Peter G. Bain

Direct economic impact of Parkinson's disease: A research survey in the United Kingdom

The direct costs of care were evaluated prospectively in a sample of people with Parkinsons disease (PD) in the United Kingdom in 1998. The subjects were drawn from a random sample of general practitioner practices within a representative sample of 36 Regional Health Authorities and the equivalent. A total of 444 resource use questionnaires with usable data were returned (response rate, 59%). The total mean annual cost of care per patient for all patients by age was £5,993 (€9,554, n = 432). Hoehn and Yahr stage significantly (P < 0.001) influenced expenditure by stage as follows: 0 and I, £2,971 (€4,736, n = 110); II, £3,065 (€4,886, n = 89); III, £6,183 (€9,857, n = 120); IV, £10,134 (€16,155, n = 87); V, £18,358 (€29,265, n = 17). National Health Service costs accounted for approximately 38% and social services for 34% of the direct costs of care. Drug expenditure accounted for 24% of overall costs in the <65 years age group and 10% in patients aged >85 years. A move from home to residential care was associated with an approximately 500% cost increase. In conclusion, PD imposes significant direct costs on public services and on individuals. These costs should be taken into account when allocating public funds.

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.

Cannabis for dyskinesia in Parkinson disease A randomized double-blind crossover study

Background: The long-term treatment of Parkinson disease (PD) may be complicated by the development of levodopa-induced dyskinesia. Clinical and animal model data support the view that modulation of cannabinoid function may exert an antidyskinetic effect. The authors conducted a randomized, double-blind, placebo-controlled crossover trial to examine the hypothesis that cannabis may have a beneficial effect on dyskinesia in PD. Methods: A 4-week dose escalation study was performed to assess the safety and tolerability of cannabis in six PD patients with levodopa-induced dyskinesia. Then a randomized placebo-controlled crossover study (RCT) was performed, in which 19 PD patients were randomized to receive oral cannabis extract followed by placebo or vice versa. Each treatment phase lasted for 4 weeks with an intervening 2-week washout phase. The primary outcome measure was a change in Unified Parkinson’s Disease Rating Scale (UPDRS) (items 32 to 34) dyskinesia score. Secondary outcome measures included the Rush scale, Bain scale, tablet arm drawing task, and total UPDRS score following a levodopa challenge, as well as patient-completed measures of a dyskinesia activities of daily living (ADL) scale, the PDQ-39, on-off diaries, and a range of category rating scales. Results: Seventeen patients completed the RCT. Cannabis was well tolerated, and had no pro- or antiparkinsonian action. There was no evidence for a treatment effect on levodopa-induced dyskinesia as assessed by the UPDRS, or any of the secondary outcome measures. Conclusions: Orally administered cannabis extract resulted in no objective or subjective improvement in dyskinesias or parkinsonism.

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.

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson's disease patients.

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinsons disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.

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.

The effect of cannabis on tremor in patients with multiple sclerosis.

Background: Disabling tremor is common in patients with multiple sclerosis (MS). Data from animal model experiments and subjective and small objective studies involving patients suggest that cannabis may be an effective treatment for tremor associated with MS. To our knowledge, there are no published double-blind randomized controlled trials of cannabis as a treatment for tremor in MS patients. Methods: The authors conducted a randomized double-blind placebo-controlled crossover trial to examine the effect of oral cannador (cannabis extract) on 14 patients with MS with upper limb tremors. There were eight women and six men, with a mean age of 45 years and mean Expanded Disability Status Scale score of 6.25. Patients were randomly assigned to receive each treatment and the doses escalated over a 2-week period before each assessment. The primary outcome was change on a tremor index, measured using a validated tremor rating scale. The study was powered to detect a functionally significant 50% improvement in the tremor index. Secondary outcomes included accelerometry, an ataxia scale, spiral drawing, finger tapping, and nine-hole pegboard test performance. Results: Analysis of the data showed no significant improvement in any of the objective measures of upper limb tremor with cannabis extract compared to placebo. Finger tapping was faster on placebo compared to cannabis extract (p < 0.02). However, there was a nonsignificant trend for patients to experience more subjective relief from their tremors while on cannabis extract compared to placebo. Conclusions: Cannabis extract does not produce a functionally significant improvement in MS-associated tremor.

Tremor in multiple sclerosis

Tremor, which is an involuntary rhythmic oscillatory movement of a body part, is estimated to occur in 75% of patients diagnosed as having multiple sclerosis.1 2 It can be severely disabling and is extremely difficult to treat.3-23 The tremor of multiple sclerosis is frequently embedded in a complex movement disorder, which often includes dysmetria and other ataxic features.8 There is considerable controversy surrounding the precise definition and identification of the different components of this movement (tremor, dysmetria, and other ataxic features).1 24-26 Resolution of this controversy is critical to treatment because these separate components respond differently to various interventions.7 8 17 19 21 The incidence and prevalence of tremor in multiple sclerosis is difficult to estimate accurately, although tremor of moderate and severe magnitudes were found in 32% and 6% respectively of patients in one study.22 In part this is because of the problem of distinguishing intention tremor from serial dysmetria, which is the result of the voluntary sequential correction of movement errors, and some types of postural tremor from other postural instabilities.27 In addition, the natural history of multiple sclerosis and in particular the transience of the neurological signs during the relapsing and remitting phase make prevalence studies difficult. This problem is compounded by the structure of the Kurtzke functional systems deployed for the assessment of patients with multiple sclerosis, because subscale part B (cerebellar function) does not isolate tremor.28 In a 3 year follow up study of multiple sclerosis, cerebellar deficits of functional importance were found to occur in 33% of 259 patients and to be predictive of a worse prognosis.29 30 A similar proportion was found to have ataxic symptoms in an extensive epidemiological survey undertaken in the United Kingdom and involving over 300 patients with multiple sclerosis. …

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.