Effect of bilateral subthalamic electrical stimulation in Parkinson’s disease

Functional Neurosurgery

Effect of Bilateral Subthalamic Electrical Stimulation in Parkinson’s Disease Giovanni Broggi, MD,* Angelo Franzini, MD,* Paolo Ferroli, MD,* Domenico Servello, MD,* Ludovico D’Incerti, MD,‡ Silvia Genitrini, MD,† Paola Soliveri, MD,† Floriano Girotti, MD,† and Tommaso Caraceni, MD† *Departments of Neurosurgery, †Neurology, and ‡Neuroradiology, Istituto Nazionale Neurologico “C. Besta,” Milan, Italy

Broggi G, Franzini A, Ferroli P, Servello D, D’Incerti L, Genitrini S, Soliveri P, Girotti F, Caraceni T. Effect of bilateral subthalamic electrical stimulation in Parkinson’s disease. Surg Neurol 2001;56:89 –96. BACKGROUND

Bilateral high frequency subthalamic stimulation has been reported to be effective in the treatment of Parkinson’s disease and levodopa-induced dyskinesias. To analyze the results of this surgical procedure we critically reviewed 17 parkinsonian patients with advanced disease complicated by motor fluctuations and dyskinesias. METHODS

Between January 1998 and June 1999 these 17 consecutive patients (age 48 – 68 years; illness duration 8 –27 years) underwent bilateral stereotactically guided implantation of electrodes into the subthalamic nucleus in the Department of Neurosurgery of the Istituto Nazionale Neurologico “C. Besta.” Parameters used for continuous high-frequency stimulation were: frequency 160 Hz, pulse width 90 ␮sec, mean amplitude 2.05 ⫾ 0.45 V. Parts II and III of the UPDRS were used to assess motor performance before and after operation by the neurologic team. The follow-up ranged between 6 and 18 months. RESULTS

At latest examination, mean UPDRS II and III scores had improved by 30% (on stimulation, off therapy) with mean 50% reduction in daily off time. Peak dyskinesias and early morning dystonias also improved in relation to therapy reduction. Side effects were persistent postoperative supranuclear oculomotor palsy and postural instability in one case, worsened off-medication hypophonia in three, and temporary nocturnal confusion episodes in three. Postoperative MRI revealed a clinically silent intracerebral haematoma in one case. One electrode required repositioning. CONCLUSIONS

Continuous high frequency STN stimulation is an effective treatment for advanced PD. A functionally useful and safe

Address reprint requests to: Dr. Giovanni Broggi, Istituto Nazionale Neurologico “C. Besta”, Dipartimento di Neurochirurgia, Via, Celoria 1120133, Milano, Italy. Received July 7, 2000; accepted May 25, 2001. © 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

electrode placement can be performed without microrecording. © 2001 by Elsevier Science Inc. KEY WORDS

Brain stimulation, Parkinson’s disease, stereotactic surgery, subthalamic nucleus.

harmacological treatment of parkinsonian symptoms unfortunately cannot prevent disability in advanced disease, because long-term levodopa therapy inevitably results in increasing motor fluctuations and dyskinesias. Advances in stereotactic surgery, neuroimaging, electrophysiologic recordings, and the possibility of therapeutic responses to high-frequency deep brain stimulation have renewed the interest in the surgical treatment of Parkinson’s disease (PD) [19]. In the past 40 years, several different neurosurgical targets have been proposed with different indications and contrasting results. Recently, increasing evidence in favor of the subthalamic nucleus (STN) as the target of choice has been collected. Current concepts of the basal ganglia [11,18] improved parkinsonism in MPTP monkeys [9] and human PD patients after both STN lesioning or high-frequency stimulation [1,14,19] point toward a major role of STN hyperactivity in the pathophysiology of PD. Deep brain stimulation seems to be able to produce functional inhibition of neurons in the target structure, similar to lesioning [5]. The main advantage of this procedure is that its effects are usually reversible. To further investigate the efficacy and safety of chronic high frequency bilateral STN stimulation we critically reviewed 17 PD patients with advanced disease complicated by motor fluctuations and dyskinesias.

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Clinical Features of the 17 PD Patients Who Received STN Stimulation

PATIENTS (11 M ⴙ 6 F) Age (years) Disease duration (years) Years on L-dopa Years of motor fluctuations Follow-up (months)

MEAN ⴞ SD

RANGE

59 ⫾ 6.06 13.20 ⫾ 6.42

(48–68) (6–27)

10.47 ⫾ 5.90 5.00 ⫾ 3.34

(0–22) (0–15)

8.2 ⫾ 2.75

(6–18)

Methods PATIENTS Between January 1998 and June 1999 17 consecutive patients (age 48 – 68 years; illness duration 8 –27 years) underwent bilateral stereotactically guided implantation of electrodes into the subthalamic nucleus at the Department of Neurosurgery of the Istituto Nazionale Neurologico “C. Besta.” Baseline clinical data are shown in Table 1. All had advanced PD with severe motor fluctuations and dyskinesias despite treatment with levodopa and dopamine agonists. No other neurological impairment was found. Cerebral magnetic resonance imaging (MRI) showed moderate cerebral atrophy in 5 patients, deep white matter T2-hyperintensity of vascular origin in 3, and a small frontal meningioma in one. None of the patients had significant cognitive or mood impairment, as assessed by MMSE and DSM-IV criteria, and all were less than 70 years of age. Clinical evaluations were performed in accordance with the Core Assessment Program for Intracerebral Transplantation (CAPIT) [17]. In particular, parts II, III, and IV of the Unified Parkinson’s Disease Rating Scale (UPDRS) were used to assess, respectively, activities of daily living, motor signs, and percentages of time spent in the dyskinetic and off states. Parts II and III of the UPDRS were evaluated both in “on” and “off” conditions. Sixteen patients were taking levodopa and 10 of these were also receiving dopamineagonists (Table 6). One patient in Hoehn and Yahr stage IV was not taking levodopa or dopaminagonists because of severe gastric intolerance and was receiving anticholinergic therapy only (6 mg trihexyphenidyl HCl per day). SURGERY All patients underwent bilateral simultaneous STN implantation under local anesthesia. Stereotactic surgery was performed in off conditions. MRI (T1 and fast spin echo inversion recovery) was used to obtain high definition anatomical images to determine the inter-

commissural plane, midcommissural point, and anatomical location of the STN in relation to the GPi, thalamus, substantia nigra, and red nucleus. MR images were fused with computed tomography (CT) images obtained stereotactically (CRW frame) through an ad hoc workstation (Stereoplan, Radionics, Inc, Burlington, MA) also providing stereotactic coordinates of the virtually built 3D space. The choice of the initial target was refined by superimposing the Shaltenbrand atlas [20] onto the MRI-CT fused 3D model. Through a 6 mm precoronaric paramedian burr hole the probe for macrostimulation (Siegfried electrode SSE-TC, 300 mm, Radionics, Inc.) was inserted for neurophysiological confirmation of the target position, following well-known and previously reported criteria [3,6]. The neurologist examined the patient for reduction of rigidity, akinesia, and tremor in the limbs contralateral to stimulation and checked for mydriasis and contralateral gaze deviation. Passive movement of the contralateral wrist and elbow during stimulation at 50 and 100 Hz was used to assess the eventual decrease in rigidity. Motor and sensory responses were evoked by using the so-called collateral Siegfried electrode with low frequency (2 Hz) macrostimulation to verify the target relationships to the motor bundle and to the ventralis posterior lateralis (VPL) nucleus. After confirmation of the correct target location (clinical improvement of Parkinsonian signs without collateral effects of stimulation) a quadripolar deep brain stimulation electrode (DBS-3387, Medtronic, Inc., Minneapolis, MN) was inserted and fixed to the cranium. If the effect of stimulation was unsatisfactory, the target was moved according to data derived by macrostimulation of the “peritarget” volume (a cylinder of 6 mm radius whose height is related to the depth movement of the probe). The new target was reached through the same burr hole. The target refinement never required more than three tracks. The procedure was then repeated on the other side. The average duration of bilateral surgery was 3 hours. To identify the location of the electrode and possible brain lesions, a cerebral MRI was always performed, after the electrodes had been implanted (Figure 1), but before the pulse generator was put in place. About 3 days after implantation, the electrodes were connected to a pulse generator (Itrel II, Medtronic, Inc., Minneapolis, MN) that was placed subcutaneously in the subclavicular area, like a cardiac pacemaker. The pulse generator could be programmed by telemetry for different variables of stimulation, different contact (cathode or anode, monopolar, v bipolar), voltage (0 to 10.5 V), rate (2 to 185 Hz), pulse width (60 to 450 ␮sec), and timing (cyclic or continuous stimulation).

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Pre and Postsurgery Comparisons of UPDRS Part III (Motor Signs) Scores

PRESURGERY

POST SURGERY ON STIMULATION p

a

VALUE

On medication 15.27 ⫾ 16.68 10.47 ⫾ 10.25 p ⫽ 0.009 (range 3–72) (range 0–34) Off medication 52.07 ⫾ 17.49 32.93 ⫾ 12.99 p ⫽ 0.027 (range 24–79) (range 15–55) a

Student t test.

nian therapy was maintained unchanged during the first post operative month. Clinical evaluation was repeated with the same protocol used before surgery with a follow-up ranging from 6 to 18 months (mean 8.2 months). Preoperative and postoperative data were compared by the paired Student t test or by the paired nonparametric Wilcoxon signed-rank test as appropriate.

Results 1

T1-weighted magnetic resonance image of bilateral subthalamic electrode implant.

POSTOPERATIVE EVALUATION AND STATISTICAL ANALYSIS After surgery the neurologist evaluated the effects of different clinical settings starting with monopolar stimulation (pulse generator as the anode) at a frequency of 160 Hz with a 90 ␮sec pulse width. The voltage was progressively increased and favorable effects on parkinsonian symptoms and adverse effects, such as ocular movements, involuntary movements and muscle contractions were evaluated. The contact improving parkinsonian symptoms at the lowest voltage without collateral effects was selected for long-term stimulation. Antiparkinso-

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Pre and Postsurgery Comparisons of UPDRS Part II (Activities of Daily Living) Scores

PRESURGERY

POST SURGERY ON STIMULATION p

Mean scores in the UPDRS part II (Table 2) and III (Table 3) significantly improved after surgery. Table 4 summarizes the improvements in parts II and III of UPDRS on and off medication while being stimulated. The percentage improvement was greatest (around 50%) in activities of daily living (part II) when the patients were on medication and on stimulation, while the improvement was around 30% for UPDRS parts II and III off medication and on stimulation. The most remarkable result was the reduction in the proportion of daily time spent in the off and in dyskinetic states (Table 5), the latter usually associated with a significant reduction in levodopa dose (Table 6), but sometimes observed before levodopa reduction. In particular, early morning dystonia disappeared in 8 of the 10 patients who suffered from it before electrode implantation. STIMULATION PARAMETERS In all cases the best therapeutical response was obtained by monopolar stimulation. Parameters of stim-

4

Percentage Improvement After Surgery in UPDRS Parts II and III (means ⫾ SD)

POST SURGERY ON STIMULATION

a

VALUE

10.47 ⫾ 7.53 4.87 ⫾ 4.94 p ⫽ 0.002 (range 2–26) (range 0–19) Off medication 29.87 ⫾ 9.13 20.60 ⫾ 10.78 p ⬍ 0.0001 (range 16–47) (range 1–45)

On medication

a

Student t test.

UPDRS II on Medication UPDRS II off Medication UPDRS III on Medication UPDRS III off Medication

RANGE

50.81 ⫾ 30.03 0 to ⫹100 32.09 ⫾ 27.48 ⫺7.69 to ⫹95 18.10 ⫾ 60.63 ⫺87.50 to ⫹100 34.30 ⫾ 19.27 ⫹9.84 to ⫹76.81

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Percentage of Daily Time Spent in off and Dyskinetic States Before and After Surgery

PRESURGERY 51.93 ⫾ 19.36 (range 25–100) Dyskinetic state 48.00 ⫾ 25.48 (range 0–75) Off state

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POST SURGERY

p VALUEa

15.00 ⫾ 14.02 p ⫽ 0.0015 (range 0–50) 25.00 ⫾ 26.73 p ⫽ 0.009 (range 0–75)

Wilcoxon test.

ulation were: amplitude 2.05 ⫾ 0.45 volts; frequency 160 Hz; pulse width 90 ⫾ 30 ␮sec, continuous mode. COMPLICATIONS AND ADVERSE EFFECTS In one case, persistent postoperative supranuclear oculomotor palsy and postural instability were observed, after electrode misplacement in the mesencephalon, due to technical problems with the stereotactic device. The electrode was correctly replaced during the same operating session. Worsened offmedication hypophonia and temporary nocturnal confusion were experienced by three patients. Postoperative MRI revealed a clinically silent intracerebral haematoma in one case. One incorrectly positioned electrode required reoperation for repositioning. Intraoperative major dyskinesias were observed in three successfully treated patients, after highfrequency stimulation of the medial subthalamus as revealed by postoperative MRI evaluation with an ad hoc software (Solaris, Milan, Italy) [13]. Macrostimulation before final electrode placement revealed that initial target localization based on image fusion alone was suboptimal in two cases and required correction of electrode coordinates before final positioning.

Discussion Our results confirm that continuous high-frequency STN stimulation may improve all parkinsonian mo-

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tor signs and levodopa-induced motor complications, even in cases of advanced disease with severe motor fluctuations and dyskinesias. Although there were large between-subject variations, all patients in this series benefited significantly from electrode implantation (Figure 1) and STN stimulation. The most striking finding in our patients was that both “off” time and dyskinesias were reduced after surgery. Levodopa-induced dyskinesias sometimes even improved before levodopa reduction, as observed also by Figueiras–Mendez et al [12], but generally improvement of dyskinesias followed levodopa reduction. In this initial series the score of dyskinesia in the postoperative stage was high, probably because the antiparkinsonian therapy was maintained unchanged during the first postoperative month. In later patients the dose of antiparkinsonian drugs was progressively reduced soon after surgery to allow the increase of voltage stimulation. Major dyskinesias after intraoperative macrostimulation were observed in three patients with a satisfactory outcome; such dyskinesias should not be considered adverse effects, but favorable prognostic signs. As shown in Table 7, even patients who did not greatly improve in UPDRS III score had consistently shortened daily off time, contributing to an improvement in quality of life. UPDRS part II and III scores improved off medication and on stimulation less than the 60% or thereabouts, reported by Limousin et al [19]. The possible explanations for this discrepancy are two: 1. Different selection criteria. Some of our patients had a less positive response to levodopa and, according to Krack [16] and Charles [10], this is predictive of a less than optimal response to stimulation. Limousin [19] established strict inclusion criteria for deep brain stimulation: (1) long-term PD patients with motor fluctuations and dyskinesias; (2) pharmacological treatments ineffective; (3) no mental deterioration or psychosis; and (4)

Drug Therapy Before and After Surgery in the 17 Patients Who Received Bilateral STN Stimulation

BEFORE SURGERY MEAN ⴞ SD Levodopa mg/day Pergolide mg/day Ropinirole mg/day Bromocriptine mg/day Apomorphine mg/day Trihexyphenidyl mg/day a

1018.33 ⫾ 473.54a 2.57 ⫾ 1.17b 6.0 20.0 30.0 6.0

p ⫽ 0.005 (Student t test); bp ⫽ 0.18 (Student t test).

AFTER SURGERY NO

OF CASES

MEAN ⴞ SD

16 7 1 1 1 1

681.67 ⫾ 320.64a 2.21 ⫾ 1.03b 6.0 10.0 0 6.0

NO

OF CASES

14 7 1 1 1 1

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Individual Percentage Improvement in Part III of UPDRS off Medication After Surgery, and Percentage of Daily Time in off State Before and After Surgery

% PATIENT

AGE

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

53 56 62 48 52 62 68 63 66 59 67 58 53 56 68 61 57

IMPROVEMENT IN UPDRS III

59.49 63.41 26.67 76.81 16.67 32.14 15.38 39.06 24.53 24.24 21.95 23.44 42.86 38.03 9.84 32.31 36.29

good response to levodopa. Moreover, in three of our patients with suboptimal results, MRI showed a cerebral vasculopathy that probably should be considered an exclusion criterion. 2. Difference in electrode positioning. We used an ad hoc software able to graphically represent the electrode tip position and trajectory in an AC-PC based cartesian system to postoperatively check the position of the actual stimulating electrode [13]. We found that the technique of image fusion and subsequent intraoperative macrostimulation refinement of target position often led to an asymmetric electrode placement with a spatial distribution not perfectly superimposable to the STN shape. Other authors showed that the major factor of efficiency of this kind of surgery is the perfect microrecording-guided placement of the electrode within the STN [19]. It might be argued that imprecise electrode placement could have contributed to the relatively poor outcome of this initial series: that was the reason why in subsequent patients we started to use microrecording (Leadpoint, Medtronic). Nevertheless, there still is something unpredictable in the outcome of these patients. There are perfectly placed electrodes in ideal candidates in which the expected results are not obtained. Furthermore, the actual stimulating contacts with the best therapeutic response in single patients sometimes were not the ones inside the nucleus, as would be expected if it was the best target. Because the electrode contacts have a centre-to-centre separation of 1.5 mm, whatever the surgical technique only one or two contacts of the macroelectrode will actually be in the STN, the

%

OF DAILY TIME IN OFF PRESURGERY

100 30 50 75 25 50 25 50 50 50 50 75 50 50 50 50 50

%

OF DAILY TIME IN OFF POSTSURGERY

0 10 0 0 25 25 10 10 10 10 25 0 50 25 25 25 10

others being in adjacent structures. According to the most accepted model, [8] continuous highfrequency STN stimulation in PD should actually block the hyperactive STN neurons which facilitate the GPi and substantia nigra pars reticulata (SNPR), enhancing the cortical motor output. Maybe this is an extreme simplification of a mechanism of action which still remains unclear [2]. Although some studies seem to limit the effect of high-frequency stimulation only to cells, [4,7] the shape of the electric field induced by stimulation (in most series unipolar) and the pattern of current diffusion, naturally influenced by different tissue impedances, have not been so definitively investigated. In particular, the fact that in some patients the best therapeutic response is obtained by contacts in the structures adjacent to the STN gives credence to the hypothesis of a possible involvement of fibers and not only of cells. Increased motor output could also result from activation of the efferent fibers from the STN to the GPE or from activation of the afferents from the GPE to the STN; orthodromic activation of these afferents might inhibit the STN. Even more, also blocking the periSTN fibers of the lenticular fasciculus from the GPi to the thalamus or blocking the neighboring SNPR would result in enhancing motor output. Regarding the effects of STN stimulation on tremor, recent evidence seems to demonstrate that the site of action is not confined to the STN [2]. Thus, the definitive role of both macrostimulation and microrecording in the intraoperative refinement of the final target still remains under investigation.

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Conclusions Continuous high-frequency STN stimulation is an effective treatment for advanced PD. Functionally useful and safe electrode placement can also be performed without microrecording [15]. In our experience, it reduced the severity of parkinsonian signs and levodopa-related dyskinesias, the latter sometimes improving before levodopa reduction. The best results are obtained in younger, levodoparesponding patients, but a mild improvement, positively affecting the quality of life, may be observed even in patients older than 65. Further studies are required to better clarify the indications for and mechanism of action of this surgical procedure.

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COMMENTARY

Broggi and colleagues summarize their experience with subthalamic nucleus (STN) stimulation for advanced Parkinson’s disease. They implanted electrodes bilaterally in 17 patients and used a combination of MRI and CT for target delineation. For intraoperative physiological target confirmation the authors used macrostimulation with various frequencies and were able to complete bilateral implantation in 3 hours. Postoperatively, improvements were observed in mean UPDRS part II and III scores, as well as in the percentage of “off” time and severity of dyskinesias. The dosage of antiparkinsonian medications was decreased after the surgery, possibly adding to the reduction of dyskinesias. Overall, this is a good demonstration of the safety and efficacy of this therapeutic modality for advanced parkinsonism, show-