Stefano Calzetti

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.

Restless legs syndrome in diabetic neuropathy: a frequent manifestation of small fiber neuropathy

Abstract  As the occurrence of restless legs syndrome (RLS) in diabetes is controversial, the aim of this study was to assess the prevalence of RLS in a cohort of patients with diabetic neuropathy and to analyze the features of the associated neuropathy. We investigated the occurrence of RLS diagnosed in accordance with the criteria of the International Restless Legs Syndrome Study Group in a cohort of patients with polyneuropathy and mononeuropathy multiplex associated with diabetes mellitus (DM), or impaired glucose tolerance (IGT), or impaired fasting glucose (IFG) in a retrospective study. RLS was present in 33/99 patients with neuropathy associated with DM/IGT/IFG (84 with distal polyneuropathy and 15 with multiple mononeuropathy). Comparing patients with or without RLS, small fiber sensory neuropathy was more common in the RLS patients (15/33 vs. 15/66), as were symptoms of burning feet (10/33 vs. 6/66). In several patients, RLS was responsive to neuropathic pain medications. The frequent occurrence of RLS in association with thermal dysesthesias may reflect the involvement of small sensory fibers in the form of hyperexcitable C fibers or A‐delta fiber deafferentation. We suggest that RLS may be triggered by abnormal sensory inputs from small fibers, especially involved in neuropathy associated with DM/IGT/IFG. Our data show that RLS is a relevant feature of diabetic neuropathy, as a frequent and potentially treatable manifestation of small fiber involvement in the course of DM and IGT/IFG.

Case-control study of interactions between genetic and environmental factors in Parkinson's disease

Several environmental risk factors and some allelic variants of polymorphic drug-metabolising enzymes have been associated with sporadic Parkinson’s disease. No study has to date explored the possible interaction between individual susceptibility and exposure to chemical pollutants. We genotyped enzymes expressed by the human brain and involved in oxidative stress through the generation of free radicals (phase I enzymes) or involved in scavenging (phase II enzymes). Candidate genes were characterised by a genetic polymorphism that leads to lessened or abolished enzyme activity, and by fixed expression or homozygous allelic deletion (a theoretical correspondence between genotype and phenotype). Cytochrome P-450 2D6 (CYP2D6) is a non-inducible phase I enzyme involved in the biotransformation of various chemicals, including tetrahydroisoquinolines. Alleles CYP2D6*3 and CYP2D6*4 account for about 90% of the poor metaboliser autosomal recessive disorder, which has been associated with Parkinson’s disease. A meta-analysis of available studies showed an overall risk of borderline significance. Glutathione S-transferases (GSTs) are inducible phase II enzymes involved in the scavenging of many electrophilic reactive intermediates. Homozygous deletion of GSTM1 and GSTT1 loci affects, respectively, about 50% and 25% of white people (genotypes GSTM1*0 and GSTT1*0). We recruited 100 consecutive outpatients at the Institute of Neurology, University of Parma, with Parkinson’s disease (59 men, 41 women) aged 66·6 (SD 9·7) years, fulfilling the diagnostic criteria established by the UK Parkinson’s Disease Society Brain Bank. The mean age at the onset of Parkinson’s disease was 58·6 (9·7) years (mean duration of the disease 7·9 [4·6] years) and 15% of patients had a positive family history of the disease. We enrolled 200 controls (118 men, 82 women) aged 64·2 (9·2) years from outpatient specialist centres (nephrology clinic and taken on the same day as her baby’s and tested in parallel with her previous sera remained VZV IgG antibody positive and VZV IgM antibody negative. A month later, in February 1997, at another hospital in Surrey, the day after the birth of a healthy baby girl at term, birth weight 4·2 kg, her 2 –year-old sister developed chickenpox. The mother had had chickenpox 7 years previously (aged 24 years) and this was confirmed serologically by testing her stored antenatal booking serum (16 weeks’ gestation) which was VZV IgG antibody positive and VZV IgM antibody negative. Serological tests were not done on the infant at this time. Mother and baby were discharged home 2 days after delivery, with the baby well and breastfeeding. At 16 days of age the baby developed chickenpox. On day 4 of her illness the baby was seen in hospital and started on oral acyclovir. The typical rash involved the face and head, with a few lesions on the trunk and limbs. Serum from the baby at this time was VZV IgG positive and VZV IgM negative. A swab from the chickenpox lesions yielded VZV from routine tissue culture. Again, no illness or rash occurred in the mother and a repeat serum tested in parallel with her previous serum remained VZV IgG antibody positive and VZV IgM antibody negative. Although VZV was not isolated from the first baby the diagnosis was not in doubt. The strength of IgG reactivity of the mother and baby serum samples in the assay used are shown in the table. The first mother gave a test/positive control net absorbance ratio (T/P) of 1·2 (cutoff 0·8) for both early sera while that of the baby on day 4 of illness was significantly less at 0·46 (equivocal level). The 17 day postdelivery sample of the mother showed a boosted IgG response. The T/P ratios of the second mother/baby case were almost identical for the mother’s booking serum and the baby’s blood at 2·2 and 2·1, respectively—ie, both more than twice the reactivity of the positive control. In both babies the VZV IgG antibody detected (both at 4 days of illness) was likely to be entirely maternal and not their own. It is generally accepted that passively acquired maternal antibody protects neonates from varicella even in low-birthweight infants with neonatal titres of VZV IgG antibody usually matching maternal levels. We can only speculate that the reduced IgG titre in the first baby compared with his mother—possibly a result of being bottle fed—was a factor in his apparently failed immunity and more florid rash. Cell mediated immunity (CMI) was not studied in either baby. Non-specific, non-antibody-dependent cellmediated mechanisms, such as natural killer cells, are known to have a role in controlling the extent of disease due to primary varicella but cannot necessarily prevent infection in the first place. Although our two cases were of moderate severity, and both were treated with acyclovir, a defect in CMI might have been expected to have caused serious protracted disease which did not occur. There have been two previous reports of neonatal

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, physicians 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.

Double‐blind comparison of primidone and phenobarbital in essential tremor

In a double-blind cross-over trial, primidone was superior to both placebo and phenobarbital in reducing essential tremor in 13 patients. Phenobarbital, at a dosage yielding serum barbiturate levels greater than those seen with primidone, was not better than placebo. Thus, primidone has an effect in essential tremor independent from that of its metabolite phenobarbital.

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

Abstract. 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” Alzheimers 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.

Absence of co-morbidity of Parkinson disease and restless legs syndrome: a case–control study in patients attending a movement disorders clinic

We have carried out a case–control survey of the prevalence of restless legs syndrome (RLS) in 118 Parkinson’s disease out-patients with different stage of disease severity by using the International restless legs syndrome Study Group clinical criteria. This study failed to demonstrate a significantly augmented prevalence of either primary and secondary restless legs syndrome pooled together or primary restless legs syndrome alone among Parkinson’s disease patients as compared to age and gender matched controls. The results of our survey do not confirm a significant co-morbid occurrence of the two disorders. However, an unavoidable limitation of this and all previous studies is that most of the patients examined were already treated with dopaminomimetic drugs, which could have abolished a mild unrecognized RLS anteceding the diagnosis of Parkinson’s disease or possibly masked the subsequent emergence of the sensory-motor disorder following the onset of Parkinson’s disease.

A case-control study of Parkinson’s disease and tobacco use : gene-tobacco interactions

A case‐control study of genetic, environmental, and occupational risk factors for Parkinsons disease (PD) was carried out in five European countries (Italy, Malta, Romania, Scotland, and Sweden) to explore the possible contribution of interactions among host and environmental factors in sporadic PD. Whereas smoking habits confirmed its negative association with PD, a possible modulatory role of genetic polymorphisms was investigated to obtain further mechanistic insights. We recruited 767 cases of PD and 1989 age‐matched and gender‐matched controls. Participants completed an interviewer‐administered questionnaire including the history of smoking habits. The polymorphisms of genes involved either in metabolism of compounds contained in tobacco smoke (CYP2D6, CYP1B1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, SOD2, EPHX and NAT2) or in dopaminergic neurotransmission (MAOA, MAOB, DAT1 and DRD2) were characterized by PCR based methods on genomic DNA. We found evidence of statistically significant gene‐tobacco interaction for GSTM1, NAT2, and GSTP1, the negative association between tobacco smoking and PD being significantly enhanced in subjects expressing GSTM1‐1 activity, in NAT2 fast acetylators, and in those with the GSTP1*B*C haplotype. Owing to the retrospective design of the study, these results require confirmation.

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.

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.