Leslie J. Findley

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.

Preliminary report: activation of the cerebellum in essential tremor

Several images of cerebral blood flow were recorded during inhalation of carbon-15-labelled carbon dioxide by positron emission tomography in four patients with essential tremor and four normal controls. Unilateral involuntary postural tremor in essential tremor patients was associated with blood flow significantly greater than that at rest in the contralateral sensorimotor cortex, both lateral premotor regions, and both cerebellar hemispheres. Of these regions, only the cerebellum was not activated in normal controls holding a posture without tremor or in essential tremor patients undergoing passive wrist movement. The increased flow in the cerebellum therefore seems to represent neural activity involved in tremor generation. It is proposed that essential tremor is due to oscillation within cerebello-olivary pathways, relayed by way of the thalamus and motor cortex to the spinal cord.

Retrospective Evaluation of the Dose of Dysport and BOTOX in the Management of Cervical Dystonia and Blepharospasm: The REAL DOSE Study

The purpose of this study is to evaluate the real‐world dose utilization of Dysport and BOTOX for cervical dystonia and blepharospasm. Six investigational sites (five countries) were identified. Investigators abstracted utilization data for patients who received Dysport before switching to BOTOX or BOTOX before switching to Dysport. Patients were identified during scheduled clinic visits and selected if they met study criteria, which included treatment for at least 2 consecutive years (at least 1 year with Dysport or BOTOX, then switched and maintained on BOTOX or Dysport for at least another year). A total of 114 patients were included in the assessment. Ratios of mean dose for Dysport to BOTOX ranged from a low of 2:1 to a high of 11:1. Thirty‐one percent of patients fell into the Dysport‐to‐BOTOX ratio grouping of 5:1 to less than 6:1; 30% of patients had a mean ratio of Dysport to BOTOX of 4:1 to less than 5:1; and only 21% of all patients evaluated fell into the Dysport‐to‐BOTOX ratio grouping of 3:1 to less than 4:1. Results are consistent with United Kingdom labeling for botulinum toxins stating that units of different serotype A toxins are not interchangeable and simple dose‐conversion factors are not applicable.

A positron emission tomography study of primary orthostatic tremor

Primary orthostatic tremor (OT), a clinical syndrome in which a rapid (14 to 16 Hz), regular lower limb tremor causes unsteadiness on standing, may be associated with a postural upper limb tremor of similar frequency. We used H2 15O PET to analyze the abnormal pattern of cerebral activation associated with the postural upper limb tremor in four patients with primary OT. Patients had regional cerebral bloodflow (rCBF) measured during involuntary tremor while maintaining a posture with their outstretched right upper limb and again at rest. Tremor was associated with abnormal bilateral cerebellar and contralateral lentiform and thalamic activation. These findings were evident on group analysis of pooled PET data after transformation into standard stereotactic space and in single subjects when PET images were coregistered with structural MRI of the brain. At rest, cerebellar blood flow was significantly increased bilaterally in OT when compared with age- and sex-matched controls. We have previously demonstrated similar abnormal bilateral cerebellar activation in essential and writing tremors and conclude that abnormal bilateral overactivity of cerebellar connections is a common feature of tremulous disorders.

Assessing the impact of essential tremor on upper limb function

We compared the impact of essential tremor on the performance of three manual tasks: drawing spirals, holding a cup full of water and a joystick-controlled tracking test. Tremor amplitude and frequency were measured by accelerometry during the tracking test, when holding the cup and whilst a standard posture was maintained. The inter-relationships between tremor amplitude, frequency and task impairment were then examined. The results showed that the amplitude and frequency of essential tremor (measured from the principal spectral peak) changed with different activities, with the mildest postural tremors changing most in frequency (by up to 4–5 Hz). The amplitude of tremor decreased in almost every case during the tasks, relative to posture, and this decrement was greatest for the most severe tremors. We also demonstrate that for practical purposes, such as routine clinical situations and therapeutic trials, the effect of essential tremor upon upper limb function can be usefully assessed by two simple complementary techniques: rating spirals and measuring the volume of water split from a cup. The impairments in carrying out these tasks and the tracking test were highly correlated with one another and also with the amplitude and frequency of postural tremor. The concept of tremor “suppressability” is introduced: the relative percentage decrease in the amplitude of a particular tremor during the performance of a specific task compared to that recorded whilst holding a standard posture.

Randomized, double-blind, 3-month parallel study of the effects of pramipexole, pergolide, and placebo on parkinsonian tremor

We compared the antitremor effect of pramipexole, pergolide, or placebo in Parkinsons disease (PD). A double‐blind, randomly controlled, parallel protocol was deployed to examine the effects of placebo, pergolide, and pramipexole [doses escalated to 1.5 mg three times daily (t.i.d.) over 3 months] on a compound Tremor Index (TI) and Unified Parkinsons Disease Rating Scale (UPDRS) part III. Thirty PD patients (19 men, 11 women; mean age 69 years, range 54–80 years; mean disease duration 3.9 years, range, 0.5–10 years) participated in the study, with 10 patients in each arm. Six subjects failed to complete the study (4 on pergolide and 2 on placebo). Analysis of covariance demonstrated strong evidence for a treatment effect on both TI and UPDRS III. There was no significant difference between the active treatments on either TI or UPDRS III. Both pergolide and pramipexole were significantly better than placebo. The results indicate that pergolide and pramipexole (1.5 mg t.i.d.) have similar anti–PD tremor and UPDRS III actions that are significantly superior to placebo. Patients on pergolide were more likely to drop out because of adverse events than those on pramipexole.

Double-blind, single-dose, cross-over study of the effects of pramipexole, pergolide, and placebo on rest tremor and UPDRS part III in Parkinson's disease.

Tremor is one of the cardinal signs of Parkinsons disease (PD) but its response to antiparkinsonian medication is variable. It has been postulated that pramipexole may have a stronger antiparkinsonian tremor effect than pergolide, another direct acting dopamine agonist medication, possibly because the former has preferential affinity for the dopamine D3 receptor. The purpose of this pilot study was to compare the effects of a single oral dose of either pramipexole (Pr) or pergolide (Pe) or placebo (Pl) on parkinsonian tremor and the motor (part III) subsection of the UPDRS. Ten patients (6 men, 4 women), mean age 65.3 years, mean duration from diagnosis of 2.6 years, with tremor dominant PD were recruited. On three separate occasions a single dose of pramipexole (salt) 500 μg, pergolide 500 μg or placebo were administered in random order to each patient, who were pretreated with domperidone and had their antiparkinsonian medication withheld from midnight before study. After each medication patients were assessed at baseline and then every 30 min for 4 hr using a 0 to 10 tremor rating scale and the UPDRS (part III) in a double‐blind protocol. Adverse effects were systematically recorded. The results demonstrate that 500 μg of either pramipexole or pergolide reduced PD rest tremor scores to a similar degree, which at peak effect was significantly greater than placebo (respectively Pe v Pl: P < 0.006, Pr v Pl: P < 0.033). The two active drugs also had weaker beneficial effects on the UPDRS part III. Pergolide, however, was significantly more likely than pramipexole to cause nausea (P = 0.005) or vomiting (P = 0.014).

Exacerbation of postural tremor with emergence of parkinsonism after treatment with neuroleptic drugs.

Neuroleptic medication in three patients with prior isolated postural arm tremor led to a conspicuous deterioration; the postural tremor increased in amplitude, tremor appeared at rest, and other signs of mild parkinsonism developed. Withdrawal of neuroleptic drugs led to improvement in tremor and disappearance of parkinsonism. Positron emission tomography showed no reduction in uptake of [18F]dopa into nigrostriatal terminals suggesting that these patients did not have Parkinsons disease. Neuroleptic drugs can convert postural essential arm tremor into that characteristic of Parkinsons disease in patients with no evident nigrostriatal lesion.

Pendular nystagmus (ocular myoclonus) and related somatic tremors: their pharmacological modification and treatment

Pendular nystagmus can be defined as an involuntary oscillation of the eye or eyes. When it occurs in conjunction with other body movements, it is often termed ocular myoclonus. In previous reports (Gresty et al., 1982; Ell et al., 1982) we have outlined in detail the essential characteristics of acquired pendular nystagmus. Approximately 30% of our patients and those reviewed from the literature had associated body tremors. Our analyses led us to the conclusion that the eye and body movements were causally related. Subsequent attempts at pharmacological modification of these movements have confirmed this conclusion.