Reprinted from Diseases of the Nervous System Vol. 36 No. 8 August 1975 Pages 461 465 1975 46 1

Latent Tetany And Anxiety, Marginal Magnesium Deficit, And Normocalcemia

MILDRED S. SEELIG, M.D.,t ADOLPH R. BERGER . M D.t AND NEIL SPIELHOLZ. Ph .D.tt

Abstract The identification of marginal magnesium deficit ,

such as we have detected in a patient with anxiety, depression , and psychomatic complaints , is a difficult diagnostic problem. Electromyography of a limb, rend­ered acute ly ischemic either just before or after hyper­ventilation , can elicit latent tetany in thi s condition , as well as in calcium deficiency . We have demonstrated iterative electrical activity in our patient, whose mag­nesium deficit is auri butable to renal wasting of mag­nesium. We have e licited s imilar patterns in several other patients. who had margina lly low serum mag· nesium and who also exhibited weakness. anxiety, and psychosomatic disorders . Thi s preliminary report sug­gests the need for further cons ideratio n of the possibil­ity tha t chron i~ magnesium-defi c it may contribute to the syndro me of la tent teta ny, psychosomatic com­plaints , and weakness.

Electromyographic evidence of latent tetany has been observed in some patients with marginal mag­nesium deficit , whose multiple ill-defined complaints may be mistaken for psychon eu rosis .'-7 Defi ciency of magnesium . which i!) predominantly an intracellular cation. is not often diagnosed in this country unless the deple tion is s0 severe as to cause symptoms referable to overt te tany. o r metabolic encephalopathy , o r both . Thi!) form of encephalopath y has been clearly related to lowered brain and cerebrospinal levels of magnesium in magne!)i um-derived rats by Chutkow and his ~olleague!). M-~ · 10

Since 1958. however. lesser degree!) of magnesium Jeticit (as~oc ia ted with a neuromuscular syndrome) have been reported by Ro!>selleL2 as "cryptote tany·· , and by Durlach3 -

7 as ··spasmophilia .·· Although some patients with this !) yndrome exhibit slightl y depressed levels of serum magne~ium , low e rythrocyte levels have bee n reported to occur more consistently .5 ·6 ·7

This syndrome, which occurs more frequently in women than in men , is accompanied by many psychosomatic complaints. The physical examination is usually normal (or non-contri buto ry). The elec­trocardiogram sometimes exhibits ventricular prema­ture contrat.:tion or mildl y abnormal final deflections . The conventional electromyogram is normal. How­e ver . hyperventilation, and ischemia of the tested mus­cle , produce iterative electrical ac ti vity. We have not

t From tht' Departmt'nt (~{Medicine . Nt'\1' York University Medical Center. and Goldll'ate r Memorial H ospital

++Jnstitutt' of Rehabilation Medicine

found reference to this syndrome in the English lan­guage literature since Rosselle' s and Durlach 's monographs, 1- 7 although there have been numerous publications in French and Italian language journals (over 30 citations by Durlach in his 1969 monograph 7

).

Recently we diagnosed this condition in a post­menopausal woman .11

Case Report and Methods

SLB , a 57-year-old woman of Italian anl:estry, was ho~pitalized becau~e of weakness, depression , anxiety , ··spots before the eyes'· , generalized pruritus, swelling of the lower extremitie s and puffiness around her eyes and mo uth . This clinical picture , which also included occasional dyspnea and precordial pain , gastrointesti­nal complaints , without detectable organic cause , had persisted for over two years. Cardiologic examination was normal , psychiatric evaluation indicated only de­pressive anxiety , which yielded partially and temporar­ily to treatment , with diazepam and amitryptoline. Al­though skin testing showed no s pecific allergy , use of antihistamine therapy has been necessary for control of pruritus. The simila rity of her clinical picture to that described as ··cryptotetany" or "spasmophilia" 1- 7 led to investigation of her magnesium status (details de­scribed elsewhere'') . He r initial serum magnesium level was found to be marginally low ( 1.67 mEq/L) , by the range accepted as no rmal in the hospital laboratory ( 1.9-2.5).' 3 Conventiona l nerve conduction tests and EMGs had been found normal , but EMG s tudies (by a technique mod ified from that e mployed by RosseUet.2

and Durlach3-

7) elicited iterative a~ti v ity. * After about

three minutes (two minutes of hyperventilation , fol­lowed by one minute of ischemia) single motor unit of discharges appeared , firing at a relatively slow rate (two to three per second) . At this ti~e , there were no visible muscle twitchings or spasms . Within the next 15-30 seconds , motor unit activity increased in frequency , and the sounds characteristic of visually recorded

*The typical p~t tt erns of increa~ed electrical activity are described' as (I ) repetitive! potentials of one or more motor units, with repclltrve di~char ges (2-8 times) at frequency of 125 to 250 per se.:ond . termed doublets , triplet~ . quadriplets or multiplets, (2) ~pontaneou ~ dischar ges of a motor unit of high frequency ~~- 1 2 per second) during s light involuntary contraction . Ros!>dle 1 interprets the EMG as positive if regular repetitive activity persis ts for at leas t two minutes during the post-ischemic phase or after hyperpnea.' If the modification is used , the pa tient hyperventilates before is­che mia is induced (See Appendix).

462 DISEASES OF THE NERVOUS SYSTEM AUGUST

Figure 1: Doublets fro m abductor pnllio.:i \ hre\i~ afler two minute' of hypc:rventilation followed by 1.5 mmute~ •>f ischemia. Calibra­tion signifies 100 ms and 100 uV .

t"igure 2: Complete interference pallerns recorded simultaneously from abductor pollicis bre' i' and ahd uctor digiti quinti after :!.5 minutes of ischemia.

doublets and triplet s could he heard. (Fig . I).

During the following 60 seconds . the acti\·it j in­u eased to such an extent that a complete interference pattern was recorded (Fig. ::!) and at the same time marked wrist and finger spasm were evident. These contractions were completely in voluntary . With re­lease of the cuff after only two and a half minutes of ischemia, all electrical activity disa ppeared within 30 seconds.

The next day. to test for magnesium deficit . the patient was given an intramuscular injection of 2 ml of a 50% of solution of magnesium sulphate (to test for percentage retention of magnesium). 1

.. 12 She retained

over 60% of the parenterally administered magnesium. in contrast to the normal retention of 15-2® ..... 2

Within two hours of the injection she experienced marked relief of all of her symptoms. In the course of her ho<; pitalization the patient had received many other injections . none of which had evoked the clinical im-

provement experienced following the injection of mag­nesium. The EMG, taken shortly thereafter, was nor­mal and repetitive firing and spasm could not be pro­voked by hyperventilation , followed by ischemia for 10 minutes.

For several weeks , thereafter, she received oral magnesium supplements, and it was possible to de­crease the use of antihistamine and diazepam. How­ever, a month later, the intensity of her complaints completely returned, and she obtained brief (1-2 day) periods of relief only after intramuscular injections of magnesium. Placebo injections produced no clinical change. Rehospita lization . on several occasions. for metabolic and hormone studies, revealed that she was a renal magnesium waster. and that she had intermittent normotensive aldosteronism. with peripheral edema and sodium retention.•• Her serum magnesium level usually remained below I. 7 mEq/ L. serum calcium was normal (9.5-9.7 mg%) . Serum magnesium values of2. 1 mEq were reached after repeated intravenous or in­tramuscular injections of magnesium. On one such oc­casion. her hyperventilation/ischemia EMG did notre­vert to norm al. even when te~ted ~hile she was receiv­ing an intravenous infusion of 200 ml of dextrose and water. to which 2 ml of magnesium sulphate had been added . Her symptoms improved the next day. after a second magnesium-infusion. Two hours after comple­tion of the second infusion. her EMG was normal.

Discussion

Our patient with the abnormal hyperventi­lation/ischemic EMG pattern and carpal -.pasm. and those described in Europe_._ , a ll had marginal mag­nesium deficit.* Similar s igns are also seen with hypo­calcemic latent tetany! 4 · 15 · 16 However. Rose1Jel. 2 and Durlach3 -• have reported that their patients had similar clinica l and electrical phenomena with magnesium de­ficit, in the absence of hypocalcemia. Similarly. our patient showed these findings with margina lly low serum magnesium levels. but normal serum calcium le vels.

*We have subsequentl y obtained s imilar electrical findings on three additional patients without neuromuscular disease. In two. the hyperventilation/ ischemia EMG was found abnor­mal after the diagnosis of magnesium deficit had been made on the basis of serum magnesium levels of I. 1- 1.4 m Eq/ L and multiple psychosomatic and neuromusc ular complaints. In another. the hyperventilation/ischemia test was em­ployed because of the patient's bizarre neuromuscu lar com­plaints. When strongly positive EMG results were elicited. his serum electrolytes were analyzed. He was normocal­cemic. but his serum Mg was I .5 mEq/ L. To evaluate the significance of these pat ients· neuromu scular irritability , as demons tra ted by electromyography foll owing h yperventila­tion and ischemia. we tes ted ten normal volunteers. who did not have neuromuscular o r psychiatric abnormalities. Mag­nes ium serum levels . "'hich were done only in five. were within normal limits . None exhihited the EMG pattern de­scrihed here . .:' en "'h.:n the pl>St-h yperventilation ischemia was maintained for ten minutes.

'

1975 LATENT TETANY AND ANXIETY. MARGINAL. MAGNESI U M DEFICIT 463

Although hypocalcemia and hypomagnesemia each causes clinically ma nifest neuromuscular irritability and electromyographic abnormalities . such as are re­ported here. nerve ph ysiology studies indicate that the mechanisms are not the same . Chutkow 17 has reviewed the evidence and points out that, a lthough magnesium deple tion has electrophysiologic effects on nerve axons similar to those of calcium depletion , the calcium effect far outweighs the magnesium effect at this site. Calcium is principa lly involved in nerve membrane potential and stability ; depressive effect of hypercalcemia is caused by nerve membrane hyperpolarization, decreased sodium conductance. and resultant elevation of the de­polari zation threshold . With h ypoct~ lcemi a there i-; .m increase in depolarization that a llows for response to slow depolariza tio n and loss of accommodation, 2 .. 22 as a result of which peripheral nerves di scharge independently. 23

When a nerve impul se reaches the skeletal myoneural junction. the resultant depolariza tion of. the nerve endings re leases ace tyl choline (ACh) into the synaptic space. 2u 5 ACh molecules then diffuse across the syna ptic cleft and attach to specific receptors of the specialized area in the postsynaptic sarcolemma. which results in non-specific inc reased ionic permeability , flow of'an ionic current , and -depolarization (the end plate potential). When this depolarization reaches the excitation threshold of the adjacent sarcolemma, a muscle action potential develops, that ultimately in­itiates the mu scle contraction. Magnesium exerts its majo r neuromuscular effects at the myoneural j_unction. 17 ·24 -~0 At this site. calcium and magnesium are antagonistic . 2" -28-2 !1·30-3 1

Calcium enhances. and magnesium inhibits, there­lease of ACh. Additionally. the sensitivity of the motor end plate is diminished by high magn-esiu-m concentrations,25 such high concentrations also having cholinesterase-activating effects.32

·33 Thus, hypocal­

cemia exerts two paradoxical effects: it increases periphera l nerve excitability , but it decreases release of the neurotransmitter (ACh) into the myoneural synap­tic space . We postulate that the hypocalcemia-induced suppressio n of neuromuscular transmission may be overcome by the increased presence of ACh resulting from magnesium deficit. Increased tra nsmitter aug­ments the tendency towards repetitive sarcolemmal depolarization and muscle contraction.*

Since either hypocalcemia or hypomagnesemia can elicit similar abnormal hyperventilation/ischemia EMG patterns, both cautions must be measured to elucidate the specific deficit. The patients described here, and those reported earlier, 1-

7 all had marginally low serum magnesium and normal serum calcium levels. In our gro up, we rarely saw serum magnesium levels below 1.5 mEq/L.

In view of our patient 's la tent tetany a nd neuro­psychiatric manifestations, the findings of Chutkow et

a J8.11·10 may have special relevance. They demonstrated tha r rars with acute, subacu te or chronic magnesium­deficiency exhibit decreased brain a'hd cerebrospinal fluid magnesium levels, not necessarily closely related with changes in blood levels of magnes ium. They found that even small decrease s in brain magnesium are ac­companied by ma rked a lteratio ns in bra in excitability .t 0 Whether the slight electroencephalo­graphic abnormalities of our patient, elicited only dur­ing hyperventilation, reflect a magnesium-deficit en­cephalopathy, remains to be proved .

C hutkow and Grabow 10 also commented on the hi '\ ta mine-relea~f' of rnagnc~in rn -deprivation ,36 -37 an important point in terms of the evidence that histamine may be a central neurotransmitter.10 Note should be made. here. that one of our patient's most distressing complaints is generalized pruritus, and that her re­quirement for antihistamine therapy exceeds the amount tolerated by most subjects .

Worth mentioning , also, is the fact that 75% of Roselle 's patients with latent tetany of magnesium­deficiency improvec.'l on treatment with thyroxine.• Th is is a provocative finding. since thyroid h'ormone affects protein-binding of magnesium; its influence on the ratio·oNree to~tround •magn·esium-~i S" no't'<lefmitely established.38 Before instituting this therapeutic ap­proach in our patient , who has thyroid function at the low limit of the normal range, we considered the simi­larity of some of her findings to those of some patients with periodic paralysis or weakness, who also have intermittent aldosteronism, and who exhibit exacerba­tions in response to administration of salt:39·40 In this context, we must recall that some patients with periodic para~ysis have responded favorably to thyroid ad­ministration or stimulation, -and have experienced re­currence of weakness or withdrawal of thyroid therapy, 41 whereas others have periodic paralysis in association with hyperthyroidism. 41

·42 Whether our pa~

tient, who a lso suffers from marked weakness, presents another facet of hypokalemic periodic paralysis (mag­nesium deficit being known to predispose to.Joss of muscle po tassium, and to prevent its repletion)43

•44 re­

quires further elucidation.

Remaining to be explored is the relationship of such patients' multiple neuropsychiatric complaints with a possible metabolic encephalopathy , that may be caused by chronic magnesium deficit. 8 ·9 · 10 Study of cerebro­spinal fluid levels of magnesium. during phases of ex­acerbation and remission, possibly in association with metabolic balance data obtained during magnesium

*Combined deficits give rise to severe forms of neuromuscu­lar irri tabili t y. Whether th e convuls io ns of infanti le hypomagnesemic hypocalcemia, t hat are refractory to treatment unril borh defici t ~ (Ire correl: t e~.J. ·11 " are relevant liJ the clinical tetany that is the subjec t of this paper is moot. What happens at the myoneura l junction· in response to calcium and magnesium may differ from what happens in the central synapses.

.... -

464 D ISEASES O F THE NERVOUS SY<;l FM AUG I JSl

supplementation and restriction , may provide valuable inc;ight intn the syndrome dec;crihect here.

APPF:NOJX

I . The c;ubject . lying completel y relaxed o n a comfort­able couch , is ins tructed not to move the hand or arm (to eliminate voluntary contraction of the mu s­cles of the limb being tes ted) throughout the entire test procedure . A blood-pressure cuff i<:> wrapped around the upper arm.

2. A teflon-coated mono~)Jar needle electrode io; in­serted into the a bductor digiti quinti heing tested and a o;urface electrode is ta pt'd over the insert ion llf thio; muo;cle . A o;imilar pair nf e lectrnde' ;._employed to record from the ipsilatera l ahcluctor pollicio; hrc­vis muscle . The e lectrical ac ti vity from hoth mus­cles io; displaved o;imultaneously on tw1l c hannels llf a Teca TE-4. with constant mPnitoringon fiheroptic readout .

3. After determining whether there is electrical activity at rest , the patient is asked to hyperventilate for two minutes . Then the c uff is infla ted to a h<lut 20 mm Hg above the pressure which ohliterates the radia l pul se. If o;pontanemts discharge occurs early. pre!'­sure is maintained for two minutes. to a llow for development of the interference pattern . (A pattern

.Qf e lectrical activit y produced when numerous motor units are active so that their action potential can no longer be identified individuall y). Pressure sho uld not be mainta inerl lo nl!er tha n ten min11tes.

Ro~selle. ~ . · ElecHom) <•gr;•phoe 1n nenou~ di~ea~e and in nyp­totetany. Ed\ . E . Nauwelaert~. Pul>l. U ni versi•;j ire 2. l.ouvai n . Be lgi11m. 1951! tin F rench I. 14~4 tin Engli~h):

2. Rosselle . N .. Ooncker. K .: La tetanie magne~iprive che1 l'ho mme. Etude 1-lioc hemiqut> f't e lec tromyngraphique . Pculr Bart 7: 17- 11! . 11!35- 1!147. 19'i9.

3. Durlach. J .. Lebru n . R .: Magnesium et p<~tho~genit> de J;j 'l'a'­mo philie con~titutione lle idiopathiqut> . I R s,.,. Bioi tP<~ri~l 15l: 1973- 197.~ . 1959 .

4. Durlach . J .. Lebrun . R .: Jmportanct> de Ia forme h ypomag­nesienne de Ia ~pasmnphilie . Ann Endocrirw/1 Paris) 21 : 244-2~2 . 1960.

~ - Durlach . J .. Dreux. C. . Le l>run. R . . Jarreau F X . Ba rachet L. : Etude statistique de magne~ium e r ythrocytaire dans Ia spas­mo philie constitutionelle idiopathique. Ann Endorrinol (Pa ris) 23:83-88. 1%2 .

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I'J7:'i I A rr T TETANY AND A X I ETY. MARtd' -\I. 1\11\(iNlcSil!M DEFICIT 465

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Acknowledgement

Sinare apprrciation is exrresud to Dr. Jerry Cl111fko 11-.for his rel'iew of this mantHcript. and for his ntluahll' WRJ!I'S lion L

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