28ournalofNeurology, Neurosurgery, and Psychiatry 1993;56:268-273

Chronic thalamic stimulation improves tremorand levodopa induced dyskinesias in Parkinson'sdisease

Dominique Caparros-Lefebvre, Serge Blond, Patrick Vermersch, Nathalie Pecheux,Jean-Daniel Guieu, Henri Petit

AbstractChronic thalamic stimulation was per-formed in 10 Parkinsonian patients withdisabling tremor and poor response todrug therapy. During the stereotacticprocedure, an electrode was introducedin the ventralis intermediate nucleus ofthe thalamus. Test stimulation was per-formed during the intra-operative proce-dure and a few days after surgery usingan external stimulator. When tremor wasobviously reduced by thalamic stimula-tion, an internal stimulator was implant-ed under the clavicle. Tremor wasinitially suppressed in all cases and reap-peared whenever stimulation wasstopped. Patients were followed for 22 to34 months. Tremor was controlled ineight cases but reappeared after threemonths in two cases. Levodopa induceddyskinesias were observed before elec-trode implantation in 5 cases. They con-sisted of peak-dose choreic or ballisticdyskinesias in 4 cases and biphasic dys-tonic dyskinesias in 3 cases. Peak-dosedyskinesias were greatly improved orsuppressed in all cases. Biphasic dyski-nesias were improved in 2 cases.Thalamic stimulation was well tolerated.Mild dystonic hand posture related to thedeep brain stimulation was observed inone case. No neuropsychological side-effects were noted. Thalamic stimulationcould prove to be an adequate treatmentfor resistent tremor and levodopainduced dyskinesias.

(7 Neurol Neurosurg Psychiatry 1993;56:268-273)Department ofNeurology, CHRULille, FranceD Caparros-LefebvreP VermerschN PecheuxH PetitDepartment ofNeurosurgery, CHRULille, FranceS BlondDepartment ofNeurophysiology,CHRU Lille, FranceJ-D GuieuCorrespondence to:Dr Caparros-Lefebvre,Clinique Neurologique (PrH Petit), CHRU LILLE, F-59037 LILLE Cedex,FranceReceived 7 August 1991and in final revised form3 June 1992.Accepted 19 June 1992

Many structures of the CNS were targets forneurosurgical treatment of tremor during thefirst half of this century. The introduction ofhuman stereotaxis and development of neuro-physiology improved target area accuracy andreduced operative risks.' Recording of extra-cellular spike discharges during thalamotomythrough a microelectrode was first reportedby Albe-Fessard. Rhythmic discharges were

detected in the ventral part of the thalamus,especially in the ventral intermediate nucleus.They were time-locked with the peripheralspontaneous contralateral tremor. The VIMwas therefore considered to be the besttarget.'4 As levodopa therapy became gener-

alised, interest in thalamotomy declined dra-matically.5 Levodopa remains the treatmentof choice for Parkinsonian tremor but the use

of thalamotomy has been re-evaluated since1978, despite the risk of neurologicaldamage.6 It was suggested that thalamic stim-ulation could be a safer technique.7 Brice andMcLellan8 and Andy9 reported a decrease ora suppression of various kinds of tremor bytransient stimulation performed during stero-tactic thalamotomy. Benabid et al 10 implant-ed a stereotactic high frequency stimulationdevice in the VIM nucleus to controlParkinsonian tremor, and obtained goodresults. The favourable effect of chronic thal-amic stimulation seems to be maintained longterm.11 12 However, the effect of thalamicstimulation on levodopa induced dyskinesiashas never been evaluated. In this study, theresults of chronic VIM stimulation performedin 10 Parkinsonian patients are reported.

Material and methodsTen patients w'ith idiopathic Parkinson's dis-ease (PD) gave their informed consent forthalamic stimulation. They were selected onthe basis of prominent tremor and poorresponse of tremor to anti-Parkinsoniandrugs: levodopa, bromocriptine, anticholiner-gic agents. Despite low levodopa daily dosesin some patients, thalamic stimulation wasproposed especially where severe levodopainduced dyskinesias occurred (patients 4 and8). Patients with a mild akineto-hypertonicsyndrome also received low doses of levodopabut their tremor responded poorly to the testtreatment (250 mg + decarboxylase inhib-itor). In all cases, tremor was severely dis-abling during at least 5 hours of the day.Under general anaesthesia, the patients

were placed in a Talairach stereotactic frame.The anterior commissure (AC)-posteriorcommissure (PC) line was defined by doublecontrast ventriculography. The Sceratti arcadaptation to the instrument allowed intro-duction of a 1-3 mm in diameter, 3-5 mmlong monopolar electrode with a volume of4 mm3 volume (MEDTRONIC) through thefrontal lobe from an oblique angle in sagittaland coronal planes. The electrode was placedwith its control stylet in the VIM (target)stereotactically, 6 mm in front of the PC, 1mm above bicommissural line, and 15 mmfrom the anatomical midline. A screw madeof pure titanium was used to secure the elec-trode in a 2-5 mm burr hole. The electrodewas initially connected to a percutaneousextension for test stimulation during surgery.At high frequency (100 Hz), paraesthesiaewere noticed and tremor was blocked. Test

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Table 1 Main clinicalfeatures. For each patient, age, disease duration, Hoehm and Yahr stage, response to drugtherapy, levodopa daily dose, effect on dyskinesias andfollow up are given.

Disease Hoehn Tremor Levodopa Levodopa Effect Follow-upAge duration and Yahr response daily dose on in

Patient years (years) stage to Levodopa before after Dyskinesias months

1 60 9 III transient 300 300 PD:suppressed 342 68 8 III 0 600 600 PD:suppressed 303 (T) 57 15 IV 0 300 300 OED:unchanged 294 74 10 IV moderate 550 550 PD + OED:improved 285 62 6 II mild 300 300 - 286 59 9 III mild 300 300 - 287 (T) 58 9 III mild 400 400 - 268 (T) 56 24 III moderate 300 300 PD + OED:suppressed 259 68 4 II 0 300 300 - 2410 63 7 II mild 300 300 - 22MEANS 62-5 10-4 2-9 - 365 365 - 27

(T) = contralateral thalamotomy performed before thalamic stimulationPD = peak dose dyskinesiasOED = onset and end of dose dyskinesias

stimulation was continued for a few days dur-ing the postoperative period. If tremor con-trol was satisfactory, a neuro-pacemakerITREL I (MEDTRONIC) was implantedunder the clavicle and connected to the elec-trode. For all patients, parameters of stimula-tion programmed by telemetry were:intensity-I to 3-75 volts (mean: 2 025);pulse width-60 to 210 microseconds (mean:150); frequency: 130 Hertz. When stimula-tion was started, transient paraesthesiae of thecontralateral hand and lips corner wereevoked whereas tremor was suppressed. 4patients (cases 2, 3, 7, 9) were permanentlystimulated day and night. Stimulation wascontinued all day and stopped at night in 6patients.

Electrode coordinates were defined withgreat accuracy at the end of the surgical pro-cedure, in the stereotactic space. The mean(SD) coordinates of the electrode active tipwere: 6 (18)mm in front of the PC [23-6%(0*8) of AC-PC length], 13*8 (13)mm fromthe anatomical midline and at the level ofbicommissural line. In case 8 (in which thelevodopa induced dyskinesias were sup-pressed by stimulation), the active tip waslocated at 8 mm in front of the PC (35% ofAC-PC length), 14-5 mm lateral to the medi-al plane.Tremor was assessed according to the

Unified Parkinson's Disease Rating Scale(UPDRS)'3 before and after thalamic stimula-tion on videotape recordings. Videotapeswere analysed by three neurologists whoquantified rest and postural tremor in theupper limbs, rest tremor in the lower limbs,and axial tremor.

Dyskinesias were rated on a four-pointscale (0 = nil, 1 = mild, 2 = moderate, 3= severe) before neurosurgery and after elec-trode implantation with and without stimula-tion.

In each case, tremor was evaluated at restby surface EMG and accelerometer record-ings before and after thalamic stimulation onthe same limb. EMG activities were recordedwith pairs of surface electrodes placed 6 cen-timetres apart over the flexor and extensorradialis. An accelerometer (BLA 2 Dynamics)was fixed over the dorsal face of the first pha-lanx of the second finger. Frequency analysesof the taped signals were performed either on

OTE BFA 1264 or Nicolet PII recorder.After electrode implantation, surface EMGand accelerometer recordings were per-formed, with and without stimulation toprove tremor suppression and to define thedelay before tremor control after onset ofstimulation and the delay.before reappear-ance of tremor after stimulation was discon-tinued.

Cognition was assessed pre and post-oper-atively in 8 patients (cases 1, 2, 4, 5, 6, 8, 9,10). Frontal lobe function, memory, languageand praxis skills were tested with and withoutstimulation. The tests and results have beendescribed previously.'4

Results1) PATIENTS WITHOUT LEVODOPA INDUCEDDYSKINESIAS (table 1)In 5 patients (cases 5, 6, 7, 9, 10),Parkinsonian symptoms were not associatedwith abnormal involuntary movements(AIMs). The average age was 62 years(58-68), and the average disease durationwas 5 years (4-9). Contralateral stereotacticthalamotomy had been performed one yearbefore stimulation in one case. Hoehn andYahr stage was II in 3 cases and III in 2 cases.Tremor was suppressed by thalamic stimula-tion in 4 cases. In the last patient (with previ-ous thalamotomy), neither right thalamiclesion nor left thalamic stimulation controlledtremor which was only moderately improved.

2) PATIENTS WITH LEVODOPA INDUCEDDYSKINESIASIn 5 cases, both Parkinsonian tremor and lev-odopa duced dyskinesias were observed(tab 1). The clinical features and effects ofth amic stimulation are described in more

tail in these cases.Case 1: This right handed patient was

affected in 1973 by postural tremor whichremained isolated for 8 years. Akineto-hyper-tonic syndrome then appeared in the rightarm. Rest and postural tremor were promi-nent, and were not improved by increasingthe daily dose of levodopa. Thalamic stimula-tion of the left VIM nucleus was performed inMay 1989. Spontaneous and evoked thalamicactivities were recorded during the stereotac-tic procedure only in this patient. Tremor was

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Figure 1 Tremorfrequency analysis in case1. Tremorfrequency wasanalysed before and afterthalamtc electrodeimplantation and also withand without thalamicstimulation. Spectralanalysis was performedusing EMG records onwristflexor and extensormuscles of the right arm.A) before surgery, B) afterelectrode implantationwithout stimulation, C)during thalamicstimulation no rhythmicactivity was recorded.

IOA D 101- 461 0 121416H

Off

On

Figure 2 Accelerometer records in case 4 were performed after deep brain electrodeimplantation with and without stimulation. These records showed that delay for tremorcontrol when stimulation was started was about three seconds in case 4. Tremor reappearedwith the same delay when stimulation was stopped.

completely controlled on right limbs duringstimulation. Tremor frequency analysis (fromwrist flexor and extensor muscles of right armEMG records) showed a dominant peak at 4hertz (Hz) and fundamental frequency har-monics at 8 and 12 Hz before surgery. The 4Hz peak was reduced after deep brain elec-trode implantation. After stimulation wasstarted, all rhythmic activities disappeared(fig 1). Choreic dyskinesias of the right armand face disappeared after neurosurgeryalthough the daily dose of levodopa remainedthe same.

Case 2: This patient complained of resttremor in the dominant right leg from 1981.Prominent tremor was observed in the rightlimbs and face when he was admitted inSeptember 1989. Interdose dyskinesias werelocated in the right arm. Right limb and facialtremor was suppressed by left VIM stimula-tion, which was well tolerated. When stimula-tion was stopped a coarse tremor reappearedafter ten to twenty seconds. Interdose dyski-nesias were suppressed by thalamic stimula-tion.

Case 3: This right handed patient had restand postural tremor in the left limbs from1975. Parkinsonian signs were marked whenshe was first examined in April 1988, beforestereotactic thalamotomy. She was depressed,dependant on aid for all daily activities, andalmost confined to a wheelchair. Axial signsincluding dysarthria and postural symptomswith falls were marked. She also complainedof biphasic dystonic dyskinesias of both feet.Left limb tremor was alleviated by thalamoto-my of the right ventrolateral (VL) nucleus.Nevertheless, moderate tremor of the leftlimbs reappeared a few months later.Stimulation of the left VIM nucleus for con-tralateral tremor control was performed 17months later. Right limb tremor was initiallysuppressed. Moderate tremor reappearedafter 8 months in the right limbs under stimu-lation. Biphasic dyskinesias remainedunchanged, mild in the right foot and moder-ate in the left foot. No side-effects werenoted.

Case 4: This right handed patient exhibitedrest and postural tremor in the left limbssince 1980. AIMs which consisted of dystonicbiphasic dyskinesias in the left limbs, choreicinterdose dyskinesias in the arms and face,blepharospasm and segmental myoclonuswere observed when she was admitted forthalamic stimulation in November 1989.Both tremor and levodopa induced dyskine-sias in the left limbs were controlled by rightVIM nucleus stimulation. Right limb dyskine-sias and blepharospasm were not modified byneurosurgery. When thalamic stimulation wasswitched on, the delay for tremor control wasabout 3 seconds on accelerometer records (onthe left forefinger). When stimulation wasswitched off left limb tremor reappeared withthe same delay (fig 2). There were no adverseeffects.

Case 8: The patient complained of dis-abling tremor in the dominant right arm in1966. In 1968 thalamotomy was performed

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Chrontic thalanmic stimulation improves tremor and levodopa induced dyskinesias in Parkinson's disease

and controlled perfectly right limb tremor,but hemiparesis was noted. Disabling left armtremor was observed in 1976, postural signswith falls appeared in 1983, and dysarthriawas noted in 1988. He developed severeinterdose dyskinesias in 1984 and mild dys-tonic dyskinesias in 1987. He was also affect-ed by prominent lingual tremor. When hewas admitted for thalamic stimulation,prominent tremor was seen only in the leftlimbs without levodopa whereas disablingballistic dyskinesias were observed on thesame side with levodopa. On the right side,no tremor or dyskinesias were observed.Right VIM nucleus stimulation controlledperfectly left limb tremor with no side-effects.Lingual tremor was also controlled by thala-mic stimulation. Interdose choreic and ballis-tic dyskinesias were suppressed duringstimulation, although the daily dose of lev-odopa was not reduced. The ballistic move-ments reappeared soon after thalamicstimulation were suppressed. Dystonic dyski-nesias were suppressed by stimulation.

3) FOLLOW UPOne to three months after thalamic implanta-tion, a coarse tremor of higher magnitudethan before surgery was observed at rest andduring movement in 6 cases (1, 2, 3, 7, 8, 9)whenever stimulation was discontinued. Thisrebound-effect lasted a few minutes to a fewhours, and was so impressive in 4 cases (2, 3,7 and 9, with higher stimulation intensity)that stimulation was maintained during thenight. But in 2 cases (2, 7), after a longerinterruption for replacement of the neu-ropacemaker, the rebound-effect was progres-sively reduced and disappeared within 2 days.

4) NEUROPSYCHOLOGICAL ASSESSMENTThe main neuropsychological results havebeen previously reported. 14 Intellectual andfrontal lobe functions were not damaged bythalamic stimulation. A transient ideo-motorslowing was observed in case 1. Neitherdysarthria nor aphasia appeared after thalam-ic stimulation. A dysarthria was noted beforeneurosurgery in 2 cases (3, 8), but did notdeteriorate after surgery. Neurological exami-nation failed to show motor or sensitiveimpairment, or neglect, after neurosurgery.The effect of thalamic stimulation was

evaluated in the treatment of disabling restand postural Parkinsonian tremor. The aver-age age was 62-5 years. The average diseaseduration was 10-4 years. Levodopa induceddyskinesias affected half of them beforesurgery. Tremor suppression was obtained in8 cases. An unexpected favourable effect wasobserved on dyskinesias.

Discussion1) NEUROSURGICAL PROCEDUREa) Site of stimulation: The transient paraes-thesiae evoked every time stimulation wasstarted mainly involved the hand and cornerof the lips contralateral to the thalamus stim-ulated. This seems to indicate that the elec-

trode tip was located in the ventro-medialpart ofVIM according to somatotopic organi-sation of VIM nucleus.'5 The VIM nucleus is2mm/4 5mm/4mm (length/height/width), ac-cording to Schaltenbrand atlas,'6 with an esti-mated volume of 36 to 40 mm'. Theelectrode volume is therefore more than 9times smaller than VIM volume indicatingthat the target, the medial part of the VIM,must be accurately defined to achieve satis-factory results. The electrode site may bedefined both by deep brain microelectroderecording VIM activities, and intraoperativetest stimulation.'2 In our study, VIM activitiesrecords were obtained only for case 1, butintraoperative stimulation was performed inall cases. VIM activity records are not infalli-ble guides to lesions for the relief of tremor,'7and the increase in the duration of the opera-tion seemed to us prejudicial to old patients.Finally, intraoperative test stimulationallowed definition of the most appropriatesite for the active tip. Moreover, the meancoordinates were similar to those describedby Benabid et al,'2 although the approach tothe thalamus was parasagittal in those studies.In case 8 where AIMs were suppressed bystimulation, the location of the active tip wasmore anterior: 8 mm in front of PC, 35% ofAC-PC line length.

b) Stimulation parameters: During the fol-low up, stimulation parameters were modi-fied. Current intensity was increased in allcases to avoid reappearance of tremor.Despite moderate voltage (3 volts) and ade-quate pulse width (90 microseconds), dyston-ic posture of the right hand induced bycurrent diffusion to the internal capsule wasobserved in case 9. Impulse frequency waslimited to 130 Hz because of technical prob-lems but higher frequency stimulation couldprovide better control of tremor. 12

2) EFFECT ON TREMORTremor was suppressed in 8 of the 10patients. In the recent series of Benabid etal,'2 tremor was suppressed in 67% and great-ly improved in 94% of Parkinsonian cases butthe efficacy of thalamic stimulation appearedto be limited when tremor was axial or preva-lent in the proximal part of the limbs. In thisstudy, thalamic stimulation was effective onaxial, especially lingual tremor.

In all cases, tremor was reduced withoutstimulation during 3 to 15 days after theoperation but reappeared after that time. Thismicro-thalamotomy like effect, also reportedby Benabid et al ""12 might be related to tran-sient oedema after electrode implantation. Itwas also observed on EMG records and spec-tral analysis of tremor in case 1. The ampli-tude of the low frequency peak was reducedafter implantation without stimulation.The physiopathological explanation for the

rebound effect, which was usually observedfor a short period after thalamic stimulation isnot known. It has not been establishedwhether the effect of stimulation is related toinhibition or stimulation of thalamic neuronsbut the rebound effect and the similarity

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between thalamotomy and thalamic stimula-tion suggest that inhibition is probable.'2

At present, long-term results of thalamicstimulation cannot be evaluated or comparedwith thalamotomy. In the large series ofstereotactic thalamotomy, tremor disappearedin 75-85% of the cases. 18 19 The same efficacymay be obtained on tremor with thalamicstimulation but adverse effects appearedreversible and less common.

3) EFFECT ON DYSKINESIASThe aim of thalamic stimulation was torelieve contralateral tremor but an obviousand unexpected effect was also obtained onlevodopa induced AIMs. The alleviation ofAIMs by thalamotomy was controversial202'until Narabayashi22 demonstrated that com-bined lesion of the VIM and ventral oralis(VO) complex, which is located just in frontof VIM, could be effective on choreic andballistic levodopa induced dyskinesias.Indeed, case 8 was not affected by interdosedyskinesias on limbs contralateral to previousleft thalamotomy. Benabid,1012 however, didnot report improvement of levodopa induceddyskinesias after thalamic stimulation.

Choreic and ballistic movements inducedby levodopa may arise from inhibition of thesubthalamic nucleus23-25 which projects main-ly to the substantia nigra and medial pal-lidum.26 Primates with Parkinsonism inducedexperimentally by N-methyl-4-phenyl-1,2,3,6tetra-hydropyridine (MPTP) developed dysk-inesias after the introduction of levodopatherapy.27 The occurrence of AIMS in theseprimates seems to be related to abnormalunderactivity of the medial pallidal seg-ment2728 which projects inhibitory outputs tothe ventro-lateral nucleus.29 The underactivityof inhibitory outputs to the thalamus mightinduce thalamic disinhibition. Finally, thala-mic disinhibition may be the most relevantalteration in the occurrence of different pat-terns of movement disorders. The destructionby thalamotomy or disruption by electricalstimulation of this area could be effective onlevodopa AIMs. Our results seemed consis-tent with anatomical and physiological studiesand also with the results of thalamotomy per-formed by Narabayashi.22 The electrode coor-dinates could have a prominent role indyskinesia alleviation. This electrode which isintroduced with double obliquity crosses theventro-lateral nucleus before it reaches VIMnucleus. The dramatic improvement of lev-odopa induced dyskinesias which wasobtained in case 8 may be related to the ante-rior location of the electrode tip, probably inthe ventro-lateral nucleus (or ventral oraliscomplex).

Paradoxically, it may appear still that lev-odopa is effective on Parkinsonian symptomsbut induces AIMs, whereas thalamic stimula-tion alleviates both tremor and peak-dosedyskinesias. This may be related to the differ-ential action of levodopa, and thalamicstimulation which may influence bothdopaminergic and non-dopaminergic path-ways. The thalamic nuclei appeared to be the

last relay of complex neuronal loops whichfinally project to the motor and premotor cor-tex.23130 Inhibition of this last relay mighttherefore be effective on both movement dis-orders: tremor and dyskinesias. Dystonicdyskinesias seemed to be less influenced bythalamic stimulation. If biphasic dyskinesiasare also induced by levodopa therapy, theirpathogenesis may be different and involve adifferent dopaminergic receptor subtype,moreover they seem to be due to dysfunctionin different topographically organised sys-tems.3' It was expected that the daily dose oflevodopa could be reduced after surgery, butthis was not the case. As peak-dose dyskine-sias were improved after thalamic stimulation,the daily dose can be increased without fearof peak-dose dyskinetic side-effects whenParkinsonian signs require it.

This study suggests that thalamic stimula-tion may be an adequate choice in the treat-ment of some cases of Parkinsonian tremorsuch as: 1) When tremor is of high amplitude,severely disabling, prevalent on one side, per-sistent despite other adequate treatments; 2)When tremor affects the same limbs as lev-odopa induced dyskinesias; 3) When tremoris associated with speech disorders; 4) Whenthere has been previous contralateral thalam-otomy or thalamic stimulation for bilateralparkinsonian tremor; 5) When interdosedyskinesias in young patients are particularlydisabling.

Should use of the device become wide-spread in the future, its cost may be reduced,and this safe technique could be proposed toa greater number of patients.

We thank Professor Warter, CHRU Strasbourg and ProfessorArnott, CHRU Lille who committed some patients to ourcare during this study and we are grateful for Merle Rubergfor the critical review of the manuscript.

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