J7ournal ofNeurology, Neurosurgery, and Psychiatry 1994;57:773-777

Journal of

NEUROLOGYNEUROSURGERY& PSYCHIATRY

Editorial

Pathophysiology of spasticity

Spasticity is a frequent and often disabling feature ofneurological disease. It may result in loss of mobility andpain from spasms. The core feature of the spastic state isthe exaggeration of stretch reflexes, manifest as hyper-tonus. The stretch reflex threshold is reduced,' and itsgain may be increased.2 The result is the velocity-depen-dent increase in resistance of a passively stretched muscleor muscle group detected clinically. Often, this is associ-ated with a sudden melting of resistance during stretch,the clasp-knife phenomenon. In addition, there may beother related signs, such as weakness, impairment of finemovements of the digits, hyperreflexia, loss of cutaneousreflexes, Babinski's sign, clonus, spasms and changes inposture. Spasticity is traditionally ascribed to damage tothe pyramidal tract. Work, however, particularly in ani-mals, clearly implicates additional motor tracts in thepathophysiology of the spastic syndrome. The presenteditorial draws together old and new observations to pro-vide a working hypothesis explaining the pathophysiologyof spastic hypertonus, and some of the related elementsof the human spastic syndrome. Possible changes inspinal neuronal circuitry have been the focus of severalrecent reviews34 and will not be discussed.

Inhibitory supraspinal influencesSome instances of lesions of the pyramidal system caus-ing hypertonus and hyperreflexia have been reported inanimals, but these signs were not striking5 6 and may haveresulted from coincidental damage to non-pyramidalmotor pathways.78 More remarkable is the fact that pyra-midal tract lesions have not led to spasticity in the handsof many experimenters. Destruction of the primarymotor cortex in area 4,9-11 section of the medullary pyra-mids," '14 or lateral corticospinal tract'5 16 have lead toweakness (particularly involving fine movements of thedigits), hypotonia and hyporeflexia in monkeys and apesobserved for up to several months following lesioning.The findings in humans have been rather more diffi-

cult to interpret. Attention must be paid to the exactextent of pathological or iatrogenic lesions, and sufficienttime must be allowed for spasticity to develop. Flaccidweakness may be present for up to six weeks before spas-ticity develops after cerebral and spinal lesions.

It is often argued that the lesions of the pyramidal tractin man can cause spasticity on the basis that hypertoniamay follow surgical excision of the precentral gyrus andtherefore of the primary motor cortex in area 4.17-20 Such

operations, however, may entail damage to areas otherthan area 4, and to the cortical origins of motor systemsseparate from the pyramidal tract. Excision of the ventralprecentral gyrus (arm area) involves removal of part ofarea 4 and, in addition, the ventral portion of area 6 (thepremotor area), which occupies the anterior border of theprecentral gyrus.21 Removal of the superior part of theprecentral gyrus (leg area) risks damage to the supple-mentary motor area, and fibres leaving it.8 "1 More impor-tant therefore may be those cases in whom hemiparesis ofcortical origin is not accompanied by spasticity.22 Onesuch case was recently reported in whom MRI demon-strated a lesion confined to the precentral gyrus.23

Spasticity does not follow the unilateral section of thecorticospinal tract in the human cerebral peduncle.2425Flaccid hemiparesis has been reported after infarctsinvolving the basis pontis26 and medullary pyramid2728but tone was examined just days after the stroke. Othercases have been reported in whom spasticity hassupervened, but infarction extended beyond the pyra-mids.272930 Brown and Fang describe a case of sharplylocalised infarction of the corticospinal tract at the pon-tomedullary junction in which an initially flaccid hemi-paresis may have become spastic, but clinical details arescanty.3' Hypertonus is conspicuously absent in limitedcordotomies involving the lateral pyramidal tracts.32

In summary, it is unlikely that damage to the pyrami-dal tract alone plays a major role in the production ofspasticity. This is in contrast to weakness and loss ofsuperficial reflexes, such as the abdominal reflexes, whichare common accompaniments of isolated lesions of thepyramidal tract.'6 31 The association between corti-cospinal tract damage, and tendon hyperreflexia and theBabinski response is less clear cut.'62032-34

This does not mean, however, that the motor cortexcannot influence tone. Perhaps the most tangible proof ofthis is the common clinical observation that capsularlesions often lead to more striking spasticity than corticallesions. The implication must be that such lesions inter-rupt fibres originating in cortical areas other than the pri-mary motor cortex (area 4), and that these fibres formpart of a motor system influencing tone separate from thecorticospinal tract. Extensive cortical lesions, involvingpremotor and supplementary motor areas, add spasticityto the paralysis seen with focal lesions of area 4 in mon-keys.891' 1314 Forester reported an epileptic patient with amild hemiparesis due to traumatic injury of the precen-tral gyrus who developed a spastic hemiplegia following

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excision of the premotor cortex.35 In animal experiments,spasticity is more marked if such lesions are bilateral,"suggesting that these non-pyramidal projections can havebilateral effects. The fibres influencing spasticity run withthe corticospinal tract as far as the cerebral peduncles.3637In the cat they lie in the medial portion of the peduncleand in the area just dorsal to this, before ending in thebulbar reticular formation dorsal to the medullary pyra-mids.38 Within the internal capsule there may be someseparation of the pathways, with axons from the primarymotor cortex, premotor cortex, and supplementary areapassing through the posterior limb, genu, and anteriorlimb of the internal capsule respectively.39 This mayexplain why small capsular lesions in the anterior limbtend to be associated with spastic hypertonus, whereasthose involving the posterior limb are not.39 Large infarc-tions in the middle cerebral artery territory and subcorti-cal infarcts undercutting most of the descending fibres inthe corona radiata lead, in time, to a spastic hemiplegiaas they involve both corticospinal and corticoreticularprojections.

Although the available evidence suggests that isolatedlesions of the pyramidal tract do not cause spasticity,this, of course, need not mean that the pyramidal tracthas no influence over tone under normal circumstances.This point is admirably illustrated by Bucy's analogy thatremoval of one kidney has little effect on homeostasis.'4This does not mean that the excised kidney was withouteffect, only that the remaining kidney has assumed theentire load. Similarly, ipsilateral supplementary motorand premotor areas, or contralateral motor cortex mayassume some of the functions of the destroyed corti-cospinal fibres from the precentral gyrus. This has beenincreasingly recognised as underlying the return of powerfollowing pyramidal lesions; but its role in tone has notbeen addressed.The influence of cortical motor areas over tone is prin-

cipally mediated by a powerful inhibitory mechanism inthe bulbar reticular formation. Electrical stimulation ofthe ventromedial reticular formation dorsal to the pyra-mids inhibits the patellar reflex40 and gastrocnemius-soleus tonic vibration reflex4' in intact cats, and abolishesextensor tone in decerebrate preparations40 and in catsrendered spastic by chronic cerebral lesions.4' Theinhibitory effects in intact animals are potentiated bysimultaneous stimulation of the premotor cortex or inter-nal capsule.4' The anterior and paramedian cerebellarcortex and fastigial nucleus may also modulate theinhibitory actions of the reticular formation, at least inthe cat.4'

Inhibitory influences survive section of the pyramidaltract in the medulla37 and are conducted in the cord bythe dorsal reticulospinal tract in the dorsal half of the lat-eral funiculus.44 The available evidence suggests that thetract occupies a similar position in humans in close rela-tionship with the lateral corticospinal tract.45 It is the lossof the cortical drive to the bulbar inhibitory centre whichis principally responsible for the spastic hypertonus fol-lowing lesions of the frontal cortex or internal capsule. Incontrast, spasticity is not often a striking feature ofhuman bulbar lesions, perhaps because lesions in theregion of the inhibitory centre also involve respiratoryand vasomotor centres and are usually incompatible withlife.The inhibitory centre in the caudal brainstem and the

dorsal reticulospinal pathway tonically inhibit flexorreflex afferents as well as spinal stretch reflexes. Thusdamage to this system in the lateral funiculus releasesflexor reflexes in animals.4446 Shahani and Young47 have

pointed out that flexor spasms are qualitatively no differ-ent to the flexor reflexes recorded in patients with spinaltransections and normal subjects, raising the possibilitythat flexor spasms are a release phenomenon consequentto damage to the dorsal reticulospinal pathway. In addi-tion, it is now believed that the clasp-knife phenomenonis caused by the inhibitory effects of flexor reflex affer-ents,48 and lesions involving different levels of the dorsalreticulospinal system release the clasp-knife phenomenonin cats.49

Excitatory supraspinal influencesVestibulospinal activity is important in maintainingdecerebrate rigidity, but may have a lesser role insupporting tone in spasticity. Injury to the vestibularnuclei alone has little effect on spasticity in the spasticcat.50 In contrast, transection of the bulbopontinetegmentum leads to a marked reduction in spasticity.50Electrical stimulation of the reticular formation of thedorsal brainstem facilitates the patellar reflex in the intactanimal, and increases hyperreflexia, hypertonus, andclonus in the cat made chronically spastic by previousextirpation of the motor cortex.4' The facilitatory effects,unlike the inhibitory effects of the reticular formation, arenot affected by stimulation of the motor cortex or inter-nal capsule.41 Thus the reticular formation gives rise toboth inhibitory and excitatory systems influencing spas-ticity. The latter originates in a diffuse area extendingfrom the basal diencephalon, central grey and tegmen-tum of the midbrain, the pontine tegmentum, and thelateral bulbar reticular formation, outside of theinhibitory field.40 The spinal projections of this systeminvolve the ventral half of the cord.505' This facilitatoryreticulospinal system is central to the state of spasticity,although vestibulospinal influences may make some con-tribution as lesions of the vestibular nuclei and bulbo-pontine tegmentum have a greater effect on spasticity inthe cat than tegmental lesions alone.50 Damage tovestibulospinal and facilitatory reticulospinal pathways inthe anterior funiculus of the cord may also contribute tothe release of flexor reflexes and spasms.46

Descending spinal pathwaysThe lesions of the spinal cord affecting tone have beencarefully documented in the monkey.'6 Lesions of theventral funiculus lead to hyperreflexia in the setting ofessentially normal tone, while those confined to the lat-eral corticospinal tract in the lateral funiculus lead tohypotonia, hyporeflexia and loss of cutaneous reflexes. Incontrast, extensive lesions of the lateral funiculus (thatinclude the dorsal reticulospinal tract) are followed byspasticity and hyperreflexia, as is severing of the lateralfuniculus in animals with a previously disrupted corti-cospinal tract. Spasticity is less marked if the vestibu-lospinal tracts are also cut. The distribution of hypertoniafollowing the disruption of the dorsal reticulospinal fibresin the lateral funiculus is identical to that followingfrontal lobe lesions.

Information about the distribution of pathways influ-encing stretch reflexes and tone in humans comes fromcordotomies. Putnam52 performing this operation forparkinsonism, observed that unilateral section of the dor-sal half of the lateral funiculus was followed by a severeinitially flaccid paralysis. As power returned spasticity,hyperreflexia, and clonus appeared. Hyndman," treatingintractable pain, cut the intermediate portion of the lat-eral funiculus bilaterally at the thoracic level, and found

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that hyperactive knee and ankle jerks, ankle clonus andBabinski's sign appeared immediately, but spastic hyper-tonus only developed in one out of six patients, and thenwas only mild. Histological confirmation of the extent ofthe lesions, however, was absent in these cases. Spasticitydid not develop after bilateral anterolateral cordotomies,in some cases extending posteriorly to involve the lateralcorticospinal tracts.'25'54

Cordotomies have also been used in the treatment ofspasticity. Bucy observed that unilateral or bilateral sec-tion of the vestibulospinal tract in the anterior funiculusof patients with congenital spastic paraplegia or quadri-plegia only caused a transient reduction in extensor tonein the lower limbs." He concluded that the vestibu-lospinal tract contributes to the maintenance of humanspasticity, but other descending pathways are capable ofmaintaining spasticity at its full intensity in the absenceof vestibulospinal influences. The cordotomies performedby Bucy were said to spare the deeper sulcal regions ofthe anterior funiculi, but there was no histological confir-mation of this. In contrast, extensive unilateral or bilat-eral anterior cordotomy (which included the deepersulcal areas) was followed, after a transient period of flac-cidity, by the loss or considerable reduction of extensortone in the legs, despite the reappearance of hyper-reflexia, adductor spasm, and clonus.56On the strength of these findings it seems that lesions

must involve the dorsal half of the lateral funiculus toproduce spastic hypertonus in man. Presumably lesionshere interrupt the inhibitory dorsal reticulospinal tract tocause spasticity.45 In patients already spastic, extensiveanterior cordotomy, but not partial anterior cordotomy,abolishes extensor tone. This, like the results of animalexperiments,50 suggests that the medial reticulospinaltract originating in the excitatory areas of the brainstemreticular formation5' is more important than the vestibu-lospinal tract in maintaining spastic extensor tone. Thehuman medial reticulospinal tract runs in the sulcomar-ginal territory, in association with the median longitudi-nal bundles,45 and is likely to have been spared by Bucy'slimited incisions.55

In summary, two major balancing descending systemsexist controlling tone in humans: on the one hand, theinhibitory dorsal reticulospinal tract; and, on the other,the facilitatory medial reticulospinal and vestibulospinaltracts.

Propriospinal and segmental influencesThe striking feature of the hypertonicity and hyper-reflexia that develops following complete transection ofthe spinal cord is the variable period of spinal shock thatprecedes the tone changes. During this period, whichmay last several weeks, muscles are toneless and areflexicbelow the level of transection, as might be expected fol-lowing the simultaneous loss of inhibitory and excitatorysupraspinal influences on segmental and propriospinalreflexes. The delayed appearance of tone and reflexes haslead to the suggestion that plasticity within the spinalcord, namely receptor hypersensitivity and sprouting ofaxon terminals, is responsible for hypertonicity in com-plete spinal cord lesions.5758 This hypertonicity, may dif-fer from the velocity dependent spasticity seen in partialcord lesions, and result from virtually continuous flexorspasms.59 Loss or reduction of knee and ankle jerks, para-plegia in flexion, and mass reflexes (exaggerated flexorspasms which also involve bowel and bladder contrac-tion) are common in this situation.60

Peripheral effectsRecent studies have challenged the classic view that exag-gerated stretch reflexes are the major cause of establishedspasticity. In the swing phase of gait, the tibialis anteriorshows abnormally high levels of activity, despite the lackof any EMG activity in its antagonist, the triceps suraemuscle.61 This suggests that mechanical changes in theextensor apparatus of the ankle, rather than muscle activ-ity in the triceps surae itself, lead to increased resistanceto dorsiflexion movements. Direct measurement of theresistance of the relaxed ankle to slow displacement inhemiparetic subjects has confirmed the importance ofmechanical factors.2 Factors that might contribute to theincreased mechanical resistance to movement are alter-ations in tendon compliance2 and physiological, morpho-metric, and histochemical changes in muscle fibres.'Given the velocity dependence of the stretch reflex,62these mechanical factors may be particularly importantduring functional movements of the leg, which occur atlow angular velocities.6'How the influence of central and mechanical factors

on tone and function change with time is, as yet, unclear.There is limited evidence to suggest that stretch reflexgain reduces over the months to years following the ini-tial lesion.2 Conversely, if we are to assume that contrac-tures represent the extreme end of the mechanical factorsresisting limb movement, then there is reason to believethat their development is delayed. The issue of the nat-ural history of central and mechanical factors is animportant one, as early treatment of hypertonia mayavert mechanical changes. This has been the finding inan animal model of spasticity, and has prompted aninvestigation of the disease modifying effects of botu-linum toxin in spastic cerebral palsy.6'

ConclusionNormal tone consists of a balance between inhibitoryeffects on stretch reflexes mediated by the dorsal reticu-lospinal tract and facilitatory effects on extensor tone,mediated by the medial reticulospinal tract, and, to alesser extent in humans, by the vestibulospinal tract. Incortical and capsular lesions some of the drive on theinhibitory centre in the caudal brainstem is lost resultingin a spastic hemiplegia, in which antigravity posture pre-dominates, but flexor spasms are unusual. In practicepartial spinal lesions usually involve the lateral corti-cospinal and dorsal reticulospinal tract, as most com-monly seen in multiple sclerosis where demyelinatinglesions have a predeliction for the lateral funiculi.64Damage to the corticospinal tract leads to paresis, whileloss of inhibitory influences from the dorsal reticulospinaltract, leaves the effects of the medial reticulospinal andvestibulospinal tracts unopposed. In this situation there isoften severe spasticity with tone being greatest in theantigravity muscles, so that paraplegia in extension maybe seen. Extensor and flexor spasms are common,although the former tend to predominate.59 This is theclinical picture of multiple sclerosis relatively early in itscourse.The present hypothesis may also explain the marked

spasticity in the legs in the presence of spasms, but littleor no weakness in many patients with hereditary spasticparaparesis. Here, there is involvement of the dorsalreticulospinal tract in the thoracolumbar cord with adegree of sparing of the corticospinal tracts. Support forthis comes from pathological reports65 and from the rela-tive normality of electromyographic responses in leg

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muscles to electrical stimulation of the motor cortex inpatients with this condition.66

In severe or complete cord lesions there is loss of allsupraspinal influence on the cord. Hypertonicity is not asmarked as in some cases of incomplete cord lesions, asthe descending excitatory systems are no longer actingunopposed. Flexion spasms are very prominent, however,as flexor reflexes are released from the inhibitory influ-ences of the dorsal reticulospinal, vestibulospinal andmedial reticulospinal tracts. Paraplegia in flexion maythen supervene. This is often the clinical picture ofadvanced multiple sclerosis, when lesions have also inter-rupted function in the descending tracts of the anteriorfunniculus.Of course the pattern of spasticity is not fixed and

solely determined by the degree of damage to differentdescending pathways. Stimulation of flexor reflexafferents-for example, by pressure sores, can transformparaplegia in extension into paraplegia in flexion.Conversely, standing reduces flexor tone and favoursextensor tone, a phenomenon that is readily used toadvantage in physiotherapy. An additional factor in com-plete transection is the delayed reorganisation within theisolated cord, which may underline the change in balancefrom flexor to extensor spasms sometimes seen a year ormore after division of the cord.67

I have expanded on old hypotheses to provide aschema explaining the pathophysiology of human spastichypertonus. The hypothesis is largely based on animalwork, as relevant clinical observations are few and imper-fect. Opportunities to study spasticity in patients arecommon and it is hoped that this editorial will encouragecareful clinical observation, supported, where necessary,by lesion localisation with MRI, to refute or develop thisschema in the future. Acquired pathology rarely respectsneuroanatomical boundaries and it may be that furtherinvestigation in humans requires the technique of lesionsuperimposition that has proven so useful in other con-texts.

P BROWNMRC Human Movement and Balance Unit,

Institute ofNeurology, National Hospitalfor Neurology andNeurosurgery, Queen Square, London WCIN 3BG, and

Department ofNeurology, Guy's Hospital, London SEI 9RT, UK

I thank Dr P W Nathan and Dr J C Rothwell for their helpful comments anddiscussion.

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NEUROLOGICAL STAMP

Jan Evangelista Purkinje (1787-1869)

Purkinje was born in Libochovice, Bohemia (nowCzechoslovakia) and educated by Piarist monks. He -----

studied philosophy at the University of Prague, wasordained a priest and became Father Salverius. In 1819,aged 32, he graduated in medicine. Purkinje, who had , -- ,-already made significant contributions to physiology, __'applied unsuccessfully for several University appoint- 1 2-ments within the Austro-Hungarian Empire. Through1:friendship with Goethe he was appointed Professor of -Physiology at Breslau University in 1823 against theopposition of the Faculty. In 1850 he was invited to theChair of Physiology in Prague which he held until his K /43deathi.

His early work included the influence of the head C -position on the directional component of vertigo, and themaintenance of posture and equilibrium, culminating in 4Fi _Purkinje's Law of Vertigo. Purkinje explored aspects of i :vision and discovered in 1825 a phenomenon known as L -the Purkinje effect (as light intensity decreases, red =- : -objects are perceived to fade faster than blue objects).

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While examining birds' eggs he discovered thegerminal follicle, sometimes called the Purkinje vesicle. L_____In 1837 he located the Purkinje cells in the cerebellar ,.cortex, and two years later the Purkinje fibres lyingbeneath the endocardium.

Purkinje also introduced the term protoplasm todescribe the living embryonic material of the egg. Hemade original contributions to the histology of sweatglands, skin, bone, dental structures and was the first todiscover the uniqueness of the human fingerprint. Henoted that pancreatic extracts digested protein and hemade comparative studies of cellular structures of plantsand animals. Purkinje was among the first to use amicrotome and one of the first to teach microscopy aspart of a university course. He also studied digitalis toxic-ity (on himself) and the effects of belladonna and opium.Purkinje translated poetry from German, Russian, andPolish and wrote some of his own. At age 80, he learnedHungarian so that he could translate a libretto.He was honoured by Czechoslovakia in 1937 (Stanley

Gibbons 371 and 372, Scott 232 and 233) on the 150thanniversary of his birth.

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