Suggested Immobilization Test Research Articles

Magnesium citrate monotherapy improves RLS symptoms and multiple suggested immobilization test scores in an open-label pilot study.

An estimated 3% of the population suffers from clinically significant restless legs syndrome. Given the limited pharmacological options in the arsenal, there is a need for a therapeutic agent with a better side effect profile. Twelve treatment naïve adults (10 women and 2 men with a median age of 41.5 [32-48.5] years) with primary RLS were recruited in our open-label pilot study; magnesium citrate 200 mg was administered daily for eight weeks. Serum magnesium levels, IRLS, Kohnen QOL scale, and multiple suggested immobilization tests were performed before and after supplementation. Paired t-tests and Wilcoxon signed-rank tests were used for data analysis. Pearson and Spearman's analyses assessed the association between magnesium levels and RLS variables. Participants had a significant reduction in IRLS scores (- 6.67 [2.33-11] p=0.006) and improved Kohnen QOL scores (-8.5 [2.09-14], p=0.014) without notable differences in serum magnesium levels (p=0.3). Average PLMW across all SIT trials (30.40 [5.20, 122.40] to 8.63 [0.32, 17.47] p=0.043) and subjective measures on mSIT also demonstrated improvement. Serum magnesium levels negatively correlated with m-SIT self-reported scores and the PLMW indices. Despite the limitations of open-label design, our study's positive results indicate the need for a placebo-controlled trial with a larger sample size. clinicaltrials.gov (NCT04462796).

Hyperactivity in patients with narcolepsy and idiopathic hypersomnia: an exploratory study

IntroductionPatients with either Idiopathic Hypersomnia or Narcolepsy demonstrate excessive daytime somnolence (EDS) with resultant inattention mimicking Attention Deficit Hyperactivity Disorder (ADHD). Patients with ADHD also often express sleep problems including EDS. Thus, patients with ADHD and patients with idiopathic hypersomnia or narcolepsy may share inattention and daytime drowsiness as common features. However, it is not known whether EDS patients with idiopathic hypersomnia or narcolepsy also have increased movement (hyperactivity) like ADHD patients, the determination of which is the purpose of this study.MethodsWe studied 12 patients (7 Narcolepsy type 2 and 5 Idiopathic Hypersomnia) with EDS as shown by Multiple Sleep Latency Test which served as the gold standard for entry into the study. Twelve subjects without symptoms of EDS served as the control group. None of the participants had a previous history of ADHD. Each participant underwent a one-hour session laying at 45 degrees with surveys about the need to move and actigraphy as an objective measure of movement.ResultsSleep-disordered patients with EDS reported more symptoms of inattention and hyperactivity on the ADHD Self-Report Scale. At each of the time points patients with EDS had a clear trend to express the need to move more than controls on the Suggested Immobilization Test (SIT). For the total 60 min, a large effect size for the need to move during the SIT test was found between patients and controls (Cohen’s d = 0.61, p = 0.01). Patients with EDS did not express a need to move more to combat drowsiness than controls, nor did actigraphy show any difference in objective movement between patients and controls during the SIT.ConclusionPatients with EDS express inattention and a need to move more than controls. However, hyperactivity was not verified by objective measurement, nor did the EDS patients express a need to move to combat drowsiness more than controls. Thus, a hypothesis to be further tested, is whether narcolepsy and idiopathic hypersomnia may be more a model of the inattentive form of ADHD rather than the combined or inattentive/hyperactive form of ADHD. Further studies are needed to explore the relationship between EDS and hyperactivity.

Why the worsening at rest and worsening at night criteria for Restless Legs Syndrome are listed separately: review of the circadian literature on RLS and suggestions for future directions.

The field of circadian research on Restless Legs Syndrome (RLS) and periodic limb movements (PLMs) is reviewed in general. RLS has five obligatory criteria for diagnosis: (1) an urge to move the legs often accompanied by uncomfortable leg sensations; (2) symptoms are worse at rest, i.e., lying or sitting; (3) there is a least partial and temporary relief of symptoms by activity, e.g., walking or stretching or bending the legs; (4) symptoms are worse later in the day or at night; and (5) mimics of RLS such as leg cramps and positional discomfort should be excluded by history and physical. In addition, RLS is frequently accompanied by PLMs, either periodic limb movements of sleep (PLMS) as determined by polysomnography or periodic limb movements while awake (PLMW) as determined by the suggested immobilization test (SIT). Since the criteria for RLS were based upon clinical experience only, an early question after the development of the criteria was whether criteria 2 and 4 were the same or different phenomena. In other words, were RLS patients worse at night only because they were lying down, and were RLS patients worse lying down only because it was night? Early circadian studies performed during recumbency at different times of the day suggest that the uncomfortable sensations, PLMS, and PLMW as well as voluntary movement in response to leg discomfort follow a similar circadian pattern with worsening at night independent of body position and independent of sleep timing or duration. Other studies demonstrated that RLS patients get worse when sitting or lying down independent of the time of day. These studies as a whole suggest that the worsening at rest and the worsening at night criteria for RLS are related but separate phenomena and that criteria 2 and 4 for RLS should be kept separate based upon the circadian studies, as had been the case previously based upon clinical grounds alone. To more fully prove the circadian rhythmicity of RLS, studies should be conducted to see if bright light shifts the signs and symptoms of RLS to a different circadian time in concert with circadian markers.

Effects of acupuncture on sensory symptoms and motor signs in patients with restless legs syndrome: A crossover randomized controlled trial

Rapid effects of acupoint injection (acuinjection) at 4 acupoints (4P) (ST36, GB41, SP6, and BL60) on legs presenting sensory symptoms and motor signs in restless legs syndrome (RLS) were first described in a case report. This study aimed to confirm the beneficial effects of acuinjection. A randomized, controlled, single-blinded, prospective crossover study was conducted during 2018 to 2021. Adult volunteers (age ≥ 20 years) with RLS symptoms for > 2 weeks were included. Eight adults were enrolled and randomized to receive acuinjection (Verum group) or sham injection (Sham group). The effects of acuinjection on discomfort and periodic leg movement (PLM) were evaluated using the suggested immobilization test in a crossover design. The acupoint used was 4P, and normal saline solution (0.1-0.25 mL) was injected in both groups. Leg discomfort was measured using the visual analog scale (VAS), and PLM was measured using an electromyogram. To compare the VAS scores between the groups, repeated measures analysis of variance was used, and the Student t test was used to assess the mean discomfort score (MLDS: average of the 6 VAS scores) and PLM index (PLMI) (defined as the degree of PLM/hour). A significant difference in the VAS score was observed; however, no significant difference was noted in the PLMI between the groups. The MLDS was significantly lower in the Verum group than in the Sham group. Acuinjection at 4P remarkably inhibited leg discomfort in patients with RLS. Despite the drastic PLM suppression in 1 patient by acuinjection, a statistically significant inhibition of PLM was not confirmed. The results of our study can be applied easily and safely in clinical situations where it is necessary to temporarily reduce or eliminate RLS symptoms.

Discrepancies between self-reported and device-measured sleep parameters in adults with multiple sclerosis.

Sleep problems are a common consequence of multiple sclerosis; however, there is limited evidence regarding the agreement between device-measured and self-reported sleep parameters in adults with multiple sclerosis. The present study examined the agreement between self-reported and device-measured parameters of sleep quality in a sample of adults with multiple sclerosis. Participants (n = 49) completed a 7-day sleep diary and wore a wrist-worn ActiGraph GT3×+ (ActiGraph Corp., Pensecola, FL) for seven consecutive nights to quantify self-reported and device-measured sleep parameters, respectively. There was a significant discrepancy between self-reported and device-measured parameters of total time in bed (mean difference = 19.8 [51.3] min), sleep onset latency (mean difference = 22.2 [19.5] min), and frequency of awakenings during the night (mean difference = 12.8 [6.8]). Intraclass correlation estimates indicated poor agreement between methods on most parameters, except for total time in bed (intraclass correlation = 0.80). Bland-Altman plots suggested that total time in bed and total sleep time had acceptable levels of agreement and linear regression analyses indicated that sleep onset latency (F = 113.91, B = -1.34, P < .001), number of awakenings (F = 543.34, B = 1.85, P < .001), and sleep efficiency (F = 18.39, B = -0.77, P < .001) had significant proportional bias. Our results draw attention to the discrepancies between sleep parameter measurements and highlight the importance of including both self-report and device-measured outcomes for a complete and accurate representation of sleep in adults with multiple sclerosis. Cederberg KLJ, Mathison BG, Schuetz ML, Motl RW. Discrepancies between self-reported and device-measured sleep parameters in adults with multiple sclerosis. J Clin Sleep Med. 2022;18(2):415-421.

A Randomized, Placebo-Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome.

ABSTRACTBackgroundNew pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role.ObjectiveThe objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment.MethodsA 2‐week double‐blind, placebo‐controlled crossover study assessed the efficacy of dipyridamole (possible up‐titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Severity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response.ResultsTwenty‐eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean ± standard deviation of 24.1 ± 3.1 at baseline to 11.1 ± 2.3 at the end of week 2, versus 23.7 ± 3.4 to 18.7 ± 3.2 under placebo (P < 0.001). Clinical Global Impression, Medical Outcomes Study Sleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 ± 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 ± 3.5 versus. 28.1 ± 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%).ConclusionsDipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Validity and reliability of the suggested immobilization test for measurement of restless legs syndrome severity in adults with multiple sclerosis

Objective/backgroundAdults with multiple sclerosis (MS) often present with conditions that mimic restless legs syndrome (RLS), thereby adding complexity into the assessment of RLS severity. The current gold-standard measures of RLS severity rely on a fixed seven-day time frame, which limits the ability of these measures for studying acute changes in RLS severity. The present study examined if subjective and objective scores from the suggested immobilization test (SIT) provide a valid and reliable acute measure of RLS severity in persons with MS. Patients/methodsParticipants with MS and RLS (n = 20) and MS without RLS (n = 20) were matched by age, gender, and disability. All participants completed validated questionnaires for RLS severity followed by the SIT, conducted at 18:00 (±15 min) on the same day of the week for two consecutive weeks. Participants wore accelerometer devices for seven nights to capture periodic limb movements (PLMs) during the night. ResultsSelf-reported RLS severity during the SIT had excellent construct validity and convergent validity, but moderate test-retest reliability. Device-measured PLMs, while not themselves a direct measure of RLS severity, were significantly associated with PLMs during the night and had excellent test-retest reliability during the SIT in adults with MS. ConclusionsOur results suggest that the SIT represents a valid acute measure for capturing self-reported sensory aspects of RLS severity and should be considered in future research and clinical practice as a standardized acute measure of subjective RLS severity in adults with MS who present with RLS.

Parkinson\u2019s disease with restless legs syndrome\u2014an in vivo corneal confocal microscopy study

Small fiber neuropathy (SFN) has been suggested as a trigger of restless legs syndrome (RLS). An increased prevalence of peripheral neuropathy has been demonstrated in Parkinson’s disease (PD). We aimed to investigate, in a cross-sectional manner, whether SFN is overrepresented in PD patients with concurrent RLS relative to PD patients without RLS, using in vivo corneal confocal microscopy (IVCCM) and quantitative sensory testing (QST) as part of small fiber assessment. Study participants comprised of age- and sex-matched PD patients with (n = 21) and without RLS (n = 21), and controls (n = 13). Diagnosis of RLS was consolidated with the sensory suggested immobilization test. Assessments included nerve conduction studies (NCS), Utah Early Neuropathy Scale (UENS), QST, and IVCCM, with automated determination of corneal nerve fiber length (CNFL) and branch density (CNBD) from wide-area mosaics of the subbasal nerve plexus. Plasma neurofilament light (p-NfL) was determined as a measure of axonal degeneration. No significant differences were found between groups when comparing CNFL (p = 0.81), CNBD (p = 0.92), NCS (p = 0.82), and QST (minimum p = 0.54). UENS scores, however, differed significantly (p = 0.001), with post-hoc pairwise testing revealing higher scores in both PD groups relative to controls (p = 0.018 and p = 0.001). Analysis of all PD patients (n = 42) revealed a correlation between the duration of l-dopa therapy and CNBD (ρ = −0.36, p = 0.022), and p-NfL correlated with UENS (ρ = 0.35, p = 0.026) and NCS (ρ = −0.51, p = 0.001). Small and large fiber neuropathy do not appear to be associated with RLS in PD. Whether peripheral small and/or large fiber pathology associates with central neurodegeneration in PD merits further longitudinal studies.

Which Factors in Spinocerebellar Ataxia Type 3 Patients Are Associated with Restless Legs Syndrome/Willis-Ekbom Disease?

There is evidence of a higher prevalence of restless legs syndrome/Willis-Ekbom disease (RLS/WED) in individuals with spinocerebellar ataxia type 3 (SCA3), although the factors underlying this association remain unknown. The present study aimed to determine the prevalence of RLS/WED in SCA3 patients and to investigate which factors of SCA3 patients are associated with presence of RLS/WED. From February to August of 2006, we carried out clinical interviews in 40 controls and 40 SCA3 patients, diagnosed and followed up at Faculty of Medicine of Ribeirão Preto, University of São Paulo. Twenty-seven SCA3 patients were submitted to a detailed clinical protocol, electroneuromyography, blood work up, polysomnography (PSG), suggested immobilization test (SIT), and magnetic resonance image (MRI). RLS/WED was found in 27.5% of SCA3 patients and 2.5% of normal controls (p = 0.003). The factors related to RLS/WED in SCA3 patients were female gender, age at start of the symptoms of ataxia after 30years, presence of peripheral neuropathy, and documented iron deficiency. Among SCA3 patients, those with RLS showed higher values of maximal discomfort level and discomfort level sum compared to non-RLS individuals on SIT. There is a relation between RLS/WED and SCA3, which seems to be resultant of different factors whose identification could improve the quality of assistance to those patients as well as to promote a better comprehension of the pathophysiology of both RLS/WED and SCA3.

The urge to move: From restless legs syndrome to impulse control disorders in Parkinson's disease.

Impulse control disorders (ICDs) in Parkinson's disease (PD) are defined as a failure to resist an "urge" to behave in a way that may be debilitating for oneself or others. The suggested immobilization test (SIT) has been developed to assess the "urge" to move and support the diagnosis of restless legs syndrome (RLS) in the general population and in PD. A clinical association between RLS and ICDs has been shown in PD and in the general population. We hypothesized that there could be a semiological overlap between RLS and ICDs, and conducted SIT in PD patients with and without ICDs. Fifty PD patients with (n=17) and without (n=33) current ICDs were included. SIT, videopolysomnography, demographical treatment, and motor, psycho-behavioural and sleep characteristics, including RLS, were recorded. PD patients with ICDs reported increased subjective discomfort during SIT (SD-SIT) compared to those without ICDs (p=.024). Multivariable analysis confirmed ICDs as an independent factor associated with increased SD-SIT in PD, regardless of the presence of RLS, PD severity and dopamine agonist treatment dose. The discomfort measured by SIT might not only reflect the "urge" to move in RLS but also the ICDs in PD, suggesting that ICDs and RLS in PD could share a common phenomenology.

Sleep Disorders in Wilson's Disease.

We aimed to review the sleep disorders described in Wilson's disease (WD), focusing on their mechanisms and treatments. REM sleep behavior disorder or sleepiness can be warning signs of future WD. These early symptoms may significantly reduce the time to WD diagnosis. Early anti-copper therapies (chelators or zinc salts), reducing copper accumulation in the brain and though saving brain tissue, can allow the complete disappearance of these sleep disorders and of course improve the other symptoms of WD. Insomnia, restless legs syndrome (RLS), daytime sleepiness, cataplexy, and REM sleep behavior disorder (RBD) are present in WD and should be explored with video polysomnography and multiple sleep latency test. Suggested immobilization test could be useful in the diagnosis of RLS in WD. Motor and non-motor symptoms, dysautonomic dysfunctions, drugs, and lesions of the circuits regulating wake and sleep may be involved in the mechanisms of these sleep abnormalities. Adapted treatments should be proposed.

Increased blood pressure during the suggested immobilization test in Restless Legs Syndrome.

To investigate the relationship between sensory discomfort/motor component and cardiovascular autonomic response by continuous beat-to-beat blood pressure monitoring (CBPM) during the suggested immobilization test (SIT) in patients with restless legs syndrome (RLS). Thirty-two drug-free patients with primary RLS (10 men; mean age 60.29 ± 10.81 years) and 17 healthy controls (2 men; mean age 58.82 ± 11.86 years) underwent a 1-hour SIT starting at 8 pm with concomitant CBPM to measure the heart rate (HR) and systolic/diastolic blood pressure (SBP, DBP). In all subjects, the presence of sensory discomfort and motor component during the SIT (S-SIT+ and M-SIT+, respectively) was quantified. Mixed regression models were used to compare the SBP, DBP, and HR profiles during the SIT by taking into account the repeated measures (6 time periods of 10 minutes). In patients with S-SIT+ (n = 17), SBP (p < 0.0001), DBP (p = 0.0007), and HR (p = 0.03) increased during the SIT compared with other patients and controls. Seventeen patients had M-SIT+ (none among healthy controls). Classifying patients in 4 groups in function of the presence/absence of the SIT sensory and motor components revealed that SDB and DBP increased throughout the SIT in patients with S-SIT+, independently of the motor component (p < 0.0001 and p = 0.0008 for SBD; p < 0.0001 and p = 0.01 for DBP in the S-SIT+/M-SIT- and S-SIT+/M-SIT+ groups, respectively). During the SIT, BP concomitantly increased only in patients with RLS and sensory discomfort, with or without motor component. This highlights the link between evening sensory RLS symptoms, autonomic activation, and potential long-term cardiovascular consequences.

The urge to move in restless legs syndrome associated with Parkinson’s disease: A motor impulse control disorder?

Impulse control disorders (ICDs) in Parkinson’s disease (PD) are defined by the failure to resist an “urge to drive a conduct” that may harmful to patients themselves or others. RLS is defined by an “urge to move” the legs occurring during rest, relieved by movement, worsening in the evening or night. The suggested immobilization test (SIT) has been developed to assess the “urge to move” and support the diagnosis of RLS in general population but also in PD. We aimed to assess the impact of the presence of ICDs on the SIT in PD patients with and without RLS. Fifty consecutive non-demented PD patients participated to this cross-sectional study. Among them, patients with RLS (n = 18) and with one or more ICDs (n = 17) were identified using standard clinical criteria. All the patients underwent a SIT and a one-night videopolysomnography. Demographical, treatment, motor, psycho-behavioral and sleep characteristics were recorded. The longitudinal increase of Subjective Discomfort during SIT (SD-SIT) was higher in RLS-ICD group compared to noRLSnoICD group (p = 0,014). SD-SIT variation did not differ between patients with and without RLS (p = 0.12), however PD patients with ICD reported an increased SD-SIT variation compared to PD patients without ICDs (p = 0.024). Multivariate analysis confirmed ICD as an independent factor associated with increased SD-SIT in PD. SD-SIT could not only reflect the “urge to move” observed in RLS, but also the “urge to drive a conduct” of ICD, and more generally a motor component of impulsivity, suggesting possible semiological overlap betwen RLS and ICDs in PD.

Clinical and Polysomnographic Characteristics of Patients with Restless Legs Syndrome

Background and Objective Although restless legs syndrome (RLS) symptoms are relatively clear, many people are suffering from RLS without proper care because RLS is often underdiagnosed and misdiagnosed. Purpose of this study was to examine clinical and polysomnographic aspects of RLS to better understand the disorder for future diagnosis. Methods This study enrolled 113 idiopathic untreated RLS patients, including 74 (65.5%) women and 39 (34.5%) men. Restless legs syndrome rating scale (RLSRS) and RLS checklist were examined. All patients underwent suggested immobilization test (SIT) and polysomnogram (PSG). Results RLS occurred in all age groups. It was the most prevalent in age groups of 50s and 60s. On average, RLS was diagnosed 12.5 years after the first occurrence of RLS symptoms. RLS occurred twice as often among women than that among men. Based on average RLSRS, 57.5% and 26.5% of patients belonged to severe and very severe categories, respectively. While symptoms were the most prominent between 8 PM and 4 AM, patients reported that calves were the main site of discomfort. Of all participants, 54.9% reported family history of RLS. RLS patients’ PSGs showed lower sleep efficiency (SE), total sleep time, and slow wave percentage with higher leg movement arousal index (LMAI), arousal index, and sleep latency (SL). RLSRS was positively correlated with LMAI (r = 0.221, p < 0.05), periodic leg movement during wake index-PSG (PLMWI-PSG) (r = 0.214, p < 0.05), and SL (r = 0.207, p < 0.05). RLSRS was also negatively correlated with SE (r = -0.222, p < 0.05). RLSRS was not correlated with PLMWI-SIT or PLMI. Conclusions The results suggest that the severity of RLS patients is related to SL, LMAI, PLMWI-PSG, and SE. In order to effectively diagnose RLS, not only clinical characteristics, but also polygraphic characteristics such as SL, LMAI, PLMWI-PSG, and SE should be taken into account. Key words: Restless legs syndrome, Characteristics, Correlates, Polysomnography

Difference in Sleep Characteristics between Restless Leg Syndrome With and Without Periodic Limb Movement during Wakefulness

Objectives Restless leg syndrome (RLS) is a common sensorimotor disorder and is frequently associated with periodic limb movement in sleep (PLMS). Also about one third of patient with RLS have periodic limb movement during wakefulness (PLMW). However there is little research on the correlation between PLMW and RLS. We aimed to evaluate difference in sleep characteristics between patients with RLS with PLMW and those without PLMW. Methods Our study included twenty eight RLS patients. Subjects underwent suggested immobilization test (SIT) prior to one full-night polysomnography study. Patients were classified into two groups according to the presence of PLMW based on SIT-PLMW index. Polysomnographic findings, subjective sleep quality, and hematologic results were analyzed and compared between the two groups. Results Mean age of patient with frequent PLMW (SIT-PLMW ≥40/hr) was significantly higher. RLS patients with frequent PLMW were also significantly related to insomnia severity. The PLMS index was higher in patients with PLMW and showed a significant correlation with the PLMW index. Conclusions PLMW influence sleep quality such as insomnia and is correlated with movement during sleep. Keywords: Restless legs syndrome, Periodic leg movement during sleep, Periodic leg movement during wakefulness, Polysomnography, Suggested immobilization test.

Disconnect between sensory and motor features of restless legs syndrome during the suggested immobilization test

The Suggested Immobilization Test (SIT) was developed as an objective diagnostic tool to quantify motor restlessness periodic limb movements during wakefulness (PLMW) associated with Restless Legs Syndrome (RLS). Limited research has explored the relationship between discomfort and pain associated with motor activity in RLS during the SIT. Twenty-five RLS patients and ten control participants completed the International Restless Legs Syndrome Study Group Severity Scale and the SIT with bilateral recordings of tibialis anterior EMG (PLMW index), as well as pain and discomfort visual analogue scales every 5 min for the 60-min SIT. The discomfort score had the ability to discriminate between RLS and control participants (P = 0.0001); however, the PLMW index did not (P = 0.67). The RLS patients also exhibited greater discomfort and pain in the latter half of the SIT (P < 0.05) compared to the initial phase of the SIT and compared to controls. Despite rating significant levels of discomfort, the majority of the RLS patients did not exhibit PLMW possibly suggesting a disconnect between the sensory and motor components of RLS. These sensory and motor features may be independent and as such presentation of PLMW during the SIT may not be a reliable objective measure of RLS.

Predictors of clinical response in a double-blind placebo controlled crossover trial of gabapentin enacarbil for restless legs syndrome

ObjectivesRestless Legs Syndrome (RLS) is a sensory-motor disorder which produces sleep disturbance. Using data from a large clinical trial of gabapentin enacarbil (GEn) we sought to assess the ability of baseline, and changes from baseline, in clinical trial endpoints to predict treatment response. MethodsData were derived from a randomized, double-blind, placebo-controlled, crossover polysomnography study of gabapentin enacarbil 1200 mg (n = 121) or placebo (n = 123). Efficacy evaluations included: sleep measures from polysomnography, subjective sleep measures, Suggested Immobilization Test (SIT) measures, and International Restless Legs Severity Scale (IRLS) and Clinical Global Impression-Improvement (CGI-I). Correlations were evaluated using Spearman's rank correlation coefficients. Predictors of treatment response were separately assessed for GEn and placebo using categorical IRLS and CGI-I outcomes. Stepwise logistic regression models ascertained which combination of baseline and change from baseline variables predicted response. ResultsModerate to large correlations were observed between changes in the IRLS and changes in subjective sleep for both GEn and placebo, substantially larger for GEn than placebo. Small to moderate correlations were present between the change in IRLS and the change in SIT-discomfort for both GEn and placebo. In the stepwise regression, for both GEn and placebo, baseline and change from baseline SIT discomfort, as well as change in sleep quality, were strong predictors of response. ConclusionsChanges in sleep quality, and baseline and changes in SIT discomfort were prominent predictors of treatment response for GEn and placebo. Predictors of treatment response may allow for more targeted enrollment in future clinical trials and may provide insights into the efficacy of RLS treatments.

Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis

ObjectivesRecent animal models of restless legs syndrome (RLS) suggest that brain iron deficiency is associated with a hypoadenosinergic state, with downregulation of adenosine A1 receptors (A1R) in the striatum and cortex. We hypothesized that an increase in extracellular adenosine induced by inhibitors of adenosine transporters, such as the non-selective ENT1/ENT2 inhibitor dipyridamole, would result in an improvement in RLS symptoms. MethodsIn a prospective two-month open-label, non-placebo controlled clinical trial, 15 untreated idiopathic RLS patients began treatment with 100 mg dipyridamole (with uptitration to 400 mg if necessary). Multiple Suggested Immobilization Tests and polysomnography were performed at baseline and at eight weeks. Severity was assessed at four and eight weeks using the IRLS, and the CGI scales. The primary endpoint was therapeutic response (50% improvement in IRLS total score). ResultsThirteen patients completed the study. IRLS score improved from a mean (±S.D.) of 23.4 ± 4.6 at baseline to 10.7 ± 4.5 at eight weeks. Six out of 13 patients were full responders and four were partial responders. The mean (±S.D.) effective dose of dipyridamole at eight weeks was 281.8 ± 57.5 mg/day. Sleep variables also improved, and the mean (±S.D.) periodic leg movement index decreased from 26.7 ± 7.2 to 4.3 ± 1.9. Dipyridamole was generally well tolerated. Main side effects were abdominal cramps, diarrhea, dizziness, and flushing. ConclusionsThese preliminary results suggest that dipyridamole has significant therapeutic effects on both sensory and motor symptoms, as well as sleep. In addition, it provides evidence that hypoadenosinergic mechanisms play a central role in RLS. Classification of evidenceThe study provides class III evidence supporting the therapeutic effects of dipyridamole in RLS.

Clinical Practice Guideline on Management of Sleep Disorders in the Elderly.

Clinical Practice Guideline on Management of Sleep Disorders in the Elderly.

Treatment of restless legs syndrome with the selective AMPA receptor antagonist perampanel

ObjectivesPerampanel is a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) antagonist that has been approved for the treatment of partial seizures. Here we report on the first open study evaluating its efficacy in idiopathic restless legs syndrome (RLS). MethodsThe study was designed as a prospective two-month open trial. Twenty-two previously untreated patients diagnosed with idiopathic RLS began treatment with 2 mg perampanel, which was increased to 4 mg at week four if clinically necessary. Multiple Suggested Immobilization Tests (mSITs) followed by polysomnography were performed at baseline and at week eight. Severity ratings were performed every two weeks by means of the IRLS scale, and Clinical Global Index (CGI) subscale. The main endpoint was therapeutic response, defined as a 50% improvement in IRLS total score. ResultsTwenty patients completed the study. During the 8-week treatment period, the IRLS score improved from a mean (±standard deviation (SD)) 23.7 ± 4.2 to 11.5 ± 5.3. Twelve of 20 patients were full responders (improvement 50% in IRLS total score), and four responded partially. The mean effective dose of perampanel at the end of treatment was 3.8 mg/day. Treatment with perampanel also resulted in an improvement in the mean (±SD) periodic leg movement index from 27.8 ± 6.9 to 4.36 ± 2.0. Perampanel was well tolerated. The main side effects were dizziness, somnolence, headache, and irritability. ConclusionThese preliminary results suggest that perampanel has significant therapeutic effects on both sensory and motor symptoms. If confirmed by future controlled studies, perampanel might become a promising alternative to existing dopaminergic treatments due to its glutamatergic mechanism of action.The study provides class IV evidence supporting the therapeutic effects of perampanel in RLS/WED.