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Comparison of the antiparkinsonian action of levodopa before surgery (On-Med) with that obtained with bilateral subthalamic nucleus stimulation in patients free of levodopa after surgery (On-Stim/Off-Med) (n = 8). Data are mean ± SD. UPDRS indicates Unified Parkinson's Disease Rating Scale.

Comparison of the antiparkinsonian action of levodopa before surgery (On-Med) with that obtained with bilateral subthalamic nucleus stimulation in patients free of levodopa after surgery (On-Stim/Off-Med) (n = 8). Data are mean ± SD. UPDRS indicates Unified Parkinson's Disease Rating Scale.

Table 1. 
Daily Total Equivalent Levodopa Dose Before and After Surgery
Daily Total Equivalent Levodopa Dose Before and After Surgery
Table 2. 
Motor Symptom Scores Before and After Surgery in 15 Patients Who Underwent Bilateral Subthalamic Nucleus Stimulation*
Motor Symptom Scores Before and After Surgery in 15 Patients Who Underwent Bilateral Subthalamic Nucleus Stimulation*
Table 3. 
Percentage of Change of the Motor Symptom Scores Determined After Comparing Different Medication and Stimulation Conditions, Before and After Surgery (N = 15)*
Percentage of Change of the Motor Symptom Scores Determined After Comparing Different Medication and Stimulation Conditions, Before and After Surgery (N = 15)*
1.
Laitinen  LVBergenheim  ATHariz  MI Leksell's posteroventral pallidotomy in the treatment of Parkinson's disease. J Neurosurg. 1992;7653- 61Article
2.
Lozano  AMLang  AEGalvez-Jimenez  N  et al.  Effect of GPi pallidotomy on motor function in Parkinson's disease. Lancet. 1995;3461383- 1387Article
3.
Dogali  MFazzini  EKolodny  E  et al.  Stereotactic ventral pallidotomy for Parkinson's disease. Neurology. 1995;45753- 761Article
4.
Baron  MSVitek  JLBakay  RAE  et al.  Treatment of advanced Parkinson's disease by posterior GPi pallidotomy: 1-year results of a pilot study. Ann Neurol. 1996;40355- 366Article
5.
Siegfried  J Therapeutical neurostimulation: indications reconsidered. Acta Neurochir. 1991;52112- 117
6.
Benabid  ALPollack  PGervanson  C  et al.  Long term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 1991;337401- 406Article
7.
Limousin  PPollack  PBenazzouz  A Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet. 1995;34591- 95Article
8.
Kumar  RLozano  AMKim  YJ  et al.  Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson's disease. Neurology. 1998;51850- 855Article
9.
Pollak  PBenabid  ALJervasson  CL  et al.  Long-term effects of chronic stimulation of ventral intermediate thalamic nucleous in different types of tremor. Adv Neurol. 1993;60408- 413
10.
Siegfried  JLippitz  B Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery. 1994;351126- 1130Article
11.
Gross  CRougier  AGuehl  DBoraud  TJulien  JBioulac  B High-frequency stimulation of the globus pallidus internalis in Parkinson's disease: a study of seven cases. J Neurosurg. 1997;87491- 498Article
12.
Tronnier  VMFogel  WKronenbuerger  MSteinvorth  S Pallidal stimulation: an alternative to pallidotomy? J Neurosurg. 1997;87700- 705Article
13.
Bergman  HWichmann  TDeLong  MR Reversal of experimental parkinsoniam by lesions of the subthalamic nucleus. Science. 1990;2491436- 1438Article
14.
Aziz  TZPeggs  DAgarwal  ESambrook  MACrossman  AR Subthalamic nucleotomy alleviates parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed primate. Br J Neurosurg. 1992;6575- 582Article
15.
Guridi  JHerrero  MTLuquin  R  et al.  Subthalamotomy in parkinsonian monkeys: behavioural and biochemical analysis. Brain. 1996;1191717- 1727Article
16.
Benazzouz  AGross  CFeger  JBoraud  TBioulac  B Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci. 1993;5382- 389Article
17.
Limousin  PKrack  PPollack  P  et al.  Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med. 1998;3391105- 1111Article
18.
Krack  PPollak  PLimousin  P  et al.  Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's disease. Brain. 1998;121451- 457Article
19.
Moro  EScerrati  MRomito  LMARoselli  RTonali  PAlbanese  A Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinson's disease. Neurology. 1999;5385- 90Article
20.
Hughes  AJDaniel  SEKilford  LLees  AJ Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55181- 184Article
21.
Langston  JWWidner  HGoetz  CG  et al.  Core Assessment Program for Intracerebral Transplantations (CAPIT). Mov Disord. 1992;72- 13Article
22.
Fahn  SElton  RLmembers of the UPDRS Development Committee, Unified Parkinson's Disease Rating Scale. Fahn  SMarsden  CDCalne  DBGolgstein  Meds.Recent Developments in Parkinson's Disease Vol 2. Florham Park, NJ Macmillan Health Care Information1987;153- 164
23.
Hoehn  MMYahr  MD Parkinsonism: onset, progression and mortality. Neurology. 1967;17427- 442Article
24.
Schwab  RSEngland  RC Projection technique for evaluating surgery in Parkinson's disease. Gillingham  FJDonaldson  IMLeds.Parkinson's Disease Edinburgh, Scotland E & S Livingstone1969;152- 157
25.
Sweet  RADeSensi  EGZubenko  GS Reliability and applicability of movement disorder rating scales in the elderly. J Neuropsychiatry Clin Neurosci. 1993;556- 60
26.
Schaltenbrandt  GWahren  W Atlas for Stereotaxy of the Human Brain.  Stuttgart, Germany Thieme1977;
27.
Hutchison  WDAllan  RJOpitz  H  et al.  Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease. Ann Neurol. 1998;44622- 628Article
28.
Wichmann  TBergman  HDeLong  MR The primate subthalamic nucleus, I: functional properties in intact animals. J Neurophys. 1994;72494- 506
29.
Wichmann  TBergman  HDeLong  MR The primate subthalamic nucleus, II: neuronal activity in the MPTP model of parkinsonism. J Neurophys. 1994;72507- 520
30.
Bejjani  BPDamier  PArnulf  I  et al.  Transient acute depression induced by high-frequency deep brain stimulation. N Engl J Med. 1999;3401476- 1480Article
31.
Fraix  VPollak  PVan Blercom  N  et al.  The effect of subthalamic nucleus stimulation on levodopa induced dyskinesias in patients with Parkinson's disease [abstract]. Neurology. 1999;52 ((suppl 2)) A403
32.
Wichmann  TBergman  HDeLong  MR The primate subthalamic nucleus, III: changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism. J Neurophys. 1994;72521- 530
33.
Ceballos-Baumann  AOBoecker  HBartenstein  P  et al.  A positron emission tomographic study of subthalamic nucleus stimulation in Parkinson disease. Arch Neurol. 1999;56997- 1003Article
34.
Martin  JP Hemichorea resulting from a focal lesion of the brain (the syndrome of Luys). Brain. 1927;50637- 651Article
35.
Limousin  PPollak  PHoffmann  DBenazzouz  APerret  JEBenabid  AL Abnormal involuntary movements induced by subthalamic nucleus stimulation in parkinsonian patients. Mov Disord. 1996;11231- 235Article
36.
Krack  PLimousin  PBenabid  ALPollak  P Chronic stimulation of the subthalamic nucleus improves levodopa-induced dyskinesias in Parkinson's disease. Lancet. 1997;3501676Article
37.
Krack  PPollak  PLimousin  PBenazzouz  ADeuschl  GBenabid  AL From off period dystonia to peak-dose chorea: the clinical spectrum of varying subthalamic nucleus activity. Brain. 1999;1221133- 1146Article
38.
Figueiras-Méndez  RMarín Zarza  FMolina  JA  et al.  Subthalamic nucleus stimulation improves directly L-dopa induced dyskinesias in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1999;66549- 550Article
39.
Piallat  BBenazzouz  ABenabid  AL Subthalamic nucleus in rats prevents dopaminergic nigral neuron degeneration after striatal 6-OHDA injection: behavioural and immunohistochemical studies. Eur J Neurosci. 1996;81408- 1414Article
40.
Piallat  BBenazzouz  ABenabid  AL Neuroprotective effect of chronic inactivation of the subthalamic nucleus in a rat model of Parkinson's disease. J Neural Transm Suppl. 1999;5571- 77
41.
Molinuevo  JLValldeoriola  FRumià  J  et al.  Contribution of neurophysiological guidance to stereotactic posteroventral pallidotomy for Parkinson's disease. Acta Neurochir. 1999;1411195- 1201Article
Original Contribution
July 2000

Levodopa Withdrawal After Bilateral Subthalamic Nucleus Stimulation in Advanced Parkinson Disease

Author Affiliations

From the Neurology Service (Drs Molinuevo, Valldeoriola, Tolosa, and Valls-Solé) and Neurosurgery Service (Drs Rumià, Roldán, and Ferrer), Institut Clínic de Malalties del Sistema Nerviós, Institut d'Investigations Biomédiques August Pi i Suñer (IDIBAPS), Hospital Clínic Universitari, Barcelona, Spain.

Arch Neurol. 2000;57(7):983-988. doi:10.1001/archneur.57.7.983
Abstract

Context  Subthalamic nucleus (STN) stimulation may be effective in ameliorating parkinsonian symptoms even to the extent to permit levodopa withdrawal.

Objectives  To analyze the efficacy of STN stimulation in patients with Parkinson disease (PD) and to determine if levodopa may be withdrawn after surgery.

Design  Before-after trial.

Setting  Referral center, hospitalized care.

Patients  Fifteen patients with advanced PD.

Interventions  Microelectrode-guided bilateral STN high-frequency stimulation.

Outcome Measures  Before surgery patients were evaluated in off-medication and on-medication conditions. Dopaminergic drug dosages were reduced after surgery, aiming for complete withdrawal. Six months after surgery, patients were reeavaluated in off- and on-medication conditions, with the stimulation turned on and off.

Results  Total Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the off-medication condition improved by 65.9%; and axial symptoms, bradykinesia, rigidity, and tremor improved by 65.8%, 60.4%, 66.1%, and 81.1%, respectively. UPDRS part II scores were reduced by 71.8% and Schwab and England scores improved by 45.3%. Levodopa was withdrawn in 8 patients and the overall levodopa dose was reduced 80.4%. "Off" time was reduced 89.7% and the severity of dyskinesias decreased 80.6% after surgery. All results reached significance (P<.001). Stimulation of the STN achieved antiparkinsonian effect similar to that of treatment with levodopa. No life-threatening adverse effects occurred.

Conclusions  Bilateral STN stimulation safely improves all parkinsonian symptoms, decreases or eliminates the need for levodopa, and ameliorates motor fluctuations and dyskinesias. Complete withdrawal of levodopa is feasible with this technique and the overall motor effect of STN stimulation is quantitatively comparable to that obtained with levodopa.

FUNCTIONAL neurosurgery is a valid therapy to relieve parkinsonian symptoms and drug-induced dyskinesias in patients with advanced Parkinson disease (PD). Unilateral ablative procedures, such as posteroventral pallidotomy, have mainly contralateral effects,14 and bilateral pallidotomy is typically avoided because it incurs a high risk for severe adverse effects. In contrast, high-frequency deep brain stimulation (HF-DBS) for the treatment of PD is a reversible, adaptable, and safe technique even when applied bilaterally,5,6 although serious adverse events can occur.7,8 The target for HF-DBS was initially directed toward the thalamus to treat tremor,6,9 and subsequently displaced to the internal pallidum.1012 Subthalamic nucleus (STN) blockade was shown to be effective to alleviate parkinsonian symptoms in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–treated primates.1316 Posteriorly, STN stimulation was performed in humans with success. This technique proved to be effective to ameliorate PD symptoms and dyskinesias.7,8,1719 Although several studies have suggested that long-term bilateral stimulation of the STN can produce an antiparkinsonian effect similar to that obtained with levodopa treatment,18 this has not been adequately assessed, because, in these studies, levodopa had not been withdrawn after surgery. Therefore, the specific effect produced exclusively by STN stimulation has not been evaluated.

The main objective of this study was to analyze the efficacy and safety of bilateral microelectrode-guided STN stimulation in patients with advanced PD experiencing levodopa-induced motor complications. Secondary aims were to determine if dopaminergic medication could be withdrawn in patients with PD after long-term bilateral STN stimulation and to compare the antiparkinsonian effect of STN stimulation in patients free of levodopa after surgery with that produced by levodopa before surgery.

PATIENTS AND METHODS
PATIENTS

Fifteen consecutive patients were operated on between 1997 and 1998 at our institute. All patients met the United Kingdom Parkinson's Disease Society brain-bank clinical criteria for idiopathic PD.20 Selection criteria were age younger than 75 years and the presence of disabling motor fluctuations and drug-induced dyskinesias refractory to medical therapy adjustments. All patients necessarily showed a good response to a suprathreshold dose of levodopa. Exclusion criteria were presence of cognitive impairment, major depression, and marked cerebral atrophy on neuroimaging studies.

Patients were 10 men and 5 women, with a mean ± SD age of 60.9 ± 6.8 (range, 52-74) years, mean disease duration of 15.8 ± 9.2 (range, 7-38) years, and mean off-medication Hoehn and Yahr stage of 3.8 ± 0.8 (range, 2.5-5). All patients were treated with levodopa (Table 1); 4 patients also used oral dopamine agonists (pergolide mesylate, 3 mg/d [3 patients] and ropinirole hydrochloride, 6 mg/d [1 patient]) and 2 patients used subcutaneous apomorphine hydrochloride (3 mg two or three times daily).

SCALES USED FOR CLINICAL EVALUATIONS

Clinical assessments were done following the Core Assessment Program for Intracerebral Transplantations (CAPIT) instructions21 4 days before surgery and 6 months after surgery.

All assessments were performed by means of the Unified Parkinson's Disease Rating Scale22 (UPDRS), version 3.0. The following items were grouped as "axial symptoms": arising from a chair, gait, posture, postural reflexes, hypokinesia, facial expression, voice, axial rigidity, and axial tremor. Motor fluctuations were assessed by item 39 of the UPDRS. Patients were also graded according to the Hoehn and Yahr staging system23 and Schwab and England (S/E) scale.24 Dyskinesias were evaluated using the Abnormal Involuntary Movement Scale25 (12 items, maximum score = 48, graded 0-4).

CLINICAL ASSESSMENT BEFORE SURGERY

Patients were assessed by the same clinician. Before surgery patients were evaluated in 2 different clinical conditions: off-medication evaluation (off-med) was performed after an overnight off medication; on-medication evaluation (on-med) was assessed after a single dose of standard levodopa according to CAPIT protocol instructions.

TAPERING OF DOPAMINERGIC DRUGS AND SETUP OF STIMULATION PARAMETERS

Patients were seen weekly the first month and every 2 weeks the ensuing 6 months until stimulation and drug therapy were adequately established. Antiparkinsonian drug dosages were reduced at each follow-up visit with the aim to completely withdraw use of levodopa and all dopaminergic drugs. Drug tapering was done slowly in the first 3 patients, and, as no complications were seen, rapidly in the ensuing patients. Total levodopa equivalent dose was calculated according to previously reported instructions.4 In addition to drug tapering, electrical parameters (pole, pulse width, frequency, and voltage) were adjusted at each visit. In all cases we used monopolar stimulation with a pulse width of 60 milliseconds and frequency of stimulation of 130 Hz. The contact that improved motor symptoms with the lowest voltage without adverse effects was selected for long-term stimulation. All patients were instructed to maintain stimulation on throughout the day and night.

CLINICAL ASSESSMENT AFTER SURGERY

Evaluation of patients still taking levodopa in the off-med condition was performed as described above. Patients in whom levodopa was completely withdrawn were considered to be off medication. During the off-med condition patients were evaluated in on-stimulation (off-med/on-stim) and off-stimulation (off-med/off-stim) conditions. After the off-med/on-stim evaluation the devices were turned off for 2 hours to perform the off-med/off-stim assessment. On a different day, patients who were still taking levodopa received their usual morning levodopa dose while the stimulator was on (on-med/on-stim) to evaluate the severity of dyskinesias.

SURGICAL PROCEDURE

All patients gave their informed consent and the protocol was approved by the local ethical committee. Antiparkinsonian medication was withdrawn the night before surgery. A model G Leksell stereotactic frame was placed with the patient under local anesthesia. Images through the region of the intercommissural line were acquired at 1-mm thick slices obtained through cranial computed tomography. After selection of a slice with the anterior commissure and the posterior commissure, the theoretic anatomic target was placed 2 mm posterior, 5 mm ventral to the midcommissural point, and 12 mm lateral to the intercommissural line. We approached the target with an anteroposterior angle of 60° with respect to the intercommissural line and a sagittal angle of 10°. The stereotactic coordinates were calculated by means of a computer program containing a digitized brain atlas based on the Schaltenbrandt and Wahren atlas.26 Using local anesthesia, a single 15-mm burr hole was made in the skull 2 cm from the midline at the coronal suture. Recording of single-unit neuronal activity was performed using neurological registering equipment (Neurorack; TPM Servicio Médicos, Madrid, Spain). A platinum-iridium microelectrode (extended microelectrodes, 14-TDSC-CC; FHC Inc, Bowdoingham, Me) was inserted through the burr hole. Microelectrode recording was started 20 mm above the theoretic target and conducted by an electronic microdrive device. By means of the microelectrode recording the discharge pattern of the neurones of the thalamus, subthalamus, and substantia nigra pars reticulata could be identified. The sensorimotor area of the STN was distinguished by modification of neuronal activity in response to active and passive movements or palpation and light touch of individual contralateral body parts.2729 Microstimulation within the STN (bipolar pulses at 40-80 µA, 300 Hz, and 500- to 1000-millisecond duration) was applied to determine the threshold for beneficial and side effects. A minimum of 1 and a maximum of 4 parallel, in the parasagittal and coronal planes, exploration tracks were needed for localization of the sensorimotor STN area and its anatomic boundaries. Patients were induced with brief general anesthesia using intravenous propofol (2.5 mg/kg) during the procedure except when their collaboration was needed. Once the sensorimotor area of the STN was determined, an electrode for long-term stimulation (DBS 3389 electrode; Medtronic, Minneapolis, Minn) was inserted at this location. An external stimulation device connected to the stimulation electrode was then used to confirm that there were not any limiting side effects, such as diplopia, tonic contraction of a limb, paresthesias, dyskinesias, or vegetative symptoms, and that motor response was adequate. Cranial magnetic resonance imaging was performed in all the patients immediately before lead implant to rule out hemorrhagic complications and electrode misplacement. Programmable pulse generators (Itrel II, Medtronic) were implanted in the subclavicular region ipsilateral to the electrode 1 week after surgery.

STATISTICAL ANALYSIS

To assess the effectiveness of STN stimulation, we compared the off-med scores obtained before surgery with the off-med/on-stim scores after surgery, and the off-med/off-stim with the off-med/on-stim scores obtained after surgery. Scores of the UPDRS part II (activities of daily living) and evaluation of the S/E scale, could not be assessed for on-med condition after surgery in patients without levodopa; consequently, we only considered for data analysis the off-med/on-stim activities of daily living scores after surgery. This score was compared with the preoperative on-med and off-med scores. We also compared preoperative off-med and postoperative off-med/off-stim scores. To ascertain whether the symptomatic effect of levodopa was similar to that obtained with STN stimulation, we compared the presurgical on-med with the off-med/on-stim scores in patients who were free of levodopa for at least 2 months.

Statistical analysis was performed by means of SPSS-PC Windows 3.1 version (SPSS Inc, Chicago, Ill). All comparisons were done through a paired t test for independent data. To avoid a type I error, P = .001 was considered to indicate statistical significance.

RESULTS
MOTOR SYMPTOMS

Long-term bilateral STN stimulation significantly reduced all motor symptoms 6 months after surgery (Table 2) when comparing off-med scores obtained before surgery with the off-med/on-stim scores after surgery. Total UPDRS part III score decreased by 65.9% (P<.001); axial symptoms, bradykinesia, rigidity, and tremor improved by 65.8%, 60.4%, 66.1%, and 81.1%, respectively (P<.001). Hoehn and Yahr stage changed from 3.8 ± 0.7 before surgery to 1.9 ± 0.5 after surgery (P<.001). Patient's activities of daily living scores improved markedly as reflected by the UPDRS part II and S/E scores. UPDRS part II scores were reduced by 71.8% and S/E scores improved by 45.3% when compared with the preoperative off-med condition (P<.001), and 28.9% (P = .12) and 14.7% (P<.001), respectively, when compared with on-med condition. The comparison of the off-med/off-stim and off-med/on-stim scores after surgery revealed similar results (Table 3). The mean voltage intensity used was 3.1 ± 0.7 V. Motor scores in basal conditions (off-med vs off-med/off-stim) were not significantly changed after surgery (Table 3).

DOPAMINERGIC MEDICATION REDUCTION

Eight patients had stopped taking any dopaminergic medication 6 months after surgery, and levodopa was withdrawn in all of them for at least 4 months. In patients still taking medication, the mean reduction was superior to 60% in 6 and 20% in 1. Dopamine agonists were withdrawn in all patients except one who is still taking pergolide. Two patients with 12 months' and 2 patients with 18 months' follow-up are still without any medication. We tried to reintroduce levodopa in some of these patients to assess whether they could further benefit from it, but as they did not obtain any added useful effect they preferred to remain free of levodopa. Overall, the daily levodopa equivalent dose was reduced 80.4%, from 1338 ± 656 mg/d to 262 ± 332 mg/d (P<.001) in the whole group.

MOTOR FLUCTUATIONS

The 8 patients who were completely free of antiparkinsonian drug treatment and 3 patients still taking small doses of levodopa did not report daytime or nocturnal symptom fluctuations. The other 4 patients reported brief "wearing-off" periods characterized by the reappearance of mild motor symptoms. The UPDRS item that assesses the percentage of the day spent in "off" periods decreased by 89.7%, from 2.6 ± 1 before surgery to 0.3 ± 0.5 after surgery (P<.001).

DYSKINESIAS

All patients presented peak dose dyskinesias before surgery and none of them showed biphasic dyskinesias. Nine of the 15 patients were completely relieved of dyskinesias after surgery. The remaining 6 patients experienced only mild, painless choreiform dyskinesias at otherwise optimal antiparkinsonian stimulation parameters. Three of these 6 patients were not taking any dopaminergic medication, and the abnormal movements disappeared when stimulation intensity was decreased. The severity of dyskinesias, measured by the Abnormal Involuntary Movement Scale, decreased by 80.6% after surgery (P<.001) in the whole group and by 63.7% (P<.001) in the patients still experiencing dyskinesias.

COMPARISON OF THE EFFECTS OF STN STIMULATION VS LEVODOPA

In the subgroup of patients who were completely free of medication, comparison between on-med UPDRS motor scores and off-med/on-stim scores showed no significant differences, apart from the motor scores obtained for the axial items of the UPDRS (P<.001; Figure 1). By contrast, the comparison of the S/E scale and the Hoehn and Yahr staging system between on-med and off-med/on-stim conditions improved by 16.3% and 32.5%, respectively, after surgery (P<.001). There were no preoperative significant differences in age, disease duration, and disease severity, measured by the UPDRS, S/E, and Hoehn and Yahr scales between patients who were taking levodopa before surgery and those who were not. A Pearson test correlating preoperative and postoperative doses of levodopa (R = 0.16) and a t test comparing preoperative levodopa dose in both groups (P = .46) disclosed no significative differences.

ADVERSE EFFECTS

No life-threatening adverse effects were seen as a consequence of surgery. Transient confusion, disorientation, and abulia were observed during the first 2 weeks after surgery. One patient developed mild postoperative depression, which still persisted at 6 months' follow-up. Depression was not modified by lead polarity or current intensity changes as described by Bejjani et al.30 Two patients experienced dysarthria and hypophonia that were intense in one patient and mild in the other.

COMMENT

Bilateral STN stimulation significantly improved all cardinal symptoms of PD in our patients. This improvement, unlike the presurgical condition during which control of symptoms with levodopa was erratic and intermittent, was consistent and continuous during the whole day. These antiparkinsonian effects of bilateral STN stimulation allowed a complete withdrawal of dopaminergic drugs in more than half the patients and a marked reduction in dosage in the remaining patients. This study confirms previous reports that levodopa reduction is possible after STN stimulation, but is the first one stating that levodopa can be completely withdrawn after STN stimulation in some patients during prolonged periods of time. In addition, the dose reduction in dopaminergic drugs obtained in our patients is higher than that reported in previous studies.8,17,19 This decrease in levodopa use was associated with a reduction of dyskinesias. In consonance with previous reports,17,19 side effects were generally minor and tolerable, although this technique may present serious morbidity.7,8

In patients in whom levodopa was withdrawn, we observed that the antiparkinsonian effect of HF-DBS was quantitatively similar to that achieved with levodopa before surgery. The effects obtained with either of both therapies on bradykinesia, rigidity, and tremor were not significantly different; however, all the measures tended to improve in the on-stim condition compared with the on-med condition. The improvement in axial symptoms was significantly greater with STN stimulation than with levodopa. This could be considered to be part of a global improvement when compared with the on-drug condition that could be related to a reduction in dyskinesias after stimulation. In the other patients still requiring levodopa, STN stimulation relieved most of symptoms but some of them were relieved only at the expense of producing bothersome side effects. These residual symptoms were improved by the addition of small doses of levodopa. This group of patients was clinically and demographically similar to the group in which levodopa was completely withdrawn and the preoperative doses of levodopa were also similar in both groups. Since there were not any presurgical differences between these 2 groups of patients, the incomplete response to STN stimulation in patients still needing levodopa after surgery could reflect a suboptimal lead placement.

Motor fluctuations were not present in patients not requiring levodopa after surgery. Some patients who were still taking levodopa stayed in a continuous "on" condition with a smooth motor status, with the combined effect of stimulation and medication. Other patients with mild symptoms when the effect of medication wore off were considered to still experience mild intensity fluctuations. Improvement of motor fluctuations after STN stimulation has been described in 2 previous studies,17,19 but in other reports such effect was not clearly stated.8 The mechanisms favoring the attenuation of motor fluctuations are directly related to the clinical effect of STN stimulation, which is probably associated with the direct and complete inhibitory effect on the subthalamopallidal excitatory pathway.31,32 Therefore, the overactivation of the internal pallidum could be constantly inhibited by STN stimulation bypassing the abnormal pulsatile striatal pharmacological activation exerted through the indirect pathway. The hypothesis is further supported by the fact that some patients did not have any beneficial effect after taking single doses of levodopa, due to a possible ceiling effect over the dopaminergic responsive symptoms, reflecting a bilateral complete STN blockade. Moreover, positron emission tomographic studies have shown that STN stimulation improves activity of motor association cortex, possibly by reducing inappropriate excitation of the STN on inhibitory pallidothalamic projections.33

Subthalamic HF-DBS was also associated with a marked reduction in peak dose dyskinesias in all patients. In line with the observation that STN blockade can directly induce hyperkinesias,13,15,19,34,35 some patients in whom levodopa had been withdrawn had minimal dyskinesias together with the best clinical effect of stimulation. Consequently, we agree with the common opinion17,19,35,36 that improvement of dyskinesias after surgery is best explained by the reduction of the total daily levodopa dose rather than by a direct HF-DBS effect over the STN37,38 as suggested by others.

In addition to the prolonged symptomatic effects of STN surgery17 on parkinsonian symptoms, some authors have suggested, based on animal models, the possibility that subthalamic HF-DBS could alter the natural history of PD by exerting a neuroprotective effect.39,40 We did not observe significant changes in motor scores when comparing the off-med condition before surgery with off-med/off-stim condition after surgery. Appropriately designed studies should be done to answer the question whether STN stimulation can have neuroprotective properties. Such studies should include a comparison of PD patients with and without STN stimulation and consider that the interval needed for motor symptoms to reappear completely after HF-DBS arrest is not known; therefore, the baseline motor status may not be achieved even after several hours following stimulation arrest.

In summary, bilateral STN stimulation is an effective and generally safe procedure that improves all levodopa-sensitive symptoms, reduces motor fluctuations, and diminishes the need for dopaminergic drugs, therefore contributing to a marked amelioration in dyskinesias. Neurophysiologic evaluation is mandatory to localize the sensorimotor area of the STN since millimeter accuracy is needed to achieve the best results.41 Complete withdrawal of levodopa is feasible with this technique in some patients and the overall motor effect of STN stimulation is quantitatively comparable to that obtained with levodopa.

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Article Information

Accepted for publication January 25, 2000.

Reprints: Francesc Valldeoriola, MD, Servei de Neurologia, Hospital Clínic Universitari, Villarroel 170, Barcelona 08036, Spain.

References
1.
Laitinen  LVBergenheim  ATHariz  MI Leksell's posteroventral pallidotomy in the treatment of Parkinson's disease. J Neurosurg. 1992;7653- 61Article
2.
Lozano  AMLang  AEGalvez-Jimenez  N  et al.  Effect of GPi pallidotomy on motor function in Parkinson's disease. Lancet. 1995;3461383- 1387Article
3.
Dogali  MFazzini  EKolodny  E  et al.  Stereotactic ventral pallidotomy for Parkinson's disease. Neurology. 1995;45753- 761Article
4.
Baron  MSVitek  JLBakay  RAE  et al.  Treatment of advanced Parkinson's disease by posterior GPi pallidotomy: 1-year results of a pilot study. Ann Neurol. 1996;40355- 366Article
5.
Siegfried  J Therapeutical neurostimulation: indications reconsidered. Acta Neurochir. 1991;52112- 117
6.
Benabid  ALPollack  PGervanson  C  et al.  Long term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 1991;337401- 406Article
7.
Limousin  PPollack  PBenazzouz  A Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet. 1995;34591- 95Article
8.
Kumar  RLozano  AMKim  YJ  et al.  Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson's disease. Neurology. 1998;51850- 855Article
9.
Pollak  PBenabid  ALJervasson  CL  et al.  Long-term effects of chronic stimulation of ventral intermediate thalamic nucleous in different types of tremor. Adv Neurol. 1993;60408- 413
10.
Siegfried  JLippitz  B Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery. 1994;351126- 1130Article
11.
Gross  CRougier  AGuehl  DBoraud  TJulien  JBioulac  B High-frequency stimulation of the globus pallidus internalis in Parkinson's disease: a study of seven cases. J Neurosurg. 1997;87491- 498Article
12.
Tronnier  VMFogel  WKronenbuerger  MSteinvorth  S Pallidal stimulation: an alternative to pallidotomy? J Neurosurg. 1997;87700- 705Article
13.
Bergman  HWichmann  TDeLong  MR Reversal of experimental parkinsoniam by lesions of the subthalamic nucleus. Science. 1990;2491436- 1438Article
14.
Aziz  TZPeggs  DAgarwal  ESambrook  MACrossman  AR Subthalamic nucleotomy alleviates parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed primate. Br J Neurosurg. 1992;6575- 582Article
15.
Guridi  JHerrero  MTLuquin  R  et al.  Subthalamotomy in parkinsonian monkeys: behavioural and biochemical analysis. Brain. 1996;1191717- 1727Article
16.
Benazzouz  AGross  CFeger  JBoraud  TBioulac  B Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci. 1993;5382- 389Article
17.
Limousin  PKrack  PPollack  P  et al.  Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med. 1998;3391105- 1111Article
18.
Krack  PPollak  PLimousin  P  et al.  Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's disease. Brain. 1998;121451- 457Article
19.
Moro  EScerrati  MRomito  LMARoselli  RTonali  PAlbanese  A Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinson's disease. Neurology. 1999;5385- 90Article
20.
Hughes  AJDaniel  SEKilford  LLees  AJ Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55181- 184Article
21.
Langston  JWWidner  HGoetz  CG  et al.  Core Assessment Program for Intracerebral Transplantations (CAPIT). Mov Disord. 1992;72- 13Article
22.
Fahn  SElton  RLmembers of the UPDRS Development Committee, Unified Parkinson's Disease Rating Scale. Fahn  SMarsden  CDCalne  DBGolgstein  Meds.Recent Developments in Parkinson's Disease Vol 2. Florham Park, NJ Macmillan Health Care Information1987;153- 164
23.
Hoehn  MMYahr  MD Parkinsonism: onset, progression and mortality. Neurology. 1967;17427- 442Article
24.
Schwab  RSEngland  RC Projection technique for evaluating surgery in Parkinson's disease. Gillingham  FJDonaldson  IMLeds.Parkinson's Disease Edinburgh, Scotland E & S Livingstone1969;152- 157
25.
Sweet  RADeSensi  EGZubenko  GS Reliability and applicability of movement disorder rating scales in the elderly. J Neuropsychiatry Clin Neurosci. 1993;556- 60
26.
Schaltenbrandt  GWahren  W Atlas for Stereotaxy of the Human Brain.  Stuttgart, Germany Thieme1977;
27.
Hutchison  WDAllan  RJOpitz  H  et al.  Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease. Ann Neurol. 1998;44622- 628Article
28.
Wichmann  TBergman  HDeLong  MR The primate subthalamic nucleus, I: functional properties in intact animals. J Neurophys. 1994;72494- 506
29.
Wichmann  TBergman  HDeLong  MR The primate subthalamic nucleus, II: neuronal activity in the MPTP model of parkinsonism. J Neurophys. 1994;72507- 520
30.
Bejjani  BPDamier  PArnulf  I  et al.  Transient acute depression induced by high-frequency deep brain stimulation. N Engl J Med. 1999;3401476- 1480Article
31.
Fraix  VPollak  PVan Blercom  N  et al.  The effect of subthalamic nucleus stimulation on levodopa induced dyskinesias in patients with Parkinson's disease [abstract]. Neurology. 1999;52 ((suppl 2)) A403
32.
Wichmann  TBergman  HDeLong  MR The primate subthalamic nucleus, III: changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism. J Neurophys. 1994;72521- 530
33.
Ceballos-Baumann  AOBoecker  HBartenstein  P  et al.  A positron emission tomographic study of subthalamic nucleus stimulation in Parkinson disease. Arch Neurol. 1999;56997- 1003Article
34.
Martin  JP Hemichorea resulting from a focal lesion of the brain (the syndrome of Luys). Brain. 1927;50637- 651Article
35.
Limousin  PPollak  PHoffmann  DBenazzouz  APerret  JEBenabid  AL Abnormal involuntary movements induced by subthalamic nucleus stimulation in parkinsonian patients. Mov Disord. 1996;11231- 235Article
36.
Krack  PLimousin  PBenabid  ALPollak  P Chronic stimulation of the subthalamic nucleus improves levodopa-induced dyskinesias in Parkinson's disease. Lancet. 1997;3501676Article
37.
Krack  PPollak  PLimousin  PBenazzouz  ADeuschl  GBenabid  AL From off period dystonia to peak-dose chorea: the clinical spectrum of varying subthalamic nucleus activity. Brain. 1999;1221133- 1146Article
38.
Figueiras-Méndez  RMarín Zarza  FMolina  JA  et al.  Subthalamic nucleus stimulation improves directly L-dopa induced dyskinesias in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1999;66549- 550Article
39.
Piallat  BBenazzouz  ABenabid  AL Subthalamic nucleus in rats prevents dopaminergic nigral neuron degeneration after striatal 6-OHDA injection: behavioural and immunohistochemical studies. Eur J Neurosci. 1996;81408- 1414Article
40.
Piallat  BBenazzouz  ABenabid  AL Neuroprotective effect of chronic inactivation of the subthalamic nucleus in a rat model of Parkinson's disease. J Neural Transm Suppl. 1999;5571- 77
41.
Molinuevo  JLValldeoriola  FRumià  J  et al.  Contribution of neurophysiological guidance to stereotactic posteroventral pallidotomy for Parkinson's disease. Acta Neurochir. 1999;1411195- 1201Article
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