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

BACKGROUND: New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role. OBJECTIVE: The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment. METHODS: A 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. RESULTS: Twenty-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%). CONCLUSIONS: Dipyridamole 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.

Restless Legs Syndrome - Clinical Features.

Restless legs syndrome (RLS) is one of the most common neurologic conditions, with an estimated prevalence in European and North American heritage populations of about 2% to 5%. Because RLS diagnosis is essentially clinical, a careful evaluation of the symptoms is mandatory. It is important to exclude RLS mimics and evaluate factors that could exacerbate RLS symptoms. It is mandatory to evaluate systemic iron parameters, because the initial treatment depends on this result. Other complementary tests could help support the diagnosis or exclude mimics. The decision about when and how to treat should be carefully tailored to each patient.

Akathisia and Restless Legs Syndrome: Solving the Dopaminergic Paradox.

Akathisia is an urgent need to move that is associated with treatment with dopamine receptor blocking agents (DRBAs) and with restless legs syndrome (RLS). The pathogenetic mechanism of akathisia has not been resolved. This article proposes that it involves an increased presynaptic dopaminergic transmission in the ventral striatum and concomitant strong activation of postsynaptic dopamine D1 receptors, which form complexes (heteromers) with dopamine D3 and adenosine A1 receptors. It also proposes that in DRBA-induced akathisia, increased dopamine release depends on inactivation of autoreceptors, whereas in RLS it depends on a brain iron deficiency-induced down-regulation of striatal presynaptic A1 receptors.

Correlation between systemic iron parameters and substantia nigra iron stores in restless legs syndrome.

OBJECTIVE: To evaluate the relation between systemic iron parameters (SIP) and substantia nigra (SN) iron deposits, as assessed by transcranial sonography (TCS) in restless legs syndrome (RLS). METHODS: We conducted a cross-sectional study in RLS patients, from whom blood samples with SIP were obtained, consisting of total iron-binding capacity (TIBC), serum ferritin, hemoglobin, transferrin saturation (TSAT), serum iron, and serum transferrin. TCS was performed over the SN, and the substantia nigra echogenicity index (SNEI) was determined according to established methods. Symptom severity was evaluated using the international restless legs scale (IRLS). A Spearman correlation was performed. RESULTS: A total of 167 patients were studied. Correlations between SNEI and SIP were as follows: serum ferritin (R = 0.0422; n.s.), TSAT (R = 0.0883; n.s.), TIBC (R = -0.1091; n.s.), serum transferrin (R = -0.0420; n.s.), hemoglobin (R = 0.0185; n.s.), serum iron (R = 0.0389; n.s.). No correlation was found with age and IRLS (R = 0.1375; n.s. and R = 0.0880, n.s., respectively). CONCLUSIONS: SIP are not correlated with SN iron content in RLS, quantified by means of TCS. TCS of the SN might be a more valid estimate and could be useful in the evaluation of RLS patients.

Restless Legs Syndrome and Other Common Sleep-Related Movement Disorders.

PURPOSE OF REVIEW: In this article, the different sleep-related movement disorders are discussed with special attention given to restless legs syndrome (RLS). RECENT FINDINGS: The differential diagnosis of sleep-related movement disorders can often be challenging; therefore, it is essential to have accurate information to make a correct diagnosis. This article focuses on RLS, highlighting the change in the paradigm of initial treatment, the role played by iron (pathophysiologic and therapeutic), and how to approach possible complications occurring with long-term treatment. SUMMARY: RLS is one of the most common neurologic conditions, and it is common in clinical practice to find patients experiencing symptoms suggestive of RLS. Neurologists must be careful and thorough in the diagnosis, excluding RLS mimics. The decisions regarding which specific sleep-related movement disorder is present and how it should be treated are important because in certain cases, especially in RLS, adverse effects and long-term complications are frequently reported with the use of certain drugs.

Quantitative transcranial sonography of the substantia nigra as a predictor of therapeutic response to intravenous iron therapy in restless legs syndrome.

OBJECTIVE: To analyze changes in substantia nigra (SN) iron deposits, assessed by quantitative transcranial sonography (TCS), to obtain and compare substantia nigra echogenicity indices (SNEI) at baseline and after intravenous (IV) iron therapy in patients with restless legs syndrome (RLS)/Willis-Ekbom disease (WED). METHODS: A total of 30 consecutive subjects diagnosed with RLS/WED were recruited and underwent IV iron treatment. The SNEI, total daily dose of dopamine equivalents, and International Restless Legs Syndrome Rating Scale (IRLS) scores were obtained at baseline and following IV iron administration. Comparative statistics were performed by means of nonparametric testing. RESULTS: The sample was stratified into two groups according to the median baseline SNEI and the grade of SN hypoechogenicity: severely hypoechogenic (HE) (n = 13) and moderately HE (n = 17). Following IV iron, the increase in SNEI among severely HE subjects was 19% (0.038 ± 0.046 cm2; P < 0.01), whereas in moderately HE subjects it was 10% (0.021 ± 0.069 cm2; P = 0.28). Among severely HE subjects, the average reduction in IRLS following IV iron was 10 ± 7.12 points (P < 0.01), in contrast to 1.85 ± 9.85 (not significant) among moderately HE subjects. Finally, we quantified the percentage of patients in each group who were able to reduce by ≥30% their total daily dopaminergic requirements (TDR) after IV iron, with a 57.14% reduction in the severely HE group vs 25% in the moderately HE group (P = 0.1). Three of 30 subjects (17%) were able to completely cease all dopaminergic treatment. CONCLUSION: Intravenous iron caused changes in SNEI in both groups of patients, reflecting an increase in brain iron stores. However, the increase in SNEI was greater in patients previously defined as severely HE. Furthermore, RLS/WED symptoms also improved more in severely HE subjects, and there was a greater reduction in TDR. This study highlights the role of TCS in quantifying brain iron deposits and in predicting which patients will likely benefit from IV iron.

Low risk of iron overload or anaphylaxis during treatment of restless legs syndrome with intravenous iron: a consecutive case series in a regular clinical setting.

OBJECTIVE: To evaluate the incidence of iron overload and anaphylaxis following intravenous (IV) iron treatment of restless legs syndrome (RLS). METHODS: A total of 58 consecutive RLS patients, meeting clinical requirements for IV iron treatment according to current IRLSSG guidelines were recruited. IV iron treatment consisted of two 500 mg infusions of ferric carboxymaltose (FCM) administered five days apart. During each of the three follow-up visits we obtained blood samples, substantia nigra echogenity index (SNEI) by means of transcranial sonography (TCS), and assessed the severity of RLS symptoms (IRLS scale). "Iron overload risk" was defined as transferrin saturation (TSAT) > 45% on two consecutive follow-up visits. In patients who had a reduction in systemic iron levels following treatment, an additional 500 mg of FCM was administered when feasible. In such cases an additional two follow-up visits were performed. RESULTS: Among the total sample, only 2/58 participants met criteria for iron overload risk. They had no evidence of liver damage and did not require additional treatment. Among the 21 patients receiving an additional 500 mg infusion after, only one patient was diagnosed with iron overload risk. Among these three patients, only one was a hemochromatosis gene carrier. No anaphylaxis or other side-effects were reported. CONCLUSIONS: In real-life clinical conditions, the risk of iron overload is low when IV FCM is administered according to the safety limits defined in the current RLS treatment guidelines. However, a close clinical follow-up with periodic blood sampling for iron status, is needed.

Treating restless legs syndrome in the context of sleep disordered breathing comorbidity.

Obstructive sleep apnoea (OSA) and restless legs syndrome (RLS) are two of the most prevalent sleep disorders and can coexist within the same patient. Nonetheless, the recognition of RLS among OSA patients has important clinical implications, since RLS can disrupt sleep despite adequate treatment of sleep disordered breathing and should be treated accordingly. Furthermore, the presence of OSA can also increase the severity of RLS. Therefore, it is important to be able to correctly identify both disorders and treat them effectively. The present article reviews our current knowledge on this comorbidity and discusses potential treatment options for RLS in the context of OSA.

Non-dopaminergic vs. dopaminergic treatment options in restless legs syndrome.

Two types of drugs have been extensively investigated for the treatment of restless legs syndrome (RLS)/Willis-Ekbom disease (WED): dopamine agonists and α2δ ligands to the α2δ subunit of calcium channels. Comparative studies show that both classes of drugs are similarly effective in treating RLS symptoms over the short- and long-term. While dopamine agonists are more effective in treating periodic limb movements (PLMs), α2δ ligands are more effective in consolidating sleep. However, given the fact that dopamine agonists cause high rates of augmentation of symptoms, recent international guidelines recommend that whenever possible the initial treatment of choice should be an α2δ ligand. In fact, the most effective preventive strategy involves not using dopaminergic agents unless absolutely necessary. Indeed, should dopaminergic treatment be needed to handle the symptoms effectively, then it is recommended that the dopaminergic load be reduced by using the lowest effective dose for the shortest possible period of time. However, it must be taken into account that the only α2δ ligand approved for RLS/WED is gabapentin enacarbil, which is not yet available in Europe. Furthermore, recent studies have also reported on the efficacy of opioids as a second-line treatment of RLS/WED, following treatment failure with dopamine agonists. Recent guidelines have taken these new data into account and highlight that a low dose of an opioid (prolonged-release oxycodone or methadone) may be considered in patients with very severe augmentation of symptoms. Alternative non-dopaminergic treatment concepts based on glutamatergic and adenosinergic mechanisms are currently in development, and are likely to provide encouraging therapeutic alternatives.

Reduced response to gabapentin enacarbil in restless legs syndrome following long-term dopaminergic treatment.

OBJECTIVES: To determine whether long-term treatment with dopaminergic agents (DAs) might dampen the response to a non-dopaminergic agent, such as gabapentin enacarbil. METHODS: We performed a two-week randomized, double-blind, crossover, and placebo-controlled study in a single, referral center in dopamine treatment-naive patients and non-augmented patients continuously treated with dopaminergics for the last five consecutive years. Following washout from any previous CNS-active drugs, patients were randomized into one of two groups for two consecutive two-week treatment periods with gabapentin enacarbil (GBPen) and placebo. Treatment was administered at 7 PM at a fixed dose of 600 mg/day. RLS severity was measured weekly using the International RLS Scale (IRLS) and Clinical Global Improvement (CGI). An M-SIT was also performed between 6 pm and midnight at the end of each treatment condition. RESULTS: There were no significant differences between groups in age, sex, duration of disease, ferritin levels, RLS severity at baseline, or existing concomitant conditions. Both groups improved more during treatment with GBPen than during placebo on the IRLS scale, CGI and mSIT. However, improvements were greater in the DA-naïve group than in long-term treatment with DAs group on the IRLS (p < 0.05), CGI (p < 0.01), and mSIT (p < 0.01). CONCLUSIONS: Previous long-term treatment with DAs reduces future response to GBPen in RLS patients. Potential pathiophysiological explanations are discussed. Our finding has strong implications for the initial choice of treatment in RLS and supports the notion that initial treatment should not be started with DAs. CLASSIFICATION OF EVIDENCE: The study provides class II evidence supporting reduced effects of gabapentin enacarbil in RLS patients previously exposed to long-term treatment with dopamine agonists.

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

OBJECTIVES: Recent 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. METHODS: In 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). RESULTS: Thirteen 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. CONCLUSIONS: These 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 EVIDENCE: The study provides class III evidence supporting the therapeutic effects of dipyridamole in RLS.