 |
Printable
PDF Version
Leo Galland - Great
Smokies Diagnostic
Laboratory, Asheville,
N.C., USA
Abstract
Magnesium has a profound
effect on neural
excitability; the most
characteristic signs and
symptoms of Mg
deficiency are produced
by neural and
neuromuscular
hyperexcitability. These
create a constellation
of clinical findings
termed tetany syndrome
(TS). TS symptoms
include muscle spasms,
cramps and hyperarousal,
hyperventilation and
asthenia. Physical signs
(Chvostek's, Trousseau's
or von Bonsdorff's) and
abnormalities of the
electromyogram or
electroencephalogram can
usually be elicited.
Signs and symptoms of TS
are frequently
encountered in clinical
practice, especially
among patients with
functional or
stress-related
disorders. The role of
Mg deficit in TS is
suggested by relatively
low levels of serum or
erythrocyte Mg and by
the clinical response to
oral Mg salts, which has
been demonstrated in
controlled studies.
Among the more serious
neurologic sequelae of
TS are migraine attacks,
transient ischemic
attacks, sensorineural
hearing loss and
convulsions. Mg
deficiency may
predispose to
hyperventilation and may
sensitize the cerebral
vasculature to the
effects of hypocarbia.
Mg deficiency increases
susceptibility to the
physiologic damage
produced by stress, and
Mg administration has a
protective effect;
studies on noise stress
and noise-induced
hearing loss are taken
as an example. In
addition, the adrenergic
effects of psychological
stress induce a shift of
Mg from the
intracellular to the
extracellular space,
increasing urinary
excretion and eventually
depleting body stores.
Drugs used in neurology
and psychiatry may
affect Mg levels in
blood and may diminish
signs of tetany, making
assessment of Mg status
more difficult.
Pharmacologic use of Mg
can decrease neurologic
deficit in experimental
head trauma, possibly by
blockade of N-methyl-D-aspartate
receptors. In
conjunction with high
doses of pyridoxine, Mg
salts benefit 40% of
patients with autism,
possibly by an effect on
doparnine metabolism.
Text
Magnesium ions have a
well-established
depressant effect on the
central nervous system
[1] and on neuromuscular
transmission [2]. The
cardinal symptoms of
severe Mg deficiency in
humans are
neuropsychiatric:
asthenia, tremor,
convulsions,
irritability, tetanic
spasms, muscle cramps
and confusion [3-9].
These symptoms are
largely produced by
heightened neural and
neuromuscular
excitability [3, 7], a
condition called tetany.
In experimental human Mg
deficiency, asthenia and
tetany are usually
accompanied by
hypocalcemia and
hypokalemia, leading
some authors to
speculate that Magnesium
and Stress http://www.mdheal.org/magnesiu1.htm
(1 of 18) [10/19/2000
9:41:41 PM] the symptoms
of Mg deficiency result
from ionic interactions
and are not Mg specific
[9]. In most clinical
studies [3-7], however,
asthenia and tetany
occur when serum calcium
and potassium are
normal, suggesting that
Mg deficit may produce
neuromuscular symptoms
without altering
circulating levels of
other ions. Furthermore,
when mild hypocalcemia
occurs in Mg-deficient
tetany, administration
of intravenous Ca does
not improve symptoms or
signs, whereas
intravenous Mg improves
clinical status and
raises both Mg and Ca in
blood, substantiating
the ability of Mg
deficiency alone to
cause tetany [6, 7, 9].
Although mild
hypomagnesemia is quite
common in hospitalized
patients [10, 11], the
identification of tetany
caused by mild Mg
deficiency is so
uncommon in the US that
individual case reports
are published [12]. One
explanation for this
discrepancy is that
hypomagnesemia can occur
without alteration of
cerebrospinal fluid
(CSF) Mg concentration
[13]. Another
explanation is that the
signs and symptoms of
tetany are usually so
subtle or nonspecific
that they go
unrecognized.
Tetany Syndrome and Mg
Deficiency
Tetanic seizures were
treated with mineral
salts as early as the
seventeenth century
[14]. The naming and
description of the
tetany syndrome (TS),
with manifestations that
varied from emotional
lability and
paresthesias to
carpal-pedal spasm and
epileptiform
convulsions, occurred
during the second half
of the nineteenth
century [15]. The
recognition of physical
signs (Trousseau's,
Chvostek's and von
Bonsdorff's) led to an
understanding that
tetany could occur in a
latent form with
symptoms occurring only
intermittently or not at
all [15]. Interest in
the diagnosis of latent
tetany in
English-speaking
countries was primarily
related to tetany as a
sign of Ca deficiency
[16, 17]. Once accurate
measurements of serum Ca
and ionized Ca became
commonplace, interest in
the phenomenon of tetany
waned. On the European
continent, in contrast,
research and speculation
concerning the phenomena
of tetany continued
[15]. Electromyography (EMG)
[18] and
electroencephalography
[19] characteristics of
tetany were described.
The syndrome of latent
tetany or Ispasmophilia'
was recognized as a
common, multifaceted
disorder [15]; its
researchers recognized
that it was very similar
to the condition
described in the English
literature by the names
neurocirculatory
asthenia and
hyperventilation
syndrome [20, 21].
Physicians treating TS
identified subtle
abnormalities in Ca or
electrolyte transport in
the disorder [22, 23].
Kugelberg studied the
mechanisms of Chvostek's
sign [24] and
Trousseau's and von
Bondorff s signs [25].
He concluded that tetany
is primarily a disorder
of accomodation of
nerves which adapt to a
gradual decline in
transmembrane electrical
potential by altering
the voltage requirements
for generating an action
potential [26]. This
process protects nerves
from discharging
inappropriately in
response to changes in
their physical or
chemical milieu. It is
impaired, he found, by
Ca deficiency and by
ischemia; he did not
study the effects of Mg.
In 1959, Roselle and de
Doncker [27] described
the EMG in TS associated
with chronic Mg
deficiency. Since 1960,
Durlach [20] has
maintained that chronic
Mg deficit is the
commonest cause of TS.
He divides the symptoms
into five categories:
(1) central
manifestations of
emotional lability,
breathlessness and
hyperventilation,
tremor, headache,
dizziness, insomnia and
asthenia; (2) peripheral
manifestations of
paresthesia,
http://www.mdheal.org/magnesiu1.htm
(2 of 18) [10/19/2000
9:41:41 PM] formication,
fasciculation, cramps,
radicular pain and poor
exercise tolerance; (3)
organ-specific
functional disorders
producing palpitation,
chest pain, pallor,
diaphoresis, Raynaud's
phenomenon, biliary
dyskinesia or spastic
colon; (4) 'trophic'
phenomena with fragility
of nails, hair and
teeth; (5) acute crises
characterized by
hyperventilation,
syncope, convulsion,
carpal-pedal spasm. TS
due to chronic Mg
deficiency may be
separated from other
neuropsychiatric
disorders with similar
symptoms by the presence
of Chvostek's sign
(found in 8 5 %),
midsystolic cardiac
clicks (found in 3 5 %)
or Trousseau's sign
(found only in the
severer cases). EMG of
the intrinsic muscles of
the hand during or after
ischernia or
hyperventilation shows
repetitive spontaneous
discharges in most
cases;
electroencephalography
often manifests 'diffuse
irritative'
abnormalities with
spikes and sharp waves;
an echocardiogram may
confirm the presence of
mitral valve prolapse,
which is found in over a
third of cases. The
number of signs present
is generally
proportional to the
severity of the Mg
deficit. Serum and
erythrocyte Mg
concentrations are
generally lower in a
population with TS than
in control populations,
but in any individual
case, the serum and/or
erythrocyte Mg may be
normal when symptoms
occur. Indeed, the
central
hyperexcitability
symptoms tend to be
greater when either
serum or red cell Mg is
reduced than when both
blood compartments show
low Mg levels [28].
Difficulty in precisely
differentiating TS
caused by Mg dificit
from other conditions
can be anticipated from
Durlach's [20] own
observation that central
symptoms may occur in
the absence of
peripheral symptoms,
Chvostek's sign or EMG
abnormalities,
especially in men.
Furthermore, Chvostek's
sign can be elicited in
4.5-36 % of 'normal
subjects' [17, 29, 30],
and the EMG
abnormalities of tetany
occur in 17-45% of
normal subjects under
certain experimental
conditions [29, 31].
These tetanic
manifestations in
healthy subjects, called
'spasmorhythmia', are
thought to represent a
constitutional
susceptibility to the
development of TS, which
becomes manifest under
conditions of Mg or Ca
deficiency, alkalosis or
emotional distress [29].
A Belgian team studied
the correlates of
tourniquet-induced
repetitive EMG activity
and Chvostek's sign in
39 healthy females and
39 healthy males,
defining spasmorhythmia
as 2 min or more of
repetitive activity
induced by 10 min of
forearm ischernia.
Individuals with
spasmorhythmia differed
from individuals without
spasmorhythmia in having
a slightly lower plasma
Mg concentration (0.79
vs. 0.82 mmol/l, p <
0.005) and a greater
tendency to emotional
lability, anxiety,
depression, crying
spells, mental anguish
and phobias elicited on
blinded psychiatric
interview by two
different observers
[32]. Duc et al. [33]
reported results on
5,645 patients examined
for TS over a 10-year
period. Their principal
symptoms were insomnia,
headache, back pain,
paresthesia,
fasciculation, muscle
cramps, chest pain,
palpitation, palpebral
fluttering, dizziness,
dyspepsia and
constipation. Chvostek's
sign was present in 60%,
and tetanic crises
occurred in 25%; EMG
signs of latent tetany
could be elicited in 89%
of patients not taking
psychotropic drugs.
There was no significant
difference in plasma Mg
between patients with TS
and a control group, but
erythrocyte Mg was 10%
lower in the tetanic
patients (p < 0.001). In
the subgroup subject to
tetanic crises,
erythrocyte Mg was 7.5%
lower than in the
subgroup without tetanic
crises (p < 0.005).
The reader may well
wonder whether TS is
commonly a manifestation
of Mg deficiency, as
advocated by Durlach
[20], or anxiety
neurosis, or the result
of habitual http://www.mdheal.org/magnesiu1.htm
(3 of 18) [10/19/2000
9:41:42 PM]
hyperventilation and
hypocapnia, as advocated
by Lum [34]. Fehlinger
and Seidel [35]
concluded that
'so-called genuine
tetany' and
hyperventilation
syndrome
wereindistinguishable by
history, physical
examination,
psychological testing or
electrodiagnostic
testing. They considered
some psychometric
parameters, such as
impaired concentration
and increased reaction
time, to indicate an
organic component to the
disorder. When compared
to control patients,
serum Ca and Mg were
both significantly
reduced. When they
separated tetanic
patients with attacks of
hyperventilation from
patients without
hyperventilation
attacks, they found that
hyperventilators had
significantly lower Mg
levels than
nonhyperventilators and
concluded that Mg
deficiency was a
probable cause of
hyperventilation. They
postulate that Mg
deficiency, by impairing
mitochondrial function,
increases the relative
amount of
anaerobic glycolysis in
the brain, creating a
local metabolic acidosis
which stimulates
hyperpnea [36].
Fehlinger et al. [37]
performed a
double-blind,
placebo-controlled study
of a pyrrolidone
carboxylic acid salt of
Mg in 64 patients with
TS and found a
significant improvement
in overall symptoms and
in hyperventilation
attacks associated with
the active drug. The
therapeutic effect was
accompanied by a small
but significant increase
in plasma Mg and K
concentrations. It is of
interest that muscle
cramps, paresthesias and
changes in the EMG were
similarly affected by
active and placebo
therapy, without
significant difference.
In another study,
comparing Mg citrate
with placebo, the
authors found
significant improvement
in muscle strength and
mental concentration and
a decrease in
hypocapniainduced
cerebral
vasoconstriction with
active drug [38].
Although these studies
do not prove that TS is
a distinct disorder
commonly caused by a
primary Mg deficiency,
they do demonstrate that
tetanic phenomena are
common occurrences
associated with symptoms
generally regarded as
functional or anxious,
and are usually
accompanied by low
levels of Mg in one
blood compartment or
another. Fehlinger [21]
attributes some
neurologic disorders
which accompany TS, such
as migraine headaches,
to the combined
vasospastic effects of
Mg deficiency and
secondary hypocapnia.
Support for this notion
comes from studies
showing a high
prevalence of migraine
symptoms (28%) in
patients with mitral
valve prolapse P9], a
condition which shows a
strong correlation with
TS [20]. Although serum
Mg is no different
between migraine
patients and controls,
CSF Mg is significantly
lower in migraine
patients than in
controls (p < 0.001)
[40]. A group at Henry
Ford Hospital measured
intracellular Mg in
brains of migraine
patients using
31pnuclear magnetic
resonance spectroscopy
[41]; levels were 19%
lower in migraine
patients studied during
an attack than in
controls (p <0.02). The
small number of patients
studied between attacks
prevented adequate
analysis to determine
whether low brain Mg
occurs interictally as
well. Dexter [42]
reported that
rebreathing aborted
migraine attacks in 6
migraine patients; this
would suggest that the
cerebral vasculature in
migraine patients is
very sensitive to pC02,
a possible effect of Mg
deficit [38].
Fehlinger [21] has also
attributed some of the
infrequent neurologic
disorders encountered in
TS patients to
vasoconstriction induced
by Mg deficit. The
Alturas were the first
to suggest and
demonstrate that Mg
deficits can induce
cerebrovasospasm [43].
Transient ischemic
attacks (TIA) and
specific prolonged
reversible ischemic
neurologic deficits
occur in about 10 % of
TS patients evaluated in
Fehlinger's Berlin
clinic [36]. Over
http://www.mdheal.org/magnesiu1.htm
(4 of 18) [10/19/2000
9:41:42 PM] 90% of
neurologic events in
these patients are
rapidly reversible; the
remainder are prolonged.
No deaths have occurred
in any of the 103
patients reported, nor
has there been any
evidence of myocardial
infarction or of
extracranial
cerebrovasular
obstruction. The median
age for the first TIA
was 34 years; 88.3% of
patients were female.
This is in marked
contrast to the
epidemiology of TIA
associated with
arteriosclerotic
cardiovascular diseases.
In 19.4%, the first TIA
was associated with the
onset of a more
generalized TS, in 5.6%
TS developed some time
after the TIA and in 75
% TS had been present
for several years prior
to the first TIA.
Convulsions were
reported by 10.7% of TS
patients with TIA,
compared to 5 % of TS
patients without TIA.
Hyperventilation attacks
were equally present in
TS patients with or
without
TIA (75% vs. 69%); serum
Mg was nonsignificantly
lower in the presence of
TIA. Hypomagnesemia
(<0.7mmol/1) was present
in 22.9% of TS/TIA+
patients, 15.8% of
TS/TIA- patients and 4.2
% of controls (p<0.01).
Fehlinger et al. [44]
also evaluated patients
with idiopathic sudden
deafness for the
presence of TS. Signs
and symptoms of latent
or manifest tetany were
present in 93% of
females and 38 % of
males. There were no
significant differences
in serum or erythrocyte
Mg between sudden
deafness patients and
controls. Among women
whose hearing loss had
improved spontaneously
after the initial
episode of deafness,
however, erythrocyte Mg
was 15.7% higher than
among women whose
hearing loss remained
constant or worsened (p
= 0.01). These data do
not establish a clear
relationship between
sudden deafness and Mg
or a role for TS in the
pathogenesis of
sensorineural hearing
loss; they do suggest a
protective role for
erythrocyte Mg in women
with sudden deafness.
Mg, Noise and
Sensorineural Hearing
Loss
Experimental support for
a relationship between
Mg status and
sensorineural hearing
loss comes from the work
of Ising et al. [45].
They first studied
auditory-evoked
potentials in guinea
pigs fed an Mg-deficient
diet and then variably
repleted with
Mg-enriched drinking
water. There was a
significant negative
correlation between the
Mg content of perilymph
and the degree of
hearing loss induced by
chronic noise stress (r
= -0.86) [45]. Next,
they studied
auditory-evoked
potentials in rats on
Mg-enriched and Mg-poor
diets exposed to noise
stress for 16 h a day
[46]. The relatively
mild Mg deficiency
sustained over a period
of 3 months produced a
20-35% decrease in Mg
concentrations of
plasma, erythrocytes and
perilymph, yielded none
of the pathological
effects associated with
severe Mg deficiency in
rats and had no effect
on auditory threshold.
Noise stress produced
low levels of hearing
loss (7-14 dB) in rats
fed Mg-enriched food and
much greater hearing
loss (24 dB) in
Mg-deficient rats. The
degree of hearing loss
was negatively
correlated with plasma
and erythrocyte Mg
levels. In a subsequent
study [47] they found
that Magnesium and
Stress http://www.mdheal.org/magnesiu1.htm
(5 of 18) [10/19/2000
9:41:42 PM] gentamycin-induced
hearing loss was
markedly increased by
mild Mg deficiency.
Administration of
gentamycin for 5 days to
normal rats caused an
elevation of hearing
threshold of 11 dB at 10
kHz and 13 dB at 20 kHz,
which had decreased to 2
and 6 dB, respectively,
a week later. In Mg
deficiency, the hearing
loss was 42 dB at 10 kHz
and 43 dB at 20 kHz; I
week later, despite a
normal diet, hearing
loss had not improved in
the Mg-deficient group.
Complete irreparable
deafness occurred in 36%
of Mg-deficient rats and
in none of the normal
rats given gentamycin.
In a human study,
fighter pilots
occupationally exposed
to noise stress
underwent evaluation of
hearing thresholds at 3,
4 and 6 kHz and serum Mg
concentrations [48]. The
correlation between
age-adjusted hearing
loss and serum Mg was
-0.61 (n = 24, p <
0.001). The authors
speculate that
alterations in K, Na and
Ca transport induced by
mild Mg deficiency are
responsible for impaired
function of cochlear
hair bundles [49].
Stress/Mg Interactions
The effect of Mg status
on hearing loss is
complicated by the
effect of noise stress
on Mg metabolism; this
well-studied interaction
has yielded considerable
support for clinical
theories concerning the
relationship between
stress and Mg in diverse
situations.
Consequently, it is
reviewed here in detail.
Two hours of noise
stress in guinea pigs
causes a mean reduction
in erythrocyte Mg of 2
mmol/g dry weight and a
simultaneous
increase in serum Mg by
0.8 mmol/l, suggesting a
shift of Mg from the
intracellular to the
extracellular
compartment [50]. In
rats, chronic noise
stress causes an
increase in serum Mg and
a decrease in
erythrocyte and
myocardial Mg [46, 50].
When Mg intake is
normal, 20 days of noise
stress raises the mean
serum Mg from 0. 9 5 to
1. 15 mmol/l and lowers
mean erythrocyte Mg from
about 5.8 to 4.8 mmol/kg
dry weight. After 24 h
of silence, the serum Mg
drops below the control
level to 0.90 mmol/l,
and the erythrocyte Mg
increases but does not
reach control levels,
failing to rise above
5.4 mmol/kg dry weight,
even with a fourfold
increase in dietary Mg.
Myocardial Mg decreases
in parallel with
erythrocyte Mg [50]. The
implication is that a
net excretion of Mg
occurs in response to
noise stress, leaving
the animal depleted. In
fact, Mg excretion
increases from a control
value of 6 to 16 mmol/g
creatinine under noise
stress [50]. Similar
results occur in humans.
Ising et al. [51]
exposed 57 human
volunteers to work under
7 h of traffic noise or
7 h of quiet. Under
noise stress, the serum
Mg increased by 2.4% (p
0.01), the urine Mg
increased by 15 % (p
0.01) and the
erythrocyte Mg decreased
by 1.5% (p = 0.05). The
degree of increase in
serum Mg correlated with
a decrease in work
performance (r = 0.37, p
= 0.05). Brewery workers
laboring for I week in a
noisy hall (95 dB) lost
5% of their blood cell
Mg content compared to a
similar group using ear
protectors [52].
The metabolic effects of
noise stress in humans
and animals are
accompanied by changes
in catecholamine
metabolism. Brewery
workers working for 1
day with ear protection
and 1 day without
excrete significantly
more norepinephrine (NE)
and its metabolite
vanilly1mandelic acid in
urine under the noise
stress condition [52].
In a similar study of
male volunteers exposed
to traffic noise,
urinary NE increased
8.5% (NS) and urinary
epinephrine increased 27
% (p = 0.01) during the
7-hour period of noise
stress [51]. Pronounced
increases in
catecholamine excretion
also occur in rats
exposed to noise [53,
54], although it appears
that preexisting Mg
deficiency is necessary
for this effect to
http://www.mdheal.org/magnesiu1.htm
(6 of 18) [10/19/2000
9:41:42 PM] occur [53].
The effect of Mg status
on the behavioral and
biochemical response to
noise completes the
cycle. Urinary
catecholarnine excretion
increases progressively
with increasing dietary
Mg deprivation in rats
without noise stress.
The addition of noise
further increases NE but
not epinephrine
excretion; the more
pronounced the noise and
the greater the Mg
deficit, the higher the
catecholamine excretion,
with epinephrine and NE
excretion reaching 5 and
10 times control levels
under extreme but
nonlethal conditions
[48]. Noise stress in
Mg-deficient rats causes
a decrease in myocardial
Mg and an increase in
cardiac Ca concentration
that is independently
proportional to the
degree of Mg deficiency
and the duration of
noise [55]. The decrease
in myocardial Mg
displayed a negative
linear correlation with
the excretion of NE
[50].
Erythrocyte Mg levels
are inversely
proportional to some
effects of noise stress
in humans and animals.
Erythrocyte Mg is
negatively correlated
with self-reported noise
sensitivity (r = -0.27,
p = 0.05), with
noiseinduced emotional
lability (r = 0.37, p =
0.01) and with
noise-induced feelings
of tenseness (r = -0.29,
p = 0.05) in human
volunteers [46]. The
hypertensive effect of
injected NE in
noise-stressed rats was
negatively correlated
with erythrocyte Mg (r =
-0.70, p < 0.01) [47].
Deposition of collagen
in the rat heart, a sign
of physiologic aging, is
synergistically
accelerated by noise
stress and Mg deficiency
[56]. Mg supplementation
prevents this effect;
caffeine feeding
increases it [57]. In
summary, noise exposure
causes an increased
excretion of
catecholamines and a
shift of Mg from the
intracellular to
extracellular space with
a resulting increase in
Mg excretion. This
effect on Mg metabolism
is initially protective;
the relatively high
serum Mg level of acute
stress is thought to
buffer the physiologic
response to stress.
Prolonged noise exposure
causes a gradual Mg
depletion associated
with accelerated
physiologic aging.
Dietary Mg deficiency
aggravates in a
synergistic fashion all
the effects of noise
stress, including
ototoxicity, adrenergic
hyperactivity, Mg
depletion, psychological
and physiologic
deterioration. Mg
supplementation appears
to protect against some
of the effects of noise.
Humans with relatively
high intracellular Mg as
measured by the
erythrocyte level are
less adversely affected
by noise than are humans
with relatively low
erythrocyte Mg. The
extra-aural effects of
noise can be produced by
a wide variety of
stressors, including
overcrowding and
prolonged handling of
animals [39,45]. Guinea
pigs are so sensitive to
the effects of handling
that serum Mg changes
induced by noise and
diet can be obscured by
experimental design that
does not control for
handling stress [39].
Rats injected with
direct- and
indirect-acting
sympathornimetic amines
similarly develop
intracellular Mg
depletion, which is
associated with an
increase in
intracellular Ca and Na;
adrenergic activity
appears to mediate the
impact of stress on Mg
metabolism [58]. Dietary
Mg depletion accelerates
these electrolyte
shifts; Mg
supplementation reduces
them [53, 59]. The type
A or 'coronary prone
'behavior pattern in
humans is characterized
by time urgency,
impatience, extreme
competitiveness
and hostility when
compared to itsopposite
or type B pattern [60].
When stressed
psychologically, type A
individuals show
significantly greater
increases in plasma and
urinary catecholamines
and cortisol than type B
individuals [61], and
correspondingly greater
changes in heart rate,
blood pressure and
vascular resistance
[62]. In 1980, Altura
[63] first suggested
that the type A behavior
pattern may be
associated with Mg
deficiency. Henrotte et
al. [64] studied the
effect of a signal
detection task on Mg
metabolism of 20 type A
and 19 type B French
http://www.mdheal.org/magnesiu1.htm
(7 of 18) [10/19/2000
9:41:42 PM] university
students. Mental stress
increased the urinary
catecholamines and serum
free fatty acids of both
groups; the effects were
significantly greater in
type A than in type B
individuals. Plasma Mg
increased by 1.5% (p <
0.05), and erythrocyte
Mg decreased by 0.5% (p
< 0.01) in type A
subjects; there was no
change in these levels
for the type B subjects.
The high degree of
statistical significance
for these small changes
was due to the
homogeneity of response
in type A subjects,
producing a very low
standard deviation.
Henrotte [65] attributes
the flux of Mg from
erythrocyte to plasma to
the stimulation of
0-adrenergic receptors
on the erythrocyte
membrane. The
experimental
observations of the
effects of various types
of stress on electrolyte
and catecholamine levels
are consistent with
clinical observations of
patients with TS.
Excretion of
catecholamines is 89%
greater (p < 0.001), and
excretion of
vanillylmandelic acid is
53% greater (p < 0.01)
in TS patients than in
controls; this increase
in adrenergic activity
correlates with lower
serum K and serum and
erythrocyte Mg and
higher venous blood pH
[66]. Ca and Na content
of erythrocytes from TS
patients is greater in
patients with TS than in
controls [67].
Administration of Mg
salts produces a small
increase in
serum K and serun and
erythrocyte Mg in these
patients but does not
affect erythrocyte Ca or
Na levels [68]. There
are no data to indicate
that Mg therapy by
itself lowers
catecholamine excretion
in these patients and
most clinicians favor
the use of P-blockers in
addition to Mg [20, 21,
29]. In reviewing his
experience treating
nervous children with
TS, Ducroix [69]
concluded that the
pathogenesis of the
syndrome is still
unclear, particularly
with regard to the
interaction of
psychogenic and
metabolic factors, and
that the best test of Mg
deficiency was a trial
of oral Mg therapy. This
is the ultimate position
of Durlach [20] and
Fehlinger [21] also.
Both authors recommend
the use of acidic salts
of Mg, believing that
they have superior
absorption and do not
aggravate the alkalosis
manifested by some TS
patients. Durlach
recommends 5 mg/kg/day,
and Fehlinger prefers
6-7 mg/kg/day. Ducroix
prefers 10 mg/kg/day for
children because of
their low body weight
and increased
requirements for growth.
Fehlinger has described
a group of patients with
a continuous requirement
for oral Mg at doses of
400-1,400 mg/day. When
hospitalized and given
placebo instead of Mg,
these patients drop
their plasma Mg from a
mean of 0.85 to 0.74
mmol/1 within 1 week and
become acutely
symptomatic [21].
In summary, there are
groups of individuals
among whom asthenia and
dysphoria are common
complaints, who show
elevated urinary
catecholarnines and
mildly depressed
circulating Mg levels.
When properly examined,
almost all these
patients show sings of
latent tetany. Their
symptoms generally
improve with oral Mg
supplementation. It is
not clear why these
individuals are so
sensitive to the effects
of mild Mg deficit or
whether their
deficiencies are
primarily caused by diet
or metabolism. The
biological and
psychological profiles
of these patients can be
predicted from studies
of humans and animals
subjected to prolonged
noise; it is likely that
an interaction between
the effect of chronic
stress and inadequate Mg
intake can explain the
appearance of this
syndrome and also the
variability of serum Mg
levels, which are raised
by stress and lowered by
deficient diet.
Interest in this
phenomenon in the
English-speaking world
is likely to be
stimulated by a recent,
highly publicized
British study of
patients with chronic
fatigue 'syndrome [70].
http://www.mdheal.org/magnesiu1.htm
(8 of 18) [10/19/2000
9:41:42 PM] Their mean
erythrocyte Mg was 0.1
mmol/1 lower than that
of a carefully selected
control group (p <
0.001). Thirty-two
patients were randomly
treated with weekly
injections of MgS04, 1
g, or placebo, for 6
weeks. Erythrocyte Mg
increased significantly
in the active treatment
group and did not change
in the placebo group.
Fatigue, muscle pain and
emotional lability were
significantly improved
by Mg injections. This
study is important
because of the
correlation between
biochemical and symptom
response and the use of
a randomized
double-blind
placebo-controlled
design, which is rarely
used in European studies
of Mg therapy.
Mg and Epilepsy
Although epileptic fits
occasionally occur in TS
and were reported in
5-10 % of Fehlinger's
cases, the prevalence of
TS or Mg deficiency in
idiopathic epilepsy has
not been established. A
Brazilian study found
lower serum Mg in
epileptic patients than
in controls (1.868 vs.
2.087 mEq/1, p < 0.001),
but all levels were
within the normal range
[71]. Immediately
following a seizure,
both serum and CSF Mg
increased. Others have
found CSF Mg to increase
after a seizure [72],
but serum Mg does not
increase consistently
[73]. Epilepsy itself
does not cause Mg
depletion, but
anticonvulsant drug
therapy may [74-77].
Steidl et al. [78]
studied serum and
erythrocyte Mg in
relationship to drug
use, serum drug
concentrations and Mg
therapy in epileptics.
No significant effects
on serum Mg were found;
erythrocyte Mg was
significantly lowered (p
< 0.05) in patients with
phenobarbital levels >
20 gg/ml or with
diphenylhydantoin levels
> 10 gg/ml. Mg lactate 3
g/day produced an
increase of 25.6% (NS)
in erythrocyte Mg when
administered to patients
taking both
phenobarbital and
diphenylhydantoin; in
patients taking
phenobarbital,
diphenylhydantoin and
primidone, the same dose
of Mg lactate raised
erythrocyte Mg by 46.7%
(p < 0.05). The clinical
significance of Mg
depletion and repletion
in these patients was
not clear in that most
patients had been free
of seizures
for 1 year before the
study commenced.
The Major Psychoses and
Mg Status
Kirov [79] has recently
reviewed the literature
on Mg status of patients
with schizophrenia or
bipolar affective
disorder. There was no
consistent effect of
schizophrenia, mania or
depression on serum Mg
across 40 studies or on
CSF Mg across 12
studies. Neuroleptic
therapy in chronically
ill patients
consistently lowered
serum Mg in 8 studies
reviewed by Kirov.
Decrease in stress
hypermagnesernia may
explain the effect [80].
Lithium, on the other
hand, does not alter
serum Mg when
administered over
several months [81, 82].
In that a single dose of
Li given to patients and
healthy volunteers
acutely raises serum
[83] and plasma [84] Mg,
it is likely that Li has
direct and indirect
effects that alter
extracellular Mg in
opposite directions. The
effect of imipramine
with or without
electroconvulsive
therapy on Mg metabolism
appears to be variable
[85]. Although disorders
in Mg metabolism do not
play a primary role in
the major affective
disorders or psychoses,
Kirov [79] has proposed
a secondary role for Mg
deficiency in some
acutely ill psychiatric
patients. He speculates
that the higher than
http://www.mdheal.org/magnesiu1.htm
(9 of 18) [10/19/2000
9:41:42 PM] normal
variability of serum or
plasma Mg in psychiatric
patients may represent
the
combined effects of
stress, medication and
deficiency and may
produce clinically
significant depletion.
He has observed an
association between
severity of anxiety or
depression and low
plasma Mg. Pliszka and
Rogeness [86] measured
serum Mg in 165 boys
admitted to a
psychiatric hospital and
found low Mg levels to
be associated with
dysphoric mood and sleep
disorders. A French team
has recently
demonstrated that Mg
aspartate-HCI was as
effective as Li in
stabilizing the mood
swings of rapid-cycling
bipolar depressives
[87].
Mg/Pyridoxine
Responsiveness of
Childhood Autism
The combined effect of
oral Mg (5 mg/kg/day)
and high-dose vitamin B6
(15 mg/kg/day) has been
studied repeatedly in
infantile autism. In the
initial uncontrolled
trials conducted by
Rimland [88], pyridoxine
alone produced
impressive improvement
in speech and behavior
of some children; side
effects of enuresis,
sound sensitivity and
irritability were common
with high-dose
pyridoxine, but addition
of Mg 300-500 mg/day
alleviated them. A
subsequent
placebo-controlled,
double-blind study of
the subgroup of
pyridoxine responders
found that pyridoxine
300-500 mg/day plus Mg
200400 mg/day produced
significant improvement
in behavior: better eye
contact, less
self-stimulation, fewer
tantrums, more interest
in the world, more
frequent speech; in no
case did complete
remission occur, however
[89]. Subsequent studies
in France confirmed the
value of combined
Mg/vitamin B6 therapy in
a large subgroup of
autistic patients but
failed to demonstrate
any effect of Mg or
vitamin B6 alone
[90-92]. In these
studies, the combination
therapy lowered the
abnormally high urinary
excretion of the
doparnine metabolite
homovanillic acid of
some autistic children
but did not affect its
excretion of normal
children. Mg/vitamin B6
also corrected the
abnormal amplitude and
morphology of cortical
evoked potentials in
autistic individuals.
LeLord et al. [93]
report that 47% of
autistic patients
respond positively to
Mg/vitamin B6 therapy.
Rimland [94] asked the
parents of more than
1,000 autistic children
to evaluate the effects
of various treatments on
their children. He found
that 43% of 318 patients
who had tried the
Mg/vitamin B6 regimen
experienced benefit
compared to an
improvement in 20-40% of
autistics who had taken
various neuroleptics,
tranquilizers and
stimulants. Adverse side
effects occurred in only
5% of children receiving
Mg/vitamin B6 and in
19-49% of children
on drug therapy [94].
The mechanism of action
of Mg/vitamin B6 in
autism is unknown. Rats
rendered
moderately Mg deficient
have a selective
doubling of cerebral
doparnine, which is
restored to normal with
Mg feeding [95]. Mg,
therefore, seems to have
a unique relationship to
dopamine; the therapy
may partially correct an
error in dopamine
metabolism in some
autistic people.
Mg Effects in Cerebral
Trauma
Vink and McIntosh [96]
recently reviewed the
relationship between Mg
and traumatic
http://www.mdheal.org/magnesiu1.htm
(10 of 18) [10/19/2000
9:41:42 PM] brain
injury, the major cause
of death in individuals
under the age of 44
living in industrialized
countries. Brain-injured
rats develop a marked
decline in intracellular
free Mg as demonstrated
by 31p magnetic
resonance imaging. Rats
rendered Mg deficient by
diet show a
significantly worse
outcome with brain
injury than do normal
rats. Intravenous
infusion of Mg sulfate
prior to trauma
attenuates the decline
in free Mg and improves
neurologic outcome. Mg
chloride infusion 30 min
after trauma at doses of
12.5 or 125 umol
produces a significant
improvement in motor
function at 4 weeks
after the injury when
compared to saline
infusion. They found
that other pharmacologic
agents which reduce the
neurologic deficits of
head trauma, such as
opiate and
N-methylD-aspartate
antagonists, improve the
outcome to the extent
that they restore
cerebral free Mg levels
toward normal. Mg ion
protects neurons in
vitro from anoxic damage
[97]; excitatory
neurotransmitters which
activate N-methyl-D-aspartate
receptors amplify such
damage [98]. Rats
injected with the
N-methyl-D-aspartate
agonist quinolinate
experience hippocampal
degeneration and
convulsive seizures;
rats given subcutaneous
injections of Mg sulfate
(600 mg/kg) up to 3 h
after the quinolinate
injection showed
significant protection
against neurotoxicity
[99].
Conclusions
Mg ions have nutritional
and pharmacologic
actions that protect
against the
neurotoxicity of agents
as diverse as
environmental noise,
sympathornimetic amines
and physical trauma. Mg
deficiency, even when
mild, increases
susceptibility to
various types of
neurologic and
psychological stressors
in rodents, healthy
human subjects and
diverse groups of
patients. Repletion of
deficiency reverses this
increased stress
sensitivity, and
pharmacologic loading of
Mg salts orally or
parenterally induces
resistance to
neuropsychologic
stressors. Mild Mg
deficiency appears to be
common among patients
with disorders
considered functional or
neurotic and appears to
contribute to a symptom
complex that includes
asthenia, sleep
disorders, irritability,
hyperarousal, spasm of
striated and smooth
muscle and
hyperventilation. By
increasing the
sensitivity of cerebral
arteries to the
regulatory effects of
CO2, Mg deficiency may
contribute to the
cerebral vasospasm of
some patients with
migraine headache or TIA
[100, 101]. The
application of
increasingly sensitive
methods for measuring
intracellular Mg levels
is likely to clarify the
nature of Mg deficit in
such patients; when
physical and
electrodiagnostic
evidence of
neuromuscular
hyperexcitability
accompanies such
symptoms, the
therapeutic
administration of Mg
salts is warranted,
whether blood Mg
levels are low or
normal.
Printable
PDF Version
|
