non-eclamptic status epilepticus [11].
literature dostupno o tome [42]. Prolonged SE (lasting longer than 60 min), show-
ing resistance to the standard therapy with benzodiaz-
ZAKLJUČAK epines and non-sedating antiepileptics, is designated
Nivo jona Mg2+ u serumu i likvoru ima veliki značaj za as the refractory status epilepticus (RSE). Magnesium
normalnu funkciju nervnog sistema, u zdravlju i u bo- is also useful in the treatment of refractory epilepsy
lesti. Zbog svoje regulatorne uloge u funkciji neurona i [27,38] and refractory status epilepticus [39,40]. Intra-
CNS-a, kao i uloge disbalansa magnezijumskog statusa venous MgSO4 infusions are also considered to be use-
u nastanku određenih neuroloških, neuropsihijatrijskih ful for pediatric RSE [41]. In some patients RSE persists

184 Jun 2023. | Volumen 4 / Broj 2 | Srpski medicinski časopis Lekarske komore
preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. et al.
revising the role of magnesium in epilepsy research and management

i neuromišićnih poremećaja i oboljenja, magnezijum even longer than 24 hours despite the therapy with
ima svoje mesto kao predmet proučavanja u širokoj general anesthetics. This is the super-refractory status
oblasti neuronauka. epilepticus (SRSE). These three entities: SE, RSE and
Pregled literature o značaju magnezijuma u ba- SRSE are associated with high morbidity and mortality.
zičnim i kliničkim studijama u epileptologiji pomaže Currently, there is no single therapeutic algorithm for
u razumevanju uloge koju poremećaji homeostaze the control of SRSE. Among the many available thera-
magnezijuma imaju u patofiziološkim mehanizmima peutic approaches of varying efficacy, administration
odgovornim za nastanak epilepsije. S obzirom da je of MgSO4 intravenous infusions can be considered for
deficit magnezijuma u organizmu veoma čest u opštoj the control of SRSE, although there is scarce literature
populaciji, mogao bi biti češći od pretpostavljenog i dealing with this particular issue [42].
među bolesnicima sa epilepsijom. Imajući sve ovo u
vidu, potrebno je da rutinske laboratorijske pretrage CONCLUSION
kod ovih bolesnika obuhvate, između ostalog, i prove- The level of Mg2+ in the serum and the cerebrospinal
ru magnezijumskog statusa, posebno nivoa jonizova- fluid is very important for proper functioning of the
ne frakcije Mg2+ u serumu bolesnika. nervous system, both in health and disease. Due to its
Magnezijum pokazuje višestruka neuroaktivna dej- regulatory role in the function of neurons and the CNS,
stva, kao i značajan efekat stabilizacije patofiziološke as well as the role of magnesium status disbalances in
hiperekscitabilnosti neurona, kakva postoji u epilep- the development of certain neurological, neuropsychi-
tičkim pražnjenjima. Ipak, potrebna su dodatna istraži- atric and neuromuscular disorders and diseases, mag-
vanja koja bi se specifično fokusirala na procenu efika- nesium has its place as a research focus in the broad
snosti primene preparata magnezijuma kod bolesnika field of neurosciences.
sa epilepsijom, a posebno na procenu korisnosti oralne Literature review dealing with the importance of
suplementacije magnezijumom kao dopunske terapije magnesium in basic and clinical studies in epileptol-
za bolju kontrolu epileptičkih napada u slučaju razvoja ogy helps us understand the role that the disorders
refraktarnosti na postojeće lekove. of magnesium homeostasis have in the pathophysio-
logical mechanisms responsible for the development
NAPOMENA: Ovaj rad je podržalo Ministarstvo
of epilepsy. Given that magnesium deficiency is very
prosvete, nauke i tehnološkog razvoja Republike Srbije,
common in general population, it could be more com-
broj projekta: 175023.
mon than believed among patients with epilepsy as
SPISAK SKRAĆENICA well. Bearing all this in mind, it is necessary that rou-
tine laboratory tests in these patients should include,
SUDEP – engl. sudden unexpected death in epilepsy among other analyses, checking magnesium status of
SE – lat. Status epilepticus the patient, especially the level of the ionized fraction
EEG – elektroencefalogram of Mg2+ in the serum.
AEL – antiepileptički lekovi Magnesium shows multiple neuroactive effects,
CNS – centralni nervni sistem as well as a significant effect of stabilizing the patho-
CST – cerebrospinalna tečnost physiological hyperexcitability of neurons, present in
TRPM – engl. transient receptor potential melastatin epileptic discharges. However, additional research are
NMDA – N-metil-D-aspartat needed to focus specifically on the evaluation of the
AP – akcioni potencijal effectiveness of the use of magnesium preparations in
KCa – kalcijumom aktivirani K+ kanali patients with epilepsy, and especially on the evaluation
i.v. – intravenski of the usefulness of oral magnesium supplementation,
ACTH – adrenokortikotropni hormon (engl. adrenocor- as an additional therapy for better control of epileptic
ticotropic hormone) seizures in case of the development of refractoriness to
RSE – refraktarni status epilepticus existing drugs.
SRSE – super-refraktarni status epilepticus
ACKNOWLEDGEMENTS: This study was supported by
Sukob interesa: Nije prijavljen. the Ministry of Education, Science and Technological
Development of the Republic of Serbia, grant number:
175023.

Serbian Journal of the Medical Chamber | Volume 4 / No. 2 | June 2023 185
 preispitivanje uloge magnezijuma u istraživanjima epilepsije i zbrinjavanju pacijenata sa epilepsijom
Stanojević M. i sar.
revising the role of magnesium in epilepsy research and management

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