411 Functional changes in motoneurones of hemiparetic patients.pdf

7/27/2019 411 Functional changes in motoneurones of hemiparetic patients.pdf

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bell, M. J (19/of In).IllUSCle., M. J., and lJin pa PIOn,Nel


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I

184 A. J. McComas. R. E. P. Sica, A. R. M. Upton, and N. Aguilera

must be considered as an additional cause ofwasting.Th e final hypothesis is that trans-synapticchanges take place in motoneurones after de

generation of corticospinal fibres. In the presentpaper we have set out to explore this last possibility using a recently described electrophysiological technique which enables numbers offunctioning motor units to be estimated (Mc-Comas, Fawcett, CampbeU, an d Sica, 1971c).Th e results of this study have shown in a con-vincing manner that after a hemiplegic episode,a substantial proportion of motoneurones in-nervating the paralysed limbs cease tofunction.Th e onset an d time course of this process, it smagnitude, and the consequences fo r survivingmotoneurones are considered. A preliminaryaccount of this work has already appeared(McComas, Sica, Upton, Aguilera, an d Currie,1971d).

METHODSSUBJECTS The study involved 46 patients who hadbeen rendered hemiplegic or hemiparetic after acerebrovascular lesion. In the younger patients thecommonest lesion was rupture of a cerebral aneurysm. In older patients thrombotic or haemorrhagiccomplications of atherosclerosis had been diagnosedon the basis of the clinical and laboratory findings.In all of the patients the weakneSs ha d been sufficient to prevent walking for one or more days. Withthe exception of a man who had been hemiplegic forthree days only, the patients had recovered sufficientlyto be able to walk and many were back to work. Inview of the recovery of movement in the affectedlimbs, the term hemiparesis has been preferred tohemiplegia in the text as a description of the patient'sdisability at the time of investigation.

In those patients in whom the cerebrovascularepisode had occurred more than a month previouslythere were, in addition to extensor plantar responses,increased muscle tone and exaggerated tendonreflexes; muscle wasting was usually evident. In 38of these patients, it was possible to compare theresults on the affected and normal sides. In a furthereight patients, also with cerebrovascular disease, itwas not possible to study an unaffected limb. In twothere had been a fracture in the opposite limb, whilein the remaining six there was evidence of bilateralupper motor neurone lesions. Coincidental causes ofmuscle wasting were eliminated from the study byrejecting patients who were over the age of 60 years

(Campbell and McComas, 1970) or who had wcalipers or taken anticonvulsant drugs. 0ELECTROPHYSIOLOOICAL TECHNIQUES The numbeof functioning motor units in extensor digitorllbrevis (BDB) muscles were estimated by the m e t hof McComas et al. (197lc). In some patients ismetric twitches of the extensor hallucis brevmuscle (most medial subdivision of EDB)recorded using the technique of Sica and M C C o m(1971). Measurements of conduction velOcity anterminal latency were made in the manner describeby McComas, CampbeU, and Sica (1971).STATISTICAL TREATMENT Mean values are showwith their standard errors. The significance of tdifference between two means was estimatedStudent's t test. while recognizing that in sominstances the data did not fall into normal distribtions.

8

2o 2 6 8 10 12

86

2o 2 6 8 10 1M WAVE AMPLITUDE (mVl

FIG. 2. Maximum M wave amplitudes of Dmuscles in 38 hemiparetic patients. Upper histogramnormal limbs (mean = 65 03 mV); lower histogramaffected limbs (mean=49O-4 mV, p


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-- -- ------- --- ----

Functional changes in motoneurones ofhemiparetic patients/ 185had wOrn ,I RESULTS et al., 1971c). The sizes of the responses CM\The numbersdigitorumby the methodiso.brevisEDB) wereand McComasanddescribed

are shownof theestimated byin Somedistribu

10 12

10 12(mY)of EDB

histogram,

waves') evoked in EDB muscles after maximalMUSCLE ATROPHY Muscle atrophy may be stimulation of deep peroneal nerves in 38 patientsassessed by a simple electrophysiological method are shown in Fig. 2. In this Figure the amplitudeswhich compares the maximum responses evoked of the M waves developed by the muscles on thein corresponding muscles in affected and normal normal and hemiparetic sides have been comlimbs. The amplitudes of these responses will be pared (upper and lower histograms respectively).proportional to the total cross-sectional areas of It can be seen that the pooled results for thethe active muscle fibres in each muscle, providedthat the stigmatic recording electrode averages affected sides showed a shift towards low valuesall the muscle fibre action potentials. In the of M wave amplitude and that eight observapresent study this requirement was met by the tions fell beyond the lower limit of the normaluse of a silver strap fixed to ,the skin across the range. In addition the mean amplitude for thefuU width ofthe EDB muscle belly (see McComas normal sides (6'S O3 mV) differed significantly

350

I 300I f/ )l !::zJIX 2500t- I~.... 2000IXwCA~=> 150Z0w ----_. ----_ ... - --t-- 100l- f /) w I0

~ - - - - _ r - - - - - - ~ - - - - ~ - - - - ~ ~ - - ~ ~ - - - - ~ ~ ~ ~o 10 20 30 40 50 60 120. 240DURATION Of .HEMIPARESIS (MONTHS)

:10. 3. Numbers off ~ n c t i o ~ i n g motor units in EDB muscles of46 paiientswith upper motor neurone lesions,t who';138 were hem/paretlc (see text) . Open and filled circles denotevalu(!s in normal and affected limbsl e s p e c t / ~ e l y . Duration of illness shown on abscissa. Lower limit ofnormal range (121 units) indicated by inter-rupted lme. . .


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186 A. J. McComas, R. E. P. Sica, A. R. M. Upton, and N. AguiIera

from that for the affected sides (4'9 04 mV,P=


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I Functional changes in motoneurones o fhemiparetic patients 187a loss"n the other(hat furthersix

ofthese patients(If(r",

e 27 patients8'4 andlegs ofP


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188 A. J. McComas, R. E. P. Sica, A. R. M. Upton, and N. Aguilera

legs, 20528'8 g; 0I>P>O05). When theresults for a further II affected legs wereincluded, for which no control observations werepossible, the corresponding mean was 209 82 g.This new mean differed significantly from thevalue of 310 94 g obtained from muscles ofhealthy subjects aged between 17 and 60 years(P1l-3 >0-2 < 0-001


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norm Iwas measured ~of theofmuscle. Inbeen foundof the 53 affectedwere re-60 msec and the0,11 msec

ofun-(395 0'09


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190 A. J. McComas, R. E. P. Sica, A. R. M. Upton, and N. Aguilera

restricted to this region during the first threeyears of life produced marked failure of growthof bones and muscles on the contralateral side.More recently, Botez (1971) has developed theargument in favour of the postcentral gyrus andhas raised the possibility of hemispheric dominance for a somatic trophic influence. In anextensive study of patients with cerebral tumour,he noted that wasting was clinically evident inmost of those with lesions of the minor hemisphere but occurred infrequently when thedominant hemisphere was involved. The neuroanatomical and physiological basis for a trophicinfluence of the postcentral gyrus on alphamotoneurones undoubtedly exists, since Penfieldand Boldrey (1937) have found that stimulationof this region in man can produce movement andit is now recognized that there is a heavy projection of fibres from the parietal lobe into thepyramidal tracts (Levin and Bradford, 1938).Against parietal lobe specificity for muscleatrophy are the observations of Fenichel et al.(1964) who found wasting in two patients without sensory loss and who cite similar observations by earlier authors. Fenichel et al. (1964)emphasize the importance of the precentralgyrus and it is relevant that Ful ton (1936, 1949)was able to produce marked wasting in chimpanzees after ablation of the motor strip, thoughlesions of the postcentral gyrus were ineffective.In the present study only patients with hemiparesis were investigated and all those withmuscle atrophy demonstrated the signs usuallyassociated with a lesion of the motor cortex orpyramidal tract fibres on the opposite s ide-hyperactive tendon reflexes, spasticity, and aBabinski response. Nevertheless, there were fivepatients with signs of an upper motor neuronelesion in whom atrophy was absent and theestimated numbers of motor units were withinthe normal range. I t was unlikely that thesepatients were exempted from atrophy by thepresence of lesions which did not involve thecritical area of cortex, since some had evidenceof more severe loss of cortical function thanothers in whom the reductions in functioningmotor units were marked. While accepting thatinvolvement of the corticospinal fibres issuingfrom the motor cortex will induce trans-synapticdegeneration of motoneurones in man, we areleft with the possibility that this degeneration

may sometimes be prevented by compensatospinal mechanisms (see below). SQ far assignificance of laterality was concerned. It l ' I~ j : l e to :find any correlatIOn ~ n th___abSence of motor urnt loss and tnsidt!Of die lesion R8&ldts1.


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I Functional changes in motoneurones ofhemiparetic patients 191fiG. 7. Postulated sequence o fevents after an upper motorreurOlle lesion. (a) shows situation in health with alpha-~ ( ) t o n e u r o n e (mn) receiving corticospinal and segmental (seg)inputS. ilt (b) a cerebrovascular lesion destroys cells in motorcortex or emergent axons. Motoneurone now becomes dys-functiollal and may lose part o f motor unit. At rophy ofmuscle la)(mu) ensues. Two developments are now possible. In one (c)

muthe motoneurone ceases to limction and may actually degener- ate. In the other (d) the segmental input to the motoneurone is increased by axonal sprouting. The improved supply of trophic material restores the motoneurone to full function and collateral reinnervation o f muscle fibres can now proceed (e).

Ib]

I(c)

(d)

(e)

the parietal lobe. Nevertheless, in the present muscles. These differences indicate a greaterstudy it has been shown that at least two months susceptibility of some motoneurone pools toare required before motoneurone dysfunction trans-synaptic changes than others and prereaches the stage at which the axon becomes sumably reflect inequalities in the density of theelectrically inexcitable. I t is also evident from the fibre projection normally received from thework of Goldkamp (1967), among others, that cortex. So far as the EDB muscle is concerned.muscle degeneration is likely to be more severe cortical mapping studies have shown that thein some muscles than others. Distal muscles, area of motor ,cortex devoted to movements ofespecially those of the hand, usually show more the toes is considerably less than the area for thewasting and, in GoIdkamp's study, a higher fingers (Penfield and Boldrey, 1937). In keepingincidence of fibrillation potentials, than proximal with this difference is the recent observation that


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192 A. 1. McComas, R. E. P. Sica, A. R. M. Upton, and N. Aguilera

voluntary potentiation of segmental reflexes ismore marked for those reflexes involving handmuscles than for those of the foot (Upton, Sica,and McComas, 1971). In the EDB muscle abouthalf the motor units retained function after acerebral lesion. It is possible that the corresponding motoneurones may have been the ones whichhad received smallest corticospinal inputs andthe largest segmental ones. The measurements oftwitch contraction time suggested that these surviving motoneurones tended to innervate musclefibres having relatively slow isometric twitches.I t is consequently of interest that in a histochemical study of muscle biopsies from hemiplegic patients, Edstrom (1970) has found evidence of hypertrophy in type I muscle fibres andatrophy in fibres of type n. I t is unlikely that t hesurviving motor units are a homogeneous slowtwitch population, however, since comparison ofthe mean EDB contraction time with values forsingle units in normal subjects (Sica andMcComas, 1971) indicates that some units withrelatively fast twitches must also have beenspared.

In the present study the amplitudes of themotor unit potentials were of considerableinterest, insofar as they gave an indication of thefunctional status of the motoneurones. I t wasfound that in the 6 to 19 month period after anupper motor neurone lesion the potential amplitudes generated by the surviving motor unitsremained unchanged. This finding suggested thatthe corresponding motoneurones cannot havebeen 'healthy', since otherwise they would haveresponded to the presence of denervated musclefibres by axonal sprouting and collateral fibrereinnervation. This observation, together withthe frequent occurrence of decremental responsesto repetitive motor nerve stimulation and thesometimes prolonged terminal latencies, indicated that many of the surviving motoneuroneswere dysfunctional. After 19 months, however,the measurements of M wave amplitude suggested that there was some regression of the muscleatrophy. This was not due to recovery of function in motor units, since the numbers of viableunits remained unchanged. Instead, the meanmotor unit potential size increased, due either toaxonal sprouting and the adoption of denervatedfibres or to muscle fibre hypertrophy, or to both.Irrespective of the mechanism involved, it

appeared that most surviving motoneurones h dchanged back from a dysfunctional to a h e a l t ~state. The reason for this improvement Was n Yclear but one possibility was that the motOtneurones had received increased trophic i n p u ~from other spinal neurones. These last neuronesby axonal sprouting, would have been abletake over the synaptic territory relinquished bythe degenera ting corticospinal fibres on the alpha.motoneurones (see McCouoh, Austin, Lin, andLiu, 1958). Not only should the excitatory Orinhibitory effects of the spinal neurones havebeen larger, bu t the trophic inftuences of thesecells on the a1pha-motoneurones should alsohave been greater. I t is therefore conceivablethat the return of the motoneurones to completefunction may have resulted from compensatoryenhancement of trophic inputs from spinalsources. Although the findings of the presentstudy are only strictly applicable to man, it is ofinterest that, in the rat, Solandt and Magladery(1942) observed that there was some restorationof muscle bulk six weeks after spinal sectionrostrally. The postulated sequence of eventsafter an upper motor neurone lesion is showndiagrammatically in Fig. 7.

In conclusion, the present investigation hasconfirmed those early studies in which transsynaptic degeneration of motoneurones wasreported. Because the approach applied here hasbeen a physiological rather than a morphologicalone, it has had the advantage of increased sensi-tivity and of enabling the reduction in moto-neurone function to be measured and its timecourse established. The patient with an uppermotor neurone lesion has provided a satisfactorymodel for the study of trophic mechanisms withinthe central nervous system. It is hoped that, inturn. the information acquired may ultimatelylead to improved methods for the rehabilitationof such patients.Financial support was received from the MedicalResearch Councils of Great Britain and Canada. Weare indebted to Mrs. B. McLean and Mrs. l. Englishfor secretarial assistance and to Mr. T. Blogg fortechnical services. We also wish to thank thephysicians at the Hospital Ramos Mejia in BuenosAires, the St. lames University Hospital in L e e ~ s ,Newcastle General Hospital, and at the hospitals In.Hamilton for permission to study their patients.


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COOK, W. H., Walker, J. H., and Barr, M. L.. (1951). A cytological study of transneuronal atrophy In the cat andrabbit. Journal of Comparative Neurology. 94, 267-291.Dejerine, J. (1889). De la nevrite peripherique dans I'atrophiemusculaire des hCmiplegiques. Comptes Rendus Hebdomadaires des Seances et Memoires de la Societe de Biologie,41,523-530.Edstrom, L. (1970). Selective changes in the sizes of red andwhite muscle fibres in upper motor lesions and Parkinsonism. Journal of the Neurological Sciences, 11, 537-550.Fenichel, G. M., Daroff, R. 8. , and Glaser, G. H. (1964).Hemiplegic atrophy: histological and etiologic considerations. Neurology (Minneap.), 14, 883-890.Fulton, J. F. (1936). The interrelation of cerebrum andcerebellum in the regulation of somatic and autonomicfunctions. Medicine (Baltimore), IS, 247-306.Fulton, J. F. (1949). Physiology of the Nervous System, 3rdedn. Oxford University Press: New York.Glees, P., and Cl ark, W. E. Le Gros (1941). The terminationof optic fibres in the lateral geniculate body of the monkey.Journal ofAnatomy. 75, 295-308.Goldby, F. (1957). A note on transneuronal atrophy in thehuman lateral geniculate body. Journal of Neurolo/J.v,Neurosurgery, and Psychiatry, 20, 202-207.Goldkamp, O. (1967). Electromyography and nerve conduction studies in 116 patients with hemiplegia. Archives ofPhysical Medicine, 48, 59-63.Hall, M. (1836). Lectures on the Nervous SVstem and itsDiseases. Sherwood, Gilbert and Piper: London. Cited byG. M. Fenichel, R. B. Daroff, and G. H. Glaser. InNeurology (Minneap.) (1964),14,883-890.Hess. A. (1957). The experimental embryology of the foetalnervous system. B i o l o g i ~ a l Reviews, 32, 231-260.Levin, P. M., and Bradford, F. K. (1938). The exact origin ofthe cortico-spinal tract in the monkey. JournalofComparalice Neurology, 68,411-422.

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., Sica, R. E. P., and Campbell, M. J. (l97Ia).Sick' motoneurones. A unifying concept of muscle disease.Lancet, 1, 321-325.McComas, A. J., Fawcett. P. R. W., Camp bell, M. J., andSica, R. E. P. (l97lc). Electropbysiological estimation ofthe number of motor units within a human muscle.Journal of Neurology, Neurosurgery, and Psychiatry, 34,121-131.McComas, A. J., Sica, R. E. P., Upton, A. R. M., Aguilera,N., and Currie, S. (l97Id). Motoneurone dysfunction inpatients with hemiplegic atrophy. Nature New Biology,233,21-23.McCouch, G. P., Austin, G. M., Liu, C. N., and Liu, C. Y.(1958). Sprouting as a cause of spasticity. Journal ofNeuro-physiology, 21,205-216.Matthews, M. R., Cowan, W. M., and Powell, T. P. S. (1960).Transneuronal cell degeneration in the lateral geniculatenucleus of the macaque monkey. Joulllal of Anatomy, 94,145-169.Miledi, R., and Slater, C. R. (1970). On the degeneration ofra t neuromuscular junctions after nerve section. Journal OfPhysiology, '107, 507-528.Namba, T., Schuman, M. H., and Grob, D. (1971).Conduction velocity in the ulnar nerve in hemiplegicpatients. Journal of the Neurological Sciences, 1:1, 177-186.Notermans, S. L. H. (1968). EMG in patients with so-calledparietal atrophy. (Abstract.) Electroencephalography andClinical Neurophysiology, 25, 405P.Penfield, W., and Boldrey, E. (1937). Somatic motor andsensory representation in the cerebral cortex of man asstudied by electrical stimulation. Brain, 60, 389-443.Penfield, W., and Robertson, J. S. M. (1943). Growth_asymmetry due to lesions of the postcentral cen:bralcortex. Archivesof Neurology and Psychiatry, SO, 405-430.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.Silverstein, A.. (1955). Diagnostic localizing value of muscleatrophy in parietal lobe lesions. Neurology (Minlleap.), 5,30-55.Solandt, D. Y., and Magladery, J. W. (1942). A comparisonof effects of upper and lower motor neurone lesions onskeletal muscle. Journal of Neurophysiology,S, 373-380_Tower, S. S. (1937). Trophic control of non-nervous tissuesby the nervous system: a study ofmuscle and bone innervated from an isolated and quiescent region of spinal cord.Journal of Comparative Neurology, 67, 241-267.Upton, A. R. M., McComas, A. J., and Sica, R. E. P.(1971). Potentiation of 'late' responses evoked in musclesduring effort. Journal of Neurology, Neurosurgery. alii/Psychiatry, 34, 699-711.Young, I. J. (1966). Morphological and histochemical studiesof partially and totally deafferented spinal cord segments.Experimental Neurology, 14, 238-248.

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