J. Carsten Möller

Patch application of the dopamine agonist rotigotine to patients with moderate to advanced stages of Restless Legs Syndrome: A double-blind, placebo-controlled pilot study

Efficacy and safety of the dopamine agonist rotigotine (RTG) was investigated in patients with moderate to severe idiopathic restless legs syndrome (RLS), including daytime symptoms. Three fixed doses of rotigotine (1.125 mg, 2.25 mg, and 4.5 mg) and placebo were applied by patches (size, 2.5 cm2 per 1.125 mg) in a double‐blind, randomized, parallel‐group, multicenter, 1‐week, proof‐of‐principle trial. The primary efficacy measure was the total score on the International Restless Legs Syndrome Scale (IRLS). Additionally, the RLS‐6 scale, the Clinical Global Impressions (CGI), and a sleep diary were used. Of 68 enrolled patients, 63 (mean age, 58±; 9 years; 64% women) were randomly assigned. RLS severity improved related to dose by 10.5 (1.125 mg RTG/die; P = 0.41), 12.3 (2.25 mg RTG/die; P = 0.18), and 15.7 points (4.5 mg RTG/die; P < 0.01) on the IRLS compared to placebo (8 points). According to the RLS‐6 scales, daytime symptoms significantly improved with all rotigotine doses. The CGI items supported the favorable efficacy of the 4.5‐mg dose. Skin tolerability of the patches and systemic side effects were similar between rotigotine and placebo. This pilot study suggests that continuous delivery of rotigotine by means of a patch may provide an effective and well‐tolerated treatment of RLS symptoms both during night and day.

Long-term efficacy and safety of pramipexole in advanced Parkinson's disease: Results from a European multicenter trial

A double‐blind, placebo‐controlled study with a subsequent open‐label phase was conducted in 354 patients with Parkinsons disease (PD) and motor fluctuations under individually adjusted therapy with levodopa. During the double‐blind phase 174 patients received pramipexole and 180 placebo. In agreement with previous studies, pramipexole treatment improved UPDRS sum scores of parts II and III by 30% and off times by approximately 2.5 hours per day. Differences between the treatment groups became significant at a daily dose of 0.75 mg of pramipexole dihydrochloride. We, furthermore, performed post hoc analyses with respect to resting tremor and depression. Patients with pronounced resting tremor derived a clear benefit from pramipexole treatment compared with placebo. In addition, pramipexole significantly improved the subitems motivation/initiative and depression in a subpopulation with increased Unified Parkinsons Disease Rating Scale I scores at the time of inclusion. There were 262 patients who were subsequently enrolled into the open‐label study featuring a maximum duration of up to 57 months. Statistical analysis revealed good long‐term efficacy and tolerability of pramipexole. Overall, only a low prevalence of somnolence was found. In summary, this study provides additional level I evidence of the usefulness of pramipexole, suggests a particular tremorlytic and a possible antidepressant action of this compound, and addresses for the first time its efficacy and safety during long‐term administration in advanced PD.

Alpha-synuclein and Parkinson's disease: Implications from the screening of more than 1,900 patients

Data on the frequency of α‐synuclein mutations in Parkinsons disease (PD) are limited. Screening the entire coding region in 1,921 PD patients with denaturing high performance liquid chromatography and subsequent sequencing we only detected silent mutations (g.2654A>G, g.10151G>A, and g.15986A>T) and the c.209G>A substitution corresponding to the p.A53T mutation. These results demonstrate that mutations in the α‐synuclein gene are rare and suggest that other factors contribute to α‐synuclein aggregation in the majority of PD patients.

Evaluation of sleep and driving performance in six patients with Parkinson's disease reporting sudden onset of sleep under dopaminergic medication: A pilot study

Six patients with Parkinsons disease (PD) reporting unusually fast or sudden onset of sleep under the addition of dopamine agonists to a previous levodopa‐containing therapy were examined using a sleep–wake diary, the Epworth sleepiness scale (ESS), polysomnography, multiple sleep latency tests (MSLT), a standardized vigilance test, and driving simulation. In all patients, ESS scores were increased and polysomnography showed disruption of the sleep pattern, a tendency towards poor sleep efficiency, and reduced proportions of slow‐ wave and rapid eye movement sleep. Pathological results in the MSLT or the vigilance test were obtained in five cases. For evaluation of driving performance, the standard deviation from the mean lane position during driving simulation was calculated. Three of five patients had clearly increased mean SDLP values. With respect to the measurement of daytime sleepiness (ESS, MSLT, vigilance test, and driving simulation), each patient had pathological results in at least two of these examinations. However, only a limited transfer of the routine vigilance assessment to driving performance was possible. In summary, this pilot study indicates that unusually fast or sudden onset of sleep in PD patients is a phenomenon of daytime sleepiness.

Normal dopaminergic and serotonergic metabolites in cerebrospinal fluid and blood of restless legs syndrome patients

Cerebrospinal fluid (CSF) and blood obtained from 22 untreated or scarcely treated patients with moderate to severe restless legs syndrome (RLS; mean age, 58.6 ± 13 years) and 11 control subjects (mean age, 56.6 ± 12.9 years) were investigated for biogenic amines between 6:00 and 8:00 PM. We did not find any significant differences in the CSF concentrations of homovanillic acid, 3‐ortho‐ methyl‐dopa, levodopa, 5‐hydroxytryptophan, 5‐hydroxyindoleacetic acid, tetrahydrobiopterin, dihydrobiopterin, 5‐methyltetrahydrofolate, and neopterin. In addition, serotonin in whole blood and plasma activity of aromatic amino acid decarboxylase were all normal. Our results suggest that dopaminergic and serotonergic release is not substantially affected in RLS.

Dopamine receptor gene polymorphisms in Parkinson's disease patients reporting “sleep attacks”

Genes encoding proteins involved in dopaminergic transmission are potential candidate genes for the induction of somnolence in Parkinsons disease (PD) because dopaminergic agents have been shown to be associated with sudden onset of sleep (SOS) in PD. We conducted an association study on dopamine D2, D3, and D4 receptor gene polymorphisms comparing 137 PD patients with SOS and 137 PD patients without SOS matched according to drug therapy, disease duration, sex, and age. Our results show a significant association between the dopamine D2 receptor gene polymorphism Taq IA and SOS in PD. No significant association between two other investigated polymorphisms and the phenomenon of “sleep attacks” in PD was observed.

Evaluation of the Unified Wilson's Disease Rating Scale (UWDRS) in German patients with treated Wilson's disease

Wilsons disease (WD) is an inherited autosomal‐recessive disorder of copper metabolism characterized by a wide variety of neurological, hepatic, and psychiatric symptoms. The aim of the present study was the development and evaluation of a clinical rating scale, termed Unified Wilsons Disease Rating Scale (UWDRS), to assess the whole spectrum of clinical symptoms in WD. Altogether 107 patients (mean age 37.6 ± 11.9 years; 46 male, 61 female) with treated WD participated in the study. Cronbachs alpha as a measure of the internal consistency for the entire scale was 0.92, whereas the intraclass correlation coefficient (ICC) was 0.98 (confidence interval (CI95%) 0.97–0.99), indicating an excellent interrater reliability as determined in 32 patients. Besides the total score was significantly correlated with the earning capacity of the patients as indicated by an estimated Spearmans ρ ≈ 0.54 (CI95% 0.40–0.69, P < 0.001). In summary, the UWDRS appears to be a promising tool to assess the disease severity in WD. Its usefulness in clinical research and drug trials should be further addressed.

Dopamine transporter imaging and SPECT in diagnostic work‐up of Parkinson's disease: A decision‐analytic approach

As a diagnostic test for patients with suspected Parkinsons disease (PD), single photon emission computed tomography (SPECT) using [123I]FP‐CIT tracer has better sensitivity but is more expensive than regular clinical examination (CE). Our objective was to evaluate the clinical and economic impacts of different diagnostic strategies involving [123I]FP‐CIT SPECT. We developed a decision tree model to predict adequate treatment‐month equivalents (ATME), costs, and incremental cost–effectiveness ratio (ICER) during a 12‐month time horizon in patients with suspected PD referred to a specialized movement disorder outpatient clinic. In our cost– effectiveness analysis, we adopted the perspective of the German health care system and used data from a German prospective health care utilization study (n = 142) and published diagnostic studies. Compared strategies were CE only (EXAM+), SPECT only (SPECT+), SPECT following negative CE (SINGLE+), and SPECT following positive CE (DOUBLE+). Costs of SPECT amounted to €789 per investigation. Based on our model, expected costs (and ATME) were €946 (52.85 ATME) for EXAM+, €1352 (53.40 ATME) for DOUBLE+, €1731 (32.82 ATME) for SINGLE+, and €2003 (32.96 ATME) for SPECT+; performance of SPECT was induced in 0%, 54%, 56%, and 100% of the patients, respectively. DOUBLE+ was more effective and less expensive than SINGLE+ or SPECT+; thus these two do not offer reasonable choices. The ICER of DOUBLE+ compared to EXAM+ was €733 per ATME gained. In sensitivity analyses, the ICER of DOUBLE+ versus EXAM+ ranged from €63 to €2411 per ATME gained. Whether the diagnostic work‐up of patients referred to a specialized movement disorder clinic with a high prevalence of PD should include [123I]FP‐CIT SPECT depends on patient preferences and the decision makers willingness to pay for adequate early treatment. SPECT should be used as a confirmatory test before treatment initiation and limited to patients with a positive test result in the clinical examination. These results should be adjusted to the specific setting and individual patient preferences.

Prolonged generalized dystonia after chronic cerebellar application of kainic acid

Dystonia has traditionally been considered as a basal ganglia disorder, but there is growing evidence that impaired function of the cerebellum may also play a crucial part in the pathogenesis of this disorder. We now demonstrate that chronic application of kainic acid into the cerebellar vermis of rats results in a prolonged and generalized dystonic motor phenotype and provide detailed characterization of this new animal model for dystonia. c-fos expression, as a marker of neuronal activation, was increased not only in the cerebellum itself, but also in the ventro-anterior thalamus, further supporting the assumption of a disturbed neuronal network underlying the pathogenesis of this disorder. Preproenkephalin expression in the striatum was reduced, but prodynorphin expression remained unaltered, suggesting secondary changes in the indirect, but not in the direct basal ganglia pathway in our model system. Hsp70 expression was specifically increased in the Purkinje cell layer and the red nucleus. This new rat model of dystonia may be useful not only for further studies investigating the role of the cerebellum in the pathogenesis of dystonia, but also to assess compounds for their beneficial effect on dystonia in a rodent model of prolonged, generalized dystonia.

Daytime sleep latency in medication‐matched parkinsonian patients with and without sudden onset of sleep

Currently, it is unclear whether sleep attacks in Parkinsons disease (PD) represent a novel entity or just a phenomenon of daytime sleepiness. We investigated 10 PD patients with sleep attacks and compared them with 10 PD patients without any daytime sleepiness. The patients were matched according to their dopaminergic medication and subjected to a sleep medical investigation. The mean sleep latency on the multiple sleep latency test was in the normal range and not significantly different between the groups. These data suggest that sleep attacks can occur against a background of normal alertness.