|Year : 2019 | Volume
| Issue : 2 | Page : 186-193
Serum magnesium in adult patients with idiopathic and symptomatic epilepsy in Maiduguri, Northeast Nigeria
I Abdullahi1, MM Watila2, N Shahi3, YW Nyandaiti4, SA Bwala5
1 Federal Medical Center Azare, Bauchi State, Nigeria
2 Neurology Unit, Department of Medicine, University of Maiduguri Teaching Hospital, Maiduguri, Borno State; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
3 Neurosurgery Department, Kings College Hospital, London, UK
4 Neurology Unit, Department of Medicine, University of Maiduguri Teaching Hospital, Maiduguri, Borno State, Nigeria
5 Department of Medicine, National Hospital Abuja, Abuja, Nigeria
|Date of Acceptance||19-Oct-2018|
|Date of Web Publication||7-Feb-2019|
Dr. M M Watila
Neurology Unit, Department of Medicine, University of Maiduguri Teaching Hospital, PMB 1414, Maiduguri, Borno State
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Alteration in the homeostasis of trace elements such as magnesium may play a role in the development of epileptic seizures. This study aims to investigate the levels of serum magnesium in people with idiopathic generalized epileptic (IGE) seizures and symptomatic seizures in Northeast Nigeria. Materials and Methods: Serum magnesium level was measured using atomic absorption spectrometry among 40 adults with IGE, 20 adults with symptomatic epileptic seizures, and 30 healthy controls. Serum calcium, potassium, phosphate, and albumin were also measured. Results: The mean serum magnesium level was significantly lower among people with epilepsy compared with the controls [0.79 ± 0.18 mmol/L vs 0.90 mmol/L ± 0.17, P = 0.007, 95% confidence interval (CI): (−0.189 to −0.031)]. People with IGE had significantly lower levels of magnesium compared with those with symptomatic seizures [0.74 ± 0.17 mmol/L vs 0.9 ± 0.16 mmol/L, P < 0.001 95% CI: (−0.251 to −0.069)]. The mean magnesium level for all groups was in the reference range, but the lowest levels were observed in those with IGE. There is no significant correlation between the level of serum magnesium and the severity of seizure attacks. There was significantly lower level of calcium in people with IGE compared with those with symptomatic seizures [2.3 ± 0.13 mmol/L vs 2.4 ± 0.16 mmol/L, P = 0.012, 95% CI: (−0.177 to 0.023)] or controls [2.3 ± 0.13 mmol/L vs 2.4 ± 0.12 mmol/L, P < 0.01, 95% CI: (−0.156 to −0.044)]. No significant differences were observed in the levels of potassium, phosphate, and albumin. Conclusion: This study suggests that low serum magnesium and calcium may play a role in IGE, and supplementation may be useful in reducing seizures in Black patients with epilepsy.
Keywords: Epilepsy, magnesium, Nigeria, seizure, trace elements
|How to cite this article:|
Abdullahi I, Watila M M, Shahi N, Nyandaiti Y W, Bwala S A. Serum magnesium in adult patients with idiopathic and symptomatic epilepsy in Maiduguri, Northeast Nigeria. Niger J Clin Pract 2019;22:186-93
|How to cite this URL:|
Abdullahi I, Watila M M, Shahi N, Nyandaiti Y W, Bwala S A. Serum magnesium in adult patients with idiopathic and symptomatic epilepsy in Maiduguri, Northeast Nigeria. Niger J Clin Pract [serial online] 2019 [cited 2019 Jun 16];22:186-93. Available from: http://www.njcponline.com/text.asp?2019/22/2/186/251781
| Introduction|| |
Epilepsy is a condition characterized by an enduring predisposition to generate epileptic seizures, with neurobiologic, cognitive, and psychosocial consequences, which can arise from structural brain damage, genetic defects, and metabolic abnormalities. Magnesium being the most abundant intracellular divalent cation regulates many intracellular functions and has a profound effect on neural excitability.,,,,,, It is thought to be involved directly or indirectly in many diseases including schizophrenia,,,, depression,,,, attention deficit hyperactivity disorder,,, migraine,,,, and cystic fibrosis.,,, Although magnesium deficiency or excess as a cause of epilepsy is generally uncommon; it may play a role in the development of epileptic seizures.,,
A lower serum magnesium in people with epileptic seizures compared with healthy controls have been demonstrated,,,,,,, with studies reporting a positive correlation of hypomagnesemia with severity of epileptic seizures.,, However, the duration of epilepsy or treatment with antiepileptic therapy has no significant influence on serum magnesium., It has been observed that disturbances in magnesium homeostasis usually do not exist alone, rather it parallels those of other trace elements.
The evidence that low levels of magnesium can cause seizure-like discharges had been observed in experimental slices of human epileptogenic neocortex obtained during neurosurgical procedures. The spontaneous epileptiform activity resembling the electroencephalographic pattern associated with tonic–clonic seizures and episodes of spreading depression appeared following perfusion with magnesium-free artificial cerebrospinal fluid (CSF). The epileptiform discharges and spreading depression did not occur during perfusion with magnesium-free CSF containing antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. In contrast, pharmacological blockage of non-NMDA receptor did not influence the epileptiform activity observed in magnesium-free artificial CSF, suggesting that NMDA receptors are the pathway through which magnesium deficiency leads to epileptiform discharges generated by human epileptogenic neocortical slices.,, A study looking at the NMDA receptor composition in malformation of cortical development observed that receptor species vary in different malformations in patients with epilepsy, with a selective increase in the NR2B subunit present in all cortical dysplasia, whereas the expression level of NR2A and NR2B subunits was significantly downregulated in all patients with heterotopias. Magnesium potentially modulates seizure activity by blocking the NMDA channel in a voltage-dependent manner and potentiates NMDA-induced responses at positive membrane potentials., Other divalent cations such as calcium and zinc have similar actions like magnesium. These observations suggest that magnesium may play a role in epilepsy, and therefore recognition and correction of hypomagnesaemia may help in seizure control and clinical outcome.,
Few studies in Black Africans have looked at the association between serum magnesium and epilepsy;, however, no study to the best of our knowledge has looked at the differences in people with idiopathic generalized epileptic (IGE) seizures and symptomatic seizures in Nigeria. This study investigated the difference in the level of serum magnesium in adult patients with IGE and symptomatic epileptic seizures on antiepileptic drugs (AEDs) therapy and compared that with the level in healthy controls. It also correlated the frequency of seizure with the serum level of magnesium and determined the level of potassium, phosphates, calcium, and albumin.
| Materials and Methods|| |
This is a hospital-based analytical cross-sectional study conducted at the University of Maiduguri Teaching Hospital (UMTH) and the Federal Neuro-Psychiatry (FNPH), Maiduguri. The two hospitals serve as the main epilepsy referral centers for northeast Nigeria. The study was approved by the Ethical Committees of UMTH and FNPH, Maiduguri, and all provisions of the Declaration of Helsinki regarding participation were followed in the study.
Sixty subjects age 18 years and above with the diagnosis of epilepsy fulfilling the International League Against Epilepsy (ILAE) criteria  were recruited consecutively as they attended the outpatient clinics of the two hospitals. Thirty healthy controls were recruited among the healthcare personnel working in these centers and among patients' relatives who never had a seizure. We excluded people on magnesium-containing drugs such as antacids and traditional medications; patients with gastrointestinal disorders such as chronic diarrhoea and malabsorption syndromes; patients with disorders such as hyperthyroidism and diabetic ketoacidosis; those on diuretics such as frusemide, thiazides, and acetazolamide; alcoholics; patients with chronic renal disease; and pregnant females.
Subject's sociodemographic and full medical history were obtained. The age of seizure onset, duration of symptoms before hospital presentation, diagnosis of seizures, seizure characteristics, numbers of seizure attacks, and medications (AEDs) used were recorded. The results of serum magnesium, calcium, potassium, phosphates, and albumin were recorded in all the study subjects. Computerized tomography (CT) scan of the brain and electroencephalography (EEG) were done in all the cases, and the parameters obtained were used to classify cases into either IGE seizures (no identifiable cause) or symptomatic seizures (those with an identifiable risk factor, both acute and chronic). Study subjects were stratified into three groups: patients with IGEs, patients with symptomatic seizures, and apparently healthy controls.
Five milliliters of venous blood sample was obtained in the morning from all subjects to measure the serum magnesium, calcium, potassium, phosphorus, and albumin levels. Samples were centrifuged at the rate of 1500 rpm for 5 min utes. At least 1 mL of serum was immediately separated from the clot and transferred into two separate acid-washed plain bottles. One bottle containing the serum was stored at –20°C for later analysis of serum magnesium at National Agency for Food and Drug Administration Control (NAFDAC) zonal laboratory, Maiduguri, whereas serum calcium, potassium, phosphate, and albumin were analyzed immediately at the chemical pathology laboratory, UMTH.
Magnesium level was determined by atomic absorption spectrophotometry using AA-6800 series Shimadzu atomic absorption spectrophotometer (Shimadzu Corporation, Kyoto, Japan). Frozen serum samples transported to the NAFDAC laboratory were allowed to thaw at room temperature. A sufficient dilution amount of lanthanum oxide solution (La) was prepared for the analyses to avoid interference by phosphate ions. Determination by atomic absorption spectroscopy is based on the fact that atoms of an element in the “ground” or unexcited state absorb light of the same wavelength as that emitted by the element in the excited state. Magnesium absorption wavelength is 285.2 nm. The direct spectrophotometric analysis used in this study is the most reliable based on the technology available in Nigeria at the time of the study. On the basis of precision and accuracy, it is a preferred method, and the coefficient of variation in the precision of the assays in the normal range is 8%–14%. Serum calcium, phosphorus, and albumin were analyzed colorimetrically using Arsenazo III, molybolate, and bromocresol green methods with DIALAB, Human, and Radox Diagnostics Kits, respectively. Potassium was determined using standard flame emission spectrophotometry method. About a quarter of serum magnesium is bound to albumin, hence serum albumin level is needed to measure the true serum Mg level.
We calculated the sample size to be at least 55 people with epilepsy. Data generated were entered into “SPSS Version 16.0” (SPSS Inc., Chicago, IL, USA) and analyzed. Descriptive summaries were expressed as means ± standard deviations and percentages for numerical and categorical variables, respectively. A Chi-square test (or Fisher's exact test) was used to compare categorical variables, whereas an independent sample t-test was conducted to compare means. Pearson's correlation coefficient (r) was used to test the strength of association between variables. The level of significance was set at P < 0.05.
| Results|| |
We recruited 60 subjects (31 males and 29 females) with epilepsy and 30 controls (15 males and 15 females), with a mean age of 35.9 ± 12.0 and 33.7 ± 13.4 years, respectively. There were no significant differences in the sociodemographic characteristics of the cases and controls. [Table 1] shows the sociodemographic and clinical characteristics of the 40 persons with IGE seizures and 20 with symptomatic seizures. Those with IGE were significantly younger compared with those with symptomatic seizures (mean age 28.3 ± 8.2 and 43.5 ± 15.7 years; P < 0.001). There were 22 (55%) females and 18 (45%) males with IGE, and 13 (65%) were males and 7 (35%) were females among those with symptomatic seizures. Sixteen (40%) of the IGE cases had a family history of epilepsy compared with 15% of those with symptomatic seizures. Three (7.5%) of the IGE cases had febrile convulsions and 31 (77.5%) had no significant medical history. The age of seizure onset for those with IGE were predominantly below the age of 20 years, whereas those with symptomatic seizures were mostly above 20 years. We observed that 40% of the IGE cases presented to the hospitals for the first time for diagnosis after 5 years of seizure onset compared with none among the symptomatic cases (P = 0.004), whereas a majority (85.0%) of the symptomatic seizure cases presented within the same month compared with 15% of those with IGE (P = 0.001). All the IGE cases had episodes of generalized tonic–clonic seizure compared with 25.0% of symptomatic seizure cases (P = 0.008). Most of the symptomatic cases (70%) had partial seizures with secondary generalization compared with none among IGE case (P < 0.001). At the time of diagnosis, 14 (35%) of the patients with IGE had a frequency of three to five seizure attacks per month, 12 (30%) had two seizures per month, and 8 (20%) had one seizure per month. While 8 (40%) with symptomatic seizure had three to five seizure attacks per month, 5 (25%) had two seizures per month, and three (15%) had one seizure attack per month. There were no statistical differences between the two groups regarding seizure frequency. A year after commencing AED, 37.5% IGE cases were seizure-free, whereas 40% of the symptomatic cases were seizure-free, with no significant difference. The majority were on one AED, with phenobarbitone being the most (65%) prescribed for IGE case and phenytoin (70%) for symptomatic seizures. These drugs are the most readily available and affordable. In all, 25 (62.5%) patients with IGE and 18 (90%) symptomatic seizure cases were compliant to medication based on the word-of-mouth. Thirty-four (85%) cases of IGE and six (30%) among the symptomatic group used other forms of nonorthodox therapy.
|Table 1: Demographic and seizure characteristics of patients with IGE and symptomatic seizures|
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All the 40 cases with IGE had a normal CT brain. Seven (35%) of symptomatic seizure cases had features of stroke, five (25%) had features of brain tumors, four (20%) had features of traumatic brain injury, and four (20%) had features of central nervous system infections. The routine awake EEG were normal in 36 (90%) cases of IGE and showed generalized epileptiform activities in only 4 (10%) cases.
The mean serum magnesium, calcium, potassium, phosphate, and albumin in cases and controls is shown in [Table 2]. The serum magnesium was significantly lower among the 60 cases compared with the control (0.79 ± 0.18 mmol/L vs 0.90 ± 0.17 mmol/L; P = 0.007). The mean serum calcium in the 60 cases was significantly lower than the control cases (2.3 ± 0.13 mmol/L vs 2.4 ± 0.12 mmol/L; P < 0.001). There was no significant difference between serum potassium, phosphate, and albumin levels in the 60 cases and controls.
|Table 2: Serum magnesium, calcium, potassium, phosphate, and albumin in cases and controls|
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[Table 3] shows that the mean serum magnesium in patients with IGE was significantly lower than the controls (0.74 ± 0.17 mmol/L vs 0.9 ± 0.17 mmol/L; P < 0.001). Similarly, the mean serum calcium in the IGE cases was significantly lower than that of the control (2.3 ± 0.13 mmol/L vs 2.4 ± 0.12 mmol/L; P = 0.002), there was no significant difference in the serum potassium, phosphate, and albumin.
|Table 3: Serum magnesium, calcium, potassium, phosphate, and albumin in idiopathic seizure cases and controls|
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[Table 4] shows no significant difference in the serum magnesium, calcium, potassium, phosphate, and albumin between cases of symptomatic seizures and controls. [Table 5] shows that the serum magnesium and calcium levels in the cases of IGE were significantly lower than the level in the symptomatic seizure cases (P = 0.001 and 0.012), with no significant difference in serum potassium, phosphate, and albumin.
|Table 4: Serum magnesium, calcium, potassium, phosphate, and albumin in symptomatic seizures and controls|
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|Table 5: Serum magnesium, calcium, potassium, phosphate, and albumin in idiopathic and symptomatic seizures|
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There was no significant correlation between the number of seizure attacks before starting therapy and 1 year after starting AED therapy with serum magnesium level among both cases of IGE and symptomatic seizure (rs = 0.065, P = 0.62; rs = 0.01; P = 0.94, respectively).
| Discussion|| |
Clinical and experimental investigations have shown that magnesium has an important role in neuronal excitability, and depletion causes a marked irritability of the nervous system eventually resulting in epileptic seizures.,, The molecular mechanism why low serum magnesium facilitates epileptic activity is not fully known. However, hypomagnesemia alters calcium mobilization, destabilizes excitable membranes, and exerts a voltage-dependent blockage of the NMDA-receptor channel. These channel abnormalities associated with hypomagnesemia are thought to play a role in epilepsy.,
Our study shows that patients with IGE had significantly lower magnesium and calcium compared with those with symptomatic seizures and controls, even though both values were within the reference interval. Although there are few studies on serum magnesium in patients with epilepsy in Nigeria,, our study is the first to consider its role in idiopathic versus symptomatic seizures in adult patients in northern Nigeria. Oladipo et al., reported a similar finding among Nigerian adults and children, but with no associated significant difference in calcium level. Similar studies have revealed lower magnesium levels in epileptics than in controls ,,, and an associated significant increase in the serum calcium level in epileptic in the interictal and postictal periods. In contrast, Hamed et al. and Smith and Bone  reported no significant difference in serum magnesium between epileptics and controls. Our study showed no significant difference in serum magnesium level between symptomatic cases and controls in this study, whereas the mean serum magnesium and calcium level in the IGE cases was significantly lower than the level in the symptomatic cases and controls. These findings suggest that lower serum magnesium may play a role in people with IGE; however, no correlation was found with seizure frequency. Other similar studies revealed no relationship between the level of serum magnesium and severity of seizure attacks.,,, Gupta et al. observed significantly lower serum magnesium level in patients with idiopathic epilepsy than in controls, and the serum magnesium level was lower in those with severe epilepsy compared with those with mild to moderate epilepsy.
Many monogenic IGEs are ion-channelopathies, and seizure can be provoked by many different insults in several different brain networks, thus low serum magnesium level may serve as a trigger. It has been reported that lowering of the extracellular magnesium concentration induces various patterns of epileptiform activity in combined rat entorhinal cortex-hippocampal brain slices. Magnesium may have an effect on the development of drug resistant epilepsy (DRE) by causing a depletion of synaptically released gamma aminobutyric acid. The use of magnesium supplement was associated with decreased number of seizure days per month in drug-resistant patients, and therefore the use of oral magnesium supplement may be a useful adjunct in the treatment of epilepsy and DRE.,
This study had several limitations. First, we measured the total free magnesium levels rather than ionized magnesium which would have given a better level of physiologically active form that is in equilibrium with the intracellular magnesium. The most preferably method would have been to measure the intracellular concentration of magnesium in erythrocytes, since magnesium is predominantly an intracellular cation. Serum magnesium levels may not truly reflect intracellular magnesium levels, and the finding of lower serum magnesium levels may simply be an epiphenomenon rather than a true pathophysiological finding. Second, due to cost, CT was used to differentiate IGEs from symptomatic seizures instead of magnetic resonance imaging which is most appropriate for diagnosis of cerebral abnormalities in epilepsy., However, CT has been found to be both sensitive and relatively specific for identifying the presence of lesions like tumors, stroke, arteriovenous malformations, and some infective lesions. Third, the level of serum magnesium was not measured at the time of diagnosis before commencing AEDs, and we did not analyze our data based on the type of AED patients were taking. Studies have shown that treatment with valproate may increase serum magnesium concentration in treated patients compared with untreated patients , Fourth, this study did not consider the effect of age or gender on serum magnesium level. Most of our IGE cases were significantly younger compared with symptomatic cases. Studies have observed no appreciable age influence on the effect on serum magnesium on epilepsy. While studies have observed no gender difference in magnesium levels,, the study by Prasad et al. reported lower serum calcium in females compared with males. Finally, we acknowlegde the lower sample size for the controls; this may have affected the statistical power of the study.
| Conclusion|| |
The findings in this study demonstrate that serum magnesium level may play an important role in epilepsy especially in people with IGE. These findings are inconclusive and would require further studies, as it will be difficult to conclude that the lower serum magnesium level found in patients with IGE was a contributory trigger to seizure generation or propagation, or were as a result of the diseases or the influence of medications. Based on the findings in this study, the next step will be to study the underlying mechanisms and genetic susceptibility of hypomagnesemia in people with IGE. The benefit of treating hypomagnesemia calls for translational research, with robust trials to inform clinical practice, but such trials cannot be undertaken without basic epidemiological data from various populations.
This work was carried out at the UMTH and FNPH, Maiduguri. The authors would like to acknowledge the staff of the NAFDAC laboratory and those of the chemical pathology department, UMTH, for their assistance with chemical analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]