Evidence for reversible motoneurone dysfunction in thyrotoxicosis · Evidencefor reversible...

Journal of Neurology, Neurosurgery, and Psychiatry, 1974, 37, 548-558

Evidence for reversible motoneurone dysfunctionin thyrotoxicosis

A. J. McCOMAS, R. E. P. SICA, A. R. McNABB,W. M. GOLDBERG, AND A. R. M. UPTON

From the Department of Medicine, McMaster University, Hamilton, Ontario, Canada,and the Canadian Medical Research Council's Developmental Neurobiology Research Group

SYNOPSIS Motor unit estimating techniques have been employed as part of a comprehensiveelectrophysiological survey of peripheral nerve and muscle in 20 patients with thyrotoxicosis. In allpatients there was evidence of a loss of operational motor units; the selective nature of this involve-ment suggested that the motoneurone soma was the site of the primary lesion. The reversible natureof the postulated motoneurone dysfunction was demonstrated by the increased motor unit counts insix patients who were studied again after treatment of their thyrotoxicosis.

Patients with thyrotoxicosis will often admit to afeeling of weakness and may actually haveevidence of muscle wasting; in some patientsmuscle fasciculations and painful muscle crampsmay also occur. Only in recent years, however,has the extremely high incidence of myopathicfeatures in thyrotoxicosis become apparent. Intwo especially thorough studies in which electro-myographic criteria were used, evidence of'myopathy' was found in 92.6% of thyrotoxicpatients by Ramsay (1966) and in 80% byHavard et al. (1963). The results of histologicalexamination of muscles in thyrotoxicosis havebeen more variable; for while Havard et al.(1963) found remarkably little abnormality,others have described such features as atrophyand degeneration of muscle fibres, invasion bymacrophages and lymphocytes-the latter some-times forming lymphorrhages-and fatty in-filtration (Whitfield and Hudson, 1961; Schwarzand Rose, 1963).

In addition to the myopathy, there have beenoccasional reports of neuropathic changescomplicating thyrotoxicosis. For example,Birket-Smith and Olivarius (1957) described onecase of polyradiculitis, while Bronsky et al.(1964) collected four. The last authors consideredthat thyrotoxicosis favoured the development ofthe Guillain-Barre syndrome. The paper byLudin et al. (1969) is rather different in that these

workers deliberately sought electromyographicevidence of neuropathy in a population of 13hyperthyroid patients and detected it in eight.However, in spite of such definite findings, theprevailing opinion is that neuropathic changes inthyrotoxicosis are uncommon and, if present,reflect the presence of some additional aetio-logical factor (Engel, 1973).

In the present study the problem has been re-examined using recently developed techniquesfor assessing function of individual motor units,and hence of motoneurones (see Methods). Itwill be shown that 'functional' denervation ofmuscle fibres occurs in nearly every patientpresenting with thyrotoxicosis. The motoneuronedysfunction responsible for this denervationappears to be reversible once the thyrotoxicosisis brought under control. The possible relation-ship of the present findings to certain otherneurological complications of thyrotoxicosis isdiscussed. A preliminary report on some of thiswork has already appeared (McComas et al.,1973).

METHODS

PATIENTS The major part ofthe study was conductedon 20 patients in whom the clinical diagnosis ofthyrotoxicosis had been confirmed by standardradioisotope tests. These patients had either com-menced treatment with 131J during the previous week

48

Protected by copyright.

on June 26, 2020 by guest.http://jnnp.bm

j.com/

J Neurol N

eurosurg Psychiatry: first published as 10.1136/jnnp.37.5.548 on 1 M

ay 1974. Dow

nloaded from

http://jnnp.bmj.com/

Evidence for reversible motoneurone dysfunction in thyrotoxicosis

or else were about to begin. Two other patients hadrecently presented with exophthalmos but neitherclinically, nor on the basis of laboratory investiga-tions, was there evidence of thyrotoxicosis. Since it isknown that there is a loss of functioning motor unitsin healthy subjects beyond the age of 60 years

(Campbell and McComas, 1970; Campbell et al.,1973), only patients below this age were studied.Although no one was rejected from the study otherthan for reasons of age, all but one of the 20 thyro-toxic patients were female. For each type of investiga-tion control observations were made on a group of20 healthy subjects who were matched for sex and,as closely as possible, for age (61 control subjectsaltogether). The results in these normal subjectsresembled those obtained from a much largerpopulation of males and females below the age of 60who had previously been used for similar experi-ments. Informed consent was given by all the patientsand controls after the nature of the experimentalprocedure had been explained; in addition, theapproval of the Ethics Committee of McMasterUniversity Medical Centre was obtained for thisstudy.

MOTOR UNIT ESTIMATES The term 'motor unit' wasoriginally employed by Sherrington (1931) todescribe a single motoneurone and the colony ofmuscle fibres which it innervated. For conveniencewe shall follow common contemporary usage byreferring to the muscle fibre colony as the motor unitand excluding the motoneurone. The method chosenfor estimating the numbers and relative sizes ofmotor units in the extensor digitorum brevis (EDB)muscle has been reported previously (McComas et al.,1971). It involves the use of large electrodes to recordthe incremental potentials evoked in the EDB muscleby graded nerve stimulation. The method assumesthat each increment in the response reflects theexcitation of an additional motor unit. The number

of units within the muscle can then be estimated bycomparing the mean amplitude of the incrementswith the size of the maximal muscle response evokedby a larger stimulus to the nerve. The method hasnow been extended to the thenar and hypothenarmuscles by ourselves (Sica et al., 1974) and in-dependently by Brown (1972).

IMPULSE CONDUCTION VELOCITIES Measurements ofmaximum impulse conduction velocities were madefor motor fibres in the peroneal, median, and ulnarnerves. Silver strips were attached to the skin over

the end-plate zones of the appropriate muscles andserved as stigmatic electrodes. Sensory nervepotentials were recorded with two chlorided silverdisc electrodes mounted in a Perspex holder; thediscs were 1 cm in diameter and their centres were3-1 cm apart. The electrodes were mounted over thewrist to record orthodromically conducted impulsesin digital nerve fibres of the radial, median and ulnarnerves. In contrast, the sural nerve potentials wererecorded antidromically using stimulating electrodesover the calf and recording electrodes placed justbelow the lateral malleolus of the ankle.The potentials were fed through a low-noise pre-

amplifier, using a passband extending from 2 Hz to1 kHz, and were then displayed on a Hewlett-Packardtype 141B variable persistence-storage oscilloscope.The temperature of the recording room was main-tained at 25-27° C and, in addition, the limbs were

warmed with an infra-red lamp before study.

ISOMETRIC TWITCH The maximum tension and time-course of the isometric twitch in EDB was alsomeasured, using a specially designed foot-holder(Sica and McComas, 1971). The temperature of theskin overlying EDB was kept between 35-37° C.

INTRAMUSCULAR ELECTROMYOGRAPHY In 13 patientsa concentric needle electrode (Disa, type 9013L0501)

TABLE 1MEAN VALUES (± SD) FOR AMPLITUDES OF MAXIMUM EVOKED POTENTIALS (M WAVES) AND FOR NUMBERS

OF MOTOR UNITS IN MUSCLES OF THYROTOXIC AND CONTROL SUBJECTS

,7 wtave(mn V) Motor units (no.)

Controls Patients P Controls Potients P

Thenar 13-7± 6 1 6-8±2-1 < 0-001 329 ± 75 149 ± 64 < 0-001(20) (16) (20) (16)

Hypothenar 12-8 ± 3-6 9 3± 2 6 < 0 01 367 ± 99 255 ± 105 < 0 01(20) (20) (20) (20)

Extensordigitorum brevis 60± 19 34+± 15 <0001 203±57 78±41 <0001(20) (20) (20) (20)

Number of subjects given in parentheses.

549



j.com/

J Neurol N


ay 1974. Dow

nloaded from


A. J. McComas, R. E. P. Sica, A. R. McNabb, W. M. Goldberg, and A. R. M. Upton

M WAVE (mV)

0 ' 0Lo __

HYPOTHENAR THENAR

TWITCH (g)f -- 600

8110

0

0

C

S 0

0

0

0

IF

0

0

300

FIG. 1. Maximal amplitudes ofMwaves and isometric twitch tensions inmuscles ofpatients with thyrotoxicosis(@) and controls (0). Ext. dig. brev.:

200 extensor digitorum brevis.

100

0

EXT. DIG. BREV.

was used to sample spontaneous and volitionalpotentials in selected muscles. A pre-amplifier with a

passband from 2 Hz to 10 kHz was used in con-

junction with an oscilloscope time-base velocity of10 ms/cm and a vertical sensitivity of 100-500 ,V/cm. All analysis of the displayed potentials was

performed subjectively.

STATISTICAL ANALYSIS Means have been given withstandard deviations throughout the paper. Thesignificance of a difference between two means was

calculated with Student's t test, notwithstanding anyskewing of the values about the mean. In the tablesP values greater than 0-05 have been shown as NS(not significant). Only values smaller than 0-01 havebeen regarded as definitely significant but inter-mediate values (between 0-01 and 0 05) have alsobeen given in tables.

RESULTS

MUSCLE INVOLVEMENT IN THYROTOXICOSIS Two

simple electrophysiological tests were used toestablish if weakness or wasting of muscles were

present in the thyrotoxic patients. One involvedmeasurement of the amplitudes of the maximum

muscle potentials (M waves) evoked by nervestimulation and was applied to the extensordigitorum brevis (EDB), thenar, and hypothenarmuscles. The second test was restricted to theEDB and, less commonly, the hypothenarmuscles and was the determination of isometrictwitch tension. The results of both types ofinvestigation depend on the number of musclefibres available for excitation and the valuesobtained experimentally are shown in Fig. 1. Itcan be seen from Fig. 1 that in a substantialfraction of the hyperthyroid patients the M waveamplitudes and isometric twitch tensions felloutside the corresponding ranges of controlresults, the lowest values being found in the mostseverely affected patients with the greatest lossesof weight. The mean EDB twitch tensioncalculated for the 16 hyperthyroid patients was133 + 48 g and was significantly smaller than thecontrol mean (285 ± 102 g; P= < 0001). Inspec-tion of Fig. 1 reveals that the proportionalreduction in M wave amplitude was not equal forthe three muscles studied in each patient. Thereduction was greatest for the EDB and thenar

550



j.com/

J Neurol N


ay 1974. Dow

nloaded from



FIG. 2. Numbers offunctioningmotor units in muscles ofpatientswith thyrotoxicosis (0) and controls(0). Ext. dig. brev.: extensordigitorum brevis.

muscles and least for the hypothenar ones; themean values and significance levels are set out inTable 1.

NUMBERS OF FUNCTIONING MOTOR UNITS Thenumbers of functioning motor units in the EDB,thenar, and hypothenar muscles were estimatedusing techniques described previously (seeMethods). It was found that in all but two of the20 hyperthyroid patients the EDB estimate fellbelow the lower limit of the control range (120units) and the mean value of 78 + 41 units differedsignificantly from the control mean (203 + 57units; Fig. 2). Similarly, in 13 of the 16 patientstested, there was a loss of functioning thenarunits and, again, the mean value of 149 + 64 unitswas significantly reduced (Table 1). In contrast,eight out of 20 patients had normal hypothenarmotor unit populations and the mean value,though still appreciably diminished, was closerto that of the controls. In all the thyrotoxic

patients at least one of the motor unit estimateswas reduced. In Fig. 3 an attempt has been madeto show the relative involvement of the threetypes ofmotor unit population, using a simulatedthree-dimensional display.

Figure 4 also depicts numbers of functioningunits, this time in six treated subjects. Five ofthese were now clinically euthyroid, each havingbeen given a single dose of 1311 between 21 and38 weeks before the second examination. Thesixth patient (case 1) had been treated withpropylthiouracil for eight weeks and, althoughimproved, appeared to be mildly hyperthyroid.Of the 15 initially abnormal muscles only fourstill had reduced numbers of functioning motorunits and in each of these the second estimatewas appreciably larger than the first. It is ofinterest that normal results were found in the twopatients who originally presented with exoph-thalmos but had no other evidence of thyro-toxicosis either on clinical or on laboratory

600J5001

400 F

300 F

200 I-

I-z

D00

LL0

wm

z

HYPOTHENAR THENAR EXT. DIG. BREV.

0

0~~~

o o

0~~~~

0 Cb~~~~~

O * 00

CP0 ~~~~~~~~00

I 56#sO O OO~0

i* IIs* * I100 _

0

551



j.com/

J Neurol N


ay 1974. Dow

nloaded from


552 A. J. McComas, R. E. P. Sica, A. R. McNabb, W. M. Goldberg, and A. R. M. Upton

FIG. 3. Simulated three-dimensionalrepresentation of the relative

z60. l tiinvolvement of motor unit populationsw in the extensor digitorum brevis,1--00 / involvementofthenar,and hypothenar muscles of

6 0 < 40% musclesinthyrotoxic patients (o). Also shownI

are values for the eight control20

oo >< subjects from whom data were>X ~~~~~~available on all three types of muscle> ~~~~~preparation (0). Values greater than

0~~~~~~~>0

400;OYJ of control mean have beenO>

20 shown as 1000/. Note te more severe80300\ | A / / |trinvolvement of the EDB and thenarz0 4 musckes in thyrotoxicosis, comparedzI/2AI/11/Iwith the hypothenar group.

EXT. DIG.BREV. 20 TEA

PERCENTCONTROLMEAN

704 I I I /

400-

FIG. 4. Numbers offunctioning motor units in six

300 I / / / I I / / I righpatients before and afterz 1 I / 1/ esthyrotoxicosis. Duration ofcr ~~~~~~~~~~~~~~~~~~~treatmentindicated at

bottom of each column.20 Results of extensor digitorumU. ~~~~~~~~~~~~~~~~~~brevis(@), thenar (U), and0 ~~~~~~~~~~~~~~~~~~hypothenar(A) muscles, hInw ~~~~~~~~~~~~~~~~~~~~eachcase the value at theD ~~~~~~~~~~~~~~~~~~~~rightside is the second

Z 100 / estimation.

8 27 29 21 24 38 WEEKS

EDB



j.com/

J Neurol N


ay 1974. Dow

nloaded from



increments in the graded evoked potential givean indication of the relative sizes. It will beremembered that each increment is considered tohave been generated by one motor unit (seeMethods). Thus, assuming the fibre diametersdid not change, the amplitudes of the increments

o should be directly proportional to the numbers of0 muscle fibres within the corresponding motor

0 8units. An indication of the sizes of the incrementscan be gained by comparing the mean numbers of

o 0 00 units with the M wave amplitudes for each0 § - 0 muscle. In the EDB muscles, where 'denervation'

*o ^ was greatest, the potentials tended to be some-.. . . ° what larger and the mean value (44+31 uV,

.0 . * n = 195) was significantly increased (control* * mean, 30+21 ,uV, n=203, P=<0 001). A

smaller, but not significant, increase wasIII observed for the thenar motor unit potentials

50 60 70 80 90 while the hypothenar mean value was virtuallyCONTRACTION TIME (ms) unchanged.

FIG. 5. Contraction times and maximum isometrictwitch tensions ofextensor digitorum brevis muscles inthyrotoxic patients (0), control subjects (0), andeuthyroid patients with exophthalmos (A).

examination. In these patients the respectivenumbers of units were as follows; EDB, 144 and394; thenar, 221 and 424; hypothenar, 532 and361.

SIZES OF SURVIVING MOTOR UNITS It is, ofcourse, not possible to measure the sizes of themotor units directly but the amplitudes of the

TWITCH TIME COURSES The reductions in mean

twitch tension of EDB muscles in hyperthyroidpatients has already been described. The time-courses of the twitches are of special interest inthyroid disorders for it is well established thatthey are fast in hyperthyroidism and slowed inhypothyroidism (Lambert et al., 1951). In Fig. 5the contraction times and twitch tensions havebeen plotted against each other and shown forcontrol subjects as well as for patients withhyperthyroidism. It can be seen that, althoughmost contraction-time values for the thyrotoxicpatients were at the 'fast' end of the normal

3LE 2

MAXIMAL IMPULSE CONDUCTION VELOCITIES AND RESPONSE AMPLITUDES OF SENSORY AXONSIN VARIOUS NERVES OF THYROTOXIC PATIENTS AND CONTROL SUBJECTS

'Sensory' conduction velocity (nis) Response amplitude (,i P')

Nerve Controls Patients P Controls Patients P

Radial 53±6 49±7 <0 05 26+7 23±7 NS(31) (17) (31) (18)

Median (111) 55± 5 56 ± 5 NS 37± 10 33 ± 13 NS(31) (18) (31) (19)

Ulnar(V) 55±5 52±7 NS 20±7 17±7 NS(29) (18) (30) (19)

Sural 42±5 49±7 <001 13+4 11±5 NS(21) (19) (21) (19)

Numbers of observations given in parentheses. The values for the median and ulnar nerves are those obtainedby stimulation of the middle and little fingers respectively.

GOOr-

5001-

400 F

3001-

at

z0I,z

I

2001-

100o-

OL L4C

553



j.com/

J Neurol N


ay 1974. Dow

nloaded from



TABLE 3MAXIMAL IMPULSE CONDUCTION VELOCITIES IN MOTOR AXONS OF VARIOUS NERVES

IN THYROTOXIC PATIENTS AND CONTROL SUBJECTS

'Motor' conduction velocity (nmis) Terminal latency (ms)

Nerve Controls Patients P Controls Patients P

Median 59±6 61±1 NS 2 8±0 5 2-8±0-3 NS(20) (15) (20) (16)

Ulnar 61±5 62±5 NS 25±05 2-2±0-3 <005(20) (19) (20) (20)

Peroneal 51±5 49±4 NS 3-9±0-6 3.7±09 NS(20) (20) (20) (20)

Also given are corresponding values for 'terminal latency'-that is, time elapsing between stimulus to distalregion of nerve and onset of evoked muscle response. Numbers of observations given in parenthesis.

TABLE 4RESULTS OF ELECTROPHYSIOLOGICAL EXAMINATION OF VARIOUS MUSCLES WITH CONCENTRIC

NEEDLE ELECTRODES IN 13 PATIENTS WITH THYROTOXICOSIS

EDB APB QUAD. BICEPS ADM TA Total

Total examined 6 12 1 8 2 1 36Normal 0 7 6 8 1 0 22Reduced pattern 4 1 1 0 0 0 6Fibrillations 0 1 0 0 0 0 1Fasciculations 0 1 0 0 0 0 1Brief potentials 1 1 0 0 0 0 2Prolonged potentials 1 1 0 0 1 1 4

All values refer to numbers of muscles examined. EDB, extensor digitorum brevis; APB, abductor pollicisbrevis; Quad, quadriceps; ADM, abductor digiti minimi; TA, tibialis anterior.

spectrum, only one exceeded the limit of controlrange (52 ms). When the results for the hy-perthyroid population were pooled, the meancontraction time (59+6 ms) differed signifi-cantly from the corresponding control value(65 + 8 ms; P= < 0 01). In contrast, there wasno significant difference between the mean half-relaxation times for the thyrotoxic and controlsubjects (56 + 10 ms and 53 + 10 ms respec-tively). In Fig. 5 it can also be seen that nocorrelation appeared to exist between the twitchtension and contraction time in either the normalor the thyrotoxic subjects. Of particular interest(see Discussion) was the observation that, in onepatient with thyrotoxicosis, an EDB muscle witha normal number of units (171) had a relatively'fast' twitch (contraction time, 52 ms). In thissubject the hypothenar group of muscles also hada full population of units and a fast twitch, whilethe thenar unit estimate was slightly reduced.

SENSORY AND MOTOR NERVE STUDIES The maxi-mum amplitudes of compound action potentialswere measured in sensory fibres of the sural,radial, median, and ulnar nerves and aredepicted in Table 2. It is apparent that neitherthe potential amplitudes nor the impulsevelocities differed significantly between thecontrol and hyperthyroid subjects. The singleexception was the rather higher conductionvelocity in sural nerves of thyrotoxic patients.

Similarly, Table 3 shows that the maximalimpulse conduction velocities in motor axons ofthe median, ulnar, and peroneal nerves werevery similar in the two populations, as were theterminal motor latencies.

SUPPLEMENTARY INVESTIGATIONS In each of 13patients a concentric needle electrode was used tostudy at least one proximal and one distal muscle.Although the analysis of the recorded activity



j.com/

J Neurol N


ay 1974. Dow

nloaded from



was performed subjectively, it was obvious thatdistal muscles such as the extensor digitorumbrevis and the abductor pollicis brevis had muchhigher incidences of abnormality than proximalmuscles such as biceps brachii and quadriceps(Table 4). The commonest abnormality was areduction in interference pattern; fibrillationswere observed in only one patient and fascicula-tions were also seen in a solitary case. In mostmuscles the volitional potentials appearednormal (Table 3) but they were clearly prolongedin four and were brief in two.

In three patients the responses were examinedof the thenar or hypothenar muscles to indirectstimulation at 3 and 10 shocks/second. In eachinstance the muscle responses were unchanged orelse showed a slight increase (maximum increase,22% of initial value).

DISCUSSIONAll the patients with thyrotoxicosis had evidenceof a loss of functioning motor units and this wasgreatest in those most severely affected by thedisease. Since most motor units were involvedin an all-or-nothing manner, it was unlikely thatthe underlying disease mechanism was a myo-pathic one. Thus in the early stage ofa myopathy,when muscle fibres should be affected in arandom fashion, a normal number of rathersmaller motor units would be anticipated. In thisstudy, however, it was found that in the EDB orthenar muscles as much as three-quarters of thenormal population of motor units could bedestroyed while other units remained intact orwere even enlarged. Such a selective involvementof motor units argued strongly in favour of aneuropathic process; a more detailed considera-tion of the significance of motor unit sizes in thepathogenesis of disease has been presented else-where in relation to muscular dystrophy(McComas et al., 1971; McComas et al., 1974).Further evidence of a neuropathic process wasthe enlargement of motor units noted in somepatients of the present study. This observationsuggested that some muscle fibres could continueto function if adopted by a 'fresh' motoneurone,thereby becoming part of a larger motor unit. Incontrast with the results of Ludin et al., (1968)fibrillation potentials were an uncommon findingin the present study, being detected in only one ofthe 18 distal muscles examined.

If the disease process is indeed a neuropathicone, why were the muscles in any one patientaffected to different extents? For example, therewere a number of patients with significantinvolvement of the thenar and EDB motor unitsand in whom the hypothenar unit populationswere barely affected. Unfortunately, it is notpossible to answer this question satisfactorily atpresent, though it is clear from the unequalinvolvement of hand muscles that axonal lengthcannot be the sole factor determining the severityof neural involvement. It also appears that therelative sparing of hypothenar motor units is aphenomenon common to several varieties ofneuromuscular disease since it has now beenobserved in ageing (Sica et al., 1974), musculardystrophy (McComas et at., 1974), and chronicrenal failure (Upton, McComas, and Shimazu,unpublished observations). In thyrotoxicosis theproximal muscles also seemed to be affected lessseverely, as judged by the normal findings duringconcentric needle electromyography and thenormal motor unit estimates in soleus muscles(two patients studied). These observations werenot in agreement with the results of other studiesin which high incidences of abnormality werefound in proximal muscles (Havard et al., 1963;Ramsay, 1966; see also Sanderson and Adey,1952). However, since the analysis of concentricneedle electromyography was performed sub-jectively in the present study, it is certainlypossible that small but consistent abnormalitiesmight have been overlooked.The next question which might be asked

concerns the site of the neuropathic lesion-is itin the axon, Schwann cell, or motoneurone soma?Lesions of the Schwann cell cause segmentaldemyelination and, as a consequence, slowedimpulse conduction. In the present study, how-ever, the maximal motor conduction velocitieswere normal and the absence of abnormal Mwave dispersion also suggested that survivingaxons had little demyelination. Further evidenceagainst the demyelinating process was thecomplete sparing of sensory nerve fibres in thearm and legs by the neuropathic process. Whilean axonal lesion could certainly explain theobserved findings, we are tempted to identify themost biochemically active part of the moto-neurone, the soma itself, as the likeliest site ofthe primary lesion in a metabolic disorder. If this

555



j.com/

J Neurol N


ay 1974. Dow

nloaded from



identification is correct then the thyrotoxicneuropathy is but another example of a 'dying-back' process (Cavanagh, 1964). As yet, we donot know if it is simply the neuromuscularjunctions which are no longer functional orwhether the motoneurone axon can no longertransmit impulses towards them. It is certainlyintriguing that, using intravital staining, Havardet al. (1963) were able to demonstrate swellingsin the terminal motor axons together withclubbing of the end-plates.How does hyperthyroidism inactivate the

motoneurones? An important observation wasthat there was no loss of motor unit function inthe two patients presenting with exophthalmosand in whom clinical examination and laboratoryinvestigation failed to reveal evidence of hyper-thyroidism. This suggested that the neuropathywas a true effect of thyroid hormone(s) ratherthan some associated feature of the hyperthyroidsyndrome. In favour of this conclusion is thereport ofmuscle weakness in an otherwise normalsubject who had taken thyroxine to lose weight(Schwarz and Rose, 1963). Also, Hofmann andDenys (1972) were able to show that the musclefibres of rats injected with triiodothyroninedeveloped falls in resting membrane potentialand often became inexcitable, even to directstimulation.The mechanism by which the thyroid hormones

are able to disrupt function in the motoneuronescannot be analysed further by an electro-physiological approach. Nevertheless, on theor-etical grounds, at least two possibilities can beadvanced. One is that the thyroid hormones, byoverstimulating the metabolism of the moto-neurone soma itself, are able to 'exhaust' thosebiochemical reactions concerned with the trophiccontrol of muscle fibres. The alternative mechan-ism is an indirect one in which the motoneuronesbecome depleted ofsome essential substance usedup by other 'hypermetabolic' cells. Some ofthese hypermetabolic cells will be muscle fibresthemselves, for these are important contributorsto the increased basal metabolic rate charac-teristic of hyperthyroidism. Part of the action ofthe hormone on the muscle fibres is reflected inthe increased speed of contraction and relaxationduring the isometric twitch. This speeding-upcannot be due to a selective loss of function inslow twitch units since in some muscles the fast

twitches were associated with a normal popula-tion of units. Instead it appears from the work ofTakamori et al. (1971) that the thyroid hormonesare able to shorten the duration of the 'activestate' phase of muscle contraction. It is possiblethat this shortening results from potentiation bythyroid hormones of activity at the beta-adrenergic receptor sites which have beendemonstrated within muscle fibres (Marsden andMeadows, 1970).

It is obviously important to establish whetheror not the deleterious action of thyroid hormoneon the motoneurone is reversible. The mererecovery of strength after treatment cannot beregarded as conclusive evidence for it is knownthat effective compensation for denervation canbe achieved through axonal sprouting ofsurvivingmotorneurones. Fortunately, a clear answer hasbeen obtained from observations on the sixeuthyroid, but formerly hyperthyroid, patients.In these patients nearly all the motor unit countshad re-entered the normal ranges after treatmentwith 131I or, in one case, with propylthiouracil.Therefore the evidence presently availableindicates that the motoneurone dysfunction isreversible.

The changes which take place in the muscleduring the patient's recovery from thyrotoxicosisare of considerable interest. In four of the sixpatients studied a second time, it appeared thatthe restoration of muscle function had beenachieved simply by the reactivation of previously'inert' muscle fibres by 'recovered' moto-neurones. In the two remaining patients, how-ever, there was indirect evidence from acomparison of motor unit potential amplitudesand 'M' waves, that some remodelling of motorunits might have taken place. In other words,muscle fibres which had been reinnervated byadoptive motoneurones during the period ofthyrotoxicosis, had subsequently been recapturedby the recovered motoneurones. These observa-tions would also imply that during the thyrotoxicphase a proportion of the muscle fibres may havehad two end-plates, one original and quiescent,the other recent and functional. It seems im-portant to explore this possibility further, sincethis type of finding may help to prove or disprovethe existence of a system enabling highly specificrecognitions to be made between motoneurones



j.com/

J Neurol N


ay 1974. Dow

nloaded from


Evidence for reversible motoneurone dysfunctioii in thyrotoxicosis

and muscle fibres in mammals (see also Casset al., 1973).

Finally, it is interesting to speculate on thepossible relationship between motoneurone dys-function and the other recognized neuromuscularcomplications of thyrotoxicosis-myopathy, my-asthenia gravis, and familial periodic paralysis.We have argued elsewhere that another class ofmyopathic disorders, the muscular dystrophies,are in fact neuropathies with secondary de-generation of muscle fibres (McComas et al.,1971). The motor unit studies which we havenow carried out on distal muscles raise thepossibility that in thyrotoxicosis also, the weak-ness and muscle wasting of proximal muscles islargely neuropathic in origin.To incriminate the motoneurones exclusively,

however, would be imprudent, for it is probablethat thyroid hormones act on all the bodytissues, including muscle (see above). That beingso, the onset of functional denervation mightmerely signal the point at which a failing moto-neurone was no longer able to supply sufficienttrophic materials to keep pace with an increasedconsumption of the latter by its colony ofhypermetabolic muscle fibres. In 'idiopathic'myasthenia gravis, too, there is already a grow-ing suspicion that the underlying defect mayreside in the motoneurone soma with the synapticdysfunction occurring as a secondary event(McComas et al., 1971); again, it seems quitepossible that the myasthenia of thyrotoxicosismay have a similar explanation.The relationship between motoneurone dys-

function and hypokalaemic familial periodicparalysis has not yet been fully explored in thislaboratory; however, one of us (R.E.P.S.) hasobserved a loss offunctioning EDB units betweenparalytic episodes in two of three patients withthe non-thyrotoxic form of this disorder (Sicaand Aguilera, 1972). Even if the nature of theassociation between this condition and moto-neurone dysfunction cannot be determined atpresent, the possibility of a causal relationshipbetween motoneurone dysfunction and themyopathy, loss of motor unit function andmyasthenia of thyrotoxicosis seems worthy offurther investigation.

We are grateful to our colleagues, particularly Dr. F.Orr and Dr. W. C. Nicholas, for permission to study

some of the patients included in this study. We arealso indebted to Irene Csatari for secretarial services,to Bernice Crompton and Judy Leon (supported bythe Muscular Dystrophy Association of Canada) fortechnical assistance, and to Klaus Fabich forillustrations. One of us (A.J.McC.) is a member ofthe Canadian Medical Research Council's Group inDevelopmental Neurobiology, with whom R.E.P.S.held a Post-doctoral Fellowship.

REFERENCES

Birket-Smith, E., and Olivarius, B. de F. (1957). Polyradiculo-myopathia in transient thyrotoxicosis. Danish MedicalBulletin, 4, 217-219.

Bronksky, D., Kaganiec, G. I., and Waldstein, S. S. (1964).An association between the Guillain-Barr6 syndrome andhyperthyroidism. American Journal of Medical Science,247, 196-200.

Brown, W. F. (1972). A method for estimating the number ofmotor units in thenar muscles and the changes in motorunit count with ageing. Journal ofNeurology, NeurosurgerY,and Psychiatry, 35, 845-852.

Campbell, M. J., and McComas, A. J. (1970). The effects ofageing on muscle function. Fifth Symposium on CurrentResearch in Muscular Dystrophy and Related Diseases,London (Abstracts of Communications). Abstract No. 5.Muscular Dystrophy Group of Great Britain: London.1970.

Campbell, M. J., McComas, A. J., and Petito, F. (1973).Physiological changes in ageing muscles. Journal ofNeurology, Neurosurgery, and Psychiatry, 36, 174-182.

Cass, D. T., Sutton, T. J., and Mark, R. F. (1973). Com-petition between nerves for functional connexions withaxolotl muscles. Nature, 243, 201-203.

Cavanagh, J. B. (1964). Peripheral nerve changes in ortho-cresyl phosphate poisoning in the cat. Journal of Pathologyand Bacteriology, 87, 365-383.

Engel, A. G. (1972). Neuromuscular manifestations ofGraves' disease. Mayo Clinic Proceedings, 47, 919-925.

Havard, C. W. H., Campbell, E. D. R., Ross, H. B., andSpence, A. W. (1963). Electromyographic and histologicalfindings in the muscles of patients with thyrotoxicosis.Quarterly Journal of Medicine, 32, 145-163.

Hofmann, W. W., and Denys, E. H. (1972). Effects of thyroidhormone at the neuromuscular junction. American Journalof Physiology, 223, 283-287.

Lambert, E. H., Underdahl, L. O., Beckett, S., and Mederos,L. 0. (1951). A study of the ankle jerk in myxedema.Journal of Clinical Endocrinology, 11, 1186-1205.

Ludin, H. P., Spiess, H., and Koenig, M. P. (1969). Neuro-muscular dysfunction associated with thyrotoxicosis.European Neurology, 2, 269-278.

McComas, A. J., Campbell, M. J., and Sica, R. E. P. (1971).Electrophysiological study of dystrophia myotonica.Journal of Neurology, Neurosurgery, and Psychiatry, 34,132-139.

McComas, A. J., Fawcett, P. R. W., Campbell, M. J., andSica, R. E. P. (1971). Electrophysiological estimation of thenumber of motor units within a human muscle. Journal ofNeurology, Neurosurgery, and Psychiatry, 34, 121-131.

McComas, A. J., Sica, R. E. P., and Brown, J. C. (1971).Myasthenia gravis: evidence for a 'central' defect. Jouirnalof Neurological Sciences, 13, 107-113.

557



j.com/

J Neurol N


ay 1974. Dow

nloaded from



McComas, A. J., Sica, R. E. P., and Campbell, M. J. (1971)."Sick" motoneurones. A unifying concept of muscledisease. Lancet, 1, 321-325.

McComas, A. J., Sica, R. E. P., McNabb, A. R., Goldberg,W. M., and Upton, A. R. M. (1973). Neuropathy inthyrotoxicosis. New EnglandJournal of Medicine, 289, 219-220.

McComas, A. J., Sica, R. E. P., Upton, A. R. M., and Petito,F. (1974). 'Sick' motoneurones and muscle diseases.Annals ofthe New York Academy of Sciences, 289, 219-220.

Marsden, C. D., and Meadows, J. C. (1970). The effect ofadrenaline on the contraction of human muscle. Journal ofPhysiology, 207, 429-448.

Ramsay, I. D. (1966). Muscle dysfunction in hyperthyroidism.Lancet, 2, 931-935.

Sanderson, K. V., and Adey, W. R. (1952). Electromyographicand endocrine studies in chronic thyrotoxic myopathy.Journal of Neurology, Neurosurgery, and Psychiatry, 15,200-205.

Schwarz, G. A., and Rose, E. (1963). Neuromyopathies andthyroid dysfunction. Archives of Internal Medicine, 112,555-568.

Sica, R. E. P., and Aguilera, N. (1972). Electrophysiologicalstudies in hypokalemic periodic paralysis. Medicina (BuenosAires), 32, 93-99.

Sica, R. E. P., and McComas, A. J. (1971). Fast and slowtwitch units in a human muscle. Journal of Neurology,Neurosurgery, and Psychiatry, 34, 113-120.

Sica, R. E. P., McComas, A. J., Upton, A. R. M., andLongmire, D. (1974). Numbers of motor units in smallmuscles of the hand. Journal of Neurology, Neurosurgery,and Psychiatry, 37, 55-67.

Takamori, M., Gutmann, L., and Shane, S. R. (1971).Contractile properties of human skeletal muscle. Archivesof Neurology, 25, 535-546.

Whitfield, A. G. W., and Hudson, W. A. (1961). Chronicthyrotoxic myopathy. Quarterly Journal of Medicine, 30,257-267.



j.com/

J Neurol N


ay 1974. Dow

nloaded from


Evidence for reversible motoneurone dysfunction in thyrotoxicosis · Evidencefor reversible...

Documents

Transcript of Evidence for reversible motoneurone dysfunction in thyrotoxicosis · Evidencefor reversible...