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Objective: Restless legs syndrome (RLS) is a sensorimotor disorder that is characterized by uncomfortable and unpleasant sensations mainly in the legs. Two placebo-controlled studies (Phase II/III and post-marketing) in Japanese patients with RLS failed to demonstrate the efficacy of gabapentin enacarbil (GE) 600 mg in the change from baseline in International Restless Legs Syndrome Rating Scale (IRLS) score at the end of the treatment period. The high response to placebo is thought to be a possible reason why the post-marketing study failed. The objectives of these post hoc analyses were to determine potential predictive factors associated with improvement in IRLS score with GE treatment and to identify subgroups with higher placebo responses., Methods: We combined data from the two Japanese studies and analyzed change from baseline in IRLS score in the pooled population and subgroups defined by several patient characteristics. Moreover, we calculated the variable importance of each factor and performed predictive enrichment analysis to identify an enrichable subpopulation with greater improvement by GE treatment., Results: The post hoc analyses suggested that higher baseline IRLS score (≥21) and higher body mass index (≥25 kg/m 2 ) were associated with higher placebo responses. On the other hand, positive family history of RLS, prior use of dopaminergic receptor agonists, and higher baseline ferritin level (≥50 ng/mL) were associated with higher responses to GE., Conclusions: Our results suggest that patients with typical idiopathic RLS characteristics, including positive family history and no low ferritin level, would be expected to derive the greatest benefits from GE treatment., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To elucidate the prevalence and clinical characteristics of daytime restless legs syndrome (RLS) among patients with idiopathic RLS and investigate the effectiveness of rotigotine for daytime RLS., Methods: In 256 enrolled RLS patients, we investigated factors associated with the presence of RLS symptoms throughout the day. We also assessed the duration of daytime RLS symptoms at hourly intervals, time of initial symptom onset during the day, and associations between duration of daytime and nighttime RLS symptoms. In addition, we compared changes in duration and frequency of RLS symptoms during daytime and nighttime after randomly assigning patients to a 13-week treatment with rotigotine, a dopamine agonist patch with 24-hour action, or placebo., Results: Eighty-one (31.6%) patients had daytime RLS symptoms. Only the International Restless Legs Syndrome Study Group rating scale total score was significantly associated with the presence of daytime RLS symptoms (p < 0.01) on multiple logistic regression analysis. Daytime RLS symptom onset was at 6 a.m. in 44.4% of patients; symptom duration increased significantly toward nighttime. There was a significant positive association between duration of daytime and nighttime RLS symptoms (p < 0.0001) and a greater statistically significant reduction of daytime RLS symptom duration with rotigotine treatment than with placebo (p = 0.03)., Conclusions: Daytime symptoms are frequent in patients with RLS and may be associated with increased severity of the disorder and prolonged nighttime RLS symptoms. Rotigotine could become an important treatment choice for daytime symptoms., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: We aimed to ascertain the efficacy and safety of transdermal rotigotine (2 and 3mg/24h) in Japanese patients with restless legs syndrome (RLS)., Methods: In our double-blind placebo-controlled study, 284 Japanese patients with idiopathic RLS were randomly assigned to receive rotigotine 2mg/24h or 3mg/24h, or placebo, for 13 weeks. The primary endpoint was the change in International Restless Legs Syndrome Study Group rating scale (IRLS) total score., Results: The placebo-subtracted decreases in IRLS total score for rotigotine 2 mg/24 h and 3 mg/24 h were -2.8±1.3 and -3.1±1.3, respectively, which were significant (P<0.05). The interaction between baseline Pittsburgh Sleep Quality Index (PSQI) and treatment group for the change in IRLS total score was significant, indicating greater improvements in IRLS total score in patients with severe insomnia. Overall, 80.0%, 86.2%, and 51.6% of patients in the rotigotine 2 mg/24 h, 3 mg/24 h, and placebo groups, respectively, experienced adverse events (AEs) including application site reactions in 42.1%, 50.0%, and 7.4% of patients, respectively. None of the AEs were severe., Conclusions: Our results showed that rotigotine was effective without major safety concerns at doses of up to 3 mg/24 h in Japanese patients with RLS., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To evaluate the efficacy of pramipexole on polysomnographic measures, patient ratings and a clinical rating in Japanese patients with primary restless legs syndrome (RLS)., Methods: Patients with moderate to severe RLS having periodic limb movements in bed index (PLMI)>or=5 were randomly assigned to receive pramipexole or placebo in a 6-week, double-blind, placebo-controlled study with forced titration from 0.125 to 0.75mg/day. Both polysomnography (PSG) and the suggested immobilization test (SIT) were performed at baseline and 6weeks after starting treatment., Results: The analysis of covariance of log-transformed PLMI showed that the adjusted means at the end of study were significantly smaller in the pramipexole group than in the placebo group (p=0.0019). In all patients, variables on SIT did not show any differences between the two groups, whereas a significant improvement was shown in the pramipexole group compared with the placebo group for patients with a SIT-PLM index at baseline >or=15. Pramipexole group showed a significant reduction in the International Restless Legs Syndrome Study Group rating scale (IRLS; p=0.0005), a significant improvement in both Patient Global Impression (PGI; p<0.0001) and Clinical Global Impressions (CGI-I; p=0.0488), and a significantly greater mean reduction in the Pittsburgh Sleep Quality Index (PSQI; p=0.0016), when compared with those of placebo group at week 6., Conclusions: Pramipexole is highly efficacious in the reduction of PLMI and in the improvement of subjective severity of RLS and subjective sleep disturbance caused by the disorder., (Copyright 2009 Elsevier B.V. All rights reserved.)

Abstract: Background: Substantia nigra (SN) hyperechogenicity determined by transcranial sonography (TCS) and olfactory dysfunction are common findings in Parkinson disease (PD), which may reveal a prodromal synucleinopathy in idiopathic REM sleep behavior disorder (iRBD). Methods: TCS and the Odor Stick Identification Test for Japanese (OSIT-J) were performed in 34 consecutive patients with iRBD (67.9±6.1years), 17 consecutive patients with PD (66.4±6.7years), and 21 control group subjects (64.4±5.8years). Results: There was a significantly increased area of echogenicity in the SN in the iRBD group (0.20±0.13cm2) and PD group (0.22±0.11cm2) compared with the control group (0.06±0.06cm2). We found pathological SN hyperechogenicity (⩾0.20cm2) in 41.2% of the iRBD group, 52.6% of the PD group, and 9.5% of the control group. Further, there were abnormal findings of both pathological SN hyperechogenicity (⩾0.20cm2) and functional anosmia or hyposmia in 4 (11.8%) or 9 (26.5%) of the iRBD group subjects, respectively, and 7 (57.9%) or 2 (11.8%) of the PD group subjects, respectively. Conclusion: Pathological SN hyperechogenic abnormality and functional anosmia in iRBD may be a disease state in the transition to a neurodegenerative disease. [Copyright &y& Elsevier]