Dopaminergic therapy and subthalamic stimulation in Parkinson’s disease: a review of 5-year reports

The long-term efficacy and safety of deep brain stimulation (DBS) implant for Parkinson’s disease (PD) is described in several recent papers. This procedure has been reported to permit a stable reduction of dopaminergic therapy requirements for up to 5 years, although some expectation of deterioration in non-dopaminergic signs has been recently stated. Our aim is to perform a literature-based review of papers available describing long-term post-operative follow-up after a bilateral implant for subthalamic DBS (STN-DBS). Only peer-reviewed published papers with a post-operative follow-up of at least 5 years were considered. Clinical outcome, disease progression and side effects were assessed at baseline and 2 (or 3 years) and 5 years after surgery. Seven papers were included in the review. A total of 238 patients were analyzed. STN-DBS was confirmed to be an effective treatment for selected patients with PD. In all studies, off-related motor symptoms improved dramatically, compared with pre-implant, at 2 (or 3, according to the study) years and this result persisted at 5-year evaluations. Antiparkinsonian drug reductions, improvements in motor fluctuations and dyskinesias, functional measures and the progression of underlying PD were also reported in all series. Some axial scores, in particular postural stability and speech, improved transiently. Persisting adverse effects included eyelid opening apraxia, weight gain, psychiatric disorders, depression, dysarthria, dyskinesias, and apathy. The present review of the 5-year observations confirms that STN-DBS is a powerful method in the management of PD, but its long-term effects must be thoroughly assessed.

     

Bilateral subthalamic nucleus stimulation in advanced Parkinson’s disease

Objective To assess the long-term efficacy and safety of chronic bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced Parkinson’s disease (PD). Methods 36 consecutive patients with idiopathic Parkinson’s disease treated with bilateral stimulation of the STN were studied. Parkinsonian status was assessed preoperatively and at 1 and 3 years postoperatively using the Unified Parkinson’s Disease Rating Scale (UPDRS) and neuropsychological evaluation in on and off-medication / on and off stimulation conditions. Results At 3 years follow-up, STN stimulation reduced the UPDRS motor score by 54.2 % compared to baseline in the off-medication conditions. Tremor, rigidity, bradykinesia, postural stability, and gait improved by 72.2 %, 62.4 %, 56.8 %, 40.5 % and 45.3 %, respectively. UPDRS part II scores were reduced by 41.4 %. The overall dopaminergic drugs dose was reduced by 48.6 % after surgery and four patients were no longer taking antiparkinsonian medication at three years. However, axial dopa-unresponsive signs worsened in some patients. The most frequent transient adverse event consisted in mood disorders in 23 patients. Conclusions Our data demonstrate that: 1) bilateral STN stimulation is relatively safe, improves the motor symptoms and drug-related motor complications of PD, and reduces the daily dosage of medication; 2) this benefit is sustained over time despite the occurrence of axial doparesistant signs in some patients.     

Long-term follow-up of subthalamic nucleus stimulation in glucocerebrosidase-associated Parkinson’s disease

Journal of Neurology -     

Effects of bilateral subthalamic stimulation on sleep in Parkinson’s disease

Abstract.Objective: Sleep disturbances are frequently observed in Parkinsons disease (PD). Bilateral chronic subthalamic nucleus (STN) stimulation is an alternative treatment for advanced PD. Improvements in motor disturbances after STN stimulation are well documented and seem to be associated with better sleep quality, even though the objective effect on sleep structure remains unclear. We have therefore studied the sleep/wakefulness cycle before and after surgical treatment in 10 consecutive parkinsonian patients.Methods: Subjective sleep quality and sleep recordings were evaluated one month before and three months after initiation of STN stimulation. After surgery, the recordings were performed under two conditions: with stimulation (the on condition) and—if patients had given their consent—in the absence of stimulation (the off condition).Results: With STN stimulation, subjective and objective sleep qualities were improved. Total sleep time, sleep efficiency and the durations of deep slow wave sleep and paradoxical sleep increased significantly. When stimulation was absent, sleep disturbances were similar to those observed before surgery.Conclusion: Chronic STN stimulation is associated with a sleep improvement, which can be explained in part by the concomitant decrease in motor disturbances but also by the reduction in dosages of antiparkinsonian medication. However, we can not exclude a direct effect of STN stimulation on sleep regulatory centres.     

Postural instability and gait disorders after subthalamic nucleus deep brain stimulation in Parkinson’s disease: a PET study

Journal of Neurology - Patients with Parkinson’s disease sometimes report postural instability and gait disorders (PIGD) after subthalamic nucleus deep brain stimulation (STN-DBS). Whether...     

Aggressive behavior as a rare side effect of subthalamic stimulation in Parkinson’s disease

Although deep brain stimulation (DBS) has a well-established position in the treatment of Parkinson’s disease (PD), it may be accompanied by different side effects including behavioral changes. We present a patient with advanced PD after bilateral stimulation of the subthalamic nucleus (STN) who developed attacks of aggressive behavior. The patient with a 12 year history of PD underwent the procedure of DBS with one-stage bilateral stereotactic approach using the Leksel G stereotactic frame. For STN identification microrecording technique was applied (5 microelectrodes). Four weeks after surgery STN stimulation was switched on. With increasing the amplitude of stimulation on the right (active contacts 1 and 2) the patient experienced transient episodes of aggression. Change of stimulation mode led to withdrawal of all side effects. We hypothesize that aggression episodes in the patient were caused by stimulation of limbic circuit probable within STN although we cannot exclude simultaneous stimulation of neighboring structures. Aggression episodes are rare side effect of STN-DBS, nevertheless they may be expected in more posteromedial placement of the electrode within STN. The presented case extends the evidence for non-motor functions of STN and highlights its role as an integrating structure within the basal ganglia system.     

Thalamic,subthalamic nucleus and internal pallidum stimulation in Parkinson’s disease

The limits of drug therapy in severe forms of Parkinson’s disease have lead to a renewal of functional neurosurgery of the basal ganglia and the thalamus. Deep brain stimulation (DBS) of these structures was developed with the aims of reducing the morbidity of surgery and of offering an adaptative treatment. DBS was first applied to the thalamus in patients with severe tremor. Tremor of the hemibody is greatly reduced by stimulation of the contralateral electrode in 85% of the cases. There is little change in other symptoms. However, motor fluctuations and dyskinesias are a more frequent problem than severe tremor, in attempt to treat these symptoms, DBS has recently been applied to the subthalamic nucleus (STN) and the internal pallidum (GPi). STN stimulation greatly decreases off motor symptoms and motor fluctuations, which allows a reduction of drug dosage and consequently of dyskinesias. GPi stimulation decreases dyskinesias in most patients, but the effect on off motor symptoms is more variable from one series to another, from very good to nil. The severe morbidity of DBS applied to these 3 targets is low. Comparative studies of the cost and the efficacy of DBS and lesions applied to these different targets are now required.

     

Tremor reduction by subthalamic nucleus stimulation and medication in advanced Parkinson’s disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has proved to be effective for tremor in Parkinson’s disease (PD). Most of the recent studies used only clinical data to analyse tremor reduction. The objective of our study was to quantify tremor reduction by STN DBS and antiparkinsonian medication in elderly PD patients using an objective measuring system. Amplitude and frequency of resting tremor and re-emergent resting tremor during postural tasks were analysed using an ultrasound-based measuring system and surface electromyography. In a prospective study design nine patients with advanced PD were examined preoperatively off and on medication, and twice postoperatively during four treatment conditions: off treatment, on STN DBS, on medication, and on STN DBS plus medication. While both STN DBS and medication reduced tremor amplitude, STN DBS alone and the combination of medication and STN DBS were significantly superior to pre- and postoperative medication. STN DBS but not medication increased tremor frequency, and off treatment tremor frequency was significantly reduced postoperatively compared to baseline. These findings demonstrate that STN DBS is highly effective in elderly patients with advanced PD and moderate preoperative tremor reduction by medication. Thus, with regard to the advanced impact on the other parkinsonian symptoms, STN DBS can replace thalamic stimulation in this cohort of patients. Nevertheless, medication was still effective postoperatively and may act synergistically. The significantly superior efficacy of STN DBS on tremor amplitude and its impact on tremor frequency in contrast to medication might be explained by the influence of STN DBS on additional neural circuits independent from dopaminergic neurotransmission. Received in revised form: 27 April 2006     

Does subthalamic nucleus stimulation induce apathy in Parkinson’s disease?

Background Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) has been shown to significantly improve motor symptoms in advanced Parkinson’s disease (PD). Only few studies, however, have focused on the non-motor effects of DBS. Methods A consecutive series of 15 patients was assessed three months before (M-3), then three months (M3) and six months (M6) after surgery. Mean (± SD) age at surgery was 59.7 (7.6). Mean disease duration at surgery was 12.2 (2.8) years. The Mini International Neuropsychiatric Inventory was used to assess psychiatric disorders three months before surgery. Depression was evaluated using Montgomery and Asberg Rating Scale (MADRS). Anxiety was evaluated using the AMDP system (Association for Methodology and Documentation in Psychiatry). Apathy was particularly evaluated using the Apathy Evaluation Scale (AES) and the Starkstein Scale. All these scales were performed at every evaluation. Results Apathy worsened at M3 and M6 after STN-DBS in comparison with the preoperative evaluation: the AES mean score was significantly impaired between the preoperative (38.4±7.1) and both the postoperative M3 (44.6±9.5, p = 0.003) and M6 scores (46.0±10.9, p = 0.013). Significant worsening of apathy was confirmed using the Starkstein scale. There was no evidence of depression: the mean MADRS score did not differ before surgery (9.1±7.4) and at both M3 (8.6±8.2) and M6 (9.9±7.7) after STN-DBS. The anxiety level did not change between preoperative (9.4±9.2) and both M3 (5.5±4.5) and M6 (6.6±4.6) postoperative states. Conclusion Although STN-DBS constitutes a therapeutic advance for severely disabled patients with Parkinson’s disease, we should keep in mind that this surgical procedure may contribute to the inducing of apathy. Our observation raises the issue of the direct influence of STN- DBS on the limbic system by diffusion of stimulus to the medial limbic compartment of STN.     

Transient gender-related effects in Parkinson’s disease patients with subthalamic stimulation

Little is known about the gender-related long-term efficacy and safety after subthalamic nucleus deep brain stimulation (STN DBS) implant for Parkinson’s disease (PD), although some differences could be expected as recently stated in a short-term report. We assessed the possible gender-related differences in clinical outcome and disease progression along a 5-year period after STN DBS for PD. A prospective cohort of PD patients who underwent STN DBS and reached the 5-year follow-up (FU) was considered. Clinical outcome, disease progression and side effects were assessed at baseline and 1, 3, and 5 years after surgery. Eleven men and nine women were included in the study. At baseline, no inter-gender difference of age at implant, disease duration and severity or levodopa responsiveness was detected. A higher motor responsiveness in men compared to women was detected only at 1-year FU: this difference was mainly related to worse lower limb akinesia and gait score in women. The difference was not confirmed at 3 and 5 years. Antiparkinsonian drugs reduction, improvement in motor fluctuations and dyskinesias, functional measures and progression of underlying PD, were comparable in both groups. Women had persistent adverse events comparable to men. The present long-term observation confirms the occurrence of slight gender-related differences in PD patients treated with STN DBS, indicating a transient poorer outcome in women. Further observational time and a wider number of patients are needed to better analyze the dimension of long-term gender-related differences.     

Long-term cognitive outcome of bilateral subthalamic deep brain stimulation in Parkinson’s disease

The effect of subthalamic deep brain stimulation (STN DBS) on cognition in Parkinson’s disease (PD) remains controversial, and it is unclear which factors are related to cognitive decline and dementia after STN DBS, especially over the long term. To this end, we analyzed the cognitive outcome of 103 non-demented patients with PD who were followed-up for at least 12 months after bilateral STN DBS surgery. Preoperatively, the patients were evaluated with the Unified Parkinson's Disease Rating Scale and neuropsychological tests. The rate of global cognitive decline and the incidence of dementia during follow-up for up to 7 years (mean 42.4 ± 24.5 months) were calculated, and preoperative clinical and neuropsychological factors associated with postoperative global cognitive decline or dementia were analyzed. The prevalence of mild cognitive impairment (MCI) and its relation to later cognitive decline or dementia were also evaluated. The annual decline in the mini–mental state examination score was 0.4 ± 1.7 with impaired attention and executive function and a higher levodopa equivalent dose at baseline being the predictors of a faster global cognitive decline after STN DBS. Dementia developed in 13 patients with an incidence rate of 35.7 per 1,000 person-years. Impaired executive function at baseline predicted dementia. At baseline, 63.1 % of the patients had PD-MCI, and these patients were more likely to develop dementia than those without PD-MCI. This study showed that dysfunctions in the frontostriatal circuitry at baseline were associated with a risk of subsequent global cognitive decline and dementia in patients with PD who underwent STN DBS. In addition, preoperative PD-MCI was a risk factor for dementia after STN DBS.     

Effective long-term subthalamic stimulation in PARK8 positive Parkinson’s disease

Whether patients with genetically defined Parkinson’s disease (PD) may be particularly eligible to benefit from deep brain stimulation of the nucleus subthalamicus (STN-DBS) is currently the subject of debate. We report on a patient with advanced PD due to R793M missense mutation in the LRRK2 gene successfully treated by STN-DBS. Disease onset was at age 42 with bradykinesia, rigidity and rest tremor. During the course of the disease he developed severe motor fluctuations, dyskinesias, postural instability with falls, but preserved levodopa responsiveness. At age 60 the patient was treated by bilateral DBS of the STN. At one year after surgery a 66% improvement of the UPDRS motor score in the off-medication state was determined. During the long-term follow-up there was sustained benefit with 56% improvement of motor score after 8 years. Our report adds evidence that patients with LRRK2 monogenetic Parkinsonism are well suited candidates for DBS treatment and may indicate a potential genetic predictor for positive long-term effect of STN-DBS treatment.     

Effect of subthalamic deep brain stimulation on non-motor fluctuations in Parkinson’s disease

The non-motor consequences of subthalamic stimulation are largely questioned. Cognition, motivation, anxiety, depression and even occurrence of suicides have been considered as a potential consequence of the surgical intervention. Non-motor fluctuations are present in all the patients with motor fluctuations and may sometimes be even more invalidating. Interestingly, subthalamic deep brain stimulation alleviates non-motor fluctuations allowing strikingly successful effects on sensory, dysautonomic and cognitive fluctuations while psychic fluctuations respond less consistently to this treatment. Nevertheless, severe mood fluctuations, oscillating from Off dysphoria to ON hypomania, are frequently associated with addictive behaviors and improve dramatically after subthalamic stimulation. This may be a further argument to support the indication of surgery for these patients.     

Bilateral subthalamic nucleus stimulation in advanced Parkinson’s disease: Five year follow-up

Objective   To assess the long-term efficacy and safety of bilateral subthalamic nucleus (STN) stimulation in patients with advanced Parkinson’s disease (PD). Methods   42 consecutive patients with idiopathic PD treated with bilateral STN stimulation were enrolled. Parkinsonian status, medication intake and neuropsychological evaluation were assessed preoperatively and at 1 and 5 years postoperatively in on and off medication/on and off stimulation conditions. Results   23 patients could be followed-up 5 years after surgery. In the remaining cases, 5 died, 1 could not be assessed because of device removal for infection, 1 decided not to be stimulated, and 11 were lost of follow-up (one because of a liver carcinoma and the others because they refused the formal four conditions of assessment). STN stimulation reduced the UPDRS motor score by 55 % compared to baseline in the offmedication conditions. Tremor, rigidity, bradykinesia, postural stability, and gait improved by 74 %, 66 %, 59 %, 17 % and 37 %, respectively. UPDRS part II scores were reduced by 38 %. The dopaminergic treatment daily dose was reduced by 54.4 % after surgery. Axial dopa-unresponsive signs worsened in some patients. Among the 42 initial patients we observed the following: 2 brain hemorrhages, 3 infections of the device, 2 phlebitis and 1 pulmonary embolism. In addition, 2 patients needed a repositioning of the electrode. Among the 23 patients followed at 5 years, long lasting side effects consisted in dysarthria (56 %), depression (39 %), eyelid opening apraxia (30.4 %) and apathy (4.3 %). Conclusions   Our data confirm that bilateral STN stimulation is beneficial in the long-term for PD patients but does not prevent disease progression and the occurence of axial levodopa unresponsive signs in some patients.     

Successful subthalamic stimulation, but levodopa-induced dystonia, in a genetic Parkinson’s disease

Recently, it is under scrutiny the possibility to anticipate the stereotactic implantation of the subthalamic nucleus (STN) even in relatively mild Parkinson’s disease (PD) patients with an unsatisfying response to drugs. In addition, it is debated whether levodopa (LD) and deep brain stimulation (DBS) are congruent or, instead, mutually exclusive. A 56-year-old LRRK2-positive PD patient, with 7 years of disease history, dominated by severe left resting tremor, was submitted to bilateral implantation of the subthalamic nucleus (STN). Before surgery, the combination of LD and dopamine agonists failed to handle tremor unless administered at doses, which induced undesirable adverse events. STN deep brain stimulation (DBS) abolished tremor but did not provide satisfying control of hypokinetic-rigid symptoms. The condition STIM-ON plus LD, albeit transiently beneficial, installed a painful dystonia developing slowly after 24–36 h. Only a chronic therapy combining rotigotine plus STN-DBS proved effective without side effects. This case report, based upon the surprising difference between the therapeutic response to the combination of LD and dopamine agonist (before surgery) and the combination of DBS and agonist after surgery, emphasizes how STIM and LD target different motor domains through mechanisms with differential plasticity and confirms the efficacy of STN-DBS in LRKK2 patients.     

Intra-operative characterisation of subthalamic oscillations in Parkinson’s disease

Objective

This study aims to use the activities recorded directly from the deep brain stimulation (DBS) electrode to address the focality and distinct nature of the local field potential (LFP) activities of different frequency.

Chronic subthalamic nucleus stimulation and striatal D2 dopamine receptors in Parkinson’s disease

Abstract. Context: Subthalamic nucleus (STN) stimulation mechanism of action remains a matter for debate. In animals, an increased striatal dopamine (DA) release due to STN stimulation has been reported. Objective: To determine in Parkinsons disease (PD) patients using positron emission tomography (PET) and [¹¹C]-Raclopride, whether STN stimulation induces a striatal DA release. Methods: Nine PD patients with bilateral STN stimulation were enrolled and underwent two [¹¹C]-Raclopride PET scans. The scans were randomly performed in off and on stimulation conditions. Striatal [¹¹C]-Raclopride binding potential (BP) was calculated using regions of interest and statistical parametric mapping. Results: For PD patients, the mean [¹¹C]-Raclopride BP (± SD) were, in Off stimulation condition: 1.7 ± 0.3 for the right caudate nucleus, 1.8 ± 0.4 for the left caudate nucleus, 2.6 ± 0.5 for the right putamenand 2.6 ± 0.5 for the left putamen. In On stimulation condition: 1.7 ± 0.4 for the right caudate nucleus, 1.9 ± 0.5 for the left caudate nucleus, 2.8 ± 0.7 for the right putamen and 2.7 ± 0.8 for the left putamen. No significant difference of BP related to the stimulation was noted. Conclusion: STN stimulation does not produce significant variations of striatal DA release as assessed by PET and [¹¹C]-Raclopride.