Pedunculopontine nucleus deep brain stimulation in Parkinson's disease: A clinical review.

Pedunculopontine nucleus region deep brain stimulation (DBS) is a promising but experimental therapy for axial motor deficits in Parkinson's disease (PD), particularly gait freezing and falls. Here, we summarise the clinical application and outcomes reported during the past 10 years. The published dataset is limited, comprising fewer than 100 cases. Furthermore, there is great variability in clinical methodology between and within surgical centers. The most common indication has been severe medication refractory gait freezing (often associated with postural instability). Some patients received lone pedunculopontine nucleus DBS (unilateral or bilateral) and some received costimulation of the subthalamic nucleus or internal pallidum. Both rostral and caudal pedunculopontine nucleus subregions have been targeted. However, the spread of stimulation and variance in targeting means that neighboring brain stem regions may be implicated in any response. Low stimulation frequencies are typically employed (20-80 Hertz). The fluctuating nature of gait freezing can confound programming and outcome assessments. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggests that medication refractory gait freezing and falls can improve. The impact on postural instability is unclear. Most groups report a lack of benefit on gait or limb akinesia or dopaminergic medication requirements. The key question is whether pedunculopontine nucleus DBS can improve quality of life in PD. So far, the evidence supporting such an effect is minimal. Development of pedunculopontine nucleus DBS to become a reliable, established therapy would likely require a collaborative effort between experienced centres to clarify biomarkers predictive of response and the optimal clinical methodology. © 2017 International Parkinson and Movement Disorder Society.

Implementing novel trial methods to evaluate surgery for essential tremor.

INTRODUCTION: Deep brain stimulation (DBS) can provide dramatic essential tremor (ET) relief, however no Class I evidence exists. MATERIALS AND METHODS: Analysis methods: I) traditional cohort analysis; II) N-of-1 single patient randomised control trial and III) signal-to-noise (S/N) analysis. 20 DBS electrodes in ET patients were switched on and off for 3-min periods. Six pairs of on and off periods in each case, with the pair order determined randomly. Tremor severity was quantified with tremor evaluator and patient was blinded to stimulation. Patients also stated whether they perceived the stimulation to be on after each trial. RESULTS: I) Mean end-of-trial tremor severity 0.84 out of 10 on, 6.62 Off, t = - 13.218, p < 0.0005. II) N-of-1: 60% of cases had 12 correct perceptions (p = 0.001), 20% had 11 correct perceptions (p = 0.013). III) S/N: > 80% tremor reduction occurred in 99/114 'On' trials (87%), and 3/114 'Off' trials (3%). S/N ratio for 80% improvement with DBS versus spontaneous improvement was 487,757-to-1. CONCLUSIONS: DBS treatment effect on ET is too large for bias to be a plausible explanation. Formal N-of-1 trial design, and S/N ratio method for presenting results, allows this to be demonstrated convincingly where conventional randomised controlled trials are not possible. CLASSIFICATION OF EVIDENCE: This study is the first to provide Class I evidence for the efficacy of DBS for ET.

Phase dependent modulation of tremor amplitude in essential tremor through thalamic stimulation.

High frequency deep brain stimulation of the thalamus can help ameliorate severe essential tremor. Here we explore how the efficacy, efficiency and selectivity of thalamic deep brain stimulation might be improved in this condition. We started from the hypothesis that the effects of electrical stimulation on essential tremor may be phase dependent, and that, in particular, there are tremor phases at which stimuli preferentially lead to a reduction in the amplitude of tremor. The latter could be exploited to improve deep brain stimulation, particularly if tremor suppression could be reinforced by cumulative effects. Accordingly, we stimulated 10 patients with essential tremor and thalamic electrodes, while recording tremor amplitude and phase. Stimulation near the postural tremor frequency entrained tremor. Tremor amplitude was also modulated depending on the phase at which stimulation pulses were delivered in the tremor cycle. Stimuli in one half of the tremor cycle reduced median tremor amplitude by ∼10%, while those in the opposite half of the tremor cycle increased tremor amplitude by a similar amount. At optimal phase alignment tremor suppression reached 27%. Moreover, tremor amplitude showed a non-linear increase in the degree of suppression with successive stimuli; tremor suppression was increased threefold if a stimulus was preceded by four stimuli with a similar phase relationship with respect to the tremor, suggesting cumulative, possibly plastic, effects. The present results pave the way for a stimulation system that tracks tremor phase to control when deep brain stimulation pulses are delivered to treat essential tremor. This would allow treatment effects to be maximized by focussing stimulation on the optimal phase for suppression and by ensuring that this is repeated over many cycles so as to harness cumulative effects. Such a system might potentially achieve tremor control with far less power demand and greater specificity than current high frequency stimulation approaches, and may lower the risk for tolerance and rebound.

Pallidotomy after chronic deep brain stimulation.

Recent publications have demonstrated that deep brain stimulation for Parkinson's disease still exerts beneficial effects on tremor, rigidity, and bradykinesia for up to 10 years after implantation of the stimulator. However with the progression of Parkinson's disease, features such as cognitive decline or "freezing" become prominent, and the presence of an implanted and functioning deep brain stimulator can impose a profound burden of care on the clinical team and family. The authors describe their experience in treating 4 patients who underwent removal of the implanted device due to either progressive dementia requiring full-time nursing or due to infection, and who subsequently underwent a unilateral pallidotomy.

Rechargeable vs. nonrechargeable internal pulse generators in the management of dystonia.

OBJECTIVE: To test if deep brain stimulation (DBS) treatment of dystonia was similar in patients before and after implantation of rechargeable internal pulse generators (IPGs). MATERIALS AND METHODS: The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) severity and disability scores were compared in patients before DBS insertion, 24 months after DBS insertion with a nonrechargeable IPG, and after implantation of a rechargeable IPG. RESULTS: No significant differences were observed between dystonia control in patients before and after implantation of a rechargeable IPG. CONCLUSIONS: Rechargeable IPGs should be the IPGs of choice for dystonic patients receiving DBS as IPGs offer similar treatment efficacy to nonrechargeable IPGs with advantages in terms of costs and reductions in reimplantation frequency.

A torque-based method demonstrates increased rigidity in Parkinson's disease during low-frequency stimulation.

Low-frequency oscillations in the basal ganglia are prominent in patients with Parkinson's disease off medication. Correlative and more recent interventional studies potentially implicate these rhythms in the pathophysiology of Parkinson's disease. However, effect sizes have generally been small and limited to bradykinesia. In this study, we investigate whether these effects extend to rigidity and are maintained in the on-medication state. We studied 24 sides in 12 patients on levodopa during bilateral stimulation of the STN at 5, 10, 20, 50, 130 Hz and in the off-stimulation state. Passive rigidity at the wrist was assessed clinically and with a torque-based mechanical device. Low-frequency stimulation at ≤20 Hz increased rigidity by 24 % overall (p = 0.035), whereas high-frequency stimulation (130 Hz) reduced rigidity by 18 % (p = 0.033). The effects of low-frequency stimulation (5, 10 and 20 Hz) were well correlated with each other for both flexion and extension (r = 0.725 ± SEM 0.016 and 0.568 ± 0.009, respectively). Clinical assessments were unable to show an effect of low-frequency stimulation but did show a significant effect at 130 Hz (p = 0.002). This study provides evidence consistent with a mechanistic link between oscillatory activity at low frequency and Parkinsonian rigidity and, in addition, validates a new method for rigidity quantification at the wrist.

Permanent tremor reduction during thalamic stimulation in multiple sclerosis.

BACKGROUND: Unlike thalamic lesioning, thalamic stimulation is considered a reversible treatment for tremor. However, tremor in multiple sclerosis (MS) can sometimes permanently improve during thalamic stimulation. Such 'permanent tremor reduction' (PTR) has been attributed to limb weakness preventing tremor expression. In this study, 11 consecutive patients with MS tremor treated with thalamic stimulation were assessed for PTR. Eighteen upper limbs had tremor, of which 16 received contralateral stimulation. METHODS: Tremor severity and limb strength were assessed preoperatively, early postoperatively (within 1 year) and late postoperatively (after 3 years). Tremor severity was rated using validated clinical scales both on and off stimulation. Following explantation, the parenchyma surrounding three electrode tracts was examined with MRI. RESULTS: At final review (mean 5.2 years) PTR was evident in 11 of the 18 upper limbs with tremor. PTR often rendered stimulation redundant. PTR could occur when limb strength was conserved and could arise remotely from the initial surgery. PTR was significant (and universal) in limbs that received long-term (>2 years) effective (tremor suppressing) stimulation. PTR was not a significant finding in limbs that had not received long-term, effective stimulation. Contralateral to a limb with PTR, MRI revealed a thalamic lesion adjacent to the electrode tract. Thalamic lesions were not identified contralateral to two limbs without PTR. CONCLUSIONS: MS tremor often permanently improves during thalamic stimulation, even when limb strength is conserved. PTR may simply reflect natural history. Alternatively, these findings appear consistent with the recent proposal that thalamic stimulation in MS might promote local 'demyelinative lesioning.'

Comparison of contralateral pallidotomy vs. pallidal stimulation after prior unilateral pallidotomy for Parkinson's disease.

OBJECTIVES: Pallidal stimulation and pallidotomy are known to improve the symptoms of Parkinson's disease (PD). However, it is not known which modality produces greater benefit in patients who have already undergone unilateral pallidotomy. It is also suggested that the original pallidal surgery provides a greater benefit than subsequent pallidal surgery. The aim of this study was to analyze which modality produced greater PD symptom improvement in patients with a prior pallidotomy and whether the chronological order of the pallidal surgery influenced the size of the improvement. METHODS: Five patients who had undergone a prior unilateral pallidotomy for PD were studied. Because of ongoing Parkinsonian symptoms, all patients subsequently underwent contralateral pallidal surgery, either a further pallidotomy or pallidal stimulation. All surgeries were performed by a single functional neurosurgeon and the patients prospectively assessed and scored at routine follow-ups. Paired-sample t-tests were used to detect differences in outcomes after first and second surgeries. RESULTS: Two patients underwent pallidal stimulation and three underwent a second pallidotomy. Mean follow-up was 13.5 months and 12.3 months, respectively. Greater percentage improvements in the majority of scores were found after pallidal stimulation compared with a second pallidotomy, namely Unified Parkinson's Disease Rating Scale (UPDRS) II off (25.22% vs. -3.27%), UPDRS III off (36.15% vs. 5.21%), rigidity (58.34% vs. 11.54%), tremor (5.56% vs. -30.48%), bradykinesia (48.55% vs. -2.23%), gait composite (16.52% vs. -51.79%), dyskinesia duration (83.33% vs. 66.67%), dyskinesia disability (100% vs. 66.67%), speech (10% vs. -50%), and the proportion of the day spent in the "off" state (50% vs. 25%). Comparing outcomes after the first surgery to those after the second surgery, statistical differences were found in dyskinesia duration improvement and ipsilateral dyskinesia improvement after the second surgery (p < 0.004 and p = 0.021, respectively). CONCLUSIONS: Pallidal stimulation produced greater symptom improvement than a second pallidotomy and subsequent surgery did not produce inferior results to the original pallidal surgery.

Changes in cognition and health-related quality of life with unilateral thalamotomy for Parkinsonian tremor.

Cognitive functioning and health-related quality of life were assessed pre- and post-operatively in a consecutive series of 31 Parkinson's disease patients who underwent stereotactic unilateral thalamotomy (22 left-sided, 9 right-sided) for tremor alleviation. Neuropsychological functions assessed included verbal and visual memory, language and speech production, verbal and non-verbal reasoning, and attention and working memory. Health-related quality of life measures included both general and disease-specific questionnaires. We found a statistically significant post-operative decline in phonetic verbal fluency scores for left-operated patients, as well as improvements in self-ratings of stigma and bodily discomfort on the disease-specific quality of life questionnaire. These findings suggest that thalamotomy, when indicated, has limited cognitive sequelae and may result in improved quality of life in areas specific to Parkinson's disease.

Use of surface electromyography to assess and select patients with idiopathic dystonia for bilateral pallidal stimulation.

OBJECT: The object of this study was to identify a preoperative physiological index by using surface electromyography (EMG) signals that would correlate with clinical outcome in dystonic patients following bilateral pallidal stimulation. METHODS: In 14 patients with spasmodic torticollis, generalized dystonia, and myoclonic dystonia, surface EMG signals were recorded from the most affected muscle groups. Although the dystonia affected different body segments, the EMG signals in all patients could be decomposed into bursting and sustained components. Subsequently, a ratio of the EMG amplitude was calculated between the two components and then correlated with clinical outcome. Patients who experienced rapid improvement following bilateral pallidal stimulation had a significantly higher EMG ratio compared with those who did not. Furthermore, a significant correlation was found between the EMG ratio and clinical improvement during the 12-month period following pallidal stimulation. CONCLUSIONS: The authors concluded that surface EMG studies could be used to predict the clinical outcome of and to select patients for pallidal stimulation for dystonia.

A dominant bursting electromyograph pattern in dystonic conditions predicts an early response to pallidal stimulation.

Although chronic pallidal deep brain stimulation (DBS) is effective in the treatment of medically intractable dystonia, there is no way of predicting the variations in clinical outcome, partly due to our limited understanding of the pathophysiological mechanisms underlying this condition. We recorded electromyographic (EMG) activity from the most severely affected muscle groups in seven dystonia patients before and after pallidal DBS. Patient EMG recordings could be classified into two groups: one consisting of patients who at rest demonstrated a dominant low frequency component of activity on power spectral analysis (ranging from 2 to 5 Hz), and one group in which this dominant pattern was absent. Early postoperative improvements (within 2-3 days) were observed in the former group, whereas the latter group benefited more gradually (over several months). Analysis of EMG activity may provide a sensitive means of identifying dystonic patients who are likely to be most responsive to functional neurosurgical intervention.

Deep brain stimulation for generalised dystonia and spasmodic torticollis.

Dystonia appears distinct from the other tremulous disorders in that improvement following deep brain stimulation frequently appears in a delayed and progressive manner. The rate of this improvement and the point at which no further progress can be expected are presently unknown. The establishment of these parameters is important in the provision of accurate and relevant prognostic information to these patients, their carers, and their treating physicians. We studied 12 consecutive patients with generalised dystonia (n=6) and spasmodic torticollis (n=6) who underwent bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) and were followed up for a minimum of 2 years postoperatively. Standard rating scales were used to quantify their neurological improvement. Both groups experienced a statistically significant improvement in their rating scores at both one and two years following surgery. At 2 years follow-up, the spasmodic torticollis group exhibited a 59% improvement in their total Toronto Western Spasmodic Torticoilis Rating Scale (TWSTRS) rating score and the generalised dystonia group attained a 46% improvement in their overall Burke, Fahn and Marsden Dystonia Rating Scale (BFMDRS) evaluation. Ninety-five percent of the final improvement was attained by 6.4 months in the generalised dystonia group and by 6.6 months in those with spasmodic torticollis. There was no significant improvement after one year postoperatively. These findings add further support to GPi DBS as an effective treatment for generalised dystonia and spasmodic torticollis, and furnish important information as to the expected rate of improvement and the point at which no further gains can be reasonably anticipated.

Thalamotomy versus thalamic stimulation for multiple sclerosis tremor.

Disabling intractable tremor occurs frequently in patients with multiple sclerosis (MS). There is currently no effective medical treatment available, and the results of surgical intervention have been variable. Thalamotomy has been the mainstay of neurosurgical therapy for intractable MS tremor, however the popularisation of deep brain stimulation (DBS) has led to the adoption of chronic thalamic stimulation in an attempt to ameliorate this condition. With the goal of examining the relative efficacy and adverse effects of these two surgical strategies, we studied twenty carefully selected patients with intractable MS tremor. Thalamotomy was performed in 10 patients, with chronic DBS administered to the remaining 10. Both thalamotomy and thalamic stimulation produced improvements in postural and intention tremor. The mean improvement in postural tremor at 16.2 months following surgery was 78%, compared with a 64% improvement after thalamic stimulation (14.6 month follow-up) (P > 0.05). Intention tremor improved by 72% in the group undergoing thalamotomy, a significantly larger gain than the 36% tremor reduction following DBS (P < 0.05). Early postoperative complications were common in both groups. Permanent complications related to surgery occurred in four patients overall. Following thalamotomy, long-term adverse effects were observed in three patients (30%), and comprised hemiparesis and seizures. Only one patient in the thalamic stimulation group experienced a permanent deficit (monoparesis). We conclude that thalamotomy is a more efficacious surgical treatment for intractable MS tremor, however the higher incidence of persistent neurological deficits in patients receiving lesional surgery may support the use of DBS as the preferred surgical strategy.

Thalamic field potentials during deep brain stimulation of periventricular gray in chronic pain.

Stimulation of the central gray matter areas has been used for the treatment of chronic pain for decades. To better understand the mechanism of action of such treatment we studied the effects of stimulation of the periventricular gray (PVG) on the sensory thalamus in two patients with chronic central pain. In each case, two electrodes were implanted in the PVG (Medtronic 3389) and the ventroposterolateral thalamic nucleus (Medtronic 3387), respectively, under guidance of CT/MRI image fusion. The PVG was stimulated in the frequency range of 2-100 Hz in alert patients while pain was assessed using the McGill-Melzack visual analogue scale. In addition, local field potentials (FPs) were recorded from the sensory thalamus during PVG stimulation. Maximum pain relief was obtained with 5-25 Hz stimulation while 50-100 Hz made the pain worse. This suggests that pain suppression was frequency dependent. Interestingly, we detected low frequency FPs at 0.2-0.4 Hz closely associated with the pain. During 5-25 Hz PVG stimulation the amplitude of this potential was significantly reduced and this was associated with marked pain relief. At the higher frequencies (50-100 Hz) however, there was no reduction in the FPs and no pain suppression. We have found an interesting correlation between thalamic activity and chronic pain. This curious low frequency potential may provide an objective index for quantifying chronic pain, and may hold further clues to the mechanism of action of PVG stimulation.

Camptocormia treated with bilateral pallidal stimulation.

The authors report the neurological, neurophysiological, and neuropsychological effects of using long-term bilateral pallidal high-frequency deep brain stimulation (DBS) in a case of disabling camptocormia. Deep brain stimulation electrodes were implanted stereotactically to target the globus pallidus internus (GPi) bilaterally. Local field potentials (FPs) were recorded using the DBS electrodes and concurrent abdominal flexor electromyography (EMG) potentials during camptocormic episodes. Videotaped assessments of the movement disorder and neuropsychological evaluations of the patient before implantation and 6 months after initiation of pallidal stimulation were recorded. There was significant functional improvement following long-term pallidal stimulation, and some improvement was noted in neuropsychological scores. A temporal correlation between the GPi FPs and EMG-recorded rectus abdominis potentials was evident. There were no treatment-related adverse effects. The authors have found that long-term pallidal stimulation was safe and offered functional benefit to a patient with this severely disabling condition. The physiological studies may help further the understanding of the pathophysiology of this rare entity.

Camptocormia treated with bilateral pallidal stimulation: case report.

The authors report the neurological, neurophysiological, and neuropsychological effects of using chronic bilateral pallidal high-frequency deep brain stimulation (DBS) in a case of disabling camptocormia. Deep brain stimulation electrodes were implanted stereotactically to target the globus pallidus internus (GPi) bilaterally. Local field potentials (FPs) were recorded using the DBS electrodes and concurrent abdominal flexor electromyography (EMG) potentials during camptocormic episodes. Videotaped assessments of the movement disorder and neuropsychological evaluation before implantation and at 6 months after initiation of pallidal stimulation were recorded. There was significant functional improvement following chronic pallidal stimulation, and some improvement was noted in neuropsychological scores. The GPi FPs showed temporal correlation with EMG-recorded rectus abdominis potentials. There were no treatment-related adverse effects. The authors have found that chronic pallidal stimulation was safe and offered functional benefit in this severely disabling condition. The physiological studies may help further the understanding of the pathophysiology of this rare entity.

Peri-ventricular grey stimulation versus motor cortex stimulation for post stroke neuropathic pain.

Central post stroke pain is often difficult to manage satisfactorily with conventional treatment modalities for pain. In the last decade functional neurosurgery has offered hope with motor cortex stimulation achieving significant alleviation of pain in some patients. Unfortunately this has led to the neglect of chronic stimulation of deep grey matter as another modality of treating this condition. In this article we present our experience with motor cortex stimulation and that with deep grey matter stimulation in patients with post stroke pain. We argue that both modalities have a significant role and that what is required are better methods of identifying particular patients who are more likely to respond to one or the other.

Twiddler's syndrome in a patient with a deep brain stimulation device for generalized dystonia.

Deep brain stimulation (DBS) is the technique of neurostimulation of deep brain structures for the treatment of conditions such as essential tremor, dystonia, Parkinson's disease and chronic pain syndromes. The procedure uses implanted deep brain stimulation electrodes connected to extension leads and an implantable pulse generator (IPG). Hardware failure related to the DBS procedure is not infrequent, and includes electrode migration and disconnection. We describe a patient who received bilateral globus pallidus internus DBS for dystonia with initially good clinical response, but the device eventually failed. Radiographs showed multiple twisting of the extension leads with disconnection from the brain electrodes and a diagnosis of Twiddler's syndrome was made. Twiddler's syndrome was first described in patients with cardiac pacemakers. Patients with mental disability, elderly and obese patients are at increased risk. Twiddler's syndrome should be suspected whenever there is a failure of the DBS device to relieve symptoms previously responsive to stimulation. Surgical correction is usually required.

Chronic pedunculopontine nucleus stimulation restores functional connectivity.

The mechanisms of deep brain stimulation (DBS) are poorly understood. Earlier, high-frequency DBS has been thought to represent a depolarization block of the target area and low-frequency stimulation has been thought to 'drive' neuronal activity. We investigated the long-term effect of low-frequency DBS in a longitudinal imaging study of a patient who received bilateral pedunculopontine nucleus stimulation. We used the diffusion tensor imaging techniques including probabilistic tractography and topographic mapping to analyze long-term changes in connectivity with low-frequency DBS. Post-DBS connectivity analysis suggested a normalization of pathological pedunculopontine nucleus connectivity with DBS therapy. These findings may help elucidate the mechanisms of DBS, suggesting neuroplasticity involving a reorganization of target connectivity long term. This is the first reported case showing neuroimaging evidence of neuroplasticity after low-frequency DBS.