REM sleep behaviour disorder in Parkinson's disease: a questionnaire-based study.

The aim of the study was to determine the clinical frequency and features of REM sleep behaviour disorder (RBD) in a large population of Parkinson's disease (PD) patients using defined diagnostic criteria both for RBD and PD. Six trained neurologists used a semistructured questionnaire based on ICSD-R diagnostic criteria for RBD to evaluate 200 PD patients and their caregivers. Interobserver reliability for the diagnosis of RBD was "substantial" (Kappa 0.65). Five patients were excluded from the study because of an MMSE lower than 25. The demographic and PD clinical features were compared in the clinically defined RBD group and in those without RBD (NRBD). Then the RBD features during the last year were analysed in the affected group. Out of 195 patients, 66 fulfilled the ICSD-R criteria for RBD; 62 patients reported RBD during the last year (frequency 31.8%). RBD features: two or more episodes per week in 35.5%; upper limb movements in 87%; lower limb movements in 79%; vocalisations during events in 85%. RBD onset was before PD in 27% of patients; 69% of the RBD group had injured themselves or their caregivers during sleep. According to multivariate analysis, RBD was associated with male gender, age and PD duration. Brief training and the use of a semistructured questionnaire may help the neurologist in dealing with sleep disturbances in PD patients. The search for RBD symptoms in PD is highly recommended, especially in patients with a long disease duration, the risk of sleep-related injuries being high.

Frontal intermittent rhythmic delta activity (FIRDA) in patients with dementia with Lewy bodies: a diagnostic tool?

The accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) remains poor, especially in early phases of the disease, in spite of applying current consensus diagnostic criteria. The need for supportive diagnostic tools is therefore warranted. In this study EEG recordings showed a main pattern of bilateral frontal intermittent rhythmic delta activity (FIRDA) in 7 of 10 patients, aged 58-83 years, 8 of whom were diagnosed as affected by "probable" and 2 by "possible" DLB. Conversely, the same EEG abnormality was found only in 2 of 9 age-matched patients, 8 of whom had "probable" and 1 "possible" Alzheimer's disease, according to NINCDS-ADRDA criteria, taken as controls. The degree of cognitive impairment was comparable among the two groups of patients. If these findings will be confirmed in a larger series, FIRDA, even though an aspecific EEG pattern, could be of value in improving the diagnostic accuracy of DLB.

Clinical and genetic study of essential tremor in the Italian population.

Essential tremor (ET) is one of the most common movement disorders. The pathogenesis is as yet unknown, although a genetic cause has long been recognised. Clinical and molecular evidence suggested that the ET gene contains a CAG expanded region. We examined a cohort of 240 Italian ET patients, classified as familial (193 cases) and sporadic (47 cases). The clinical manifestations of ET patients confirmed that the disorder is characterised by a large phenotypic variability. Repeat expansion detection (RED) approach did not demonstrate large CAG expansions. Six families were genotyped with 12 microsatellites markers of 2p and 3q regions and analysed according to parametrical methods. Lod scores values obtained in these families excluded the association of ET with 2p and 3q loci. Our findings confirm the presence of genetic heterogeneity and suggest that at least a third locus is involved in the pathogenesis of familial essential tremor.

The status of dopamine nerve terminals in Parkinson's disease and essential tremor: a PET study with the tracer [11-C]FE-CIT.

Neuroimaging studies of the striatal dopamine transporter (DAT) are useful in the assessment of the dopaminergic system in Parkinson's disease (PD). We used positron emisson tomography (PET) and the tracer [11C]FE-CIT to measure DAT binding in the caudate nucleus and putamen of 31 patients with PD, 5 with essential tremor and 8 healthy control subjects. Of the patients with PD, 17 were drug naive, while the others were either on levodopa or dopamine agonist monotherapy. DAT binding was significantly reduced in the caudate nucleus and to a greater extent in the putamen of PD patients compared to both healthy controls and essential tremor individuals. No overlap was observed between putamen values in PD and normals. No differences were found between controls and essential tremor subjects. These data confirm that measurements of DAT binding can provide an accurate and highly sensitive measure of degeneration in the dopamine system in PD.

Long-term persistence of symptomatic effect of selegiline in Parkinson's disease. A two-months placebo-controlled withdrawal study.

Following a two-months of placebo-controlled withdrawal, the MAO-B inhibitor selegiline was found to maintain a long term significant mild to moderate symptomatic effect on bradykinesia and tremor at rest in nine patients with Parkinson's disease (stage II and III of H&Y), whose functional impairment had also required a dopaminergic therapy with low-dose bromocriptine. Both motor signs found worsened during the wash-out showed a full recovery to pre-withdrawal condition within two months after reinstitution of the drug.

A case-control study of occupational and environmental risk factors for Parkinson's disease in the Emilia-Romagna region of Italy.

A questionnaire-based case-control study was carried out on 86 patients with neurologist-confirmed idiopathic Parkinson's disease (PD) and 86 controls similar in sex and age. The control group was recruited in outpatient specialist centers of the same University Hospital (glaucoma, psoriasis vulgaris, essential arterial hypertension and renal diseases). Exposure was defined as occupational or residential contact with a given factor for at least 10 consecutive years prior to the onset of PD. Smoking habits were defined by exclusion of those subjects who never smoked. The following risk factors were identified: cranial trauma (OR: 2.88; 95% CI: 0.98-8.49), well water use (OR: 2.78; 95% CI: 1.46-5.28) and occupational exposure to industrial chemicals (OR: 2.13; 95% CI: 1.16-3.91). Among industrial chemicals, only organic solvents were identified as significant risk factors for PD (O.R. : 2.78, 95% C.I. : 1.23-6.26). Whereas no exposure to neurotoxic metals occurred among controls, making the assessment of the O.R. impossible, exposure pesticides and herbicides was similar in the two groups (O.R. : 1.15; 95% C. : 0.56-2-36). Smoking habits was negatively associated with PD (OR: 0.41; 95% CI: 0.22-0.75), confirming the "protective" role of tobacco smoking suggested by many studies. As a whole, these results support the role of environmental factors in the etiology of PD.

Clinical and genetic study of a family with spinocerebellar ataxia type 1 (SCA1) and beta-thalassemia.

We report a family affected by autosomal dominant ataxia, in which numerous members also showed microcytosis. Genetic analysis demonstrated a CAG expansion in the SCA1 locus in five members, while all subjects with microcytosis revealed a C-T substitution at codon 39 of the beta-globin gene. A pure cerebellar syndrome with prominent gait ataxia characterized the first stages of the neurological disease. The fully developed disease included additional clinical findings such as dysarthria and dysphagia, and instrumental signs of axonal involvement of the peripheral nerves. Ophthalmoplegia was not observed. The coexistence of hereditary spinocerebellar degeneration and erythropathies or hemoglobinopathies has been previously described. We discuss the possible linkages between these two pathologies.

A long-term follow-up study of cinnarizine- and flunarizine-induced parkinsonism.

The natural course of calcium-entry blocker-induced parkinsonism was evaluated in 13 elderly patients previously exposed to cinnarizine or flunarizine or both for a median period of 7 months. Clinical assessments were carried out before drug discontinuation and twice thereafter over a period lasting < or = 7 years. None of the patients showed a full recovery of extrapyramidal signs, indicating that the long-term prognosis of the parkinsonism is less benign than previously reported. Two main patterns of clinical outcome were recognized (i.e., "remittent" and "persistent and not progressive" parkinsonism), whereas the development of a progressive disorder was observed only in one patient. No significant correlation was found between the patterns of outcome and some clinical variables, such as total duration of exposure to cinnarizine and flunarizine, cumulative drug dosages, and age at onset of parkinsonism. There was no significant difference in terms of family history of essential tremor or parkinsonism or both among patients with the two main patterns of clinical course.

L-deprenyl as an adjunct to low-dose bromocriptine in early Parkinson's disease: a short-term, double-blind, and prospective follow-up study.

The therapeutic efficacy of L-deprenyl (10 mg daily) as an adjunct to low-dose bromocriptine monotherapy (up to 25 mg daily) in patients with early Parkinson's disease (PD) was evaluated in a double-blind placebo-controlled short-term study (11 patients) and subsequently in a long-term prospective open follow-up (21 patients) until L-dopa was required, over a 4-year period. The combined regimen of bromocriptine plus L-deprenyl produced a mildly significant improvement, as shown by the majority of clinical rating scales used after 6 weeks of sustained treatment (as compared to bromocriptine alone and bromocriptine plus placebo). In the prospective long-term study, a stabilization of the clinical status was observed until 12 months of sustained treatment, whereas after that, a gradual worsening of the scores on all motor rating scales occurred. However, at 24 months, fewer than one third of the patients had required L-dopa, a proportion comparatively smaller than that reported in the literature with bromocriptine alone. This finding could be related to the persistence of initial symptomatic effect of L-deprenyl, but a slowing action on the course of the disease process exerted by the monoamine oxidase typeB (MAO-B) inhibitor cannot be ruled out.

Effect of propranolol in head tremor: quantitative study following single-dose and sustained drug administration.

The effect of the beta-adrenoceptor antagonist propranolol has been investigated in nine patients suffering from isolated (six patients) or prominent (three patients) essential tremor of the head. In a double-blind, placebo-controlled study the tremorolytic efficacy of propranolol has been assessed by a quantitative accelerometric method after a single oral dose (120 mg) and following 2 weeks of sustained treatment with two different dosage regimens of the drug (120 and 240 mg daily). As compared with placebo, a significant reduction in tremor magnitude was found following a single oral dose but not on sustained administration of the beta-blocker at either dosage. The results suggest that the efficacy of sustained propranolol on isolated or prominent essential head tremor is less predictable and satisfactory than expected on the basis of the single-dose response, as compared with hand tremor.

Calcium-entry blockers-induced parkinsonism: possible role of inherited susceptibility.

The risk of developing drug-induced parkinsonism (DIP) has been related to a number of factors but it remains up to now poorly defined. The aim of this survey has been to evaluate retrospectively the possible role of inherited components in 25 patients with parkinsonism induced by chronic exposure to the calcium-entry blockers cinnarizine and flunarizine. The finding of higher occurrence of a positive family history for Parkinson's disease (PD) and/or essential tremor (ET) and of higher frequency of secondary cases with PD and/or ET among close relatives of the patients as compared to age-matched controls, suggests the involvement of genetic susceptibility in developing this drug-induced disorder. DIP could be regarded as a multifactorial disease process resulting from potential neurotoxicity of drugs on a background of inherited predisposition.

Quantitative comparison of barbiturates in essential hand and head tremor.

The tremorolytic effects of primidone and phenobarbital in essential tremor of hands and head were compared in a double-blind, placebo-controlled trial. Quantitative measurements of tremor were obtained in 15 patients by means of an accelerometric method. Only primidone proved to be superior to placebo in reducing hand tremor, suggesting that its tremorolytic effectiveness is largely dependent on the parent drug rather than its metabolite phenobarbital. Head tremor tended to improve only in three out of six patients with both primidone and phenobarbital, but, likely due to the small number of affected patients, the effect failed to reach statistical significance.

The disposition of primidone in elderly patients.

1. The pharmacokinetics and metabolism of primidone at steady-state were studied in 10 elderly patients aged 70-81 years and eight control subjects aged 18-26 years. 2. Primidone half-lives and clearance values (mean +/- s.d.) were similar in the elderly and in the young (12.1 +/- 4.6 vs 14.7 +/- 3.5 h and 34.8 +/- 9.0 vs 33.2 +/- 7.2 ml h-1 kg-1 respectively. 3. The serum concentrations of the metabolites phenylethylmalonamide (PEMA) and phenobarbitone relative to those of parent drug were higher in the elderly than in the young, the difference being significant (P less than 0.01) in the case of PEMA. 4. The renal clearances of primidone, phenobarbitone and PEMA were moderately decreased in the elderly but this reduction was statistically significant only for PEMA. Elderly patients excreted a reduced proportion of unchanged primidone and an increased proportion of PEMA in urine. 5. Ageing is associated with a greater accumulation of PEMA, which is unlikely to have a major clinical significance.

Clinical and computer-based assessment of long-term therapeutic efficacy of propranolol in essential tremor.

Despite a large number of studies demonstrating the effectiveness of propranolol in relieving essential tremor (ET) the long-term therapeutic outcome of these patients remains poorly defined. The results of a one-year follow-up study in 18 patients with mild to severe ET performed by using clinical and computer-based methods of assessment indicate that the initial therapeutic benefit of propranolol is apparently retained. However, following 3-6 months of sustained treatment a proportion of patients required an increase in daily dosage of propranolol in order to maintain adequate symptomatic control of tremor, indicating a relative decrease in tremorolytic efficacy of the drug possibly due to long-term tolerance.

Simultaneous VEP and PERG investigations in early Parkinson's disease.

To evaluate whether visual evoked potential (VEP) and pattern electroretinogram (PERG) abnormalities may be detectable early in the course of Parkinson's disease (PD) and to assess a possible interdependence between retinal and cortical potentials, simultaneous VEP and PERG were carried out in nine patients with early PD. The mean (SD) duration of the disease was 10 (6) months. None of the patients had been previously treated with levodopa or other anti-parkinsonian drugs. The results show VEP and PERG abnormalities that are spatial stimulus dependent, with higher frequencies being more involved and also indicate that VEP changes are not entirely dependent on alterations at the retinal level.

Primidone in the long-term treatment of essential tremor: a prospective study with computerized quantitative analysis.

The long-term efficacy of primidone (375-750 mg/day) in essential tremor was evaluated prospectively in 11 patients who had shown a favorable response to 4-week treatment with the drug under placebo-controlled conditions. On accelerometric evaluation, the magnitude of tremor after 3, 6, and 12 months on primidone was still significantly reduced compared with the initial placebo period. After discontinuation of primidone, tremor amplitude reverted to the placebo levels. Some loss of efficacy during long-term administration, however, was suggested by the results of self-assessment, physician's assessment, and performance tests. Three patients discontinued prematurely the drug because the sedative effects outweighed the potential therapeutic benefit. Side effects (especially drowsiness and sedation) were common at 4 weeks and 3 months but tended to subside thereafter. It is concluded that primidone retains at least part of its tremorolytic effect for up to 1 year, although the overall clinical benefit is limited in most patients.