Subthalamic nucleus stimulation in Parkinson's disease patients intolerant to levodopa

Levodopa responsiveness has been shown to be the best predictor of improvement after subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson's disease (PD). The objective of this study was to assess the effect of STN DBS on PD patients intolerant to levodopa due to severe acute side effects such as intolerable nausea. There were 10 patients in the study who received STN DBS for PD. Five patients who were intolerant to levodopa were matched based on age, disease duration, sex and presurgical disease severity to 5 patients taking levodopa and demonstrating a good levodopa response. Both groups had a significant improvement in Unified Parkinson's Disease Rating Scale activities of daily living and motor subscales as well as tremor, rigidity and bradykinesia scores at 3, 6 and 12 months after surgery compared to baseline, and these improvements were equivalent between the two groups. Patient global ratings also indicated significant improvements at all follow-up visits. There were no differences in stimulator settings between the two groups at the 3-, 6- or 12-month follow-up visits. In conclusion, although levodopa responsiveness is the best predictor for outcome after STN DBS, carefully selected PD patients intolerant to levodopa can have significant improvement.     

Subthalamic stimulation in Parkinson's disease. Preliminary results

OBJECTIVES: We wanted to evaluate chronic subthalamic nucleus (STN) stimulation as an alternative to pallidotomy for severe Parkinson's disease symptomatology. METHODS: Nine patients met clinical criteria for unilateral standard pallidotomy. All had severe medically refractory drug-induced dyskinesia and had reached maximal daily levodopa therapy. Pre- and postoperative videos, neuropsychometric testings and clinical stagings were administered. Three patients were selected to undergo stereotactic implantation of a deep brain stimulator (DBS) after Institutional Review Board approval and informed consent. These were performed using digitized microrecordings. The other group received unilateral pallidotomy. RESULTS: At a mean follow-up of 6 months, our results support recent findings of significant major improvement in motor scores, activity of daily living and decrease in amount of daily levodopa intake by close to 50% after 3 months of stimulation. CONCLUSIONS: Chronic stimulation of the STN appears to provide significant motor improvement in patients with severe Parkinson's disease and is more beneficial than pallidotomy.     

Subthalamic nucleus deep brain stimulation for Parkinson's disease: magnetic resonance imaging targeting using visible anatomical landmarks

BACKGROUND: The aim of the present study was to validate a magnetic resonance imaging (MRI) visual procedure to target the subthalamic nucleus (STN) based on surrounding anatomical landmarks. METHODS: 31 consecutive bilaterally implanted parkinsonian patients were included in this study. After identification of the anterior commissure (AC), posterior commissure (PC) and midcommissural point on a three-dimensional T1-weighted sequence, inversion recovery (IR) T2-weighted coronal slices were performed orthogonal to the AC-PC line. On the slice showing the anterior pole of the red nucleus (RN), the target was placed in the inferolateral portion of the subthalamic zone, limited superiorly by the thalamus, laterally by the internal capsule, inferiorly by the substantia nigra and medially by the midline. The distribution of the targets was analyzed in the AC-PC referential. RESULTS: The mean target coordinates were as follows: anteroposterior (AP) = -2.54 mm (+/-1.37 mm), lateral (LAT) = 12.03 mm (+/-0.91 mm) and vertical (VERT) = -6.10 mm (+/-1.52 mm) for the right side, and AP = -2.65 mm (+/-1.36 mm), LAT = -11.97 mm (+/-1.30 mm) and VERT = -5.89 mm (+/-1.52 mm) for the left side. They projected in the inferior portion of the STN on the Schaltenbrand and Wahren atlas [Stuttgart, Thieme, 1977]. CONCLUSION: Identification of the anterior pole of the RN and the subthalamic zone on coronal IR T2-weighted MRI performed orthogonal to the AC-PC line provides a precise visual procedure to target the STN.     

Subthalamic nucleus stimulation for Parkinson disease: benefits observed in levodopa-intolerant patients.

OBJECT: A blinded evaluation of the effects of subthalamic nucleus (STN) stimulation was performed in levodopa-intolerant patients with Parkinson disease (PD). These patients (Group I, seven patients) were moderately or severely disabled (Hoehn and Yahr Stages III-V during the off period), but were receiving only a small dose of medication (levodopa-equivalent dose [LED] 0-400 mg/day) because they suffered unbearable side effects. The results were analyzed in comparison with those obtained in patients with advanced PD (Group II, seven patients) who were severely disabled (Hoehn and Yahr Stages IV and V during the off period), but were treated with a large dose of medication (500-990 mg/day). METHODS: The patients were evaluated twice at 6 to 8 months after surgery. To determine the actual benefits afforded by STN stimulation to their overall daily activities, the patients were maintained on their medication regimen with optimal doses and schedules. Stimulation was turned off overnight for at least 12 hours. It was turned on in the morning (or remained turned off), and each patient's best and worst scores on the Unified Parkinson's Disease Rating Scale during waking daytime activity were recorded as on- and off-period scores, respectively. The order of assessment with respect to whether stimulation was occurring was determined randomly. The STN stimulation markedly improved daily activity and total motor scores in Group I patients. The percentage time of immobility (Hoehn and Yahr Stages IV and V) became 0% in patients who were intermittently immobile while not receiving stimulation. Improvements were demonstrated in tremor, rigidity. akinesia, and gait subscores. The STN stimulation produced less marked but still noticeable improvements in the daily activity and total motor scores in Group II patients. The percentage time of immobility as well as the LED was reduced in patients who displayed intermittent immobility with pronounced motor fluctuations while not receiving stimulation. Improvements were demonstrated in tremor, rigidity, and dyskinesia subscores in these patients. In contrast, STN stimulation did not improve the overall daily activities at all in patients who had become unresponsive to a tolerable dose of levodopa and were continuously immobile, even though these patients' tremor and rigidity subscores were still improved by stimulation. CONCLUSIONS: Consistent with earlier findings, the great benefit of STN stimulation in levodopa-intolerant patients is that STN stimulation can reduce the level of required levodopa medication. This suggests that STN stimulation could be a therapeutic option for patients with less-advanced PD by allowing levodopa medication to be maintained at as low a dose as possible, and to prevent adverse reactions to the continued use of large-dose levodopa.     

Deep brain stimulation for Parkinson's disease: how to select candidates for pallidal or subthalamic stimulation

Chronic deep brain stimulation therapy has the reversibility, selectivity and adjustability needed to achieve an adequate effect, so that it represents an ideal tool for functional neurosurgery designed to treat parkinsonian symptoms. Some kinds of chronic stimulation have become an alternative to lesion-making surgery, supported by the fact that high-frequency stimulation induces quite a small area of inactivity around the stimulating electrode compared with the lesions induced with a lesion-maker, and stimulation directed at a particular target exerts more specific effects on particular symptoms of Parkinson's disease (PD). Thus, whenever stimulation therapy is to be applied to patients, an effective stimulation target must be selected depending on the nature of the symptom to be improved. For example, ventral intermediate nucleus (VIM) thalamic stimulation is able to stop tremor completely, but has no appreciable effects on other symptoms. Bilateral globus pallidum interna (GPi) stimulation and subthalamic nucleus (STN) stimulation have been applied to reduce the pathological inhibitory effects on the thalamocortical circuit from the GPi and/or the substantia nigra pars reticular nucleus (SNr), which produces the final output of the basal ganglia circuits. However, there is still controversy about both the indications for and the role of GPi versus STN stimulation. This article presents a review of recent reports that describe follow-up results and double-blind studies on the signs for relief of each type of parkinsonian symptom, following GPi or STN stimulation. It also includes a discussion of how further research should be organized in order to identify whether GPi or STN stimulation exerts the greatest effect on particular kinds of parkinsonian symptoms.     

Deep brain stimulation for Parkinson's disease. A critical re-evaluation of STN versus GPi DBS

Deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) is increasingly being used for the treatment of advanced Parkinson's disease (PD). Although both targets have demonstrated clinical efficacy in the treatment of the cardinal motor signs of PD, the STN has gained greater popularity and is now considered the site of choice by most centers performing these procedures. This preference stems predominately from the belief that STN DBS provides greater improvement in reducing the motor manifestations of PD and allows a reduction in dopaminergic medication not permitted with GPi DBS. There are, however, a number of issues that must be considered before abandoning GPi in favor of STN as the surgical target of choice for DBS. The maximal benefit reported for GPi stimulation is not significantly different than that reported for the STN, 67 versus 71%, and while reductions in medication are required with STN stimulation to avoid inducing dyskinesia, GPi stimulation may directly suppress dyskinesia obviating any need to reduce medication. As such, many centers may not attempt to reduce antiparkinsonian medication with GPi DBS. In addition, there are significantly more reports of changes in mood, behavior and a higher incidence of adverse events reported for STN stimulation. Most studies of DBS are nonrandomized, assessment protocols are not standardized, and lead locations are not reported. Thus, before drawing conclusions regarding the optimal site for DBS for advanced PD we must take a critical eye to the present data and address the outstanding questions that remain with well-designed clinical trials that evaluate motor, nonmotor and adverse events and address the above clinical variables by randomizing patients, using standardized methods of assessment and defining the lead location.     

Long-term outcomes of bilateral subthalamic nucleus stimulation in patients with advanced Parkinson's disease

BACKGROUND: In patients with advanced Parkinson's disease (PD), deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to improve motor function and decrease medication requirements in the short term. However, the long-term benefits of DBS are not yet established. OBJECTIVE: It was the aim of this study to evaluate long-term outcomes of patients with PD treated with bilateral DBS of the STN. DESIGN AND METHODS: Thirty-three subjects who had bilateral STN DBS were followed prospectively after surgery. We evaluated subjects, using the Unified Parkinson's Disease Rating Scale (UPDRS), preoperatively, 12 months after surgery and at a long-term follow-up visit. Ratings were performed on and off dopaminergic medications. We compared postoperative UPDRS scores, dyskinesia ratings and medication dosages with preoperative values. RESULTS: Twenty-seven subjects had evaluations beyond 18 months (median 33.7 months). Total UPDRS scores in the 'medication-off' state were improved by 37% (p < 0.001) at 12 months and 17.7% (p = 0.0051) at the long-term evaluation. Medication-off state UPDRS part III scores were significantly improved at both 1 year and at the last evaluation (37.6 and 29.3%; p < 0.001). Dopaminergic medication requirements were decreased by 35.3% (p < 0.001) during the first postoperative year and remained below preoperative levels at the long-term evaluation. Average duration of 'off' time remained decreased by about 40% at both 1 year and at the time of last evaluation. Subjects had a sustained reduction in dyskinesia severity (88.6% at 1 year and 68.8% at last evaluation). CONCLUSIONS: In this cohort of subjects with advanced PD, bilateral STN stimulation improved 'off' medication motor function, reduced time spent in the medication-off state and reduced medication requirements for up to 4 years after surgery. We conclude that STN DBS is an effective long-term therapy for selected patients with advanced PD.     

Subthalamic deep brain stimulation for severe idiopathic Parkinson's disease. Location study of the effective contacts

The subthalamic nucleus (STN) is the main target of deep brain stimulation (DBS) treatment for severe idiopathic Parkinson's disease. But there is still no clear information on the location of the effective contacts (used during the chronic phase of stimulation). Our aim was to assess the anatomical structures of the subthalamic area (STA) involved during chronic DBS. Ten patients successfully treated were included. The surgical procedure was based on direct STN targeting (stereotactic MRI based) pondered by the acute effects of intraoperative stimulation. We used a formaldehyde-fixed human specimen to compare by matching MRI images obtained at 1.5 Tesla (performed in clinical stereotactic conditions) and at very high field at 4.7 Tesla. This allowed accurate analysis of the anatomy of the STA and retrospective precision of the location of the center of effective contacts which were located within the STN in 4 patients, at the interface between the STN and the ZI and/or FF in 13, at the interface between ZI and FF in 2 and between the STN and the substantia nigra in one. These results were consistent with the literature, revealing the implication of neighboring structures, especially the zona incerta and Forel's Field, in the clinical benefit.     

Subthalamic nucleus stimulation in patients with a prior pallidotomy

OBJECT: A substantial number of patients with Parkinson disease (PD) who have undergone unilateral stereotactic pallidotomy ultimately develop symptom progression, becoming potential candidates for further surgical treatment. Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) has been shown to be effective in the treatment of a subset of patients with refractory PD. Microelectrode recording is performed to help localize the STN and guide final placement of the electrode. Potential alterations in physiological features of the STN after pallidotomy may complicate localization of this structure in this group of patients. METHODS: Bilateral STN DBS surgery guided by microelectrode recording was performed in six patients who had undergone previous unilateral pallidotomies. Physiologically obtained parameters of the STN, including trajectory length, mean firing rate, cell number, and cell density were calculated. These data were compared with those from the side without prior pallidotomy within each patient, as well as with those from our series of 49 subthalamic nuclei explored in 26 patients who had not undergone prior pallidotomy but who underwent bilateral STN stimulator placement. In all patients, analysis of STN cellular activity on the side ipsilateral to the pallidotomy demonstrated a lower mean firing frequency than on the contralateral, intact side. The physiological features on the intact side were not significantly different from those found in our series of patients who had not undergone prior pallidotomy. CONCLUSIONS: Physicians who perform STN surgery in patients with prior pallidotomy should be aware of the electrophysiological differences between the STN that had undergone pallidotomy and the one that had not, to avoid prolonging recording time to search for the typical STN. The implications of these findings for the current models of information processing in the basal ganglia are discussed.     

Complications of subthalamic nucleus stimulation in Parkinson's disease

Subthalamic nucleus deep brain stimulation (STN-DBS) is effective for medically refractory Parkinson's disease. We retrospectively analyzed complications in 180 consecutive patients who underwent bilateral STN-DBS. Surgery-related complications were symptomatic intracerebral hemorrhage in 2, chronic subdural hematoma in 1, and transient deterioration of medication-induced psychosis in 2 patients. Device-related complications involved device infection in 5, skin erosion in 5, and implantable pulse generator malfunction in 2 patients. All of these patients required surgical repair. Surgery and device-related complications could be reduced with increased surgical experience and the introduction of new surgical equipment and technology. Treatment or stimulation-related complications were intractable dyskinesia/dystonia in 11, problematic dysarthria in 7, apraxia of eyelid opening (ALO) in 11, back pain in 10, and restless leg syndrome in 6 patients. Neuropsychiatric complications were transient mood changes in some, impulse control disorder in 2, severe depression related to excessive reduction of dopaminergic medications in 2, rapid progression of dementia in 1, and suicide attempts in 2 patients. Most complications were mild and transient. Dysarthria and ALO were the most frequent permanent sequelae after STN-DBS. Treatment-related adverse events may be caused not only by the effect of stimulation effect but also excessive reduction of dopaminergic medication, or progression of the disease. In conclusion, STN-DBS seems to be a relatively safe procedure. Although serious complications with permanent sequelae are rare, significant incidences of adverse effects occur. Physicians engaged in this treatment should have a comprehensive understanding of the probable complications and how to avoid them.     

Results of chronic subthalamic nucleus stimulation for Parkinson's disease: a 1-year follow-up study

BACKGROUND: Deep brain stimulation (DBS) has been established as an alternative approach for the treatment of advanced Parkinson's disease (PD). Recently, the subthalamic nucleus (STN) has been identified as the optimal target for DBS. METHODS: Thirty-eight patients have undergone surgery for advanced PD since 1996. They include 12 females and 26 males with a mean age of 55.6 years. The mean stage on the Hoehn and Yahr Scale was 3.5 (off condition). Electrodes (Medtronic DBS 31389) were stereotactically implanted into the STN bilaterally. Targeting was performed using computerized tomography (CT) scans and ventriculography (VG). After 4 days of external stimulation, permanent neurostimulators were implanted. Patients were evaluated preoperatively and 1, 6, and 12 months postoperatively. Evaluations were performed in defined on and off states using the Unified Parkinson's Disease Rating Scale (UPDRS) as well as the Hoehn and Yahr Scale, the dyskinesia scale, and the Activities of Daily Living (ADL) Scale. RESULTS: Significant improvement of all motor symptoms was found in all patients (UPDRS motor score 32/48 preoperatively versus 15/30 at 12-month follow-up, p < 0.001). Daily off-times were reduced by 35%. Dyskinesias also improved markedly (UPDRS IV: 3.2/3.1 [on/off] vs. 0.9/1.3 at 12 months follow-up). Postoperative L-dopa medication was adjusted (mean reduction: 53%). Complications occurred in two patients (5%) who developed infections, leading to system removal. Systems were replaced after 6 months. Two patients (5%) had a permanent worsening of a previously known depressive state and developed progressive dementia. CONCLUSIONS: TN stimulation is a relatively safe procedure for treating advanced PD. The possibility of readjusting the stimulation parameters postoperatively improves the therapeutic outcome and reduces side effects in comparison to ablative methods.     

The optimal stimulation site for chronic stimulation of the subthalamic nucleus in Parkinson's disease

To determine the optimal stimulation site within the subthalamic nucleus (STN), monopolar stimulation of four electrode contacts and the resulting effects on parkinsonian symptoms were evaluated in 10 consecutive patients. The UPDRS score for rigidity and akinesia improved significantly after stimulation at each of the contacts, compared to the pre-evaluation state (Fisher's test, p < 0.05). The most significant improvement was obtained after stimulation at contact-2 (rigidity: 74.4 +/- 20.4%, akinesia: 53.7 +/- 14.3%) (Fisher's test, p < 0.001). Contact-2 was located at the dorsal border of the STN at a mean distance of 0.3 +/- 0.7 mm. DBS at the dorsal border of the STN, where the stimulation affects the neurons as well as their axonal fibers, produces the greatest clinical improvement in parkinsonian symptoms.