Revising the role of magnesium in epilepsy research and management

Magnesium is a bioessential mineral with multiple neuroactive effects. 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 completely understood yet. A literature review on the role of magnesium in basic and clinical epileptology has been made in order to enlighten 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 the cerebrospinal fluid (CSF) is even higher than in the blood. In experimental epilepsy research, perfusing hippocampal slices with artificial CSF containing low concentration of extracellular Mg²⁺ 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⁺ efficiently controls seizures in several epileptic encephalopathies in adults and children (in eclampsia, uremia, porphyria, febrile seizures, infantile spasms), and also helps control status epilepticus.

Subclinical magnesium deficiency, very frequent in 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.

INTRODUCTION

Epilepsy is a chronic disease of the central nervous system characterized by repetitive, sudden and reversible episodes of brain dysfunction, which occur in a stereotyped pattern. These episodes are termed as the epileptic seizures, and they arise spontaneously as a result of abrupt and excessive generalized or focal electrical discharge of neurons in the gray matter of the brain. Epileptic seizures can present with different clinical manifestations. Apart from the first epileptic attack that patient experiences, to diagnose epilepsy as a neurological condition, a permanent tendency of the brain to develop repeated seizures must be present. Abruptness, stereotypy and repetition are the three basic features of seizures in epilepsy.

Epilepsy is one of the most common neurological diseases, affecting 1 out of a 100 people worldwide on average. Epilepsy affects the quality of life and the lifespan of the diseased. The mortality of people suffering from epilepsy is significantly increased, as compared to the general population. Fatal outcomes are most often related to the underlying cause of the disease, the consequences of accidents and trauma, drowning, sudden unexpected death in epilepsy (SUDEP), etc.

According to their etiology, epilepsies are classified as being idiopathic, primary or symptomatic. In idiopathic epilepsy, patients have no known structural, metabolic or other brain disease or damage. Primary epilepsies are caused by monogenic defects. Symptomatic epilepsy occurs as a result of brain damage of known etiology. Epileptic seizures can also occur in people who do not have epilepsy, as a symptom of some other brain disease or damage, i.e. as acute symptomatic or provoked epileptic seizures. The basic pathophysiological mechanisms of onset of epileptic seizures (ictogenesis) and the development of epilepsy as a disease (epileptogenesis) are not sufficiently elucidated yet, but it is known that synaptic and non-synaptic processes of the development of neuronal hyperexcitability and the hypersynchronization of their electrical discharge contribute the most [1].

Various motor, sensitive, sensory, vegetative and psychological manifestations, alterations of behavior, disorders of consciousness and other abnormalities may occur as clinical presentation of epileptic seizures. Main types of seizures in epilepsy are focal and generalized seizures. Focal seizures develop when epileptic discharges arise from a specific and limited region of the brain. Status epilepticus (SE) is an emergency condition in neurology and the most severe condition in epileptology, implying epileptic activity of prolonged duration or repeated epileptic seizures between which the patient does not regain consciousness [2].

The diagnosis of epilepsy is electro-clinical, based on seizure semiology and the findings in recordings of the electroencephalogram (EEG). Epilepsy is characterized by changes in the EEG trace that can be observed during seizures (ictally) and between seizures (interictally). The presence of EEG changes in between seizures suggests abnormal electrical activity of the brain and a tendency of spontaneous seizure occurrence. However, the absence of EEG changes during a clinically asymptomatic period, does not exclude the diagnosis of epilepsy.

The treatment of epilepsy is tailored to the individual patient, i.e. the decision on the therapy is made for each patient separately, due to different causes of the disease, different forms of the disease, differences in the effectiveness and side effects of drugs, possible presence of comorbidities, and other factors. The use of antiepileptic drugs (AEDs) aims to establish stable seizure control, that is to abort ongoing seizures and suppress their future repetition. Monotherapy with antiepileptics is advantageous, as it is less toxic, simple to administer and achieves a more regular patient compliance, whereas it avoids drug interactions, etc. However, there is a large number of patients who do not respond appropriately to pharmacological treatment of epilepsy (pharmacoresistant or refractory form of the disease). In these cases, epilepsy can be treated with electrostimulation methods, epilepsy surgery (e.g. operative resection of the epileptic focus), or other treatment approaches [2].

THE IMPORTANCE OF MAGNESIUM IN THE PROPER FUNCTIONING OF THE NERVOUS SYSTEM

Magnesium is a mineral found in abundance in mammalian organisms. Mg²⁺ ion is present in higher concentration in the intracellular fluid (second to K⁺ ion), than in the extracellular fluid (the fourth most abundant cation). Its intracellular and extracellular concentrations are regulated by the function of cell membrane ion channels, as well as by the control mechanisms regulating its storage in cell organelles. Maintaining magnesium homeostasis is very important for preserving the general state of health [3].

Magnesium has many metabolic functions in the body (a cofactor of numerous enzymes), but it is also a cation bio-essential for all excitable cells and tissues. As such, magnesium is particularly important for the proper functioning of the central nervous system (CNS). In mammalian brain tissue, magnesium content is 6 – 7 mmol/kg (predominantly present in brain gray matter). Under physiological conditions, blood plasma and cerebrospinal fluid (CSF) differ regarding the content of individual ions. Thus, the level of Cl^- is higher, the evel of K⁺ is lower, levels of Na⁺ and Ca²⁺ are almost the same, whereas the level of Mg²⁺ is significantly higher in the CSF as compared to plasma. Differences in ionic composition of plasma and CSF exist due to choroid plexus activity [4]. Mg²⁺ ion is the only cation actively secreted by the choroid plexus epithelium with a concentration higher in the CSF than in the blood (except for H⁺). Magnesium transport i.e. its active secretion occurs through cation channels permeable to Mg²⁺ – the transient receptor potential melastatin channels types 6 and 7 (TRPM6 and TRPM7) [5].

Magnesium exerts multiple neuroactive effects on a molecular, cellular and systemic level. The effects of magnesium on the nervous system as a whole include the antidepressant, anxiolytic, anesthetic, analgesic, antimigraine, anticonvulsant, antiepileptic and neuroprotective effects [3]. Magnesium exerts an overall stabilizing effect on cell membranes of individual neurons. Electrophysiological research shows that Mg²⁺ ion contributes to the regulation of the intrinsic properties of the neuronal cell membrane (excitability, conductivity, and resistance), and performs complex modulation of neuronal electrical activity through its synaptic and non-synaptic effects, i.e. Mg²⁺ effects on ion channels, transporters and pumps, and receptors in the cell membrane [6]. Magnesium suppresses chemical synaptic neurotransmission by binding to voltage dependent Ca²⁺ channels of presynaptic nerve endings, thereby suppressing the release of neurotransmitters from central as well as peripheral synapses (neuromuscular junction). In addition, extracellular Mg²⁺ ions block N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors in a voltage-dependent manner.

Regarding the non-synaptic effects, it is known that intracellular Mg²⁺, among other things, can block voltage-gated Na⁺ channels. Large hydrated Mg²⁺ ions competitively bind to Na⁺ channels in their activated state, thus leading to a decrease in action potential (AP) firing rate and AP amplitude [7]. Certain studies also indicate the activating effect of Mg²⁺ ions on calcium-activated K⁺ channels (K_Ca) [8]. Finally, Mg²⁺ ion is also necessary for the proper functioning of the Na⁺/K⁺ pump [9]. All of these findings confirm the significant role of Mg²⁺ in the regulation of neuronal excitability, as well as high neuronal requirements for magnesium.

Concerning that Mg²⁺ blocks the depolarizing ion currents through voltage-gated Na⁺ and Ca²⁺ channels and channels of glutamatergic NMDA receptors, and potentiates the hyperpolarizing ion currents through K_Ca channels and the Na⁺/K⁺ pump, Mg²⁺ ion exerts a strong effect of overall stabilization of cell membrane electrical potential and activity. This simultaneously contributes to the important neuroprotective effect of magnesium, since it counteracts the excessive membrane depolarization and the development of the pathophysiological mechanism of excitotoxicity, which mediates neuronal damage and death in numerous pathophysiological conditions (neurodegenerative processes, ischemic brain lesions, craniocerebral trauma, epileptic discharges etc). Magnesium also induces increased production of vasodilator prostaglandins in the brain. It is also known that magnesium increases neuroplasticity and facilitates learning and memory.

The level of magnesium in the blood is rarely tested routinely, and even when measured – it is usually the level of total magnesium in the blood serum that is measured (normal range: 0.75 – 0.95 mmol/l). The sample should be the serum, and not blood plasma, because various anticoagulants added (ethylenediamine tetraacetate, citrate, oxalate) can bind Mg²⁺ ions, resulting in errors in the measurement of its concentration. In order to determine magnesium status of the organism and test the patient for hypomagnesemia (as a potential cause or contributing factor for epileptic seizures), a more sensitive indicator should be used, i.e. the concentration of the free, ionized fraction of Mg²⁺ should be measured, as it represents the biologically active form of Mg²⁺ ions. Normal range of the concentration of ionized Mg²⁺ in the serum is between 0.50 and 0.70 mmol/l [3].

Hypomagnesemia is a condition of reduced serum magnesium concentration. Magnesium deficiency in humans can occur for several reasons: insufficient intake, lack of magnesium in the soil, but also in foodstuff of herbal and animal origin, malabsorption and maldigestion, renal loss of magnesium, redistribution from the extracellular to the intracellular space, and other causes [10]. Acute deficiency may undergo unnoticed, i.e. it may be asymptomatic, or it may manifest as nausea, vomiting, lethargy and agitation. Chronic magnesium deficiency leads to more severe pathophysiological conditions. Hypomagnesemia as an electrolyte imbalance is often unrecognized. Its signs appear when serum magnesium levels drop below 0.50 mmol/l. This is when signs of nervous and neuromuscular irritability and brain hyperexcitability develop: tetanic muscle spasms, cardiac arrhythmias, anxiety, confusion, and in severe hypomagnesemia, delirium and convulsions develop, leading even to status epilepticus [11].

In the treatment of hypomagnesemia, MgO and magnesium salts of inorganic and organic origin are used. Different magnesium salts have different bioavailability. Thus, for example, magnesium pidolate has a higher bioavailability and penetrability on a cellular level and can regulate the lack of magnesium causing headaches soon after its administration [12]. Some of the magnesium salts whose preparations are used in therapy are the following: sulfate, chloride and carbonate (inorganic salts) and citrate, acetate, lactate, glycinate, aspartate, gluconate, pidolate and threonate (organic magnesium salts).

Latent and mild hypomagnesemia can be treated with oral magnesium preparations (e.g. magnesium gluconate). Manifested and severe hypomagnesemia, especially with heart rhythm disorders and epileptic seizures present, requires immediate parenteral compensation with injections and infusions of MgSO₄ until heart rhythm normalizes and the seizures cease. In doing so, caution is required in case of kidney failure – if the patient has kidney damage, the dose of magnesium should be reduced.

Magnesium plays a role in the prevention and treatment of a number of neurological and neuropsychiatric disorders, such as anxiety, depression, migraine and tension headaches, chronic pain conditions, but also Alzheimer’s disease, Parkinson’s disease, stroke and epilepsy [13]. Magnesium supplementation also helps to treat insomnia, the most common sleep disorder [14]. Intracisternal, intrathecal and epidural application of magnesium have proven useful in prolonging the effects of anesthesia, in achieving analgesia, as well as the treatment of arterial hypertension. Intranasal application of magnesium is an alternative route of drug administration when its distribution in the brain is needed. The drug is then transported via the olfactory nerve fibers directly into the CNS [4].

MAGNESIUM IN EPILEPSY RESEARCH

Epilepsy is a chronic disease of insufficiently known etiopathogenesis and of varying clinical manifestations. Medical treatment of epilepsy with standard antiepileptic drugs available today is associated with numerous difficulties, due to the risk of dose-dependent drug toxicity, the need for monitoring drug concentration in the plasma, long duration of the therapy, as well as the unwanted drug interactions in case of need for polytherapy [15]. Antiepileptic drugs can also interact with other drugs that the patient is using. They can also cause depletion of certain vitamins and minerals, and thus affect the occurrence of seizures. For all these reasons, as well as the large total number of epilepsy patients, the possible serious side effects of AEDs, and the large number of pharmacoresistant epilepsy cases (about 30 % of all epilepsy patients), the search for new antiepileptic drugs and new modalities of epilepsy treatment still continues, for the purpose of achieving greater efficiency and better tolerability of epilepsy therapy. This also includes additional alternative and complementary treatment approaches, which can contribute to establishing better control of epileptic seizures.

Magnesium, as a simple antiepileptic agent, has therapeutic potential which surpasses its current clinical application for this indication [16]. As an addition to the existing armamentarium of applied antiepileptic agents, it could contribute to improving the prognosis, course and outcome of the disease in at least some patients with epilepsy. Therefore, it is necessary first of all to gather experiences from clinical practice to date, as well as scientific knowledge from published basic and clinical studies and trials, on the role of disorders of magnesium homeostasis in the onset of epilepsy and the importance of using magnesium in the treatment of epilepsy. A review of relevant literature can be of use for this cause. This review attempts to include preclinical in vitro and in vivo research, carried out with the common goals to reveal the contribution that sometimes latent magnesium deficiency in the body has in the processes of ictogenesis and epileptogenesis, as well as to determine the mechanisms of antiepileptic and antiepileptogenic magnesium effects. Finally, clinical studies and case reports on the use of magnesium in the therapy of certain types of epileptic seizures and epileptic state have also been included.

MAGNESIUM IN PRECLINICAL EPILEPSY RESEARCH

In basic neurophysiological research, experiments are performed on different animal models of disease – starting from the whole organism level in experiments in vivo, including invertebrate and mammalian species, over in vitro experiments on isolated organs, brain slices, cell cultures etc, down to the subcellular - molecular level of isolated individual ion channels, as well as on computer model systems. Numerous fundamental studies of the basic mechanisms in epilepsy show that the defficiency of Mg²⁺ in the body may be directly linked to ictogenesis and epileptogenesis [16].

A decrease in the extracellular Mg²⁺ concentration acts on the membranes of central neurons to lower the excitation threshold level and increase neuronal excitability [17]. A decrease in Mg²⁺ content in the CSF and the interstitial fluid of the brain tissue (neuropil immediately surrounding the neurons), can lead to the spontaneous development of the epileptiform activity.

The mechanisms of epileptogenesis have not been fully elucidated, which is why the existing knowledge on the importance of Mg²⁺ in epilepsy is also incomplete. However, there is a significant body of knowledge regarding the role of magnesium in experimental epilepsy. There are numerous examples of this in basic studies of epilepsy on in vitro models. For example, Mg²⁺ reversibly suppresses in a dose-dependent manner the non-synaptic Na⁺-dependent epileptiform discharge induced in leech Retzius neurons by the application of nickel [18],[19].

A decrease in the concentration of Mg²⁺ in the extracellular fluid causes pathophysiological hyperexcitability of mammalian neurons. Low extracellular Mg²⁺ concentration or complete removal of Mg²⁺ from the perfusion solution (zero Mg²⁺ artificial CSF) induces spontaneous development of epileptiform activity of pyramidal neurons in experimental models of intact mouse hippocampus and rat hippocampal slices [20].

Magnesium deficiency also has an epileptogenic effect in experimental animals in vivo. Focal experimental epileptic activity acutely induced by topical application of penicillin to the cortex of an experimental animal is suppressed by intravenous (i.v.) administration of Mg²⁺, the degree of suppression of the induced interictal EEG discharge being directly proportional to the achieved Mg²⁺ concentration in the serum of the animal. Magnesium achieves a central anticonvulsive effect upon reaching the epileptic focus by passing the damaged and permeable blood-brain barrier [21].

Magnesium deficiency in the diet of sheep directly causes a drop in both plasma and CSF Mg²⁺ levels, as well as the onset of convulsions, which can be suppressed by i.v. administration of Mg²⁺ [22]. Likewise, a dietary magnesium restriction lowers the rat brain convulsive threshold for pentylene-tetrazole induced seizures, the effect being corrected by oral magnesium supplementation [23].

Oral administration of MgO in low doses shows a protective effect against the development of epileptic seizures induced in rats by applying maximal electroshock, while supplementation with MgO in high doses enhances the effect of standard AEDs phenytoin and carbamazepine on this experimental model [24].

MAGNESIUM IN CLINICAL EPILEPSY RESEARCH

Although disorders of magnesium status resulting in Mg²⁺ deficiency are often associated with epileptic seizures, in clinical practice today unfortunately the level of Mg²⁺ in the blood is still rarely tested and monitored in patients with epilepsy. While magnesium deficiency has a proconvulsant effect, magnesium compensation shows an efficient central anticonvulsant effect. Administering infusions of Mg²⁺ salts was previously used more widely in clinical epileptology. However, since the development and introduction of new AEDs, magnesium sulfate continued to be applied only in the treatment of certain specific types of epileptic seizures – MgSO₄ has mainly remained the anticonvulsant of choice only for the convulsions in certain hypertensive and metabolic epileptic encephalopathies.

However, an increasing number of clinical studies has recently once again drawn attention to the clinically significant, but underutilized potential of antiepileptic effect of magnesium preparations for parenteral and oral administration. The mechanisms of the antiepileptic action of magnesium are as yet insufficiently elucidated, but they are likely to be mediated by those synaptic and non-synaptic effects through which Mg²⁺ ion physiologically exerts a stabilizing effect on the electrical potential and electrical activity of the neuronal cell membrane (under non-epileptic conditions), as well as by the possibility of Mg²⁺ penetration, upon therapeutic administration, from the blood to the CNS tissue, under pathophysiological conditions of damage to and an increase in the permeability of the blood-brain barrier in these diseases.

A significant decrease in Mg²⁺ concentration was found in the serum of people diagnosed with idiopathic epilepsy. Magnesium deficiency has been recognized among others, in adult patients with generalized convulsive attacks and in children with febrile convulsions, compared to healthy population [25],[26]. The greatest deficit of magnesium was found in status epilepticus and in severe forms of epilepsy [27]. In patients with drug-resistant epilepsy, hypomagnesemia increases the frequency of seizures, and thus the risk of SUDEP [28].

Regarding the use of magnesium in the treatment of epilepsy in clinical studies and review papers, in therapeutic protocols there are mentions of magnesium as means of treating certain types of epileptic seizures. There are studies showing that convulsive seizures are controlled better with an adequate magnesium supplementation [27]. Daily administration of 450 mg of magnesium in patients with convulsions has been shown to reduce the need for AEDs [29]. Oral magnesium supplementation in epilepsy also helps to reduce the frequency of seizures in patients with epilepsy [30].

THERAPEUTIC APPLICATION OF MAGNESIUM IN EPILEPSY

Since the discovery of antiepileptic drugs, MgSO₄ has remained the anticonvulsant of choice for a very limited number of indications in the field of epilepsy in adults. Magnesium is given for the emergency management of eclampsia and severe preeclampsia, a hypertensive syndrome that occurs during pregnancy, labor or postpartal confinement, characterized by the development of generalized convulsions of the mother. The pathogenesis of eclamptic convulsions is still incompletely investigated. Eclampsia is an urgent condition in obstetrics, life-threatening for both mother and child.

The use of magnesium has proven to be very beneficial in the treatment of generalized convulsive attacks in eclampsia. For this indication magnesium has a therapeutic advantage over other antiepileptics due to its high efficacy and a strong safety profile for the mother and the child. Therefore, i.v. infusion of MgSO₄ remains even today the drug of first choice for the prevention and control of eclamptic convulsions, as it significantly reduces maternal mortality in eclampsia [31]. The anticonvulsant effect of parenterally administered MgSO₄ also has its clinical application for the prevention and termination of recurrent convulsive seizures in uremia, porphyria, hypomagnesemia and in eclamptic status [32],[33].

Magnesium has its place in clinical application in pediatric epileptology as well, primarily in the treatment of infantile epileptic encephalopathies. A number of clinical studies have found that serum magnesium levels in children with febrile seizures (convulsions) are lower as compared to controls, and that parenterally administered MgSO₄ can be used in their treatment [26],[33].

West syndrome is a form of early childhood epilepsy characterized by the electro-clinical triad: infantile spasms, psychomotor retardation and hypsarrhythmia in the EEG trace. In children with epileptic spasms and West syndrome, treatment with adrenocorticotropic hormone (ACTH) in combination with i.v. magnesium sulfate gives better results than the hormone monotherapy alone, especially regarding the normalization of the EEG recording of the child [35].

Status epilepticus (SE) is one of the most common emergency conditions in neurocritical patients. Shortly after Lazard had published success of the first attempt to treat eclampsia giving i.v. magnesium sulfate, which he conducted in 1925 [36], Storchheim published his findings concerning the follow-up and comparison of the outcomes of status epilepticus treatment with standard therapy and with i.v. MgSO₄ . Magnesium treatment was shown to facilitate the stabilization of the patients’ condition after the given therapy, as well as their favorable survival [37]. Recent data from the literature indicate that magnesium salt infusions can be given to patients in SE with or without hypomagnesemia, in eclamptic and non-eclamptic status epilepticus [11].

Prolonged SE (lasting longer than 60 min), showing resistance to the standard therapy with benzodiazepines and non-sedating antiepileptics, is designated as the refractory status epilepticus (RSE). Magnesium is also useful in the treatment of refractory epilepsy [27],[38] and refractory status epilepticus [39],[40]. Intravenous MgSO₄ infusions are also considered to be useful for pediatric RSE [41]. In some patients RSE persists even longer than 24 hours despite the therapy with general anesthetics. This is the super-refractory status epilepticus (SRSE). These three entities: SE, RSE and SRSE are associated with high morbidity and mortality. Currently, there is no single therapeutic algorithm for the control of SRSE. Among the many available therapeutic approaches of varying efficacy, administration of MgSO₄ intravenous infusions can be considered for the control of SRSE, although there is scarce literature dealing with this particular issue [42].

CONCLUSION

The level of Mg²⁺ in the serum and the cerebrospinal fluid is very important for proper functioning of the nervous system, both in health and disease. Due to its regulatory role in the function of neurons and the CNS, as well as the role of magnesium status disbalances in the development of certain neurological, neuropsychiatric and neuromuscular disorders and diseases, magnesium has its place as a research focus in the broad field of neurosciences.

Literature review dealing with the importance of magnesium in basic and clinical studies in epileptology helps us understand the role that the disorders of magnesium homeostasis have in the pathophysiological mechanisms responsible for the development of epilepsy. Given that magnesium deficiency is very common in general population, it could be more common than believed among patients with epilepsy as well. Bearing all this in mind, it is necessary that routine laboratory tests in these patients should include, among other analyses, checking magnesium status of the patient, especially the level of the ionized fraction of Mg²⁺ in the serum.

Magnesium shows multiple neuroactive effects, as well as a significant effect of stabilizing the pathophysiological hyperexcitability of neurons, present in epileptic discharges. However, additional research are needed to focus specifically on the evaluation of the effectiveness of the use of magnesium preparations in patients with epilepsy, and especially on the evaluation of the usefulness of oral magnesium supplementation, as an additional therapy for better control of epileptic seizures in case of the development of refractoriness to existing drugs.

LIST OF ABBREVIATIONS/ACRONYMS

SUDEP – sudden unexpected death in epilepsy
SE – status epilepticus
EEG – electroencephalogram
AED – antiepileptic drug
CNS – central nervous system
CSF – cerebrospinal fluid
TRPM – transient receptor potential melastatin
NMDA – N-methyl-D-aspartate
AP – action potential
K_Ca – calcium activated K⁺ channel
i.v. – intravenous
ACTH – adrenocorticotropic hormone
RSE – refractory status epilepticus
SRSE – super-refractory status epilepticus