High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN-HFS) is the preferred surgical treatment for advanced Parkinson's disease. In the 15 years since its introduction into clinical practice, many studies have reported on its benefits, drawbacks, and insufficiencies. Despite limited evidence-based data, STN-HFS has been shown to be surgically safe, and improvements in dopaminergic drug-sensitive symptoms and reductions in subsequent drug dose and dyskinesias are well documented. However, the procedure is associated with adverse effects, mainly neurocognitive, and with side-effects created by spread of stimulation to surrounding structures, depending on the precise location of electrodes. Quality of life improves substantially, inducing sudden global changes in patients' lives, often requiring societal readaptation. STN-HFS is a powerful method that is currently unchallenged in the management of Parkinson's disease, but its long-term effects must be thoroughly assessed. Further improvements, through basic research and methodological innovations, should make it applicable to earlier stages of the disease and increase its availability to patients in developing countries.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(08)70291-6.pdf

Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease

Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the 'off' medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the 'off' medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the 'on' time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the 'on' medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson's disease.

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Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up

Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the most common therapeutic surgical procedure for patients with Parkinson's disease (PD) who have failed medical management. However, a recent summary of clinical evidence on the effectiveness of STN DBS is lacking. We report the results of such a systematic review and meta-analysis. A comprehensive review of the literature using Medline and Ovid databases from 1993 until 2004 was conducted. Estimates of change in absolute Unified Parkinson's Disease Rating Scale (UPDRS) scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Patient demographics, reduction in medication requirements, change in dyskinesia, daily offs, quality of life, and a ratio of postoperative improvement from stimulation compared to preoperative improvement by medication from each study were tabulated and average scores were calculated. Adverse effects from each study were summarized. Thirty-seven cohorts were included in the review. Twenty-two studies with estimates of standard errors were included in the meta-analysis. The estimated decreases in absolute UPDRS II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%-61.8%). Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%). Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. No evidence of publication bias in the available literature was found. The most common serious adverse event related to surgery was intracranial hemorrhage in 3.9% of patients. Psychiatric sequelae were common. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. These data provide an estimate of the magnitude of the treatment effects and emphasize the need for controlled and randomized studies.

Subthalamic nucleus deep brain stimulation: Summary and meta-analysis of outcomes

Objective
To determine the frequency and correlates of impulse control disorders (ICDs) in Parkinson’s disease (PD).

https://jamanetwork.com/journals/jamaneurology/articlepdf/791794/noc60032.pdf

Association of dopamine agonist use with impulse control disorders in Parkinson disease.

Summary Background Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces motor symptoms in patients with Parkinson's disease (PD) and improves their quality of life; however, the effect of DBS on cognitive functions and its psychiatric side-effects are still controversial. To assess the neuropsychiatric consequences of DBS in patients with PD we did an ancillary protocol as part of a randomised study that compared DBS with the best medical treatment. Methods 156 patients with advanced Parkinson's disease and motor fluctuations were randomly assigned to have DBS of the STN or the best medical treatment for PD according to the German Society of Neurology guidelines. 123 patients had neuropsychological and psychiatric examinations to assess the changes between baseline and after 6 months. The primary outcome was the comparison of the effect of DBS with the best medical treatment on overall cognitive functioning (Mattis dementia rating scale). Secondary outcomes were the effects on executive function, depression, anxiety, psychiatric status, manic symptoms, and quality of life. Analysis was per protocol. The study is registered at ClinicalTrials.gov, number NCT00196911. Findings 60 patients were randomly assigned to receive STN-DBS and 63 patients to have best medical treatment. After 6 months, impairments were seen in executive function (difference of changes [DBS–best medical treatment] in verbal fluency [semantic] −4·50 points, 95% CI −8·07 to −0·93, Cohen's d =−;0·4; verbal fluency [phonemic] −3·06 points, −5·50 to −0·62, −0·5; Stroop 2 naming colour error rate −0·37 points, −0·73 to 0·00, −0·4; Stroop 3 word reading time −5·17 s, −8·82 to −1·52, −0·5; Stroop 4 colour naming time −13·00 s, −25·12 to −0·89, −0·4), irrespective of the improvement in quality of life (difference of changes in PDQ-39 10·16 points, 5·45 to 14·87, 0·6; SF-36 physical 16·55 points, 10·89 to 22·21, 0·9; SF-36 psychological 9·74 points, 2·18 to 17·29, 0·5). Anxiety was reduced in the DBS group compared with the medication group (difference of changes in Beck anxiety inventory 10·43 points, 6·08 to 14·78, 0·8). Ten patients in the DBS group and eight patients in the best medical treatment group had severe psychiatric adverse events. Interpretation DBS of the STN does not reduce overall cognition or affectivity, although there is a selective decrease in frontal cognitive functions and an improvement in anxiety in patients after the treatment. These changes do not affect improvements in quality of life. DBS of the STN is safe with respect to neuropsychological and psychiatric effects in carefully selected patients during a 6-month follow-up period. Funding German Federal Ministry of Education and Research (01GI0201).

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(08)70114-5.pdf

Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson's disease: a randomised, multicentre study

We studied 48 patients after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) who were evaluated 6 months after the surgical procedure using the Unified Parkinson's Disease Rating Scale (UPDRS) in a standardized levodopa test. Additional follow-up was available in 32 patients after 12 months and in 20 patients after 24 months. At 6 months follow-up, STN-DBS reduced the UPDRS motor score by 50.9% compared to baseline. This improvement remained constant at 12 months with 57.5% and at 24 months with 57.3%. Relevant side effects after STN-DBS included intraoperative subdural hematoma without neurological sequelae (n = 1), minor intracerebral bleeding with slight transient hemiparesis (n = 1), dislocation of impulse generator (n = 2), transient perioperative confusional symptoms (n = 7), psychotic symptoms (n = 2), depression (n = 5), hypomanic behaviour (n = 2), and transient manic psychosis (n = 1). One patient died because of heart failure during the first postoperative year. The current series demonstrates efficacy and safety of STN-DBS beyond the first year after surgical procedure. Complications of STN-DBS comprise a wide range of psychiatric adverse events which, however, were temporary.

/pdf/two-year-follow-up-of-subthalamic-deep-brain-stimulation-in-3entif59r7.pdf

Two‐year follow‐up of subthalamic deep brain stimulation in Parkinson's disease

Deep brain stimulation of the thalamus (thalamic DBS) is an established therapy for medically intractable essential tremor and tremor caused by multiple sclerosis. In both disorders, motor disability results from complex interaction between kinetic tremor and accompanying ataxia with voluntary movements. In clinical studies, the efficacy of thalamic DBS has been thoroughly assessed. However, the optimal anatomical target structure for neurostimulation is still debated and has never been analysed in conjunction with objective measurements of the different aspects of motor impairment. In 10 essential tremor and 11 multiple sclerosis patients, we analysed the effect of thalamic DBS through each contact of the quadripolar electrode on the contralateral tremor rating scale, accelerometry and kinematic measures of reach-to-grasp-movements. These measures were correlated with the anatomical position of the stimulating electrode in stereotactic space and in relation to nuclear boundaries derived from intraoperative microrecording. We found a significant impact of the stereotactic z-coordinate of stimulation contacts on the TRS, accelerometry total power and spatial deviation in the deceleration and target period of reach-to-grasp-movements. Most effective contacts clustered within the subthalamic area (STA) covering the posterior Zona incerta and prelemniscal radiation. Stimulation within this region led to a mean reduction of the lateralized tremor rating scale by 15.8 points which was significantly superior to stimulation within the thalamus (P < 0.05, student's t-test). STA stimulation resulted in reduction of the accelerometry total power by 99%, whereas stimulation at the ventral thalamic border (68%) or within the thalamus proper (2.5%) was significantly less effective (P < 0.01). Concomitantly, STA stimulation led to a significantly higher increase of tremor frequency and decrease in EMG synchronization compared to stimulation within the thalamus proper (P < 0.001). In reach-to-grasp movements, STA stimulation reduced the spatial variability of the movement path in the deceleration period by 28.9% and in the target period by 58.4%, whereas stimulation within the thalamus was again significantly less effective (P < 0.05), with a reduction in the deceleration period between 6.5 and 21.8% and in the target period between 1.2 and 11.3%. An analysis of the nuclear boundaries from intraoperative microrecording confirmed the anatomical impression that most effective electrodes were located within the STA. Our data demonstrate a profound effect of deep brain stimulation of the thalamic region on tremor and ataxia in essential tremor and tremor caused by multiple sclerosis. The better efficacy of stimulation within the STA compared to thalamus proper favours the concept of a modulation of cerebello-thalamic projections underlying the improvement of these symptoms.

Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor.

We recorded resting-state neuronal activity from the human subthalamic nucleus (STN) during functional stereotactic surgeries. By inserting up to five parallel microelectrodes for single- or multiu...

Neuronal Activity of the Human Subthalamic Nucleus in the Parkinsonian and Nonparkinsonian State

Background: Recent animal experiments suggest an important role of descending input from basal ganglia to brainstem and via the reticulospinal tract (RST) to spinal cord in the genesis of motor symptoms in Parkinson disease (PD). In humans, a marker for RST activity is Ib mediated autogenic inhibition, which is reduced in PD patients. The authors investigated the effect of high frequency stimulation of the subthalamic nucleus (STN-HFS) on autogenic inhibition in PD. Methods: In 10 controls and 10 PD patients with chronically implanted STN electrodes, the soleus H-reflex conditioned by gastrocnemius nerve stimulation (interstimulus interval 2 to 10 msec) was used to examine the effect of STN-HFS on the activity of Ib spinal interneurons. Results: STN-HFS was able to restore the abnormally reduced autogenic inhibition. The H-reflex changes during STN-HFS significantly correlated with the clinical improvement of gait and posture. Conclusions: Observed changes in spinal autogenic inhibition may allow measurement of the contribution of subcortical routes to the STN-HFS induced motor benefit in PD.

The effect of subthalamic nucleus stimulation on autogenic inhibition in Parkinson disease

We report on an unusual presentation of a task-specific focal oromandibular dystonia in a 47-year-old man of Turkish descent. His speech was affected exclusively while reciting Islamic prayers in Arabic language, which he otherwise did not speak.

M. Pötter

Papers

Two‐year follow‐up of subthalamic deep brain stimulation in Parkinson's disease

Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor.

Neuronal Activity of the Human Subthalamic Nucleus in the Parkinsonian and Nonparkinsonian State

The effect of subthalamic nucleus stimulation on autogenic inhibition in Parkinson disease

Praying-induced oromandibular dystonia.