Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson's disease

Current models of basal ganglia functioning suggest that many symptoms of PD are caused by reduced activation of primary motor cortex, premotor cortex, and supplementary motor area (SMA)¹ secondary to overactivity of the globus pallidus internus (GPi)/substantia nigra reticulata (SNr) that occurs, in large part, because of excessive excitatory drive from the subthalamic nucleus (STN). Lesioning or blocking the activity of the GPi or STN should theoretically reverse these functional abnormalities and thus improve parkinsonism. Several studies have demonstrated consistent benefit from unilateral pallidotomy with respect to contralateral levodopa-induced dyskinesias and parkinsonism.^2-4 Deep brain stimulation (DBS) provides an alternative to lesioning that may not be accompanied by the same risk of permanent complications, an important advantage particularly when considering bilateral procedures.^5,6 Thalamic DBS appears equally effective for tremor as thalamotomy and has encouraged the application of this technology to the GPi and STN.^7-11 Preliminary results have been encouraging, but no prospectively studies series has been reported evaluating STN DBS in a double-blind fashion.

Methods. Surgical procedures. Methods were similar to those previously reported by our group for microelectrode guided posteroventral medial pallidotomy.¹² No sedation was used, and antiparkinson medication was withheld overnight and during surgery. The physiologic attributes of the STN target are reported separately.¹³ A target was selected in the STN in an area in which there were neurons whose activities were modulated by movements(especially if tremor was present). The target was at least 3 mm from any point where microstimulation up to 100 µA (at 300 Hz) evoked motor, oculomotor, or sensory responses. A permanent quadripolar DBS electrode(Medtronic model 3382; Minneapolis, MN) was implanted under fluoroscopic guidance usually with the second of four electrode contacts over the target. Bilateral implantation was performed in all cases.

After implantation of the macroelectrode, intraoperative test stimulation was performed using a hand-held programming device (Medtronic model 3625). Bipolar stimulation using the most distal two electrodes and the proximal two electrodes was performed at frequencies of 100 to 200 Hz and pulse widths of 50 to 100 microseconds. The macroelectrode position was considered acceptable if stimulation induced choreiform dyskinesias or arrested tremor or if the threshold for tonic contraction was greater than 4.0 V. The cables were later internalized and connected to an internal pulse generator (Medtronic Itrel model 3625).

Patients. Our initial and consecutive nine patients who underwent surgery to implant electrodes in the STN were enrolled in this study. All patients undergoing DBS had a diagnosis of idiopathic PD and had initially obtained a good response from levodopa but subsequently developed significant motor fluctuations with off-period immobility and disabling levodopa-induced dyskinesias despite optimization of antiparkinson drugs. Eight of these patients were participating in a multicenter study of STN and GPi DBS sponsored by Medtronic Inc. (to be reported elsewhere). The double-blind evaluation protocol conducted at 6 to 12 months reported here was not part of the multicenter protocol and was performed only in the seven patients who underwent chronic stimulation. Two patients operated during this time period who never underwent chronic DBS were excluded from our evaluation protocol: one with preexisting mild cognitive dysfunction who developed paranoia intraoperatively, necessitating abandonment of the procedure before electrode implantation; and another who developed a perioperative hardware infection as a result of hematogenous spread from an infected intravenous catheter, necessitating removal of one of his DBS systems. Exclusion criteria included significant cognitive dysfunction, active psychiatric symptoms, other neurologic or unstable medical disorders, and MRI evidence of other CNS disease. The study was approved by The Toronto Hospital Committee for Research on Human Subjects, and informed written consent was obtained from all patients.

Evaluations and statistical analysis. Patients were assessed in an open-label fashion preoperatively, and a 2-day double-blind evaluation was performed postoperatively at the 6-month follow-up in six patients and at the 12-month follow-up in one patient using a modified Core Assessment Protocol for Intracerebral Transplantation (CAPIT) (including timed tapping and walking tasks) and a dyskinesia rating scale(figure).^14-17 Before each day's evaluation, the internal pulse generator was turned off overnight for at least 12 hours. On day 1, patients were assessed in the morning in a manner identical to the preoperative evaluation while receiving optimal medication therapy (including levodopa, dopamine agonists, and other antiparkinson medication) in a randomly determined order of stimulation off and stimulation on conditions with at least 2 hours allowed between evaluations. On day 2, the evaluations were performed in the same fashion as on day 1 except that medication was withheld overnight at least 12 hours before and during the evaluations. The same physician performed all assessments. Neither the rating physician nor the patient was informed of the status of stimulation for the assessments. At the conclusion of each day's assessments, patients were administered a questionnaire and asked to guess which of the assessments was performed with the stimulator on and to describe any symptoms that may have resulted in unblinding. Before formal clinical assessments, stimulation settings were extensively adjusted in each patient to achieve optimal benefit. Pairwise comparisons were made between the"stimulation off" condition and the "stimulation on" condition in the medication on and off states and between the follow-up evaluations and the baseline evaluation using a Student's t-test. Comparison between baseline drug off and follow-up drug off/stimulator off states provided an indication of any effect of the procedure alone (i.e., microlesion) in the absence of any direct effect of DBS, may have reflected the carry-over of chronic DBS effects, or alternatively placebo effects resulting from the intervention. For 2 days before each evaluation, patients completed standardized diaries every half hour indicating whether their predominant motoric status was "on," "off," "on with dyskinesias," or"asleep." Pairwise comparisons were made of the total duration of time considered unevaluable (incomplete or more than one motoric state marked) and the percentage of evaluable time spent in each of the four states between the preoperative and the postoperative conditions using a Student's t-test.

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Figure. Flow chart of study enrollment and double-blind evaluation protocol for subthalamic nucleus deep brain stimulation.

Results. The seven fully evaluated patients consisted of four men and three women with a mean age of 67 years (range, 55 to 75 years) and mean duration of PD 14.3 years (range, 11 to 21 years). Antiparkinson medication was reduced postoperatively by a mean of 40% (p = 0.05) from a levodopa equivalent dosage² of 1,612 ± 518 mg/day to 967 ± 515 mg/day. At 6-month follow-up(table), mean UPDRS total motor score while off medication improved by 58% when the stimulators were turned on(p = 0.002). All major features of parkinsonism improved. The most profound improvements were seen in patients with severe tremor. Bradykinesia as objectively measured by a timed tapping task improved 37% (p = 0.002). All five patients unable to walk without medication preoperatively were able to walk with bilateral DBS at 6-month follow-up. These changes correlated with a 30% improvement in off-period UPDRS Activities of Daily Living (ADL) score (obtained for the week before evaluation) (p = 0.04). Some improvement resulted directly from microelectrode recording and macroelectrode insertion. The greatest improvements in off-drug/off-stimulator functioning were commonly observed immediately after surgery with subsequent waning. At 6-month follow-up, the mean UPDRS total motor score was improved 17% (p = 0.08) and three patients previously unable to walk without medication were able to ambulate; because the washout period for the effects of STN DBS is unknown, this may reflect the cumulative effects of DBS in addition to the microlesion effect.

Motor function when on medication was also improved by STN DBS. Although all major features of parkinsonism improved, the greatest benefit occurred in medication-refractory refractory tremor and rigidity. Compared with the preoperative state: Mean UPDRS motor score improved 41% (p= 0.02); without stimulation, tremor and bradykinesia worsened, likely because of reduction in antiparkinson medication; and on-period UPDRS ADL scores were not significantly changed despite improvements in on-period parkinsonism and levodopa-induced dyskinesias. Levodopa-induced dyskinesias were reduced by 83%(p = 0.001), in part possibly because of reduction in drug dosage, although three patients had marked improvement in dyskinesias immediately after surgery before any reduction in drug dosage and before the initiation of chronic stimulation. We have not observed a direct antidyskinetic effect of STN DBS (i.e., there was no reduction in dyskinesias when the stimulators were turned on); in contrast, ipsilateral or contralateral stimulation-induced dyskinesias were produced in five of seven patients during the process of searching for optimal stimulation settings during DBS programming (beginning within 1 minute of turning on the stimulators or as long as 24 hours after initiating stable stimulation). Stimulation-induced dyskinesias resembling the patients' preoperative levodopa-induced dyskinesias were generally accompanied by a very good antiparkinson effect; reduction in stimulation amplitude(usually accompanied by a reduction in medication dosage) could often preserve most of the antiparkinson effect while eliminating stimulation-induced dyskinesias.

All patients were able to guess which assessments were performed with the stimulators on. Two of six patients reported mild paresthesias transiently at the onset of stimulation that did not persist with chronic stimulation. All other patients denied adverse effects of stimulation and stated that unblinding occurred solely because of the clinically obvious beneficial effects of stimulation. The amount of diary time considered unevaluable did not differ significantly in the preoperative versus postoperative states (2.9± 2.8 versus 0.7 ± 0.7 hours, p = 0.19). The mean percentage of evaluable time spent in the "on" state increased significantly from 25.7% to 51.7% (p < 0.005); similarly, "off" time was reduced from 30.3% to 5.9% (p < 0.05). Several patients reported improvement in sleep, possibly because of improved nocturnal mobility, and mean percentage of time asleep increased from 25.0% to 33.0%(p < 0.05). Four patients kept their stimulators on overnight at home because of excessive akinesia or tremor that interfered with sleep. Although three patients were free of dyskinesias postoperatively, the overall reduction in time "on with dyskinesias" was not significant.

Adverse effects. Transient adverse effects occurred in almost all patients as the optimal stimulation settings were being sought, including paresthesias, dysarthria and tonic contraction contralateral to the side of stimulation, and diplopia. These adverse effects subsided almost immediately when stimulation was turned off or the voltage reduced. Stimulation was then adjusted to eliminate these side effects.

Operative complications were common. A cortical venous thrombosis resulting in infarction at the site of electrode insertion resulted in marked postoperative dysarthria in one patient. This largely resolved over 3 months, leaving him with only subtle worsening of his long-standing parkinsonian hypophonia. Another patient developed a small thalamic lesion along one of the electrode tracts associated with mild reduction in verbal memory confirmed with preoperative and serial postoperative neuropsychological testing. Both of these patients had pronounced postoperative confusion that resolved in 1 to 2 weeks. Family members of a third patient noted mild personality change with intermittent disinhibited or childlike behavior since surgery; this did not significantly impair social functioning, and other aspects of neuropsychological testing were essentially unchanged. Finally, a 74- year-old nondemented man with progressive cognitive decline before surgery had an abrupt decline in most areas of cognition postoperatively, but his motoric improvement resulted in less dependence in ADLs. Despite these problems, part I of the UPDRS that measures mentation, behavior, and mood did not differ significantly between the preoperative and postoperative states(2.5 ± 1.5 versus 2.1 ± 1.9, p = 0.53). Neuropsychological results will be presented in detail in a separate publication. During macroelectrode insertion, mild, transient (<48 hours) hemichorea developed in two patients. All patients and spouses confirmed that the motoric benefit resulting from DBS outweighed any problems resulting from complications and the incovenience of the lengthy stimulator programming process.

Discussion. Our cohort of late-stage, disabled patients with PD obtained approximately a 65% reduction in off-period parkinsonism, 40% improvement in on-period parkinsonism, and 85% reduction in levodopa-induced dyskinesias. The overall clinical importance of these motoric improvements is underscored by the increase in "on" time and decrease in "off" time reported on patient diaries. Although our results represent a small number of patients receiving follow-up for only 6 to 12 months, the blinded nature of the assessments, large magnitude of benefit, reproducibility between patients, and similarity of our results to those obtained by other centers in open-label studies are convincing and strongly suggest that clinically important improvements can be achieved with this therapy.^7,11,18-20 The improvement in on-period parkinsonism contrasts with results of a recent open evaluation.¹¹ Unlike this study, to better emulate daily day functioning, our patients were given their usual antiparkinson medication and not a suprathreshold dose of levodopa. Although on-period functioning improved, we cannot state whether parkinsonian features refractory to a suprathreshold dose of levodopa will respond to STN DBS.

The mechanism of action of DBS is unknown. Physiologic studies of STN DBS in rodent models of parkinsonism suggest that STN stimulation improves parkinsonism by blocking the activity of the overactive STN and reducing GPi and SNr excitation.²¹ The similar clinical effects produced by STN stimulation and STN lesioning in humans and MPTP-treated nonhuman primates also support this putative mechanism of action.^22-25 PET studies suggest that these effects on parkinsonism are mediated through increased activation of the SMA, dorsolateral prefrontal cortex, and anterior cingulate and decreased activation of primary motor cortex.^26,27

Although the major beneficial effect on parkinsonism occurs as a direct result of stimulation, STN electrode implantation alone improves parkinsonism and may produce transient chorea probably caused by a microlesion effect. When patients are given the same drug dosage as administered preoperatively, the combined effect of STN electrode implantation and STN stimulation moderately reduces levodopa-induced dyskinesias¹⁸; however, the individual effects of electrode implantation and STN stimulation have not been fully defined and the ameliorative effect of chronic levodopa dosage reduction must also be considered. In our experience, electrode implantation alone commonly persistently reduces levodopa-induced dyskinesias possibly as a result of lesioning pallidal outflow fibers (especially the lenticular fasciculus) through which the electrode tract passes. In contrast, we have not observed a direct antidyskinetic effect of STN stimulation, and stimulation-induced dyskinesias (as described earlier) are common.²⁸ We have observed that the effect of STN stimulation may be additive to that of levodopa. This was confirmed during intravenous levodopa studies of one of our patients in whom there was a 70% reduction in levodopa threshold for induction of dyskinesias during stimulation (personal communication, P. Blanchet and T. Chase, July 1997). Therefore, a reduction in levodopa dosage is often necessary to maximally reduce levodopa-induced dyskinesias and maximize response of parkinsonism to stimulation by allowing the use of higher stimulation amplitudes.

We experienced a significant operative complication rate. In part this may be because these represent our initial cases of STN surgery and the mean age of our patients was greater than in previously reported series.^7,11,17-20 Our more recent experience suggests that intraoperative and postoperative confusion and agitation (lasting 1 to 2 weeks) are common in elderly patients undergoing bilateral STN mapping and electrode implantation. In contrast, patients younger than 60 years seem to tolerate the procedure better and remain lucid throughout surgery. Because patients with young-onset PD represent a small minority of those disabled by advanced PD, the applicability of this procedure in elderly patients is important.¹¹ Significantly, all patients and spouses believed that the clinical benefit obtained far outweighed the problems experienced from surgery and postoperative DBS programming.

Unilateral pallidotomy results in approximately 30% reduction in off-period UPDRS motor and ADL score, 30% improvement in on-period ADL score, and an 80% to 90% reduction in contralateral levodopa-induced dyskinesias.^2-4 Our limited experience with staged bilateral pallidotomy for PD suggests that a second lesion results in only modest further improvement in parkinsonism but striking amelioration of residual levodopa-induced dyskinesias ipsilateral to the initial lesion.⁵ Our patients undergoing bilateral STN DBS obtained considerably greater improvement in off-period parkinsonism. In contrast to most reports of unilateral pallidotomy, our bilateral STN DBS patients has significant improvement in on-period parkinsonism, whereas levodopa-induced dyskinesias were reduced bilaterally almost to the same extent as occurs contralateral to pallidotomy. Bilateral GPi DBS can also result in significant antidyskinetic and antiparkinsonian effects possibly with less risk to bulbar and cognitive function than bilateral pallidotomy.^29-31 Electrode insertion in the globus pallidus has a striking antidyskinetic effect and results in mild improvement in off-period parkinsonism.²⁹ However, response to GPi stimulation is very complex, and recent reports suggest that there may be at least two functionally distinct sites in the pallidum.^32,33 The relative indications and benefits of GPi versus STN DBS will require a large randomized clinical trial.

STN DBS may profoundly improve off-period parkinsonism, on-period parkinsonism, and levodopa-induced dyskinesias. This procedure can be performed safely, although operative complications in our initial patients were not uncommon. Nevertheless, the marked motoric benefits obtained in these severely disabled patients outweighed adverse effects. Further studies of this promising therapeutic modality will be necessary to compare its value to other surgical procedures for the treatment of PD including pallidotomy, GPi DBS, and STN lesioning.