Background In many patients with idiopathic Parkinson's disease,treatment with levodopa is complicated by fluctuations betweenan "off" period (also referred to as "off medication"), whenthe medication is not working and the motor symptoms of parkinsonismare present, and an "on" period, when the medication is causingimproved mobility (also referred to as "on medication"), oftenaccompanied by debilitating dyskinesias. In animal models ofParkinson's disease, there is overactivity in the subthalamicnucleus, and electrical stimulation of the subthalamic nucleusimproves parkinsonism. We therefore sought to determine theefficacy and safety of electrical stimulation of the subthalamicnucleus in patients with Parkinson's disease.
Methods We studied 24 patients with idiopathic Parkinson's diseasein whom electrodes were implanted bilaterally in the subthalamicnucleus under stereotactic guidance with imaging and electrophysiologictesting of the location. Twenty were followed for at least 12months. Clinical evaluations included the Unified Parkinson'sDisease Rating Scale, a dyskinesia scale, and timed tests conductedbefore and after surgery, when patients were off and on medications.
Results After one year of electrical stimulation of the subthalamicnucleus, the patients' scores for activities of daily livingand motor examination scores (Unified Parkinson's Disease RatingScale parts II and III, respectively) off medication improvedby 60 percent (P<0.001). The subscores improved for limbakinesia, rigidity, tremor, and gait. In the testing done onmedication, the scores on part III improved by 10 percent (P<0.005).The mean dose of dopaminergic drugs was reduced by half. Thecognitive-performance scores remained unchanged, but one patienthad paralysis and aphasia after an intracerebral hematoma duringthe implantation procedure.
Conclusions Electrical stimulation of the subthalamic nucleusis an effective treatment for advanced Parkinson's disease.The severity of symptoms off medication decreases, and the doseof levodopa can be reduced, with a consequent reduction in dyskinesias.
In many patients with idiopathic Parkinson's disease, thereis an initial satisfactory response to levodopa, but then motorfluctuations develop that are difficult to control. The patientsalternate between a state of severe parkinsonism (the "off"period, when the medication is not working, also referred toas "off medication") and a state of improved mobility, whenthe medication is working (the "on" period, also referred toas "on medication"), which is often impaired by dyskinesias.Neurosurgery offers additional therapeutic possibilities forthese patients. Originally, lesioning procedures (pallidotomyand thalamotomy) were performed.1,2,3,4,5,6,7,8,9,10,11 Subsequently,high-frequency electrical stimulation of implanted electrodeswas developed primarily to decrease the morbidity induced bybilateral thalamotomy.12,13
Thalamic stimulation is effective mainly for tremor and thereforeis useful to only a small proportion of patients with Parkinson'sdisease. The problem of motor fluctuations affects a much largernumber of patients.14 Studies performed in monkeys treated with1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an animal modelof Parkinson's disease,15 found hyperactivity of the subthalamicnucleus–internal pallidum pathway16,17,18 and improvementof parkinsonian symptoms after the creation of lesions17,18,19,20,21or high-frequency stimulation of the subthalamic nucleus.22
We therefore applied the stimulation procedure to the subthalamicnucleus in patients with Parkinson's disease who had disablingmotor fluctuations. Preliminary results in three patients showeda reduction in disability during off periods.23 We now reportlong-term follow-up in 24 consecutive patients, 20 of whom haveundergone bilateral stimulation of the subthalamic nucleus forat least one year.
Methods
Patients
Twenty-four patients (11 men and 13 women) with a mean (±SD)age of 56±8 years at the time of surgery and a mean durationof disease of 14±5 years were selected for implantationof electrodes in the subthalamic nucleus. The selection criteriawere clinically diagnosed idiopathic Parkinson's disease,24disabling motor fluctuations despite all drug therapies, ageunder 70 years, normal magnetic resonance imaging (MRI) studiesof the brain, and no severe dementia (score on the Mini–MentalState Examination, 2425). During off periods, all were severelyimpaired in performing activities of daily living (Table 1 andFigure 1), and 19 had painful dystonia. During on periods, theycould cope with most activities of daily living (Figure 1 andTable 2) but had levodopa-induced dyskinesias (Table 2). TheirHoehn and Yahr rating, indicating the global stage of the disease,was 4 to 5 during the off period and 2 to 3 during the on period(a lower score indicates improvement).26 All 24 patients weretreated with levodopa plus a peripheral decarboxylase inhibitor.Twenty-one also received an oral dopaminergic agonist, and 12received subcutaneous apomorphine. The dosage of antiparkinsoniandrugs was kept constant during the two months before surgery.The study was approved by the ethics committee of the GrenobleUniversity Hospital, and the patients gave their written informedconsent.
Figure 1. Mean (±SE) Off-Medication and On-Medication Scores for Impairment in the Performance of Activities of Daily Living before and 1, 3, 6, and 12 Months after Surgery.
After surgery, bilateral stimulation was on. The scores are for part II of the Unified Parkinson's Disease Rating Scale. The maximal possible score was 52. A reduction in scores indicates an improvement in function. The asterisks indicate P<0.001 for the comparison with the same condition before surgery.
Table 2. On-Medication UPDRS Subscores and Dyskinesia Score in 20 Patients with Long-Term Bilateral Stimulation of the Subthalamic Nucleus.
Clinical Evaluation
Clinical evaluations were based on the Core Assessment Programfor Intracerebral Transplantations, a validated protocol forthe study of surgical treatments of idiopathic Parkinson's disease.27Evaluations were performed at least twice in the month beforesurgery, once or twice at 1, 3, 6, and 12 months after surgery,and thereafter once a year. Patients were evaluated with useof the Unified Parkinson's Disease Rating Scale,26 a dyskinesiascale, and timed tests. Patients were assessed in two conditionsbefore surgery (off medication and on medication) and in fourconditions after surgery (off medication, off stimulation; offmedication, on stimulation; on medication, off stimulation;and on medication, on stimulation). The examiner, but not thepatient, knew whether the patient was receiving electrical stimulationat the time of the evaluation. The order of the off- and on-stimulationconditions was randomized. Before they were assessed off medication,patients fasted and drugs were withdrawn overnight. The sameevaluation was repeated on medication after the administrationof 100 to 300 mg of levodopa, according to the usual morningdose, plus benserazide. A subjective dyskinesia scale (maximalscore, 24) was used to assess the maximal intensity of dyskinesiasduring the levodopa challenge.23 The timed tests included ahand-tapping test and a stand–walk–sit test.23
We assessed cognitive function in the off-medication periodbefore and after surgery (on stimulation). All the patientsfollowed for 12 months were assessed with a battery of testssensitive to frontal-lobe dysfunction.28 We calculated a scorefor frontal-lobe dysfunction adapted from Pillon et al.,29 whichrated patients on a 50-point scale according to four subscores:the Wisconsin card-sorting test,30 verbal fluency, two seriesof motor sequences, and two series of graphic-writing sequences.Patients 7 to 24 were also rated according to the Mattis scalefor global cognitive assessment (maximal score, 144).31
Surgery
Bilateral surgery was performed under local anesthesia. In thefirst three patients, the second electrode was implanted from1 to 12 months after the first. In the remaining patients, bothelectrodes were implanted in a single operation. The follow-updata for the patients who had two operations were obtained afterthe second. The surgical procedure was based on that developedfor thalamic stimulation.12,13 The subthalamic nucleus was locatedby MRI, contrast ventriculography, and electrophysiologic recordingsand stimulation. We used tungsten microelectrodes (impedance,2 to 8 m; Frederick Haer, Bowdoinham, Me.) to identify areasshowing a pattern of electrical activity characteristic of thesubthalamic nucleus.16,17,18 Electrical stimulation was performedwhile a neurologist examined the patient for akinesia, rigidity,tremor, and adverse effects. An electrode for long-term stimulationwas inserted at the location where typical activity was recordedand parkinsonian symptoms decreased with the lowest intensityand no adverse effects. The electrodes used for the first sixpatients had four contacts 1.5 mm long and 1.5 mm apart (DBS-3387electrode, Medtronic, Minneapolis). In the electrodes used forsubsequent patients, the contacts were separated by 0.5 mm (DBS-3389electrode), which permitted more contacts in the target area.The average duration of a bilateral operation was 12 hours.
To identify the location of the electrodes and possible brainlesions, a brain MRI was performed after the electrodes hadbeen implanted but before the pulse generators were put in place.One week after implantation, the electrodes were connected toa pulse generator (Itrel II, Medtronic) that was placed subcutaneouslyin the subclavicular area, like a cardiac pacemaker. The pulsegenerator could be programmed by telemetry for different variablesof stimulation, contact (cathode or anode), voltage (0 to 10.5V), rate (2 to 185 Hz), pulse width (60 to 450 µsec),and timing (cyclic or continuous stimulation).
Electrical Settings
The neurologists selected electrical settings after surgeryand at each follow-up visit. The patients could not modify thestimulation themselves. The effect of different electrical settingswas first studied off medication, each contact being successivelyselected as the cathode, with the pulse-generator case as theanode (monopolar stimulation). A constant pulse width of 60µsec and a frequency of 130 Hz were initially used, andthe voltage was progressively increased. Favorable effects onakinesia, rigidity, and tremor and adverse effects, such asocular movements, involuntary movements, and muscle contractions,were evaluated. The contact that improved parkinsonian symptomswith the lowest voltage without adverse effects was selectedfor long-term stimulation. The amplitude of stimulation wasprogressively increased over the first few days after surgery.In the on-medication condition, we checked the effect of thestimulation on dyskinesias. Bipolar stimulation, with at leastone contact selected as the cathode and one as the anode, wasused when the effect was more favorable than with monopolarstimulation. In the first 10 patients, we tried not to decreasethe dosages of drugs before the three-month follow-up unlessthere were adverse effects. For subsequent patients, we decreasedthe dosages immediately after surgery.
Statistical Analysis
The primary outcome measures were the scores on parts II (activitiesof daily living) and III (motor examination) of the UnifiedParkinson's Disease Rating Scale. The secondary measures werethe subscores on part III of the Unified Parkinson's DiseaseRating Scale, which evaluated limb akinesia, limb rigidity,limb tremor, and axial symptoms (gait, arising from chair, posturalstability, and speech); the dyskinesia scale; the subscoreson part IV (complications of therapy) of the Unified Parkinson'sDisease Rating Scale; the Hoehn and Yahr global stage and theSchwab and England scores for global activities of daily living;the tapping test; neuropsychological tests; and the dose oflevodopa.
Data were analyzed by analysis of variance for repeated measures(with surgery [before or after], time [length of follow-up],stimulation [on or off], and medication [on or off] as variablesin individual patients), by the paired Student's t-test, orby the paired Wilcoxon signed-rank test. To correct for thenumber of analyses and to avoid a type I error, a P value of0.005 was considered to indicate statistical significance.
Results
Clinical Results
In the 20 patients followed for at least 12 months, long-termbilateral stimulation greatly improved motor symptoms (Figure 2and Table 1). Repeated-measures analysis of variance was usedto compare the effect of electrical stimulation on the scoreson part III of the Unified Parkinson's Disease Rating Scaleat 1, 3, 6, and 12 months after implantation in the off- andon-medication conditions. Stimulation significantly reducedthe score on part III of the rating scale (F18, 1=89.4, P<0.001),and the effect was different in the off- and on-medication conditions(F18,1 for the interaction between stimulation and drug, 108.5;P<0.001). To understand this interaction, we analyzed eachcondition separately. The effect of the stimulation was significantin both conditions but was greater off medication (60 percent;F19,1=101.8, P<0.001) than on medication (10 percent; F18,1=14.6,P<0.005). The off-stimulation score on part III of the UnifiedParkinson's Disease Rating Scale was also significantly reduced12 months after surgery (P<0.005) (Figure 2).
Figure 2. Mean (±SE) Off-Medication and On-Medication Scores for Motor Examination before and 1, 3, 6, and 12 Months after Surgery.
After surgery, bilateral stimulation was on. The scores are for part III of the Unified Parkinson's Disease Rating Scale. The maximal possible score was 108. A reduction in scores indicates an improvement in function. The asterisks indicate P<0.001 and the daggers P<0.005, for the comparison with the same condition before surgery.
Ten patients were followed for more than 24 months; their mean(±SD) off-medication score on part III of the UnifiedParkinson's Disease Rating Scale decreased from 59.0±10.1before surgery to 29.5±13.2 at 3 months, 30.1±16.2at 12 months, and 25.3±17.7 at 24 months. Five patientswere followed for more than 36 months; the treatment had a continuingbeneficial effect in all of them.
Long-term stimulation resulted in improved scores for akinesia,rigidity, and tremor of the upper and lower limbs and for impairmentin arising from chair, gait, and postural stability, when patientswere evaluated off medication (Table 1). When patients wereevaluated on medication, scores for limb rigidity were improvedbut not scores for limb akinesia (Table 2).
The score for the duration of the off period was reduced from2.2±0.7 to 0.6±1.0 (P<0.001) (Unified Parkinson'sDisease Rating Scale item 39; range, 0 to 4). The intensityof symptoms was mild during these phases, and 12 patients weretotally unaware of them. The score for the duration of the onperiod was increased correspondingly.
Performance on the hand-tapping test in patients off medicationimproved from 73±5 per minute before surgery to 117±8per minute on stimulation after surgery (P<0.001). Beforesurgery, 8 of 20 patients could perform the stand–walk–sittest when off medication, all with freezing. The mean time forthis task was 88±64 seconds, with three freezing episodesper test, on average. When tested off medication and on stimulation12 months after bilateral surgery, 19 patients could performthe stand–walk–sit test, with a mean time of 27±21seconds, and only 1 patient had freezing.
Before surgery 16 of 20 patients suffered from painful off-perioddystonia, which disappeared in 12 patients and decreased in4 after surgery. Levodopa-induced dyskinesias assessed duringthe levodopa challenge were nonsignificantly decreased aftersurgery (Table 2). At three months only, the dyskinesia scorewas significantly increased during stimulation as compared withthe score when stimulation was switched (P<0.005). The meandisability related to dyskinesias decreased from 2.2±1.2before surgery to 0.8±0.9 at 12 months (Unified Parkinson'sDisease Rating Scale part IV, item 33; range, 0 to 4). The meanscore for the duration of dyskinesias decreased from 2.0±1.0before surgery to 0.9±0.8 at 12 months (part IV, item32; range, 0 to 4).
As a result of the clinical improvement, the scores for activitiesof daily living were greatly improved in patients on stimulation(Unified Parkinson's Disease Rating Scale part II, F19,1=41.1[P<0.001]; Schwab and England, F20,1=73.6 [P<0.001]) (Figure 1and Table 1). The effect of surgery differed according towhether the patient was on or off medication (for the interactionbetween surgery and medication: part II, F19,1=103.8 [P<0.001];Schwab and England, F20,1=107.6 [P<0.001]). To understandthis interaction, we analyzed each drug condition separatelyand found that the effect of the stimulation was significantonly off medication (part II: off medication, P<0.001; onmedication, P=0.50; Schwab and England: off medication, P<0.001;on medication, P=0.75). The off-medication Hoehn and Yahr score(for global stage of disease) was significantly decreased at12 months (P<0.001) (Table 1) and remained unchanged whenthe patient was on medication (P=0.36) (Table 2). The only scoresapplicable to the whole group of 24 patients were the Schwaband England score (for global activities of daily living), whichimproved in patients off medication from 27.5±13.6 beforesurgery to 68.7±22.7 at six months (P<0.001), andthe Hoehn and Yahr score, which improved from 4.7±0.5to 2.9±0.8 (P<0.001).
On average, neuropsychological results did not change aftersurgery. The mean score for frontal-lobe dysfunction was 39.6±6.9before surgery and 37.4±8.5 12 months after surgery (P=0.30).The mean Mattis score was 138.0±4.7 before surgery and137.0±5.7 12 months after (P=0.31).
Medications and Electrical Treatment
At 12 months, the mean dose of levodopa was significantly decreased(P<0.001) (Table 3), and one patient had stopped treatment.Apomorphine treatment was stopped in 9 of 10 patients. At 12months, all the patients were being stimulated continuously.Fourteen patients were receiving bilateral monopolar stimulation,five were receiving bilateral bipolar stimulation, and one wasreceiving bipolar stimulation on one side and monopolar stimulationon the other. The voltage was adjusted at each follow-up visitaccording to the clinical effect on parkinsonian symptoms andthe adverse effects. The mean voltage was 2.0±0.6 V at1 month, 2.2±0.7 V at 3 months, 2.4±0.8 V at 6months, and 2.8±0.6 V at 12 months (P<0.001 for thecomparison between 12 months and 1 month). The frequency wasbetween 130 and 185 Hz and the pulse width was 60 µsecfor all patients.
Table 3. Dose of Antiparkinsonian Medications before and 12 Months after Surgery for 20 Patients with Long-Term Bilateral Stimulation of the Subthalamic Nucleus.
Adverse Effects
Four of the 24 patients could not be included in the 12-monthfollow-up. In one patient, an intracerebral hematoma 8 cm indiameter developed in the corona radiata during surgery, resultingin persistent severe paralysis and aphasia. Another patientlived far away and did not return for the one-year follow-up;however, she reported by telephone that she still benefitedfrom the stimulation. Another patient died of an unrelated cause11 months after implantation. In another patient, a subcutaneousinfection developed at the site of the extension lead; she wastreated with antibiotics, and the extension lead and pulse generatorwere removed for six months, then reimplanted.
In 8 of the other 20 patients, transient adverse effects onmental status developed after surgery, such as confusion, hallucinations,temporospatial disorientation, and abulia. The effects lastedfor a few days to two weeks, and the patients recovered withoutsequelae. In one patient, cognitive performance was impairedbefore surgery and worsened thereafter (the frontal-lobe scoredecreased from 16 to 6). In 18 patients, dyskinesias could beinduced by increasing the stimulation voltage above the long-termlevel, which limited the benefit of the stimulation only transientlyafter surgery. Five patients had difficulty in opening theireyes because of eyelid-opening apraxia that was induced or worsenedby the surgery. Four of them were successfully treated by injectionof botulinum toxin. Hypophonia and postural instability worsenedin one patient after three months. Eighteen patients gainedweight after surgery (mean, 4.2 kg; maximum, 10.0 kg).
Discussion
Bilateral stimulation of the subthalamic nucleus greatly improvedoff-period symptoms in this group of severely disabled patients.Motor fluctuations were attenuated, and patients with suddenon–off fluctuations before surgery had milder fluctuationsor none thereafter. All patients became independent in mostactivities of daily living. Medications could be decreased aftersurgery to about half of the initial dosage.
The three cardinal signs of parkinsonism — bradykinesia,rigidity, and tremor — were decreased by stimulation ofthe subthalamic nucleus when the patients were off medication.The average tremor score was low because few patients had alarge-amplitude tremor, but a short report on a different groupof patients confirms that tremor is reduced by stimulation ofthe subthalamic nucleus.32 Neuronal bursts in synchrony withtremor are recorded in the subthalamic nucleus of monkeys given1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.18 Arm, leg, andaxial symptoms and signs were equally improved. Unilateral stimulationof the subthalamic nucleus improves mainly contralateral symptoms.23The motor score on the Unified Parkinson's Disease Rating Scalewas reduced by only 10 percent in patients on medication.
Immediately after surgery, the voltage of the stimulation waslimited, because stimulation could induce reversible dyskinesias,probably related to inactivation of the subthalamic nucleus.33After the first 10 patients, we reduced the doses of dopaminergicdrugs more rapidly after surgery, which allowed a rapid increasein the voltage without inducing dyskinesias. In the long term,levodopa-induced dyskinesias were decreased. The reduction inthe doses of dopaminergic drugs is likely to be an importantfactor in this decrease. Because stimulation of the subthalamicnucleus greatly and rapidly improved dystonia in patients offmedication, the mechanisms might be different for dyskinesiasin patients on medication.
Patients with severe dementia were excluded from this study.Cognitive functions were on average unchanged after surgery,except in one patient who had frontal-lobe dysfunction beforesurgery. The outcome in this patient suggests that patientswith cognitive deficits may be at risk for further worseningafter surgery.
Off-medication and off-stimulation Unified Parkinson's DiseaseRating Scale motor scores were also improved after surgery.This improvement could be related either to a microsubthalamotomyeffect due to the presence of the electrode on the subthalamicnucleus or to a long-lasting effect of the stimulation. Themechanism of action of stimulation of the subthalamic nucleusis unknown. The frequency and the amplitude of the stimulationare important.23 Since stimulation of the subthalamic nucleusmimics the effect of lesions in monkeys given 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,22it is likely that the stimulation inhibits overactivity of thesubthalamic nucleus. This inhibition would decrease the inhibitoryaction of the globus pallidus internus on the ventrolateralthalamus and consequently increase excitatory input to the cortex.The results of two experiments support this hypothesis. A studyin rats showed that stimulation of the subthalamic nucleus inhibitedthe activity of the entopeduncular nucleus, the equivalent ofthe globus pallidus internus.34 A positron-emission tomographicstudy in patients with Parkinson's disease demonstrated an increasein cortical activity of the supplementary motor area, dorsolateralprefrontal cortex, and cingulate when patients performed movementswith high-frequency stimulation of the subthalamic nucleus,which is effective in the treatment of parkinsonism.35
The most severe complication was an intracerebral hematoma,an inherent risk in stereotactic neurosurgery that is estimatedto occur in 2 to 8 percent of patients.36 The transient confusionobserved in some patients may have been related to nonspecificfactors, such as the long duration of brain surgery and thewithdrawal of dopaminergic drugs. Most patients gained weight,as has been described after pallidotomy.7,8,9,10 Surgery ofthe subthalamic nucleus worsened eyelid-opening apraxia. Themechanism of eyelid-opening apraxia is unknown. It is observedin idiopathic Parkinson's disease and other degenerative diseasesinvolving the basal ganglia.37
The alternative target for surgery on the basal ganglia in Parkinson'sdisease is the globus pallidus internus. The effect of pallidotomyis well established, with a moderate improvement of parkinsonismin off periods and a major decrease in levodopa-induced dyskinesias,5,6,7,8,9,10,11but the safety of bilateral procedures is still being debated.38The data so far suggest that stimulation of the globus pallidusinternus has effects similar to those of pallidotomy.39,40,41,42In our study, the voltage was mildly increased over time, andthis raises the theoretical risk of partial loss of benefit.The principal improvement in all dopa-sensitive symptoms anddyskinesias was sustained during the follow-up period. Comparativestudies, including cost–benefit analysis, are needed todetermine the value of each procedure. Because of the risks,this procedure, like all surgical approaches, should be reservedfor severely disabled patients with good cognitive and generalstatus.
Supported by Medtronic, INSERM, and the department of Rhône-Alpes,France.
We are indebted to Professor N. Quinn and Dr. R. Brown for theirhelpful comments on the manuscript.
Source Information
From the Department of Clinical and Biologic Neurosciences, Joseph Fourier University, Grenoble, France (P.L., P.K., P.P., A.B., C.A., D.H., A.-L.B.); the Medical Research Council Human Movement and Balance Unit, Queen Square, London (P.L.); and the Neurology Department, University of Kiel, Kiel, Germany (P.K.).
Address reprint requests to Dr. Pollak at the Department of Clinical and Biologic Neurosciences, Joseph Fourier University, B.P. 217, 38043 Grenoble CEDEX 9, France.
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(2002). Effect of chronic pallidal deep brain stimulation on off period dystonia and sensory symptoms in advanced Parkinson's disease. J. Neurol. Neurosurg. Psychiatry
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Charles, P.D., Van Blercom, N., Krack, P., Lee, S.L., Xie, J., Besson, G., Benabid, A.-L., Pollak, P.
(2002). Predictors of effective bilateral subthalamic nucleus stimulation for PD. Neurology
59: 932-934
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Dauper, J., Peschel, T., Schrader, C., Kohlmetz, C., Joppich, G., Nager, W., Dengler, R., Rollnik, J. D.
(2002). Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability. Neurology
59: 700-706
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Moro, E., Esselink, R. J.A., Xie, J., Hommel, M., Benabid, A. L., Pollak, P.
(2002). The impact on Parkinson's disease of electrical parameter settings in STN stimulation. Neurology
59: 706-713
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Rocchi, L, Chiari, L, Horak, F B
(2002). Effects of deep brain stimulation and levodopa on postural sway in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry
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Vesper, J, Chabardes, S, Fraix, V, Sunde, N, Ostergaard, K
(2002). Dual channel deep brain stimulation system (Kinetra) for Parkinson's disease and essential tremor: a prospective multicentre open label clinical study. J. Neurol. Neurosurg. Psychiatry
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Cunic, D., Roshan, L., Khan, F. I., Lozano, A. M., Lang, A. E., Chen, R.
(2002). Effects of subthalamic nucleus stimulation on motor cortex excitability in Parkinson's disease. Neurology
58: 1665-1672
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Houeto, J L, Mesnage, V, Mallet, L, Pillon, B, Gargiulo, M, du Moncel, S T., Bonnet, A M, Pidoux, B, Dormont, D, Cornu, P, Agid, Y
(2002). Behavioural disorders, Parkinson's disease and subthalamic stimulation. J. Neurol. Neurosurg. Psychiatry
72: 701-707
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Pogarell, O, Gasser, T, van Hilten, J J, Spieker, S, Pollentier, S, Meier, D, Oertel, W H
(2002). Pramipexole in patients with Parkinson's disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study. J. Neurol. Neurosurg. Psychiatry
72: 713-720
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Romito, L. M.A., Scerrati, M., Contarino, M. F., Bentivoglio, A. R., Tonali, P., Albanese, A.
(2002). Long-term follow up of subthalamic nucleus stimulation in Parkinson's disease. Neurology
58: 1546-1550
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Bejjani, B-P, Arnulf, I, Houeto, J-L, Milea, D, Demeret, S, Pidoux, B, Damier, P, Cornu, P, Dormont, D, Agid, Y
(2002). Concurrent excitatory and inhibitory effects of high frequency stimulation: an oculomotor study. J. Neurol. Neurosurg. Psychiatry
72: 517-522
[Abstract][Full Text]
Welter, M. L., Houeto, J. L., Tezenas du Montcel, S., Mesnage, V., Bonnet, A. M., Pillon, B., Arnulf, I., Pidoux, B., Dormont, D., Cornu, P., Agid, Y.
(2002). Clinical predictive factors of subthalamic stimulation in Parkinson's disease. Brain
125: 575-583
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Gregory, R.
(2002). SURGERY FOR MOVEMENT DISORDERS. J. Neurol. Neurosurg. Psychiatry
72: i32-35
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Vingerhoets, F. J.G., Villemure, J.-G., Temperli, P., Pollo, C., Pralong, E., Ghika, J.
(2002). Subthalamic DBS replaces levodopa in Parkinson's disease: Two-year follow-up. Neurology
58: 396-401
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Baron, M. S., Wichmann, T., Ma, D., DeLong, M. R.
(2002). Effects of Transient Focal Inactivation of the Basal Ganglia in Parkinsonian Primates. J. Neurosci.
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Lanotte, M M, Rizzone, M, Bergamasco, B, Faccani, G, Melcarne, A, Lopiano, L
(2002). Deep brain stimulation of the subthalamic nucleus: anatomical, neurophysiological, and outcome correlations with the effects of stimulation. J. Neurol. Neurosurg. Psychiatry
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Timmermann, L., Gross, J., Dirks, M., Volkmann, J., Freund, H.-J., Schnitzler, A.
(2002). The cerebral oscillatory network of parkinsonian resting tremor. Brain
126: 199-212
[Abstract][Full Text]
2425). During off periods, all were severely impaired in performing activities of daily living (Table 1 and Figure 1), and 19 had painful dystonia. During on periods, they could cope with most activities of daily living (Figure 1 and Table 2) but had levodopa-induced dyskinesias (Table 2). Their Hoehn and Yahr rating, indicating the global stage of the disease, was 4 to 5 during the off period and 2 to 3 during the on period (a lower score indicates improvement).26 All 24 patients were treated with levodopa plus a peripheral decarboxylase inhibitor. Twenty-one also received an oral dopaminergic agonist, and 12 received subcutaneous apomorphine. The dosage of antiparkinsonian drugs was kept constant during the two months before surgery. The study was approved by the ethics committee of the Grenoble University Hospital, and the patients gave their written informed consent. 
; Frederick Haer, Bowdoinham, Me.) to identify areas showing a pattern of electrical activity characteristic of the subthalamic nucleus.16,17,18 Electrical stimulation was performed while a neurologist examined the patient for akinesia, rigidity, tremor, and adverse effects. An electrode for long-term stimulation was inserted at the location where typical activity was recorded and parkinsonian symptoms decreased with the lowest intensity and no adverse effects. The electrodes used for the first six patients had four contacts 1.5 mm long and 1.5 mm apart (DBS-3387 electrode, Medtronic, Minneapolis). In the electrodes used for subsequent patients, the contacts were separated by 0.5 mm (DBS-3389 electrode), which permitted more contacts in the target area. The average duration of a bilateral operation was 12 hours. 
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