Cost-effectiveness analysis of entacapone in Parkinson's disease: a Markov process analysis.

OBJECTIVE: The objective of this study was to examine the cost-effectiveness of a complementary treatment with entacapone versus usual care only in patients with Parkinson's disease. METHODS: The setting for this study was the Netherlands. A Markov process model was constructed to model the average quality-adjusted life years (QALYs) and the costs of both treatments. The model examined a period of 5 years in order to capture the influence of symptom improvement and disease progression. Data for the construction of the model were derived from published literature, including large, multicenter, randomized clinical trials in patients with end-of-dose motor fluctuations. Costs were obtained from published sources. RESULTS: The results of the baseline analysis showed that the use of entacapone as complementary therapy in Parkinson's disease slightly decreased the total average discounted costs from NLG 111,317 to NLG 110,038, while effectiveness increased from 2.42 to 2.56 QALYs (a 6% increase). In addition, entacapone substantially increased time without severe fluctuations by 0.63 years. Sensitivity analyses confirmed the robustness of these findings. CONCLUSION: The study shows that entacapone is a cost-effective treatment in patients with Parkinson's disease: entacapone yields higher effectiveness in terms of both effectiveness measures (time without severe fluctuations and QALYs), while costs remain quite similar to those for usual care. The additional drug costs for entacapone are offset by reductions in other costs.

Clinical and molecular correlations in spinocerebellar ataxia type 6: a study of 24 Dutch families.

BACKGROUND: Autosomal dominant cerebellar ataxias (ADCAs), or spinocerebellar ataxias (SCAs), are a heterogeneous group of neurodegenerative disorders. Mild CAG repeat expansions in the alpha(1A) voltage-dependent calcium channel gene are associated with SCA type 6 (SCA6). OBJECTIVE: To obtain further insight into the contribution of SCA6 mutations to the phenotypic variability in Dutch patients with ataxia. DESIGN: Survey and case series. SETTING: Hospitalized care, referral center. PATIENTS AND METHODS: The SCA6 locus was analyzed for CAG repeat expansions in a referred sample of 220 Dutch families with progressive cerebellar ataxia. Clinical characteristics of patients with SCA6 were investigated and correlated with molecular findings. RESULTS: The diagnosis SCA6 was confirmed in 24 families comprising 30 familial and 4 sporadic cases. Mean +/- SD age at onset was 50.1 +/- 11.1 years. Expanded CAG repeats with sizes 22, 23, and 25 were found. These sizes correlated inversely with age at onset. No intergenerational changes in CAG repeat size were detected. Despite this, 2 families showed clinical anticipation. CONCLUSIONS: This study provides the first detailed description of Dutch patients with SCA6. Clinical analysis identifies SCA6 as a late-onset ataxia in which eye movement abnormalities are prominent and consistent early manifestations. No single clinical sign can be considered specific for SCA6. Some patients have ataxia combined with episodic headaches or nausea, suggesting an overlap among SCA6, eposidic ataxia type 2, and familial hemiplegic migraine. Spinocerebellar ataxia type 6 accounts for approximately 11% of all Dutch families with ADCA. Analysis of SCA6 contributes further to the genetic classification of patients with ADCA, including patients without a clear family history of the disease.

Ambulatory objective assessment of tremor in Parkinson's disease.

Continuous ambulatory multichannel accelerometry (CAMCA) has recently been validated for the assessment of hypo-and bradykinesia and body position in patients with Parkinson's disease (PD). This study aims to validate CAMCA for the assessment of resting tremor in patients with PD. First, in seven patients with PD with varying degrees of tremor severity, a tremor detection algorithm was developed. Second, 59 patients with PD and 43 age-matched controls were assessed with CAMCA during 24 hours. Duration and intensity of resting tremor, and measures reflecting hypo-and bradykinesia and body position were calculated for the diurnal period. In part 1 of the study, the tremor detection algorithm had a high sensitivity (0.82) and specificity (0.93). Ambulatory monitoring revealed that categories with higher clinical tremor severity had increased objective values for duration and intensity of tremor. Duration and intensity of tremor were correlated with the clinical score for resting tremor (Spearman's rank correlation: 0.66-0.77). Measures for hypo-and bradykinesia differed between patients and controls, but not between groups of patients defined by tremor severity. This study has validated continuous ambulatory multichannel accelerometry for the assessment of tremor in PD, while simultaneously measuring hypo-and bradykinesia and body position.

Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy.

BACKGROUND AND METHODS: Patients with reflex sympathetic dystrophy (also known as the complex regional pain syndrome) may have dystonia, which is often unresponsive to treatment. Some forms of dystonia respond to the intrathecal administration of baclofen, a specific gamma-aminobutyric acid-receptor (type B) agonist that inhibits sensory input to the neurons of the spinal cord. We evaluated this treatment in seven women who had reflex sympathetic dystrophy with multifocal or generalized tonic dystonia. First, we performed a double-blind, randomized, controlled crossover trial of bolus intrathecal injections of 25, 50, and 75 microg of baclofen and placebo. Changes in the severity of dystonia were assessed by the woman and by an investigator after each injection. In the second phase of the study, six of the women received a subcutaneous pump for continuous intrathecal administration of baclofen and were followed for 0.5 to 3 years. RESULTS: In six women, bolus injections of 50 and 75 microg of baclofen resulted in complete or partial resolution of focal dystonia of the hands but little improvement in dystonia of the legs. During continuous therapy, three women regained normal hand function, and two of these three women regained the ability to walk (one only indoors). In one woman who received continuous therapy, the pain and violent jerks disappeared and the dystonic posturing of the arm decreased. In two women the spasms or restlessness of the legs decreased, without any change in the dystonia. CONCLUSIONS: In some patients, the dystonia associated with reflex sympathetic dystrophy responds markedly to intrathecal baclofen.

The efficacy and safety of adjunct bromocriptine therapy for levodopa-induced motor complications: a systematic review.

OBJECTIVES: To assess the efficacy and safety of adjunct bromocriptine (BR) compared with placebo in the treatment of patients with Parkinson's disease (PD) who have motor complications. DESIGN: A systematic review of the literature from 1966-1999 on randomized, controlled trials. Outcome measures were occurrence and severity of motor complications, scores on impairment and disability, and the occurrence of side effects. RESULTS: We included eight trials of which the methodologic quality of seven showed important shortcomings. All studies failed to adequately describe randomization procedures and seven studies failed to report sample size calculations. Only one trial was analyzed according to the intention-to-treat principle. It frequently remained unclear if patients with PD actually had motor complications. Differences between studies concerning the baseline characteristics, the BR titration phase, and the applied outcomes were found. The various methods used to evaluate the occurrence and/or severity of motor complications lacked a sound clinimetric basis. A great diversity of impairment and disability scales were applied. For those studies that reported the incidence of side effects, no clear pattern of BR-related side effects emerged. A trend was found for orthostatic hypotension, which more frequently resulted in withdrawal of patients in the BR group. CONCLUSIONS: Major methodologic problems and sources of heterogeneity not only hamper the comparability of trials, but also preclude a conclusion on the efficacy and safety of BR in the adjunct treatment of patients with PD who have motor complications.

A review of the assessment of dyskinesias.

Dyskinesias are most prevalent in patients with Huntington's disease (HD), patients with Parkinson's disease (PD) who have received chronic levodopa therapy, and in patients who have been treated with neuroleptics (tardive dyskinesia ITD]). Recent therapeutic developments have fueled a growing interest in the clinimetrics of dyskinesias. For dyskinesias in HD, few rating scales are available, but data on validity, reliability, and responsiveness are scarce. Only the interrater reliability of facial dyskinesias has been evaluated and found to be low. Many subjective rating scales for dyskinesias in PD exist, but only the Dyskinesia Rating Scale has undergone sufficient clinimetric evaluation. For TD, numerous rating scales are available, many of them with ample data on reliability and validity. Objective assessment of dyskinesias has been attempted with a number of techniques. All these methods require a laboratory setting, rendering them susceptible to influence of stress. Moreover, they provide only a momentary assessment of dyskinesia severity and fail to take into account diurnal fluctuations. In view of the methodologic shortcomings in the assessment of dyskinesias, more effort needs to be put into strengthening currently available modes of assessment or designing new ones. In the future ambulatory accelerometry might prove to be of value in this field.

Clinimetrics of postural instability in Parkinson's disease.

Judgement of the ability to recover balance after a sudden shoulder pull is used as a clinical measure of postural instability in Parkinson's disease. To further evaluate its merits, we compared this 'retropulsion test' with dynamic posturography in 23 Parkinson patients. Dynamic posturography involved 20 serial 'toe-up' support surface rotations, which induced backward body sway. We found a moderate correlation (Spearman's p = 0.54; P < 0.05) between the retropulsion test and body sway after platform rotations during the 'off' phase, but no correlation during the 'on' phase (Spearman's p = 0.43; P = 0.11). These results cast doubt on the use of the retropulsion test as a measure of postural instability in Parkinson's disease.

Ambulatory quantitative assessment of body position, bradykinesia, and hypokinesia in Parkinson's disease.

We used ambulatory monitoring to quantify body position, bradykinesia, and hypokinesia simultaneously in 50 patients with Parkinson's disease (PD) and 43 healthy elderly during the diurnal period. Reliable automatic detection of three defined body positions proved possible. As compared with controls, PD patients spent less time upright and more time during the day lying down, which correlated well with the self-reported time spent lying down. PD patients had significantly lower mean values of extremity acceleration and higher mean values of immobility than controls. The objective measures of bradykinesia and hypokinesia showed only a modest or no relation to the semiquantitative subjective Unified Parkinson's Disease Rating Scale (UPDRS) motor scores, which most likely was due to differences between the methods. In contrast to bradykinesia measures, hypokinesia measures showed clear sex differences in both patients and controls. Over time, trunk and arm movements occurred more frequently in women than in men. Our ambulatory monitoring assessment disclosed clinically relevant information about the mobility profile and offers a way to quantify cardinal movement features simultaneously in PD patients throughout the day.

The role of EDTA in provoking allergic reactions to subcutaneous infusion of apomorphine in patients with Parkinson's disease: a histologic study.

One of the formulations of apomorphine, used in clinical practice, contains sodium edetate (EDTA). EDTA is a chelator which indirectly prevents oxidation of apomorphine. A clinical and histologic study in four patients revealed that apomorphine with EDTA caused severe subcutaneous nodules, histologically characterized by an inflammatory infiltrate with a large amount of eosinophils, indicating a cell-mediated allergic reaction. After withdrawal of EDTA, this allergic component completely disappeared, which was accompanied clinically by less extensive nodule formation with a softer consistency. It is therefore recommended that EDTA be excluded from apomorphine formulations.

Evaluation of the Short Parkinson's Evaluation Scale: a new friendly scale for the evaluation of Parkinson's disease in clinical drug trials.

The extensive use of the Unified Parkinson's Disease Rating Scale (UPDRS) has revealed low interrater reliability in some items and redundancy in others. In view of these shortcomings, we have structured a new scale that includes a zero-to three-point scale for each item in the evaluation of PD. The mental axis includes memory, thought disorders, and depression. Activities of daily living (ADL) includes eight items: speech, eating, feeding, dressing, hygiene, handwriting, walking, and turning in bed. The motor examination includes eight items: speech, tremor, rest and posture, rigidity, finger tapping, arising from chair, gait, and postural stability. Complications of therapy were also included: dyskinesias, dystonia, motor fluctuations, and freezing episodes, collected by history. In addition, a global scoring for motor fluctuations that should complement the Hoehn and Yahr Scale was incorporated. In this report, we present a statistical analysis of the ADL, motor evaluation, and complications of therapy sections. Concerning the interrater reliability mean, Kendall's W values were >0.9 for most of the items in the Short Parkinson's Evaluation Scale (SPES). Kendall's W <0.8 (motor evaluation) was found for two items of the SPES and nine items of the UPDRS. The mean interrater reliability for both scales across all seven centers (seven Kendall's W for seven centers) (Mann-Whitney test) showed no statistical differences between the scales. Spearman's correlations between items of both scales were significant. Factor analysis of the SPES and UPDRS data revealed a four-factor solution that explained approximately 60% of the data. All participating centers found the SPES easier to apply and quicker to complete, when compared with the UPDRS. The results obtained strongly favor the introduction of SPES for clinical practice.

Hypokinesia in Huntington's disease.

Motor activity was quantitatively assessed over a period of 5 days using a wrist-worn activity monitor in 14 patients with Huntington's disease (of whom 4 used neuroleptic drugs) and 14 age- and sex-matched healthy controls. Additionally, patients were rated for dementia, depression, clinical impairment of motor tasks, chorea, and disability. A significant decrease in daytime motor activity was observed in patients compared with controls, suggesting hypokinesia rather than hyperkinesia. Hypokinesia tended to be more severe in patients using neuroleptic drugs. Lower activity levels were significantly related to lower scores of functional disability, but not to other clinical measures. We conclude that hypokinesia is a prominent manifestation in Huntington's disease that is worsened by the use of neuroleptics.

Circadian distribution of motor activity and immobility in narcolepsy: assessment with continuous motor activity monitoring.

The circadian distribution of motor activity and immobility of 14 unmedicated narcoleptics and matched controls was evaluated by monitoring continuous wrist motor activity 5 successive days and nights at home. Sleep was also assessed by sleep logs. The amplitude of the circadian rhythm of motor activity and immobility was significantly lower in narcoleptics than in controls. The variables that best distinguish narcoleptics from controls were the diurnal and nocturnal mean duration of uninterrupted immobility, which can be explained by excessive daytime sleepiness and frequent nocturnal awakenings, respectively. Thus, measures of diurnal and nocturnal motor activity and immobility appear useful for the objective assessment of some of the sleep-wakefulness manifestations of narcolepsy.

Influence of recording site on CMAP amplitude on its variation over a length of nerve.

The distinctions between blocking, abnormal temporal dispersion, and normal conduction require delineation of the normal change in amplitude of the compound muscle action potential (CMAP) over a length of nerve. Effects of the recording site on CMAP amplitude and on its variation were studied in median and ulnar nerves of 13 healthy subjects. CMAPs were recorded from three sites: halfway along the muscles and 1 cm distal and proximal. Elbow-wrist amplitude percentages (CMAP%) were calculated. CMAP amplitudes varied considerably between sites and subjects. Amplitudes were maximal at the middle site in only 16 of 26 nerves. The site of maximal amplitude could not be identified on the basis of thumb anatomy. CMAP% was not related to CMAP amplitude, and differed by up to 32% between adjacent sites. CMAP formation involves spatial factors (electrode site, limb position, and limb anatomy), temporal factors (dispersion), and their interaction, explaining why CMAP% can exceed 100%. The site of the recording electrode affects CMAP amplitude and CMAP% to clinically relevant degrees. Standardization of the recording site may improve reliability of CMAP% studies.

Sleep disruption in Parkinson's disease. Assessment by continuous activity monitoring.

OBJECTIVE: To assess differences in activity and immobility during sleep between patients with Parkinson's disease (PD) and healthy subjects and to evaluate the relations of clinical variables with the motor activity measures in patients with PD. DESIGN: Survey, case series. SETTING: University hospital outpatient neurology department and urban population in Leiden, the Netherlands. Motor activity was recorded during 6 successive nights at home with a wrist-worn activity monitor. PARTICIPANTS: Eighty-nine patients with PD and 83 age-matched healthy controls. MAIN OUTCOME MEASURES: For each subject, three mean measures reflecting activity or immobility during the nocturnal period were calculated. RESULTS: Compared with the healthy elderly subjects, patients with PD have an elevated nocturnal activity level and an increased proportion of time with movement, indicating a more disturbed sleep. The mean duration of nocturnal immobility periods was similar for both groups. This measure, however, did reflect the self-reported disturbed sleep maintenance in both groups. The daily dose of levodopa or the use of dopamine agonists in patients not receiving levodopa, rather than disease severity, proved to be the best predictors of nocturnal activity. CONCLUSIONS: We hypothesize that in mildly to moderately affected patients with PD, levodopa or dopamine agonists cause sleep disruption by their effects on sleep regulation. In more severely affected patients, the beneficial effects of these drugs on nocturnal disabilities that cause sleep disruption in PD prevail.

Autonomic nervous system dysfunction in Parkinson's disease: relationships with age, medication, duration, and severity.

Heart rate variability at rest, during deep breathing, or standing up and with the Valsalva manoeuvre did not differ significantly between 67 patients with idiopathic Parkinson's disease (PD) and 31 healthy age matched controls. Blood pressure (BP) responses to standing up and sustained handgrip revealed diminished autonomic function in the PD group. In a preliminary analysis of the PD group older age, anti-Parkinson medication and higher Hoehn and Yahr (HY) stages were each associated with poor autonomic responsiveness. Disease duration was only related to the systolic BP fall on standing up. Multiple stepwise regression analysis showed that older age explained most of the variance of heart rate variability (up to 36%), and the only significant PD related factor was the use of medication, which explained less than 7%. The HY stage accounted for 12.7% of the variance in the standing up BP test, and the use of medication explained 10.6% of the variance of the systolic BP change in the sustained hand grip test. The unmedicated PD subgroup (n = 33), who had mild disease of short duration, showed no evidence of autonomic dysfunction. Cardiovascular autonomic dysfunction in PD is mild, mainly affects blood pressure responses, and occurs only in advanced cases.