Hydrocortisone concentration influences time to clinically significant healing of acute inflammation of the ocular surface and adnexa - results from a double-blind randomized controlled trial.

BACKGROUND: The efficacy of topical ophthalmic corticosteroids depends upon small modifications in preparations, such as drug concentration.The aim of this study was to confirm that hydrocortisone acetate (HC-ac) ophthalmic ointments of 2.5% and 1% are more effective than a 0.5% eye ointment. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group clinical study, the change of signs and symptoms of acute inflammation of the ocular surface and adnexa was evaluated in 411 subjects. RESULTS: Median time to clinically relevant response as estimated by 50% reduction in clinical signs and symptoms (CSS) total score over the entire trial was similar for subjects treated with HC-ac 2.5% (73.5 h) and for subjects treated with HC-ac 1.0% (67.7 h) and was considerably and significantly longer for subjects treated with HC-ac 0.5% (111.8 h) [p < 0.001 for both dosages]. All trial medications were safe and well tolerated. CONCLUSION: Hydrocortisone acetate 2.5% and Hydrocortisone acetate 1% eye ointments are efficacious and safe treatments for acute inflammations of the ocular surface or adnexa, and showed significantly better efficacy than a control group treated with Hydrocortisone acetate 0.5% therapy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15464650.

European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society.

BACKGROUND: Since the publication of the first European Federation of Neurological Societies (EFNS) guidelines in 2005 on the management of restless legs syndrome (RLS; also known as Willis-Ekbom disease), there have been major therapeutic advances in the field. Furthermore, the management of RLS is now a part of routine neurological practice in Europe. New drugs have also become available, and further randomized controlled trials have been undertaken. These guidelines were undertaken by the EFNS in collaboration with the European Neurological Society and the European Sleep Research Society. OBJECTIVES: To provide an evidence-based update of new treatments published since 2005 for the management of RLS. METHODS: First, we determined what the objectives of management of primary and secondary RLS should be. We developed the search strategy and conducted a review of the scientific literature up to 31 December 2011 (print and electronic publications) for the drug classes and interventions employed in RLS treatment. Previous guidelines were consulted. All trials were analysed according to class of evidence, and recommendations made according to the 2004 EFNS criteria for rating. RECOMMENDATIONS: Level A recommendations can be made for rotigotine, ropinirole, pramipexole, gabapentin enacarbil, gabapentin and pregabalin, which are all considered effective for the short-term treatment for RLS. However, for the long-term treatment for RLS, rotigotine is considered effective, gabapentin enacarbil is probably effective, and ropinirole, pramipexole and gabapentin are considered possibly effective. Cabergoline has according to our criteria a level A recommendation, but the taskforce cannot recommend this drug because of its serious adverse events.

Successful treatment of blepharitis with bibrocathol (Posiformin® 2 %).

BACKGROUND: Bibrocathol is a well-established antiseptic drug for the treatment of acute eyelid diseases like blepharitis. Despite its frequent use in clinical practice, no controlled clinical trial on the efficacy of bibrocathol 2% eye ointment has been performed until now. The aim of the study was to investigate efficacy, safety and tolerability of bibrocathol (Posiformin® 2 %) eye ointment in patients diagnosed with blepharitis. METHODS: In this multi-center, randomized, double-masked, placebo-controlled parallel-group comparison, the change of signs and symptoms (sum score) of blepharitis in 197 patients (ITT (intention-to-treat-group); mean age 56 ± 18 years, 56 % female, active drug:vehicle = 97:100) over 2 weeks treatment with bibrocathol 2 % eye ointment was evaluated. RESULTS: Patients receiving bibrocathol 2 % showed greater improvement in the sum score than the placebo patients (p < 0.0001, Cohen's effect size d = 0.73). Also, the results from further efficacy assessments improvement of single symptoms and ocular discomfort measured by a VAS (visual analogue scale) supported treatment with bibrocathol. Patients and investigators provided favorable tolerability ratings preferring bibrocathol over placebo. No safety issues were observed with regard to intraocular pressure, visual acuity, or occurrence of adverse events. CONCLUSIONS: Blepharitis therapy with the antiseptic bibrocathol 2 % in this trial was highly efficacious and safe.

Parkinson's disease sleep scale--validation of the revised version PDSS-2.

BACKGROUND: The previous Parkinson's disease sleep scale (PDSS) is a 15-item visual analogue scale that assesses the profile of nocturnal disturbances in Parkinson's disease (PD) patients. OBJECTIVE: To extend the scale so that it becomes a frequency measure scale with five categories and encompasses unmet needs such as restless legs syndrome, akinesia, pain, and sleep apnea. METHODS: For validation of the PDSS-2, PD patients' ratings and investigators' interviews were compared to ratings from a semistructured interview with a caregiver/partner, and to related scales. PDSS-2 was repeated for test-retest-reliability after 1-3 days. RESULTS: A total of 113 PD patients showed a mean (SD) total score of 16.5 (±8.9) (range: 2-40) indicating mild to moderate sleep disturbances. PDSS-2 item-total correlation for proving internal consistency was satisfactory (correlations >0.30). From a factor analysis, three subscales were derived: (1) "motor problems at night," (2) "PD symptoms at night" and (3) "disturbed sleep." The alpha coefficient for the total score was 0.73, for subscales 0.47 to 0.66. The test-retest-reliability intra-class-coefficient for the total score was 0.80, with 0.69 and 0.77 within the subscales. For discriminative validity, significant differences were found in the PDSS-2 total score depending on CGI and Hoehn and Yahr severity levels. A comparison between caregivers' and patients' ratings was carried out. CONCLUSION: The PDSS-2, with an extended spectrum of nocturnal disabilities and easier use for patients, is a reliable, valid, precise, and potentially treatment-responsive tool for measuring sleep disorders in PD.

Are treatment preferences relevant in response to serotonergic antidepressants and cognitive-behavioral therapy in depressed primary care patients? Results from a randomized controlled trial including a patients' choice arm.

BACKGROUND: Little is known about the influence of depressed patients' preferences and expectations about treatments upon treatment outcome. We investigated whether better clinical outcome in depressed primary care patients is associated with receiving their preferred treatment. METHODS: Within a randomized placebo-controlled single-centre 10-week trial with 5 arms (sertraline; placebo; cognitive-behavioral group therapy, CBT-G; moderated self-help group control; treatment with sertraline or CBT-G according to patients' choice), outcomes for 145 primary care patients with mild-to-moderate depressive disorders according to DSM-IV criteria were investigated. Preference for medication versus psychotherapy was assessed at screening using a single item. Post-baseline difference scores for the Hamilton Depression Rating Scale (HAMD-17) were used to assess treatment outcome (mixed-model repeated-measures regression analysis). RESULTS: Depressed patients receiving their preferred treatment (n = 63), whether sertraline or CBT-G, responded significantly better than those who did not receive their preferred therapy (n = 54; p = 0.001). The difference in outcome between both groups was 8.0 points on the HAMD-17 for psychotherapy and 2.9 points on the HAMD-17 for treatment with antidepressants. Results were not explained by differences in depression severity or dropout rates. CONCLUSIONS: Patients' relative preference for medication versus psychotherapy should be considered when offering a treatment because receiving the preferred treatment conveys an additional and clinically relevant benefit (HAMD-17: +2.9 points for drugs; +8.0 points for CBT-G) in outcome.

Algorithms for the diagnosis and treatment of restless legs syndrome in primary care.

BACKGROUND: Restless legs syndrome (RLS) is a neurological disorder with a lifetime prevalence of 3-10%. in European studies. However, the diagnosis of RLS in primary care remains low and mistreatment is common. METHODS: The current article reports on the considerations of RLS diagnosis and management that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored task force consisting of experts and primary care practitioners. The task force sought to develop a better understanding of barriers to diagnosis in primary care practice and overcome these barriers with diagnostic and treatment algorithms. RESULTS: The barriers to diagnosis identified by the task force include the presentation of symptoms, the language used to describe them, the actual term "restless legs syndrome" and difficulties in the differential diagnosis of RLS. CONCLUSION: The EURLSSG task force reached a consensus and agreed on the diagnostic and treatment algorithms published here.

Psychological distress of patients suffering from restless legs syndrome: a cross-sectional study.

BACKGROUND: Restless legs syndrome (RLS) is a chronic disorder with substantial impact on quality of life similar to that seen in diabetes mellitus or osteoarthritis. Little is known about the psychological characteristics of RLS patients although psychological factors may contribute to unfavourable treatment outcome. METHODS: In an observational cross-sectional design, we evaluated the psychological features of 166 consecutive RLS patients from three outpatient clinics, by means of the Symptom Checklist 90-R (SCL-90-R) questionnaire. Additionally, the Beck Depression Inventory-II (BDI-II) and the International RLS Severity Scale (IRLS) were measured. Both treated and untreated patients were included, all patients sought treatment. RESULTS: Untreated patients (n = 69) had elevated but normal scores on the SCL-90-R Global Severity Index (GSI; p = 0.002) and on the sub-scales somatisation (p < 0.001), compulsivity (p = 0.003), depression (p = 0.02), and anxiety (p = 0.004) compared with a German representative sample. In the treated group, particularly in those patients who were dissatisfied with their actual treatment (n = 62), psychological distress was higher than in the untreated group with elevated scores for the GSI (p = 0.03) and the sub-scales compulsivity (p = 0.006), depression (p = 0.012), anxiety (p = 0.031), hostility (p = 0.013), phobic anxiety (p = 0.024), and paranoid ideation (p = 0.012). Augmentation, the most serious side effect of dopaminergic, i.e. first-line treatment of RLS, and loss of efficacy were accompanied with the highest psychological distress, as seen particularly in the normative values of the sub-scales compulsivity and anxiety. Generally, higher RLS severity was correlated with higher psychological impairment (p < 0.001). CONCLUSION: Severely affected RLS patients show psychological impairment in multiple psychological domains which has to be taken into account in the treatment regimen.

Levodopa for restless legs syndrome.

BACKGROUND: Levodopa plus dopamine decarboxylase inhibitor is a common treatment for restless legs syndrome (RLS). OBJECTIVES: To evaluate efficacy and safety of levodopa for RLS compared to placebo and other active agents. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, PsycINFO and CINAHL, from January 1985 to December 2008, reference lists of articles, and contacted pharmaceutical companies. SELECTION CRITERIA: We included double-blind randomised controlled trials (RCT) investigating levodopa treatment versus placebo or other treatment for at least seven days in patients with RLS (age ≥ 18 years). Outcomes included symptom severity, CGI-I, objective as well as self rated sleep parameters, quality of life, and safety parameters. DATA COLLECTION AND ANALYSIS: Two authors extracted data, assessed risk of bias, and contacted pharmaceutical companies and authors for additional information. We collected dropouts due to adverse events and patients experiencing adverse events. MAIN RESULTS: Six placebo controlled and three active controlled RCTs were included (521 participants). Symptom severity (11 point rating scale, 0 points indicating no symptoms, 10 points indicating maximally severe symptoms) was more reduced with levodopa than placebo in two studies (mean difference (MD) -1.34, 95% confidence interval (CI) -2.18 to -0.5, P = 0.002). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) improved by -26.28/h compared to placebo (95% CI -30.53 to -22.02, P < 0.00001).The CGI-I changed more with levodopa than placebo in two studies (MD -1.25, 95% CI -1.89 to -0.62, P = 0.0001). In two studies, sleep quality (sleep questionnaire, visual analogue scale) showed a large effect (standardised mean difference (SMD) 0.92, 95% CI 0.52 to 1.33, P < 0.00001) whereas quality of life (50 mm Visual Analogue Scales) improved by 3.23 compared to placebo (95% CI 1.64 to 4.82, P < 0.0001). Few patients dropped out of treatment (3 of 218 patients) but more levodopa treated patients experienced adverse events than with placebo (odds ratio 2.61, 95% CI 1.35 to 5.04, P = 0.004). Two dopamine agonist controlled studies showed smaller effects with levodopa than cabergoline and pramipexole on the IRLS (MD 5.25, 95% CI 2.10 to 8.40, P =0.001), CGI-I (MD 0.62, 95% CI 0.37 to 0.87, P < 0.00001), and quality of life (MD 5.54, 95% CI 2.65 to 8.43, P = 0.0002). AUTHORS' CONCLUSIONS: Levodopa is efficacious for the short-term treatment of RLS. Augmentation, the clinically most relevant adverse event, was not investigated sufficiently.

Dopamine agonists for restless legs syndrome.

BACKGROUND: According to clinical guidelines, dopamine agonists are the first-line treatment of restless legs syndrome (RLS). OBJECTIVES: To evaluate efficacy and safety of dopamine agonists for RLS. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, PsycINFO and CINAHL, from January 1985 to December 2008, plus reference lists of articles. We contacted pharmaceutical companies. SELECTION CRITERIA: We included double-blind randomised controlled trials (RCTs) of dopamine agonist treatment versus placebo or other treatment for a period of at least seven days in patients with RLS (≥ 18 years). Outcomes included the International RLS Severity Rating Scale (IRLS), Clinical Global Impressions (CGI-I), polysomnography and self rated sleep quality, quality of life, daytime functioning, and safety parameters. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data separately; assessed risk of bias; and contacted pharmaceutical companies and authors for additional information. We collected dropout rates due to adverse events and experience of adverse events. MAIN RESULTS: We included 35 placebo controlled and three active controlled RCTs (N = 7365). The mean reduction on the IRLS was -5.7 points lower in dopamine agonist treatment compared to placebo (95% confidence interval (CI) -6.7 to -4.7). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) were -22.4/h lower than in placebo (95% CI -27.8 to -16.9). Self rated quality of sleep and disease specific quality of life were improved by a standardised mean difference (SMD) of 0.40 (95% CI 0.33 to 0.47) and 0.34 (95% CI 0.23 to 0.44), respectively. Patients were more likely to drop out (odds ratio (OR) 1.82, 95% CI 1.35 to 2.45) and experienced more adverse events under dopamine agonist treatment than with placebo (OR 1.82, 95% CI 1.59 to 2.08). Visual inspection of forest plots showed the highest efficacy in three studies investigating cabergoline and pergolide (N = 3). Active controlled trials investigated effects of cabergoline, pergolide, and pramipexole in a number of outcomes. The IRLS score was lower with cabergoline and pramipexole compared to levodopa (MD -5.3, 95% CI -8.4 to -2.1). Only four studies investigated treatment efficacy up to seven months. The most severe side effect, augmentation, was not assessed reliably. AUTHORS' CONCLUSIONS: The meta-analyses show the superiority of dopamine agonists over placebo in RCTs up to seven months. Cabergoline and pramipexole showed larger efficacy compared to levodopa in some but not all outcomes.

A special terpene combination (Rowatinex®) improves stone clearance after extracorporeal shockwave lithotripsy in urolithiasis patients: results of a placebo-controlled randomised controlled trial.

OBJECTIVE: To investigate the safety and efficacy of a special terpene combination in the treatment of patients with urolithiasis after extracorporeal shockwave lithotripsy (ESWL). PATIENTS AND METHODS: 222 patients with clinically stable kidney or ureter stones of 0.3-2.0 cm undergoing complication-free ESWL were randomised to receive a special terpene combination (Rowatinex®; 3 × 2 capsules/day) or placebo. The study consisted of a 12-week active treatment phase and a 2-week follow-up phase. All patients had a physical examination, and diagnosis of kidney stones was made by X-ray, intravenous pyelogram or ultrasound at weeks 1, 4, 8 and 12 as well as after 2 weeks of follow-up. Stone-free status was defined as obviously successful expulsion of calculi/fragments, being without any stone. RESULTS: In all, when compared to placebo, significantly more patients receiving the terpene combination treatment in the intent-to-treat (ITT) group [72 (67.9%) vs. 49 (50.0%); p = 0.0009] and the per-protocol (PP) group [69 (78.4%) vs. 48 (52.2%); p = 0.0004] were stone-free at the end of the study. Treatment with the terpene combination was also more effective when analysed with respect to the size of the treated stone. In addition, treatment with the terpene combination significantly reduced the median time to stone-free status from 85.0 to 56.0 days (p = 0.0061) and from 85.0 to 49.5 days (p = 0.0028) in the ITT and PP populations, respectively. Nine mild-to-moderate adverse events (AE; terpene combination group: 7 AE in 4 patients; placebo group: 2 AE in 2 patients) were assessed as drug-related. CONCLUSIONS: Treatment with the terpene combination is well tolerated and safe. The terpene combination was found to be an efficacious treatment in eliminating calculi fragments generated by ESWL as compared to placebo. The pharmacodynamic properties of the terpene combination (antilithogenic, antibacterial, antiinflammatory, spasmolytic and analgesic effects), which have been also confirmed in preclinical studies, represent a valuable alternative to the different drugs used in the treatment of urolithiasis.

Effects of pharmacotherapy and psychotherapy in depressed primary-care patients: a randomized, controlled trial including a patients' choice arm.

Mild depressive syndromes are highly prevalent among primary-care patients. Evidence-based treatment recommendations need to be derived directly from this diagnostically heterogeneous group. The primary aim was to assess the efficacy of sertraline and cognitive-behavioural group therapy for treatment of depressed primary-care patients, the secondary aim was to evaluate if receiving treatment according to free choice is associated with a better outcome than randomization to a particular treatment. We conducted a randomized, placebo-controlled, single-centre, 10-wk trial with five arms: sertraline (flexible dosages up to 200 mg/d) (n = 83); placebo (n = 83); manual-guided cognitive-behavioural group therapy (one individual session and nine group sessions per 90 min) (n = 61); guided self-help group (control condition, n = 59); and treatment with sertraline or cognitive-behavioural group therapy according to patients' choice (n = 82). From 1099 consecutively screened adult patients, 368 formed the intent-to-treat population with milder forms of depression. Primary outcome was a global efficacy measure combining z-converted Hamilton Depression Rating Scale and clinician-rated Inventory for Depressive Symptomatology scores. Sertraline was superior to placebo (p = 0.03). Outcome for guided self-help groups was worse compared to cognitive-behavioural group therapy (p = 0.002) and compared to all other treatment arms including pill placebo (secondary analyses). Outcome in the patients' choice arm was similar to that in the sertraline and cognitive-behavioural group therapy. Overall, sertraline is efficacious in primary-care patients with milder forms of depression. The superiority of cognitive-behavioural group therapy over guided self-help groups might partly be explained by 'nocebo' effects of the latter.

Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch.

BACKGROUND: Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open-label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS). METHODS: Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS. RESULTS: Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 ± 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 ± 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 ± 5.9) by 17.2 ± 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2. CONCLUSIONS: Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy. TRIAL REGISTRATION: NCT00498186.

Validation of an algorithm for the diagnosis of Restless Legs Syndrome: The Restless Legs Syndrome-Diagnostic Index (RLS-DI).

BACKGROUND: There is a need for structured methods to improve sensitivity and specificity of diagnostic decision making in Restless Legs Syndrome (RLS). We present the RLS-Diagnostic Index (RLS-DI), a diagnostic algorithm which combines essential and supportive diagnostic criteria from patient interviews, polysomnography and neurological examination in an adaptive procedure. METHOD: The RLS-DI consists of 10 items which are related to the essential diagnostic criteria established by the International RLS Study Group (five items) as well as their supportive criteria (3 items) and features associated with RLS (2 items). Items have to be completed using three categories per item that address frequency of occurrence of symptoms or certainty of presence or absence of other diagnostic information. Negative weights were given when the clinically most relevant items were not present. The RLS-DI was administered in a telephone interview to 179 patients (86 with RLS, 93 with other sleep disorders) of the 21 month cohort of one sleep center in Germany. RESULTS: With receiver-operating characteristics, a cut-off of >or= 11 points on a scale ranging from -22 (no RLS) to 20 (definite RLS) was identified by comparing the RLS-DI total score to the diagnosis of two independent sleep experts. Sensitivity was 93.0%, specificity was 98.9%, and 96.1% of the patients could be correctly diagnosed. Specificity was higher in items related to supportive or associated diagnostic information (95.7%) than in those related to the essential diagnostic criteria (81.7%). Patients with RLS scored a higher RLS-DI than those with primary insomnia or other neurological or psychiatric disorders (p < .001). CONCLUSION: The RLS-DI demonstrated the ability to validly diagnose an actual and persistently present Restless Legs Syndrome in patients of a sleep lab population and to exclude those patients whose sleep disturbances have other causes.

Empirical evaluation of the accuracy of diagnostic criteria for Restless Legs Syndrome.

BACKGROUND: In accordance with the diagnostic criteria of the International Restless Legs Syndrome (RLS) Study Group, the diagnosis of RLS is exclusively based on subjective information. Patients must report an urge to move the legs (and arms) with or without unpleasant sensations which is engendered by rest, relieved by movement, and worse in the evening or at night than during the day (essential criteria). Objective information such as excessive periodic leg movements, positive response to dopaminergic medication, family history of RLS or findings of a neurological examination cannot substitute any of the essential criteria but are considered both supportive for the RLS diagnosis and important for decisions on differential diagnoses. In this article, we report a systematic empirical analysis of the accuracy of diagnostic decisions based on all diagnostic criteria being either "essential" or "non-essential." METHODS: We re-analyzed data from a validation study for the RLS Diagnostic Index, in which ten items related to diagnostic criteria were compared with an expert diagnosis of RLS (n = 86) and other sleep-related diagnoses (n = 93). The value of individual diagnostic criteria and features of RLS predictive of the expert diagnoses were analyzed with logistic regression models by increasing the set of diagnostic criteria stepwise based on delta-chi(2) tests. RESULTS: The essential diagnostic criteria share a large amount of variance in the prediction of the expert diagnosis. Three of the four essential criteria (urge to move the legs, which is engendered by rest and worse in the evening) almost completely determine the expert diagnosis. However, adding response to dopaminergic medication to the set of the essential criteria increased the effect size in the logistic regression model from 69.4% to 88.4%, indicating a relevant improvement of the accuracy in supporting or excluding the diagnosis of RLS. CONCLUSION: On the basis of our exploratory empirical analysis we conclude that the accuracy of diagnostic decision making in patients suspicious for RLS can be improved by inclusion of objective information. Response to dopaminergics is the most important criterion which both supports the "true" diagnosis of RLS, if present, and is also relevant to exclude mimics of RLS.

PLM detection by actigraphy compared to polysomnography: a validation and comparison of two actigraphs.

OBJECTIVE: To compare periodic leg movement (PLM) counts obtained with polysomnography (PSG) to those obtained from actigraphy with two devices (Actiwatch and PAM-RL). METHODS: Twenty-four patients underwent full night actigraphy with Actiwatch from both legs and simultaneous PSG. Out of these patients, 10 had additional actigraphy with PAM-RL. Bilateral and unilateral PLM indices (PLMI) for both actigraphs were calculated for time in bed and compared to polysomnographic PLMI. Additionally, a comparison between the two different actigraphs was performed. RESULTS: PLMI obtained with Actiwatch were significantly lower than those obtained with PSG (21.2+/-25.6/h versus 34.4+/-30.7/h; p<0.001), whereas the PLMI from PAM-RL were significantly higher than in PSG (63.6+/-39.3/h versus 37.0+/-33.5/h; p=0.009). In direct comparison, Actiwatch gave significantly lower PLMI than the PAM-RL (p=0.005). The correlations between Actiwatch and PSG (rho=0.835, p<0.001), PAM-RL and PSG (rho=0.939, p<0.001), and Actiwatch and PAM-RL (rho=0.915, p<0.001) were significant. Unilateral actigraphy compared to standard PSG gave less consistent findings. When comparing different settings of the PAM-RL, manual threshold setting resulted in PLMI that were no longer different from PSG (p=0.074), in contrast to the default threshold setting. CONCLUSIONS: The Actiwatch underestimated and the PAM-RL overestimated PLMI compared to PSG. Whereas PLMI obtained with two actigraphs and PSG were highly correlated, they differed in mean values. Therefore, PSG, actigraphy and also the different actigraphs cannot be interchanged in longitudinal studies, and actigraphy should not be used for diagnostic decision making based on PLM indices. The best approximation to PSG PLMI was achieved by using manual threshold setting with the PAM-RL.

Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome. Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome. METHODS: In this randomised, double-blind, placebo-controlled trial, 458 patients with moderate-to-severe idiopathic restless legs syndrome (average baseline International Restless Legs Syndrome Study Group severity rating scale [IRLS] sum score of 28.1) were randomly assigned to receive transdermal rotigotine 1 mg over 24 h (n=115), 2 mg over 24 h (n=112), or 3 mg over 24 h (n=114), or to receive placebo (n=117). Study medication was delivered via patches, applied once a day for 6 months. Randomisation was done with a computer-generated randomisation list, stratified by centre. Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions (CGI) item 1 score, assessed by analysis of covariance in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00136045. FINDINGS: Efficacy analyses were done on 112 patients in the 1 mg group, 109 in the 2 mg group, 112 in the 3 mg group, and 114 in the placebo group. Mean change in IRLS sum score from baseline at the end of the maintenance phase was -13.7 (SE 0.9) in the 1 mg group, -16.2 (0.9) in the 2 mg group, -16.8 (0.9) in the 3 mg group, and -8.6 (0.9) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Mean change in CGI item 1 score from baseline at the end of the maintenance phase was -2.09 (0.14) in the 1 mg group, -2.41 (0.14) in the 2 mg group, -2.55 (0.14) in the 3 mg group, and -1.34 (0.14) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Skin reactions, mostly mild or moderate, were seen in 145 (43%) of 341 patients who received rotigotine and in two (2%) of 117 who received placebo. Ten patients had serious adverse event that were deemed to be related to rotigotine: elevation of liver enzymes (one patient), worsening of tinnitus (one patient), non-response to anticoagulation (one patient), electrocardiogram changes (one patient), and application-site reactions (six patients). No admissions to hospital were needed for the application-site reactions, and they all resolved within a short time of patch removal without any other therapeutic intervention. The rate of typical dopaminergic side-effects in patients who received rotigotine was low; no signs of augmentation were noted. INTERPRETATION: 24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome. FUNDING: Schwarz Biosciences.

Augmentation in restless legs syndrome is associated with low ferritin.

BACKGROUND AND PURPOSE: Augmentation is a major problem with dopaminergic therapy for restless legs syndrome (RLS), and predictors of augmentation have not yet been identified. We aimed to analyze the relationship between baseline ferritin level and occurrence of augmentation in a retrospective analysis of a prospective double-blind trial of cabergoline versus levodopa on augmentation in RLS. PATIENTS AND METHODS: Patients who experienced augmentation were compared to patients who did not experience augmentation. RESULTS: Augmentation symptoms causing premature discontinuation from the study or which were tolerated (n=36, ferritin: 85+59 ng/ml) were associated with lower levels of serum ferritin compared to patients without augmentation (n=302, ferritin: 118+108 ng/ml, p=0.0062). CONCLUSIONS: Ferritin as a marker of iron storage may play an important role in the pathophysiology of RLS and may prove to be a biomarker for the development of augmentation under dopaminergic therapy.

One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome.

BACKGROUND: Long-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome. METHODS: Efficacy and safety of rotigotine (0.5-4mg/24h), formulated as a once-daily transdermal system (patch), were investigated in an open extension (SP710) of a preceding 6-week placebo-controlled trial (SP709, 341 randomized patients) in patients with idiopathic restless legs syndrome. For efficacy assessment the international RLS severity scale (IRLS), the RLS-6 scales, the clinical global impressions (CGI) and the QoL-RLS questionnaire were administered. In addition, long-term tolerability and safety were assessed. RESULTS: Of 310 patients who finished the controlled trial, 295 (mean age 58+/-10 years, 66% females) with a mean IRLS score of 27.8+/-5.9 at baseline of SP709 were included. We report results after one year of this ongoing long-term trial. Two hundred twenty patients (retention rate=74.6%) completed the 12-month follow-up period. The mean daily dose was 2.8+/-1.2mg/24h with 4mg/24h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0mg/24h. The IRLS total score improved by ?17.4+/-9.9 points between baseline and end of Year 1 (p<0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p<0.001 for pre-post-comparisons of all efficacy variables). The tolerability was described as "good" or "very good" by 80.3% of all patients. The most common adverse events were application site reactions (40.0%), which led to withdrawal in 13.2%. Further relatively frequent adverse events were nausea (9.5%) and fatigue (6.4%). Two drug-related serious adverse events, nausea and syncope, required hospitalization. Symptoms of augmentation were not reported by the patients. CONCLUSION: Rotigotine provided a stable, clinically relevant improvement in all efficacy measures throughout one year of maintenance therapy. The transdermal patch was safe and generally well tolerated by the majority of patients. Comparable to any transdermal therapy, application site reactions were the main treatment complication.

Efficacy of rotigotine transdermal system in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe.

BACKGROUND: In a pilot placebo-controlled study, low dosages of 0.5-2mg/24h rotigotine showed a dose-dependent beneficial effect in restless legs syndrome (RLS) patients. METHODS: Efficacy and safety of the dopamine agonist rotigotine, formulated as a once-daily transdermal system (patch), was investigated for five fixed dosages and compared to placebo in patients with idiopathic RLS in a double-blind, randomized, parallel-group, multicenter, six-week dose-finding trial. Primary efficacy measure was the total score of the International RLS Severity Scale (IRLS); in addition, the RLS-6 scales and the Clinical Global Impressions (CGI) were administered. RESULTS: Of 371 enrolled patients, 341 patients (mean age 58+/-10years, 67% females) were randomized. The IRLS total score improved between baseline and end of the six-week treatment period by -10.6 (0.5mg/24h rotigotine; patch area 2.5cm2), -15.1 (1mg/24h; 5cm2), -15.7 (2mg/24h; 10cm2), -17.5 (3mg/24h; 15cm2), and -14.8 (4mg/24h, 20cm2) as compared to placebo (-9.2). The hierarchical statistical test procedure demonstrated superiority of rotigotine over placebo for 4mg/24h, 3mg/24h, 2mg/24h, and 1mg/24h, with p-values of 0.0013, <0.0001, 0.0003, and 0.0004, respectively. Only the 0.5mg/24h dose was not different compared to placebo (p=0.2338). The CGI and the RLS-6 severity items supported the efficacy of the rotigotine doses beyond 0.5mg/24h. The most frequent side effects were application site reactions and nausea and tended to be more frequent with higher doses. CONCLUSIONS: This dose-finding trial identified the range for a maintenance dose of rotigotine from 1mg/24h to 3mg/24h. The lowest dose was ineffective and, with the highest dose, no additional benefit was observed.

Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute.

OBJECTIVES: Augmentation of symptom severity is the main complication of dopaminergic treatment of restless legs syndrome (RLS). The current article reports on the considerations of augmentation that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored Consensus Conference in April 2006 at the Max Planck Institute (MPI) in Munich, Germany, the conclusions of which were endorsed by the International RLS Study Group (IRLSSG) and the World Association of Sleep Medicine (WASM). The Consensus Conference sought to develop a better understanding of augmentation and generate a better operational definition for its clinical identification. DESIGN AND METHODS: Current concepts of the pathophysiology, clinical features, and therapy of RLS augmentation were evaluated by subgroups who presented a summary of their findings for general consideration and discussion. Recent data indicating sensitivity and specificity of augmentation features for identification of augmentation were also evaluated. The diagnostic criteria of augmentation developed at the National Institutes of Health (NIH) conference in 2002 were reviewed in light of current data and theoretical understanding of augmentation. The diagnostic value and criteria for each of the accepted features of augmentation were considered by the group. A consensus was then developed for a revised statement of the diagnostic criteria for augmentation. RESULTS: Five major diagnostic features of augmentation were identified: usual time of RLS symptom onset each day, number of body parts with RLS symptoms, latency to symptoms at rest, severity of the symptoms when they occur, and effects of dopaminergic medication on symptoms. The quantitative data available relating the time of RLS onset and the presence of other features indicated optimal augmentation criteria of either a 4-h advance in usual starting time for RLS symptoms or a combination of the occurrence of other features. A paradoxical response to changes in medication dose also indicates augmentation. Clinical significance of augmentation is defined. CONCLUSION: The Consensus Conference agreed upon new operational criteria for the clinical diagnosis of RLS augmentation: the MPI diagnostic criteria for augmentation. Areas needing further consideration for validating these criteria and for understanding the underlying biology of RLS augmentation are indicated.