Magnesium Research (1997) 10, 2,
Summary: The nervous form of magnesium imbalance represents the best documented experimental and clinical aspects of magnesium disorders. The nervous form of primary magnesium deficit (MD) in the adult appears as the best descriptive model for analysis of the symptomatology, aetiology, physiopathology, diagnosis and therapy of the most frequent form of MD. Nervous hyperexcitability due to chronic MD in the adult results in a non-specific clinical pattern with associated central and peripheral neuromuscular symptoms, analogous to the symptomatology previously described in medical literature as latent tetany, hyperventilation syndrome, spasmophilia, chronic fatigue syndrome, neurocirculatory asthenia and idiopathic Barlow's disease.
On encountering this non-specific pattern, the signs of neuromuscular hyperexcitability are of much greater importance. Trousseau's sign is less sensitive than Chvostek's sign, but their sensitivities, are increased by hyper- ventilation (Von Bondsdorff's test). Examination of the precordial area will be conducted in order to search clinical stigmata of mitral valve prolapse (MVP) which is a frequent dyskinesia due to chronic MD (about a quarter to one- third of cases).
The electromyogram (EMG) shows one (or several) trains of autorhythmic activities beating for more than 2 min of one of the three tetanic activities (uniplets, multiplets or 'complex tonicoclonic tracings') during one of the three facilitation procedures: tourniquet-induced ischaemia lasting 10 min, post-ischaemia lasting 10 min after the removal of the tourniquet and hyperventilation over 5 min. A repetitive EMG constitutes the principal mark of nervous hyperexcitability (NHE) due to MD. The echocardiogram (ECC) is the best tool for detecting MVP, the 2-dirnensional ECC with pulsed Doppler being more accurate than time-motion ECC.
The routine ionic investigations comprise five static tests: plasma and erythrocyte magnesium, plasma calcium and daily magnesiuria and calciuria. An evaluation of magnesium intake is desirable. Normal concentrations of magnesium in blood do not rule out the diagnosis of the nervous form of primary chronic MD. The histograms of MD group reveal Gaussian type magnesaemias with significantly lower means and the constituent elements can be individually hypo- (one-third of cases), normo- (about two-thirds of cases) and even, exceptionally, hyper-magnesaemic. The diagnosis of MD requires an oral magnesium load test. At physiological dose (5 mg of Mg/kg/day), oral magnesium is totally devoid of the pharmacological effects of parenteral magnesium. Corrections of symptomatology by this oral physiological magnesium load is the best proof that it was due to magnesium deficiency.
In particular clinical forms, more sophisticated studies may be useful: standard and quantitative electroencephalograms electropolygraphic studies of afternoon sleep, electronystagmography, optokinetic test, skin conductance reflex, psychometric inventories, standard or monitoring electrocardiogram, treadmill test, other static and dynamic investigations: e.g. ionized free Mg 2+, lymphocyte Mg, brain Mg, cerebrospinal Mg, Mg balance, Mg parenteral load test, glucose load, and even radio-isotope study, the only one able to reveal intestinal magnesium hypersecretion.
Nervous primary chronic MD progresses by phases of decompensation against a background of latency.
Marginal magnesium deficiency, that is to say an insufficient magnesium intake which merely requires simple oral physiological supplementation, is fundamental in the astrology of primary magnesium deficit. However a constitutional homeostatic lability of the nervous system or of magnesium metabolism such as belonging to the B35 type of HLA group must be involved. Part of the aetiology of this magnesium deficit is a magnesium depletion, where the disorder which induces magnesium deficit is related to a dysregulation of the control mechanisms of magnesium status which requires a more or less difficult specific correction.
MD induces diffuse NHE.
Symptomatic forms result in three direct cellular effects: disturbances in Ca distribution, decreased second messenger nucleotidic ratio and increased susceptibility to peroxidation. NHE is also linked to local and systemic mediated effects: increased activity of excitatory neuromediators with a decreased activity of inhibitory neuromediators, increased production of inflammatory and immunostimulant mediators: neuropeptides, prostanoids, cytokines and of prooxidant factors with decreased antioxidant system. These factors induce Ca i, ↑ cAMP/cGMP and ↑ polarization which cause the symptomatic form of nervous MD.
Local compensatory factors instrumental in the latency of NHE due to MD may also be direct and indirect: in the cell through modifications of Ca and Mg binding proteins, increase of Mg-like polyamines, stimulation of antioxidant system and free radical scavengers, local and systemic mediated compensatory factors: increase in several neuroprotective agents, increased production of anti-inflammatory and immunosuppressive mediators, with decreased pro-oxidant factors and an increased anti-oxidant defence.
It seems very important to highlight the difference between the pathophysiological mechanisms of magnesium deficiency and of the different types of magnesium depletion: genetic and acquired, irreversible (or partially reversible) and, reversible. These last models of depletion may constitute promising tests for screening treatment both in these magnesium depletions and in the related type of disorders such as some neurodegenerative diseases.
There is no pathognomonic sign of nervous MD. However, the diagnosis is obvious before Chvostek's sign and/or tetanic EMG tracings without hypocalcaemia and/or hypercalciuria or a pattern of idiopathic PVM. Positivity of the dynamic oral physiological magnesium load test constitutes the proof of a magnesium deficiency. Usually it is very easy to distinguish between primary or secondary MD, because the symptomatology of the causative disorder is clear. However, two eventualities raise problems: 1. MD secondary to hyper-calciuria, where systematic dosage of daily calciuria is necessary: 2. MD secondary to neurosis. Metabolic and psychological phenomena may be closely interrelated with mutual aggravation. There are, genuine 'neuromagnesiprive forms' where it is difficult to determine the predominance of neurosis and MD factors.
Physiological oral magnesium supplementation (5 mg/kg/day) is easy and can be carried out in the diet (using preferably high magnesium density nutrient with the best possible availability, particularly magnesium in water) or with magnesium salts, with practically only one contraindication: overt renal failure (creatinine clearance < 15 ml). Specific and non-specific treatments of magnesium depletion are tricky when using, for example, pharmacological doses of vitamine B6, physiological doses of vitamine D, magnesium sparing diuretics, partial magnesium 'analogues', antioxidants i.e. sulphur compound, vitamin E, selenium.
Clinical forms of nervous primary MD are multiple. There is a great variety of symptomatic forms according to the main target of the symptomatology: migraine, chronic fatigue, neurosis, restless leg syndrome, Raynaud's phenomenon with an increase of CGRP Mg-dependent, neurolability in children and attention deficit/hyperactivity disorders (ADHD). Undetected early maternal magnesium deficiency could be the fountainhead of the so called 'constitutional' characteristics of the nervous form of chronic primary MD, and even of more severe impairments: sudden infant death syndrome, some forms of infantile convulsions or psychiatric disturbances and even in adults cardiovascular diseases and non-insulin-dependent diabetes mellitus. The protocol of the multicentre trials of maternal magnesium supplementation should be followed not only in the mother, the fetus, and the neonate, but also in the child and even throughout life from infancy until older age.
The secondary forms of MD can be spontaneous or iatrogenic. Their therapy requires first treatment directed toward their specific aetiologies. When this proves impossible or inefficient the treatment of each type of secondary MD will differ according to the type of MD. If deficiency predominates, e.g. frequently in chronic alcoholism -- a mere oral physiological magnesium supplementation will be appropriate. When MD secondary to alcoholism has been corrected, no alcoholic encephalopathy will be observed within a period of five years. If depletion predominates -- e.g. in diabetes mellitus -- the specific or non-specific treatment of magnesium status dysregulation should be mainly used.
Symptomatic magnesium excess (ME) is practically always iatrogenic either by magnesium therapy in spite of renal failure or during massive parenteral magnesium therapy. Clinical signs appear only when plasma magnesium is increased 2-3 times. Drowsiness and hyporeflexia are observed first. It is only when magnesaemia is at least five times higher that areflexia is observed which precedes respiratory paralysis.
The treatment first to stop latent or hidden administration of magnesium. Afterwards the therapy should use the classical antidote intravenous Ca, artificial respiration, osmotic diuresis, anticholinesterasic drugs and cardiac glycosides, and lastly extrarenal dialysis.
Latent hypermagnesaemia may be observed in various, iatrogenic and pathogenic circumstances: inadequate excretion in chronic renal insufficiency, dysregulation of magnesium metabolism in various nervous, endocrine and immunological impairments such as some depressions, phaeochromocytomes, respiratory acidosis, systemic diseases, cancer, pharmacological magnesium therapy. It is of basic importance to contrast the non toxicity of the physiological oral magnesium supplementation and the possible toxicity of pharmacological uses of magnesium in therapeutics, which is potentially dangerous and possibly lethal.
Key words: Nervous hyperexcitability, magnesium, deficiency, depletion, Chvostek's sign, electromyogram, mitral valve, prolapse, magnesium loading tests, acetylcholine, excitatory aminoacids, taurine, cytokines, neuropeptides, oxygen free radicals, neurodegenerative diseases.
The nervous forms of magnesium imbalance represent the best documented experimental and clinical aspects of magnesium disorders.1-8
Magnesium excess is almost exclusively a complication of therapy: it is practically always of iatrogenic origin.
The nervous forms of magnesium deficit exhibit extreme clinical polymorphism and present difficult diagnostic, physiopathologic and therapeutic problems. But whatever the age they are the most commonly seen forms of magnesium deficit in clinical practice.1-8
Study of magnesium deficit (MD) is an important aspect of clinical medicine today. We will take the nervous form of primary magnesium deficit in the adult as the descriptive model for analysis of the symptomatology, aetiology, physiopathology, diagnosis and therapy of the most frequent and characteristic form of MD. We will further study some clinical forms of nervous primary and secondary magnesium deficit. Finally we will deal with magnesium excess.
Nervous hyperexcitability due to chronic MD in the adult results in a non-specific clinical pattern which associates central, peripheral and autonomic neuromuscular symptoms, analogous to the symptomatology previously described in medical literature under various names, mainly latent tetany, hyperventilation syndrome, spasmophilia, chronic fatigue syndrome, neurocirculatory asthenia, idiopathic Barlow's disease and Da Costa syndrome. According to the subject, the etiopathogenic hypotheses and the main symptomatology, many other denominations have been used: Scythian disease, Icelandic, disease, Akureyry disease, Royal Free disease, Yuppies syndrome, neurolability, hyperactivity disorder without (HD) or with attention deficit (ADHD hyperkinetic syndrome; hypochondriasis, hysteria, melancholia, neurasthenia, depression, anxiety; cryptotetany, functional disorders, neurovegetative disorders, dysautonomic. disorders, reactive hypoglycemia, pseudo-myasthenia, epidemic neuromyasthenia, myalgic encephalomyelitis, post-viral syndrome, chronic mononucleosis, chronic candidosis, total allergy; functional cardiac disorders, irritable heart, soldier's heart, effort syndrome, labile blood pressure, Raynaud's syndrome; functional digestive disorders, irritable bowel syndrome, biliary dyskinesia; allergic or pseudo-allergic disorders, seasonal rhinitis, pseudo-asthma.9-20
The symptoms of nervous primary chronic MD in the adult include non specific central peripheral and autonomic manifestations of neuromuscular hyperexcitability.1-8, 21-38
Central or rather psychiatric symptoms consist of anxiety, hyperemotionality, fatigue, headaches (and sometimes migraine), insomnia, light-headedness, dizziness, nervous fits (panic attack particularly), lipothymiae, sensation of a 'lump in the throat', of 'nuchalgia' and 'blocked breathing'. Personality disorders are of neurotic type.
Neuromuscular disturbances symptoms are acroparaesthesiae, cramps, muscle fasciculations and myalgiae occurring more frequently than tetanoid or tetanic attack.
Autonomic functional complaints include chest pain, sine materia dyspnoea, blocked respiration, asthma-like dyspnoea, hepatobiliary dyskinesia, gastrointestinal spasms, precordialgia, palpitations, extrasystoles, dysrhythmias, Raynaud's syndrome, trends to orthostatic hypotension or conversely to borderline hypertension. In fact, the dysautonomic disturbances involve both the sympathetic and the parasympathetic systems: neurovegetative disorders may be amphotonic, alpha or beta sympathicotonic, vagotonic, with reactive hypoglycemia, pseudo allergic through hyper- receptivity to histamine and/or acetylcholine, sometimes with genuine allergy (Type I mainly).
When the chest pain mimics coronary heart disease, its relief with propranolol and worsening by nitrates may help to distinguish between a benign disorder and one with a coronary origin.
The evolution may be studded with various acute paroxysmal manifestations which can also sometimes be seen as initial signs of the illness. The major crises of acute tetany or of grand mal -- even reduced to a simple loss of consciousness -- remain, relatively rare. It is more often a question of nervous crises: neurotic, from the, 'attack of nerves' to the 'hysterical crises', or autonomic: lipothymia, reactive hypoglycaemia, pseudo-asthmatic crisis, vago-vagal syncope or, on the contrary, paroxysmal tachycardia. Sometimes, centripetal tingling sensations and stiffness of the extremities confer on these nervous crises a tetanoid character. But, essentially, they all have in common the fact that they occur in the context of fits of anxiety, sometimes with the impression of imminent death (panic attack), which cause hyperventilation gaseous alkalosis and self perpetuation of the crises.
On encountering this non-specific pattern the signs of neuromuscular excitability are of much greater importance. A genuine Chvostek's sign must be systematically sought. With a small (children's) reflex hammer the examiner percusses the soft parts of the cheek at the centre of a line running from the ear lobe to the labial commissure, avoiding the lightning contraction of a 'false Chvostek's sign' by tapping the bone of the zygomatic apophysis. It is important to consider the quality, and not the intensity, of this clinical criterion of neuromuscular hyperexcitability. It is only its presence or its absence which is significant, respectively quoted 1 or 0. Trousseau's sign is less sensitive than Chvostek's sign, but both sensitivities are increased by hyperventilation (Von Bonsdorff's test). Examination of the precordial area should be carefully conducted in order to search either for a non-ejection systolic click, or for a mid- to end-systolic or pansystolic murmur, or both, particularly in orthostatism in complete expiration in the left lateral decubitus position. Mitral valve prolapse (MVP) is a frequent dyskinesia due to chronic MD (about a quarter to one-third of cases).
Two tracings are always made: a neurophysiological examination (electromyogram (EMG)) and a cardiological examination (echocardiogram, (ECC)). In EMG testing for latent tetany, a Bronck's needle is inserted into the first-dorsal interosseous muscle of the left hand. The three classical facilitation tests are used: tourniquet-induced ischaemia lasting 10 min, post-ischaemia lasting 10 min after removal of tourniquet and lastly hyperventilation lasting 5 min. If the EMG shows one (or several) train(s) of autorhythmic activities, 'beating' for more than 2 min of one of the three tetanic activities (uniplets, multiplets or complex-tonicoclonic tracing(s)) a positive response is defined. As determined for the clinical criterion of nervous hyperexcitability, this neurophysiological criterion is only considered as a two-class variable. Either its presence or its absence is significant, respectively quoted 1 or 0 (Fig. 1). A repetitive EMG constitutes the principal mark of nervous hyperexcitability due to MD.
The 'excitability index' (EI) is defined as the sum of the two criteria of tetany. It allows different classes to be distinguished: one with simultaneous clinical and neurophysiological criteria, EI = 2; the others with only one criterion of their tetanic state, EI = 1, with two subgroups, either clinical (through positivity of the Chvostek's sign alone), or electromyographic (through positivity of EMG alone).
The ECC is the best tool for detecting mitral valve prolapse (MVP). With time-motion (TM) mode, three tracings are classical: a 'cuplike' tracing of mesotelesystolic MVP (of more than 2 mm) (Fig.2); a 'hammocking' tracing of holosystolic MVP (of more than 3mm) (Fig.3); and an isolated systolic anterior motion (SAM) (Fig.4) observed without obstruction or any septal thickening sign and in the absence of false systolic anterior motion.
Two-dimensional echocardiography appears to be more accurate than TM echocardiography. It eliminates a number of artefacts, particularly in the section of parasternal longitudinal cut (Fig.5) and the apical cut of the four heart chamber (Fig.6). The criterion for mitral prolapse is the billowing of one or both leaflets below the level of the mitral ring. It is very important to assess the leaflet thickness as well as its whole morphology and to appreciate the ventricular kinetic by calculating:
|end diastolic diameter - end systolic diameter|
|end diastolic diameter|
Pulsed Doppler echocardiography allows the detection of associated mitral regurgitation.
Particular clinical forms
In particular clinical forms, more sophisticated neurophysiological or cardiological explorations may be useful. Additional neurophysiological examinations can be used in the evaluation of the psychic and neuromuscular condition, i.e., standard and quantitative electroencephalogram, elelectropolygraphic study of afternoon sleep, electromystagmography, optokinetic test, skin conductance reflex, head scan and psychometric investigations such as Minnesota Multiphasic Personality Inventory (MMPI) or evaluation of A/B behaviour pattern by Jenkin's questionnaire.
Additional cardiological examinations may allow a better appreciation of the cardiac condition, i.e. standard and/or effort electrocardiogram, ambulatory electrocardiogram (Holter), phonocardiogram, or, very exceptionally, angiocardiogram.
Routine ionic assessment
Five ionic static investigations should always be made: plasma Mg (pMg), erythrocyte Mg (eMg), calcaemia, daily magnesuria and daily calciuria which can be determined by testing for urinary infection. An evaluation of magnesium intake through dietary inventory is desirable. These must first demonstrate normocalcaemia and the absence of hypercalciura sufficient to induce a secondary magnesium deficit. Next, the evaluation of pMg and eMg with reliable methods, such as atomic absorption spectrophotometry, allows the diagnosis of primary magnesium deficit through hypomagnesaemia in one-third of the cases of latent tetany due to MDI, with or without MVP (Table 1). Normal levels do not rule out the diagnosis of MDI. The histograms of LT patients (with or without MVP) and of controls overlap. If the tetanic group reveals gaussian-type magnesaemia curves with significant lower means (p < 0.001) both for pMg and eMg, their constitutive elements can be individually hypomagnesaemic (one-third of the cases), normomagnesaemic (almost two-thirds of the cases) and even, although seldom, hypermagnesaemic (Fig.7). Nevertheless one must emphasize the remarkable constancy of magnesaemia which lends importance even to small variations of magnesaemia. In numerous cases (particularly those with normal parameters) the diagnosis requires a magnesium oral loading test. The dose of magnesium to be administered is 5mg/kg/day of a well absorbed salt for a least 1 month. At this physiological dose level, oral magnesium is totally devoid of the pharmacodynamic effects of parenteral magnesium. Correction of symptoms by this oral magnesium load constitutes the best proof that they were due to magnesium deficiency, as checked after one month of treatment. However, a negative response does not permit rejection of a diagnosis of magnesium deficit. A mere increase of the magnesium intake is sometimes inadequate to ensure uptake or maintenance of cellular magnesium, in forms of deficit corresponding to magnesium depletion due to a dysregulation of the factors which control its metabolism. Therefore, if the response remains negative after 1 month's physiological magnesium oral loading test, it should be followed by use of the best specific control of the Magnesium metabolism dysregulating factors. Otherwise the investigation may be continued with the addition of a non-specific magnesium fixing agent to the magnesium salt: for example pharmacological doses of vitamin B6, physiological doses of vitamin D metabolites or of Mg-sparing diuretics able to reduce a possible hypermagnesuria (Table 2).
Thus pMg, eMg, calcaemia and calciuria are the first minimum ionic measurements required. They are often completed by checking daily magnesuria in order to control the effectiveness of the magnesium oral loading test after the first month of treatment.
Table 1. Plasma and erythrocyte magnesium
concentration in control group and in a hypomagnesemic
population of patients with latent tetany due to primary
|Plasma Mg||Erythrocyte Mg||Plasma Mg||Erythrocyte Mg|
|Table 2. Comparison between oral parenteral magnesium load test|
|Method of administration||Oral||Parenteral|
|Criteria of evaluation|
|Clinical||+ + +||0|
|Biological||+ + +||+ + +|
|Duration||Several weeks||4 h|
|Physiological magnesium oral load test constitutes the best proof that the clinical pattern is due to magnesium deficiency and the first step of its specific treatment. Parenteral magnesium load test serves as a rapid diagnosis of magnesium deficit, but without diagnostic differentiation between magnesium deficiency and magnesium depletion. As the clinical effect of parenteral pharmacological doses might be purely pharmacodynamic the results can be only assessed on objective criteria.|
Particular clinical forms
More sophisticated studies may be carried out to determine magnesium or other metabolites. Some studies are static: magnesium balance, ionized and diffusible fractions of plasma magnesium, levels of magnesium in cerebrospinal fluid, lymphocytes, bone, muscle, even platelets and exceptionally myocardium and brain. Other investigations are dynamic. The most useful is the parenteral magnesium load test, for example, Thoren's technique, the efficiency of which is judged by the modifications of the magnesuria 4 hours after the infusion of 0.25 mM (about 6mg/kg/day). Thus a retention which exceeds 20 per cent of the magnesium supplied, corresponding to a magnesuria lower than 80 per cent of the parenteral load, supports the diagnosis of magnesium deficit without diagnostic differentiation between deficiency, and depletion (positive Thoren's test). This parenteral load test serves as a rapid diagnosis of deficit, but it can only be carried out in hospital. As the clinical effects of parenteral pharmacological doses might be purely pharmacodynamic, the results can only be assessed on the basis of objective criteria. Finally a negative Thoren's test may be observed in cases of depletion ('false negative response' for this form of magnesium deficit), as well as in cases of a balanced metabolism ('true negative response' (Table 2).
Evaluation of modifications of the magnesaemia during a standardized effort (a treadmill test and/or a mental task), after glucose or calcium, or phosphorus loads and, exceptionally, radioisotopic exploration may complete investigations into magnesium balance; it is the only one able to reveal magnesium intestinal hyperexcretion. Other metabolites may be simultaneously explored in plasma, erythrocyte, blood, urine, such as potassium, zinc, iron, phosphorus, phosphatases, ATP, creatine, creatine kinase, glucose, aminoacids, essential fatty acids.
In rare cases, it may be interesting to evaluate both the neuroendocrine factors of magnesium homeostasis and the main disrupting elements. These include on the one hand measurements of adrenaline, noradrenaline, PTH, CT, insulin, taurine, cyclic AMP and GMP and/or, on the other hand, measurements of angiotensin, renin, aldosterone, vitamin D metabolites, free T3 and T4. Sometimes, it may be useful to investigate immunological data such as neuropeptides, cytokines, peroxidant and antioxidant factors, immunoglobulin levels, histamine, acetylcholine, noradrenaline, isoprenaline receptivities, and haemorrheological data such as platelet and erythrocyte explorations, familial data (history, HLA typing etc.).
Evolution and prognosis
Usually, the prognosis of the neuromuscular form of MDI is favourable, The evolution progresses by phases of decompensation against a background of latency. It appears of major importance to distinguish between the larger group of patients (95 per cent of the cases) with a benign prognosis and even with the possibility of complete recovery, and the smaller subgroup of patients (5 per cent of the cases) running the risk of complications. In this latter population, MD appears as a nervous and cardiovascular risk factor more prone to arrhythmias, sudden death, endocarditis, cerebral or visual or inner ear ischaemic events. Among the main factors of a favourable prognosis are latency or paucity of clinical and paraclinical symptomatology: i.e. low excitability index (IE = 1), absence of auscultatory signs, non-redundant and thin leaflets, absence of mitral regurgitation, normal weight, no oestrogen intake and lastly the deficient type of the magnesium deficit with its simple treatment.
Conversely, it is important to determine some pejorative prognosis factors, i.e. a rich symptomatology particularly with ventricular arrhythmias, a high excitability index (IE = 2), not so much a click as mitral regurgitation stigmata, redundant thick mitral leaflets especially in older men, prolongation of QTc interval, underweight, thrombogenic disturbances mainly through alterations of the platelet function, immunological disorders, constitutional factors such as the carrying of the HLA B35 antigen, exceptionally a familial history of sudden death and lastly the depletion type of the magnesium deficit with its often difficult and sometimes prolonged treatment.5
Aetiology of the nervous form of primary chronic magnesium deficit : magnesium deficiency and magnesium depletion
Marginal magnesium intake is fundamental in the causation of primary chronic magnesium deficit. Magnesium deficiency merely requires simple oral magnesium supplementation1-8, 26, 30, 39 , but cannot entirely explain the etiology of the nervous form of primary chronic magnesium deficit.
Magnesium deficiency alone cannot account for the following four observations: (1). the prevalence among the population (15-20 per cent); (2) the variable time of occurrence of therapeutic improvement; (3) the frequency of total or partial failure of treatment; (4) the constitutional character of the disease, associated with a strong heritability of erythrocyte magnesium and a strong correlation between the HLA-B35 tissue antigens either with latent tetany or mitral valve prolapse or erythrocyte magnesium40-42 . A constitutional lability of the nervous system or of magnesium metabolism must be involved: it' constitutes the part of magnesium depletion in this magnesium deficit requiring a more or less specific correction.1-8, 40-42
The mechanisms which control nervous hyperexcitability in magnesium deficit have been better analyzed in magnesium deficiency than in magnesium depletions8, 43 . The blood-brain barriers reduce the importance of peripheral systemic controls. In magnesium deficit diffuse nervous hyperexcitability mainly derives from local mechanisms.
The nervous form of primary chronic magnesium deficit may be, in both clinical circumstances and experimental deficiencies, either patent with a nervous symptomatology or latent without any clinical manifestations. A general scheme of the factors controlling nervous hyperexcitability due to magnesium deficit will explain both symptomatic and latent clinical forms.
Extrapolating from data in vitro, in situ or from other pharmacological manipulations to the physiopathology of in vivo magnesium deficit remains a methodological error. The great stability of brain magnesium during magnesium deficiency particularly disagrees with the very notion of extrapolating from in vitro or in situ extracellular or intracellular magnesium modifications. The complexity of biology must not be disregarded just because the present trend focuses on one aspect of the knowledge at the expense of many others. For example the great attention given to studies on magnesium and NMDA receptors should not minimize the interest of many other mechanisms.44
General scheme of nervous hyperexcitability due to magnesium deficiency8, 43 .
Symptomatic forms result in three direct cellular effects: disturbances in Ca distribution, decreased second messenger nucleotidic ratio and increased susceptibility to peroxidation. NHE is also linked to local and systemic mediated effects: increased activity of excitatory neuromediators; neuroamines (acetylcholine, catecholamines) and aminoacids (NMDA, AMPA, KAINATE), with a decreased activity of inhibitory neuromediators: serotonin 45 , aminoacids (GABA and taurine (TA) mainly), adenosine, melatonin and opioids accessorily, increased production of inflammatory and immunostimulant mediators; neuropeptides, (substance P, CGRP, VIP), prostanoids (LTB4, PXB2, PGE2), cytokines (NO, IL1, IL6, TNF# ) and of prooxidant factors (aldehydes such as MDA, TBARS, Fe) with decreased antioxidant system ( ↑ GPX, ↑ MT, ↑ Vitamin E, ↑ Se, ↑ TA). These factors induce → Ca i, ↑ cAMP / cGMP and ↑ polarization which cause the symptomatic form of nervous magnesium deficit.
Local compensatory factors instrumental in the latency of NHE due to magnesium deficit may also be direct and indirect: in the cell through modifications of Ca and Mg binding proteins, increase in Mg-like polyamines, stimulation of antioxidant system and free radical scavengers, local and systemic mediated compensatory factors: increase in several neuroprotective agents ( TA mainly, GTA and → MT), increased production of anti-inflammatory and immunosuppressive mediators (such as → IL4, IL5, IL10, → IFN) with decreased pro-oxidant factors ( ↑ MDA, ↑ TBARS, ↑ Fe) and increased antioxidant defence ( SoD, → MT, vitamin E, Se, → TA).
General scheme of nervous hyperexcitability due to magnesium depletion
Little is known yet of the mechanisms of magnesium depletion. Because of its links with causal dysregulations from various origins there exists a great variety of clinical and experimental magnesium depletions. Diverse experimental models of unequally severe magnesium depletions are used: genetic models in rats46 and mice47-49 and acquired models.
Among the latter some are secondary to an irreversible (or partially reversible) cause such as traumatic brain injury50-55 , blast injury56 or neurotoxic metal load associated with Mg (and Ca) deficiencies57-59 . Three of acquired experimental magnesium depletions are reversible. They associate various types of stress, capable of inducing excitotoxicity, with a low magnesium intake. Physiological magnesium supplementation and pharmacological doses of Na are acetyltaurinate are ineffective, but Mg acetyltaurinate has preventive and curative effects, in both the short and long term. These magnesium depletion models may be useful for screening various drugs for treatment of this type of magnesium depletion60-63 .
Further research should stress the differences between the mechanisms of magnesium deficiency and those of various types of irreversible and reversible magnesium depletions. It would be interesting to study neuromediators and neuromodulators, their precursors and their metabolites on the greatest possible number of structures of the central nervous system and to consider their correlations with ions, neuropeptides, cyclic nucleotides, cytokines, eicosanoids, enzymes, vitamins, metabolites. For example, as a rule (except in one study, concerning 2-month-old Wistar rats57 ) no changes have been found in brain magnesium concentrations during the course of magnesium deficiency in adult rats8, 43, 64, 65 ; in the experimental and clinical type of magnesium depletion related to pollutant metal load and low Mg and Ca intake, magnesium concentrations were decreased in various structures of the nervous central system57-59 .
There is no pathognomonic sign of nervous magnesium deficit. However, diagnosis is obvious before Chvostek's sign and/or tetanic EMG tracings without hypocalcaemia and/or hypercalciuria or a pattern of idiopathic PVM. Positivity of the dynamic oral, physiological magnesium load test constitutes the proof of a magnesium deficiency and the first stage of its therapy.
Usually it is very easy to distinguish between primary or secondary magnesium, deficit, be- cause the symptomatology of the causative disorder is clear. However, two eventualities raise problems: (1) Magnesium deficit secondary to hypercalciuria, where systematic dosage of daily calciuria is necessary; (2) magnesium deficit secondary to neurosis. Metabolic and psychological phenomena may be closely interrelated with mutual aggravation. There are true 'neuromagnesiprivic forms' where it is difficult to determine the predominance between neurosis and. magnesium deficit factors.
Therapy 1-8, 31
Physiological oral magnesium supplementation (5mg/kg/day) is easy and can be carried out in the diet (using preferably high magnesium density nutrient with the best possible availability, particularly magnesium in water) or with magnesium salts, with only one contraindication: overt renal failure (creatinine clearance < 15 ml). Specific and non-specific treatments of magnesium depletion are tricky when using, for example, pharmacological doses of vitamin B6, physiological doses of vitamine D, magnesium sparing diuretics, partial magnesium 'analogues', antioxidants i.e. sulphur compound, vitamine E, selenium.
The clinical forms of nervous primary and secondary chronic magnesium deficit vary greatly according to the main target of the symptomatology, age and gender, and to the association with non nervous symptomatologies of magnesium deficit. As a result there is hardly a discipline where one or another form is not to be found.
Clinical forms of nervous primary chronic magnesium deficit
Among the actual nervous clinical forms, the forms with insomnia, headache and fatigue will be stressed.
The insomniac or rather dyssomniac form1-8 can be analyzed with polygraphic study. Standard and. quantitative EEG exhibit 'diffuse irritative tracings' without focal lesions or paroxysmal, discharges. The recordings contain spikes, a pointed appearance of alpha and/or theta waves which is facilited more often by hyperventilation than by intermittent photic simulation, (Fig.8)1-8 . Quantitative analysis of the EEG effects of marginal magnesium deficiency66-67 shows three main points. During eye closed resting condition, absolute power is increased in several brain regions (frontal regions, right temporal and parietal regions) (Fig.9); frequency specific power is increased for each frequency band (delta, theta, alpha and beta) differently in various brain regions: for example theta power is increased in all but the left temporal regions (Fig.10); mean EEG coherence is decreased (Fig.11). Simple oral physiological magnesium supplementation may reverse these effects leading to less theta activity and more EEG coherence67 . The polygraphic study of afternoon sleep may complete the data of standard EEG: brevity of the time to fall asleep, superficial character of the sleep, frequency of awakening, hypnoagnosia. This dyssomnia must be responsible for morning asthenia. Electrocorticography in the magnesium-deficient rat allows us to make observations similar to those found in humans: sleep quality shows particularly similar alterations of the hypnograms2-8,68,69 .
Nervous hyperexcitability due to magnesium deficit may stimulate various types of cephalalgia tension-type headaches and particularly migraine1-8,21-38,70-71 . Clinical, studies in migraineurs have shown heterogeneous and inconstant decreases in extra or intra-cellular, total or ionized magnesium concentrations in serum, saliva, erythrocyte, mononuclear cells, even in brain. Positive therapeutic response to oral magnesium physiological load is unreliable2-8,20-38,70-84 . These data agree with some possible dysregulation of magnesium status in migraine (magnesium depletion which requires a more or less specific correction of the dysregulation). But when chronic magnesium deficiency coexists with migraine, it only constitutes a decompensatory factor whose control with simple oral physiological, magnesium supplementation should help in migraine therapy as an adjuvant treatment. Magnesium deficiency does not constitute the cause of migraine per se.
The clinical form of nervous primary chronic magnesium deficit with predominance of asthenia defines an aetiopathogenic form of chronic fatigue syndrome (CFS). Instead of the imprecise notion of CFS devoid of heuristic content the symptom of fatigue might be investigated through an aetiological approach as a simple clinical form of chronic primary magnesium deficit. The subjective symptomatology of chronic primary magnesium deficiency may, be similar. The diagnosis must rely on a magnesium oral loading test. At the physiological dose, (5mg/kg/day) oral magnesium is totally devoid of the pharmacodynamic effects of parenteral magnesium which may be observed irrespective of the magnesium status. Criteria for evaluation of the results of this oral, magnesium load checked monthly must concern not only magnesium parameters such as erythrocyte magnesium concentrations but also the whole clinical and biological pattern e.g. on the Nottingham health profile 38,85-87 .
Psychiatric forms of magnesium deficiency have been well identified1-8, 21-38, 88-89. Personality disorders are of the neurotic type. For example the Minnesota Multiphasic Personality Inventory (MMPI) finds a direct correlation between the 'neurotic triad' (hypochondria, depression, and hysteria) and the EMG marks of NHE due to magnesium deficiency. With all the psychometric evaluations, and with the DSM III R interview, particularly, the clinical pattern induced through magnesium deficiency was always neurotic (for example: generalized anxiety, panic attack disorders, and depression) but never psychotic. Magnesium deficiency never induces dementia. Although a neurosis pattern due to deficiency is frequently observed and simply cured through oral physiological supplementation, neuroses are preeminently conditioning factors for stress. Neuroses may therefore very frequently produce secondary magnesium depletion. They require their own specific antineurotic treatment and not mere oral magnesium physiological supplementation, but genuine forms of neurosis due to primary neural magnesium deficiency and magnesium depletion secondary to a neurosis may both exist. These two conditions may be concomitant and reinforce each other. In these stressful patients it may be difficult to establish the primary of one or of the other. In practice, physiological oral magnesium supplements may be added to psychiatric treatments, at least at the start. Although the psychiatric forms of magnesium deficiency may fit into a neurotic pattern but never result in dementia, some types of magnesium depletion can be instrumental in the physiopathology of several types of dementia 8 . Garden soil and drinking water in some Western Pacific areas with high incidence of amyotrophic lateral sclerosis and parkinsonism-dementia (ALS-PD) contain high concentrations of polluting metals such as Al, Fe and Mn and low concentrations of common metals such as Mg and Ca. Decreased exposure to traditional sources of foodstuffs and drinking water resulted in a dramatic decline in ALS-PD. These data as well as the links between aluminum load, magnesium status and dialysis encephalopathy -- hypothetically, Alzheimer's disease -- highlight the interest of corresponding experimental studies. With a high Al diet alone, Al content in the nervous system in rats showed no difference with a control group although serum Al was high. No degenerative process was observed. However, with an insufficient intake of Mg (with or without an insufficient intake of Ca) the same Al load induced an increase in Al and Ca concentrations in the nervous system and neurodegeneration with precipitation of insoluble hydroxyapatites 57-59 .
The dysregulations of magnesium status can not currently be controlled either in Alzheimer's disease, dialysis encephalopathy and ALS-PD or in corresponding irreversible magnesium depletions models 8,57-59,90 . Nevertheless the description of three possibly reversible models) of magnesium depletion, induced by the association of excitotoxicity and low magnesium intake appears very important: magnesium acetyltaurinate has preventive and curative effects in both short and long terms8,60-63 . These three models may be useful not only for screening various treatments of this type of magnesium depletion but also of possibly linked psychiatric and geriatric disturbances.
Neuromuscular clinical forms of chronic primary magnesium deficit with predominance of myalgias can appear as non articular forms of rheumatism such as fibromyalgia whose nosological pattern would suggest magnesium depletion with disturbances in magnesium distribution rather, than magnesium deficiency. Simple oral physiological magnesium supplementation is usually inefficient91-94 . Chronic magnesium deficit might also cause restless legs syndrome95 .
Dysautonomic clinical forms of nervous chronic primary magnesium deficit 2-8,21-38 may be cardiovascular, digestive or bronchopulmonary functional disorders, for example Raynaud's phenomenon (with an increase of circulating calcitonin gene-related peptide (CGRP) Mg-dependent)96 and asthma-like dyspnoea (which may coexist with asthma and constitute a decompensatory factor whose control with simple oral physiological supplementation may help in asthma therapy)97-98.
The dysautonomic disturbances may be amphotonic, # or # sympathicotonic,33-99 vagotonic, with reactive hypoglycemia, pseudoallergic through hyperreceptivity to histamine and/or acetylcholine, and sometimes with genuine allergy (Type I mainly)100-103 .
Clinical forms according to age and gender: risk populations for magnesium deficit
Magnesium needs are increased during growth. Children with attention deficit and/or hyperactivity disorder (ADHD), diagnosed using the DSM IV criteria of this disorder, may represent a clinical pattern of the nervous form of primary chronic magnesium deficit104 . Nevertheless standard stimulant ADHD therapy i.e. through dextroamphetamine significantly increases plasma Mg, without changes in red blood cell and mononuclear blood cell magnesium105 . Oral physiological magnesium supplementation is an efficient treatment of the various nervous forms of primary chronic magnesium deficiency in children: ADHD, hyperkinetic children, latent tetany, functional neurovegetative disorders2-8,104-107 , sometimes with speech delay or stuttering.108
Undetected early maternal magnesium deficiency could be the fountainhead of the so called 'constitutional' characteristics of the forms of chronic primary magnesium deficit, and even of more severe impairments: sudden infant death syndrome (and possibly respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy, in premature neonate particularly), some forms of infantile convulsions or psychiatric disturbances; and even in adults cardiovascular diseases and non-insulin-dependent diabetes mellitus109-118 . The protocol of the multicentre trials of maternal magnesium physiological supplementation should be followed not only in the mother, the fetus and the neonate, but also in the child and even throughout life from infancy until older age.
Geriatric89,119-124 and sport66, 125-139 populations constitute two typical magnesium deficit risk populations where magnesium deficiency is most often associated with magnesium depletion, but primary deficit in sports medicine seems to be more frequently related to magnesium depletion than to magnesium deficiency while in ageing the two mechanisms are in most cases simply associated44,121,126 .
Clinical forms of nervous secondary chronic magnesium deficit
The secondary forms of magnesium deficit can be spontaneous or iatrogenic. Their therapy first requires treatment directed toward their specific aetiologies. When this proves impossible or inefficient the treatment of each type of secondary magnesium deficit will differ according to the type of magnesium deficit. If deficiency (that is to say an insufficient magnesium intake) predominates, as frequently found in chronic alcoholism, mere oral physiological magnesium supplementation will be appropriates6, 31, 140-142 . When magnesium deficit secondary to alcoholism has been corrected, no alcoholic encephalopathy will be observed within a period of 5 years6, 8, 31, 43, 44, 143-144 . If depletion predominates, as in diabetes mellitus, where the part of magnesium deficiency usually appears less important than the dysregulation of magnesium status6,145 the specific or non-specific treatment of magnesium status dysregulation should be mainly used while oral physiological magnesium supplementation is most often ineffective6, 31, 145-148 .
Symptomatic magnesium excess is practically always iatrogenic either by magnesium therapy in spite of renal failure or during massive parenteral therapy. Clinical signs appear only when plasma magnesium is increased 2-3 times. Drowsiness and hyporeflexia are observed first. It is only when magnesaemia is at least five time higher that areflexia which precedes respiratory paralysis is observed.
The treatment is first to stop patent or hidden administration of magnesium. Afterwards the therapy should use the classical antidote intravenous Ca, artificial respiration, osmotic diuresis, anticholinesterasic drugs and cardiac glycosides, and lastly extrarenal dialysis.
Latent hypermagnesaemia has been observed in various iatrogenic or pathologic circumstances such as inadequate excretion the case of latent chronic renal insufficiency and dysregulation of mechanisms that control or disturb magnesium metabolism in nervous, endocrine, metabolic and immunological impairments. Lithium therapy appears to be effective in manic-depressive psychosis only in the presence of magnesium. The hypermagnesaemia observed in phaeochromocytoma testifies to the role of adrenaline secretion in magnesium metabolism. Hypermagnesaemia during respiratory acidosis is used in emergency therapy of hypomagnesaemia. Levels of erythrocyte magnesium rise during the progressive development of systemic diseases and solid tumors. Links between symptoms such as hypoexcitability, asthenia, bone and coagulation disorders have sometimes been conjectured. High oral pharmacological doses of magnesium may be instrumental in therapeutic chronic magnesium overload but with latent toxicity which, unrecognized, is capable of reducing lifespan31,44 . It is of basic importance to contrast the non toxicity of the usual physiological oral magnesium supplementation and the possible toxicity of pharmacological magnesium therapy which is potentially dangerous and even lethal3l-44.
Identification of the nervous form of magnesium deficit goes further than mere rhetorical interest. In the presence of a non specific pattern of hyperventilation or chronic fatigue syndrome, of neurosis, of idiopathic tetany, of Barlow's disease or of neurovegetative dystonia, one must have in mind primary magnesium deficit which should be controlled by specific and atoxic therapy. Primary or secondary magnesium deficit calls for a differential diagnosis distinguishing between magnesium deficiency due to an insufficient magnesium intake requiring simple oral physiological magnesium supplementation and magnesium depletion related to a dysregulation of the control mechanisms of magnesium status. The various types of magnesium depletion require more or less specific correction of their causal dysregulation. Further research should provide a better insight of the pathophysiological mechanisms which differentiate magnesium deficiency from the various types of magnesium depletion and suggest efficient treatment in experimental and clinical magnesium depletions and in related types of pathologies such as neurodegenerative diseases.
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