Richard B. Scott

Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson's disease (PD SURG trial): a randomised, open-label trial

Summary Background Surgical intervention for advanced Parkinsons disease is an option if medical therapy fails to control symptoms adequately. We aimed to assess whether surgery and best medical therapy improved self-reported quality of life more than best medical therapy alone in patients with advanced Parkinsons disease. Methods The PD SURG trial is an ongoing randomised, open-label trial. At 13 neurosurgical centres in the UK, between November, 2000, and December, 2006, patients with Parkinsons disease that was not adequately controlled by medical therapy were randomly assigned by use of a computerised minimisation procedure to immediate surgery (lesioning or deep brain stimulation at the discretion of the local clinician) and best medical therapy or to best medical therapy alone. Patients were analysed in the treatment group to which they were randomised, irrespective of whether they received their allocated treatment. The primary endpoint was patient self-reported quality of life on the 39-item Parkinsons disease questionnaire (PDQ-39). Changes between baseline and 1 year were compared by use of t tests. This trial is registered with Current Controlled Trials, number ISRCTN34111222. Findings 366 patients were randomly assigned to receive immediate surgery and best medical therapy (183) or best medical therapy alone (183). All patients who had surgery had deep brain stimulation. At 1 year, the mean improvement in PDQ-39 summary index score compared with baseline was 5·0 points in the surgery group and 0·3 points in the medical therapy group (difference −4·7, 95% CI −7·6 to −1·8; p=0·001); the difference in mean change in PDQ-39 score in the mobility domain between the surgery group and the best medical therapy group was −8·9 (95% CI −13·8 to −4·0; p=0·0004), in the activities of daily living domain was −12·4 (−17·3 to −7·5; p<0·0001), and in the bodily discomfort domain was −7·5 (−12·6 to −2·4; p=0·004). Differences between groups in all other domains of the PDQ-39 were not significant. 36 (19%) patients had serious surgery-related adverse events; there were no suicides but there was one procedure-related death. 20 patients in the surgery group and 13 in the best medical therapy group had serious adverse events related to Parkinsons disease and drug treatment. Interpretation At 1 year, surgery and best medical therapy improved patient self-reported quality of life more than best medical therapy alone in patients with advanced Parkinsons disease. These differences are clinically meaningful, but surgery is not without risk and targeting of patients most likely to benefit might be warranted. Funding UK Medical Research Council, Parkinsons UK, and UK Department of Health.

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.

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.

Use of the Radionics Image Fusiontrade mark and Stereoplantrade mark programs for target localization in functional neurosurgery.

Abstract We describe the use of Radionics Image Fusion™ and Stereoplan™ in defining the target for thalamotomy and pallidotomy in functional surgery for parkinsonism and tremor. Using this to fuse and spatially correct magnetic resonance imaging (MRI) to computed tomography (CT) images our calculated targets were a mean of 0.6 ± 1.5 mm from the end target determined physiologically by stimulation. This is significantly better than the values of 2.6 ± 1.6 mm for thalamic targets and 7.1 ± 3.7 mm for pallidal targets using CT alone. As a consequence, determination of the target and the lesion making are routinely performed in one pass of the electrode allowing for faster, more accurate and, we believe, safer functional procedures.

Improved Cognitive Outcomes With Endovascular Coiling of Ruptured Intracranial Aneurysms Neuropsychological Outcomes From the International Subarachnoid Aneurysm Trial (ISAT)

Background and Purpose— The International Subarachnoid Aneurysm Trial (ISAT) reported lower rates of death and disability with endovascular versus neurosurgical treatment of ruptured intracranial aneurysms. However, assessment of functional outcome was limited to the modified Rankin Scale, which is known to be insensitive to cognitive function. A neuropsychological substudy (N-ISAT) was therefore done in all recruits from 8 ISAT centers in the United Kingdom. Methods— Detailed neuropsychological assessment was performed at a 12-month follow-up visit. Impairment was defined as performance below the 5th percentile of the study population on at least 2 tests in ≥2 major cognitive domains. Analysis was restricted to patients who were not known to be otherwise disabled according to the modified Rankin Scale (ie, modified Rankin Scale 0 to 2). Results— Of 836 patients randomized in ISAT in the 8 UK centers (411 allocated endovascular treatment versus 425 neurosurgery), 224 were dead or disabled before 12-month follow-up (78 allocated endovascular treatment versus 135 neurosurgery). Of the remaining 612 patients eligible for neuropsychological assessment, 137 (65 allocated endovascular treatment versus 72 neurosurgery) did not attend. Of the 474 nondisabled patients who were assessed, 152 (32.1%) had cognitive impairment. Patients with cognitive impairment had reduced self-reported health-related quality of life (P<0.001) in both treatment groups, but cognitive impairment was less common in those allocated endovascular treatment (70 of 262 versus 82 of 212 allocated neurosurgery, OR=0.58, 95% CI 0.38 to 0.87, P=0.0055). The incidence of epilepsy was also lower in the N-ISAT endovascular group (7 versus 18, OR=0.30, 0.11 to 0.77, P=0.005) but was independent of the effect on cognitive function. Conclusions— Cognitive impairment occurred in approximately one third of patients who were not otherwise disabled according to the modified Rankin Scale in N-ISAT and was more frequent in the neurosurgery group. These results have implications for management of ruptured intracranial aneurysms and more generally for interpretation of the outcomes of clinical trials that use the modified Rankin Scale.

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.

Electrophysiological confirmation of the zona incerta as a target for surgical treatment of disabling involuntary arm movements in multiple sclerosis: use of local field potentials

Lesioning or chronic deep brain stimulation (DBS) of the nucleus ventralis intermedius results in abolition of tremor in the contralateral limbs in Parkinsons disease (PD) and also in essential tremor. Recently, chronic DBS of the subthalamic nucleus has also proved to be very effective in reducing contralateral limb tremor in PD. These targets have been less effective in controlling the complex limb tremor often seen in multiple sclerosis (MS). Consequently, other targets have been sought in cases of MS with tremor. We describe a patient with MS with disabling proximal and distal involuntary arm movements in whom we were able to obtain sustained control of contralateral arm tremor and achieve functional improvement of the affected arm by chronic DBS of the region of the zona incerta. We also highlight the important role played by local field potentials recorded from the brain, with simultaneous recording of corresponding EMGs, in target localisation.

Brain biochemistry in Duchenne muscular dystrophy : A 1H magnetic resonance and neuropsychological study

Duchenne muscular dystrophy (DMD) is a progressive muscle disorder associated with an intellectual deficit which is non-progressive. We obtained localised 1H magnetic resonance spectra from the left frontal lobe and left cerebellum of 15 boys with DMD (mean age 106 months+/-32) and 15 similarly aged control boys (mean age 115 months+/-31); all boys underwent a battery of neuropsychological tests. We found a significant (P<0.01) increase in the ratio of choline-containing compounds to N-acetylaspartate (Cho/NA) in the left cerebellum in boys with DMD compared with control boys. There was no change in the creatine/NA ratio and a significant increase (P=0.03) in the Cho/creatine ratio, suggesting that the change in Cho/NA ratio was due to an increase in choline-containing compounds; this increase has been previously observed in the brain of the murine model of DMD, the mdx mouse. No significant changes were observed in spectra obtained from left frontal lobe in DMD compared to controls. We also observed a significant association between Cho/NA in the left cerebellum, and the performance of DMD boys on the Matrix Analogies Test (MAT). The MAT is a test of visuo-spatial ability and non-verbal reasoning which requires neither manual dexterity nor a verbal response for an adequate performance. A comparison of DMD boys whose cerebellar Cho/NA fell within 2 standard deviations of the control norm (0.56+/-0.24) with DMD boys whose cerebellar Cho/NA was outside this range (i.e. >0.80) revealed a significant difference in ability on the MAT (P<0.05). DMD boys whose Cho/NA ratio is more than two standard deviations higher than controls perform significantly better on the MAT than DMD boys whose Cho/NA ratio is within the normal range. This finding suggests that the observed elevation in Cho/NA and Cho/creatine is not associated with intellectual deficit (as sampled by the MAT), and may represent a compensatory mechanism. The possible interpretations of these metabolic changes are discussed.

Is pH a biochemical marker of IQ

We have measured intracellular brain pH in vivo in 42 boys and found a significant correlation between this biochemical parameter and samples of intelligent behaviour. To the best of our knowledge this is the first reported relation between a biochemical marker which is within normal physiological values and intellectual ability. pH is one of the most accurate parameters that can be measured by 31P magnetic resonance spectroscopy and it reflects sensitively cellular ionic status and metabolic activity. The observed correlation, although not implying a causal relation, raises the possibility that intelligent behaviour may be influenced by the ionic status of brain tissue, or vice versa.

Neuropsychological profile of DYT1 dystonia

The common belief that primary dystonia is a purely motor disorder has recently been challenged. We examined separately the cognitive profiles of symptomatic (SYM) and nonsymptomatic (N‐SYM) groups of carriers of DYT1 mutation using a comprehensive neuropsychological test battery. Self‐report inventories of anxiety, depression, and pain levels were also administered, as well as manual motor dexterity assessment. Each group was matched with healthy controls by age, sex, mother tongue, and education. No significant differences between the SYM group to its control group were found on cognitive tests evaluating verbal and nonverbal abstract abilities, attention, information processing speed, and spatial organization. However, the SYM group showed increased verbal memory retroactive interference. Interestingly, the patients also showed higher semantic fluency performance. No significant differences between the N‐SYM group to controls were found. It was concluded that symptomatic DYT1 mutation carriers do not suffer the distinctive cognitive decline that is seen in other primary degenerative extrapyramidal disorders.