Ralph Gregory

Globus pallidus internus deep brain stimulation for dystonic conditions: A prospective audit

In the current era of functional surgery for movement disorders, deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favoured target in the treatment of patients with dystonia. The results of 25 consecutive patients with medically intractable dystonia (12 with generalised dystonia, 7 with spasmodic torticollis, and 6 with other types of dystonia) treated with GPi stimulation are reported. Although comparisons were limited by differences in their respective neurological rating scales, chronic DBS benefited all groups, resulting in clear and progressive improvements in their condition. This study clearly demonstrates that DBS of the GPi provides amelioration of intractable dystonia.

Hardware-Related problems of deep brain stimulation

Deep brain stimulation for the alleviation of movement disorders and pain is now an established therapy. However, very little has been published on the topic of hardware failure in the treatment of such conditions irrespective of clinical outcome. Such device‐related problems lead to significant patient morbidity and increased cost of therapy in the form of prolonged antibiotics, in‐patient hospitalization, repeat surgery, and device replacement. We report a prospective review of our experience at the Radcliffe Infirmary Oxford from the period of April 1998 to March 2001. Overall there is a 20% rate of hardware‐related problems in this series, which falls between the 7% and 65% rates reported by other groups. The majority of these failures occurred early on in the series, and numbers declined with experience. Some of the problems may be idiosyncratic to the methodology of individual groups.

Anatomy, physiology, and pathophysiology of the pedunculopontine nucleus.

The pedunculopontine nucleus is composed of cholinergic and non‐cholinergic neurones and is located in the caudal pontomesencephalic tegmentum. Evidence suggests that the nucleus plays a role in the production and control of movement. The nucleus has dense interconnections with the basal ganglia, as well as with other areas of the brain associated with motor control. Electrical stimulation of the pedunculopontine nucleus in the decerebrate cat or rat produces organized locomotor movements. Physiological studies show that the pedunculopontine nucleus modulates its activity in response to locomotion, as well as voluntary arm and eye movements. Degeneration of the pedunculopontine nucleus is seen in post‐mortem brains in humans with Parkinsons disease and Parkinsonian syndromes. In animal models of Parkinsons disease, metabolic changes are seen in the pedunculopontine nucleus, and chemical inhibition or mechanical disruption of the nucleus can produce an akinetic state in animals and man. In this paper we review the literature in support of the suggestion that some of the symptoms of Parkinsons disease are caused by dysfunction of the pedunculopontine nucleus. In accordance with this view, direct stimulation of the nucleus can ameliorate some symptoms of the disease, as demonstrated in both experimental animals and man.

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.

Post‐operative progress of dystonia patients following globus pallidus internus deep brain stimulation

In the current era of functional surgery for movement disorders, deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favoured intervention for patients with dystonia. Here we report our results in 20 patients with medically intractable dystonia treated with GPi stimulation. The series comprised 14 patients with generalized dystonia and six with spasmodic torticollis. Although comparisons were limited by differences in their respective neurological rating scales, chronic DBS clearly benefited both patient groups. Data conveying the rate of change in neurological function following intervention are also presented, demonstrating the gradual but progressive and sustained nature of improvement following stimulation of the GPi in dystonic patients.

Unilateral and bilateral pallidotomy for idiopathic Parkinson's disease: a case series of 115 patients.

Lesioning of the internal pallidum is known to improve the symptoms of idiopathic Parkinsons disease (PD) and alleviate dyskinesia and motor fluctuations related to levodopa therapy. The benefit obtained contralateral to a single lesion is insufficient in some cases when symptoms are bilaterally disabling. However, reports of unacceptably high rates of adverse effects after bilateral pallidotomy have limited its use in such cases. We report on the outcome of unilateral (UPVP) and bilateral (BPVP) posteroventral pallidotomy in a consecutive case series of 115 patients with PD in the United Kingdom and Australia. After 3 months, UPVP resulted in a 27% reduction in the off medication Part III (motor) Unified Parkinsons Disease Rating Scale score and abolition of dyskinesia in 40% of cases. For BPVP, these figures were increased to 31% and 63%, respectively. Follow‐up of a smaller group to 12 months found the motor scores to be worsening but benefit to dyskinesia and activities of daily living was maintained. Speech was adversely affected after BPVP, although the change was small in most cases. Unilateral and bilateral pallidotomy can be performed safely without microelectrode localisation. Bilateral pallidotomy appears to be more effective, particularly in reducing dyskinesia; in our experience, the side effects have not been as high as reported by other groups.

Involvement of the medial pallidum in focal myoclonic dystonia: A clinical and neurophysiological case study.

We successfully treated a patient with familial myoclonic dystonia (FMD), which primarily affected his neck muscles, with bilateral deep brain stimulation (DBS) to the medial pallidum, and investigated the role of the medial pallidum in FMD. A patient with FMD underwent bilateral implantation of DBS electrodes during which field potentials (FPs) in the medial pallidum and electromyograms (EMGs) from the affected neck muscles were recorded. The effects of high‐frequency DBS to the medial pallidum on the FMD were also assessed by recording EMGs during and immediately after implantation, as well as 6 days and 8 weeks postoperatively. During spontaneous myoclonic episodes, increased FPs oscillating at 4 and 8 Hz were recorded from the medial pallidum; these correlated strongly with phasic EMG activity at the same frequencies in the contralateral affected muscles. The EMG activity was suppressed by stimulating the contralateral medial pallidum at 100 Hz during the operation and continuous bilateral DBS from an implanted stimulator abolished myoclonic activity even more effectively postoperatively. The phasic pallidal activity correlated with and led the myoclonic muscle activity, and the myoclonus was suppressed by bilateral pallidal DBS, suggesting that the medial pallidum was involved in the generation of the myoclonic activity. High‐frequency DBS may suppress the myoclonus by desynchronising abnormal pallidal oscillations. This case study has significant clinical implications, because at present, there is no effective treatment for focal myoclonic dystonia.

The sensory and motor representation of synchronized oscillations in the globus pallidus in patients with primary dystonia

In 15 patients with primary dystonia (six cervical and nine generalized dystonias) who were treated with bilateral chronic pallidal stimulation, we investigated the sensorimotor modulation of the oscillatory local field potentials (LFPs) recorded from the pallidal electrodes. We correlated these with the surface electromyograms in the affected muscles. The effects of involuntary, passive and voluntary movement and muscle-tendon vibration on frequency ranges of 0-3 Hz, theta (3-8 Hz), alpha (8-12 Hz), low (12-20 Hz) and high beta (20-30 Hz), and low (30-60 Hz) and high gamma (60-90 Hz) power were recorded and compared between cervical and generalized dystonia groups. Significant decreases in LFP synchronization at 8-20 Hz occurred during the sensory modulation produced by voluntary or passive movement or vibration. Voluntary movement also caused increased gamma band activity (30-90 Hz). Dystonic involuntary muscle spasms were specifically associated with increased theta, alpha and low beta (3-18 Hz). Furthermore, the increase in the frequency range of 3-20 Hz correlated with the strength of the muscle spasms and preceded them by approximately 320 ms. Differences in modulation of pallidal oscillation between cervical and generalized dystonias were also revealed. This study yields new insights into the pathophysiological mechanisms of primary dystonias and their treatment using pallidal deep brain stimulation.

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.

Executive cognitive deficits in primary dystonia.

Primary dystonia is a disorder of movement for which no consistent pathophysiology has been identified; in the absence of evidence to the contrary, it is assumed to be cognitively benign. We have studied a clinically heterogeneous group of 14 patients with primary dystonia on a battery of neuropsychological tests. Despite well‐preserved speed of information processing, language, spatial, memory and general intellectual skills relative to normal controls, we have identified a constellation of attentional–executive cognitive deficits on the Cambridge Neuropsychological Test Automated Battery (CANTAB). Specifically, patients demonstrated significant difficulties negotiating the extra‐dimensional set‐shifting phase of the IED task. The implications of these findings for the pathophysiology of primary dystonia are discussed. This is, to the best of our knowledge, the first report of a significant cognitive deficit in patients with primary dystonia.