Current and emerging pharmaceutical strategies for the treatment and management of restless legs syndrome.

INTRODUCTION: Restless legs syndrome (RLS) is a sensory-motor sleep disorder that affects up to 13% of adults in the Western world and 2-4% of children. It impairs night sleep with an impact on daily performances and life quality. Thus, moderate-to-severe RLS requires pharmacological treatment. AREAS COVERED: In the present review, which is based on PubMed searches with no time limits, the authors discuss the recommended pharmacotherapy for RLS in addition to other emerging treatment options. The authors provide coverage to the current recommendations for both adults and pediatric patients with RLS. EXPERT OPINION: Current evidence suggests removing all causes of secondary RLS, including iron deficiency, chronic renal failure, drugs, and treating other sleep disorders that may worsen symptoms. Also, intermittent RLS should be addressed with behavioral measures and on-demand therapy. For chronic persistent RLS, α2δ calcium channel ligands are a first-line pharmacological approach, whereas dopamine agonists are associated with increased risk and should be spared. When RLS is refractory to first-line treatment, polytherapy, or opioid monotherapy should be considered. Nonetheless, some patients may not reach sustained symptom relief. Further research is needed to better understand the pathophysiology of RLS and to develop newer more effective drugs.

Perampanel as add-on therapy in epilepsies with known etiology: A single center experience with long-term follow-up.

We report a retrospective monocentric study performed on 63 patients affected by epilepsy with known etiology, receiving perampanel as add-on therapy with at least 12-month follow-up. The purpose of our study was to evaluate efficacy and tolerability of perampanel in this group of epilepsies. Patients were classified into 2 groups based on the presence/absence of a single focal brain lesion on MRI, as epilepsy etiology: 48 subjects were affected by focal lesional epilepsy and 15 by non-focal lesional epilepsy. The retention rate was 76.2% and 53.9% at 12 and 24 months respectively. At 12 months, at least 40% of patients resulted responders, with a significant reduction in seizure frequency (p = 0.01), confirmed at 24 months. Considering epilepsy etiology, we found a better PER response in patients with focal lesional epilepsy. A significant correlation was observed between responder rates and EEG pattern. Only 30% of patients reported mild-moderate adverse events. Efficacy and tolerability of PER, in our study, are in line with the results reported in other real-world studies. Our data suggest the possibility of better PER response in patients with focal brain lesions, which indicates that this drug could be a therapeutic option in this population.

Orgasmolepsy in Narcolepsy Type 1 Responsive to Pitolisant: A Case Report.

We describe a case of a young male patient with narcolepsy type 1 (NT1), who developed generalized cataplexy attacks during sexual intercourses, on which we have obtained a satisfactory control with pitolisant. Orgasmolepsy is an uncommon feature of NT1 that has been poorly described in the literature. The prevalence of this condition is unclear, as it is reasonably underreported by patients for embarrassment and not well investigated by physicians. Pitolisant is a novel treatment for narcolepsy, effective on excessive daytime sleepiness and cataplexy by modulating the histaminergic system. Real-world data collection on pitolisant efficacy and safety is still ongoing. However, pitolisant effectiveness on orgasmolepsy in NT1 has no precedent in the literature. Orgasmolepsy and other sexual disturbances should be actively searched in narcoleptic patients and, if present, may guide clinicians to prefer pitolisant or sodium oxybate, avoiding antidepressants for their possible sexual side effects.

Pre-Procedural Statin Use Is Associated with Improved Long-Term Survival and Reduced Major Cardiovascular Events in Patients Undergoing Carotid Artery Stenting: A Retrospective Study.

Carotid artery stenting (CAS) is a minimal invasive procedure used to resolve carotid occlusion that can be affected by peri-procedural complications. Statin use before CAS has shown to reduce peri-procedural risk and improve survival, though time-dependent cofactors that influence mortality has not been considered. The aim of this study was to evaluate long-term survival of patients who undergo CAS considering new occurred major adverse cardiovascular event (MACE) as time-dependent cofactor. In this study, 171 high cardiovascular risk patients (age 72 ± 8 years, 125 males) were enrolled after CAS procedure and were followed for a median of 8.4 years. Death occurred in 44% of patients with a mean time to death of 69 ± 39 months and MACE in 34% with a mean time of 35 ± 42 months. In patients who used or not statins at baseline, death occurred in 33% and 65%, respectively (p < 0.001). Survival analysis showed that statin use reduced risk of death (hazard ratio HR 0.36, 95% confidence interval CI 0.23⁻0.58, p < 0.0001). Including MACE as time-dependent variable did not change beneficial effects of statins. Additionally, statin use was associated with a protective effect on MACE (HR 0.48, 95% CI 0.27⁻0.85, p = 0.012); particularly, the prevalence of stroke was reduced by 59% (p = 0.018). In multivariate analysis, effects of statins were independent of demographic and anthropometric variables, prevalence of cardiovascular risk factors, renal function, antiplatelet use, and MACE occurrence. In conclusion, use of statins before CAS procedure is associated with increased long-term survival and reduced MACE occurrence. This evidence supports the hypothesis that statin use before CAS might be beneficial in high risk patients.

Maintenance of Wakefulness and Occupational Injuries among Workers of an Italian Teaching Hospital.

BACKGROUND: To assess in a laboratory setting the ability to stay awake in a sample of workers of an Italian hospital and to investigate the association between that ability and the risk of occupational injury. METHODS: Nine workers at the University Hospital of Udine who reported an occupational injury in the study period (cases), and seven noninjured workers (controls) underwent a polysomnography and four 40-minute maintenance of wakefulness tests (MWT). Differences in sleep characteristics and in wakefulness maintenance were assessed using Wilcoxon's rank sums tests and Fisher's exact tests. RESULTS: Controls had greater sleep latency, lower total sleep time, fewer leg movements, and a higher percentage ratio of cycling alternating pattern, were more likely not to fall asleep during the MWT and were less likely to have two or more sleep onsets. Although not all the differences reached statistical significance, cases had lower sleep onset times in Trials 1-3. CONCLUSION: In the literature, the evidence of an association between MWT results and real life risk of accidents is weak. Our results suggest a relationship between the MWT results and the risk of injury among hospital workers.

Association of body rolling, leg rolling, and rhythmic feet movements in a young adult: A video-polysomnographic study performed before and after one night of clonazepam.

We report clinical and polysomnographic data of a young adult affected by several forms of rhythmic movement disorder (RMD), present in the same night, including a new kind of it, known as rhythmic feet movements. The patient was monitored by means of three consecutive video-polysomnographic recordings, the first two performed to confirm the presence of the sleep disorder and the last one to observe the acute effectiveness of clonazepam on rhythmic movements. We discuss the characteristics of the RMD and the response to the first administration of pharmacological treatment, observed in our patient.

Association of restless legs syndrome in type 2 diabetes: a case-control study.

STUDY OBJECTIVE: To look for an association between restless legs syndrome (RLS) and type 2 diabetes in a case-control study; to analyze the characteristics of RLS in diabetic patients; and to identify possible risk factors for the development of RLS in diabetic patients. DESIGN: A case-control study. SETTING: Diabetic outpatient clinic of a major university hospital. PARTICIPANTS: One hundred twenty-four consecutive outpatients with diabetes and 87 consecutive controls with a previous diagnosis of other endocrine disease. INTERVENTIONS: RLS was diagnosed using the criteria of the International RLS Study Group, and severity of RLS was assessed using the International RLS Study Group Rating Scale. Characteristics of RLS and several laboratory parameters were investigated in diabetic patients and controls affected by the sleep disorder. A clinical diagnosis of polyneuropathy was assessed to evaluate its role as a risk factor for RLS in diabetic patients. MEASUREMENT AND RESULTS: RLS was diagnosed in 22 diabetic patients (17.7%) and in only 5 controls (5.5%), 3 of whom had pituitary and 2 had adrenal gland disorders, and RLS was independently associated with type 2 diabetes (P < 0.04). Even if a clinical diagnosis of polyneuropathy was made in only 27% of diabetic patients affected by RLS, after multivariate logistic regression, the presence of polyneuropathy was the only variable associated with RLS in diabetics (odds ratio, 7.88; 95% confidence interval, 1.34-46.28; P < 0.02). RLS in diabetics showed a frequency of positive family history lower than that known for primary RLS, showed a late age of onset, and manifested itself after the diagnosis of diabetes was made. CONCLUSIONS: This is the first controlled study confirming a significant association between RLS and type 2 diabetes. In diabetic patients, polyneuropathy represents the main risk factor for RLS. However, polyneuropathy only partially explains the increased prevalence of RLS in type 2 diabetics. Clinical characteristics of RLS in diabetic patients are those of a secondary form.

The acute effect of a low dosage of pramipexole on severe idiopathic restless legs syndrome: an open-label trial.

BACKGROUND: Pramipexole is a D3 dopaminergic agonist that has shown a major effect on both sensory and motor manifestations of restless legs syndrome (RLS) in long-term trials. No data regarding the acute effect of low doses of pramipexole have been reported. OBJECTIVE: To evaluate the acute effect of a low dosage of pramipexole (0.125 mg) on sensory symptoms and motor signs of RLS and on the macro- and microstructure of sleep. METHODS: We initially recruited 13 patients affected by severe idiopathic RLS and included 10 of them in our study. For 2 consecutive nights the selected patients were evaluated. Pramipexole 0.125 mg was administered before the second night at 9:00 p.m. A visual analog scale was used to assess the sensory symptoms of RLS. The motor manifestations of RLS and the architecture of sleep were analyzed by polysomnography. RESULTS: After the acute administration of pramipexole, we observed a significant improvement of the sensory symptoms and motor signs of RLS. Several sleep macrostructure and microstructure parameters improved as well. CONCLUSIONS: Our results suggest that low doses of pramipexole are effective in reducing sensory symptoms and motor signs of RLS, even after the first administration.

Sleep disorders in patients with end-stage renal disease undergoing dialysis therapy.

BACKGROUND: Many patients with end stage renal disease (ESRD) undergoing dialysis therapy suffer from sleep disturbances. The aim of this study was to investigate the prevalence of sleep disorders in a large population of uraemic patients recruited from 20 different dialytic centres in Triveneto. METHODS: 883 patients on maintenance dialysis were enrolled in the study. Demographic, lifestyle, renal and dialysis data were recorded. Renal parameters were compared with the database of the Veneto Dialysis Register. Using a self-administered questionnaire we assessed the presence of the following sleep disorders: insomnia, restless leg syndrome (RLS), obstructive sleep apnoea syndrome (OSAS), excessive daytime sleepiness (EDS), possible narcolepsy, sleepwalking, nightmares and possible rapid eye movement behaviour disorders (RBD). Moreover, in order to determine the prevalence of sleep disturbances and the possible effect of demographic or clinical data on sleep, we divided our population into two groups: with (SLEEP+) and without (SLEEP-) sleep disorders. RESULTS: The questionnaire revealed the presence of insomnia (69.1%), RLS (18.4%), OSAS (23.6%), EDS (11.8%), possible narcolepsy (1.4%), sleepwalking (2.1%), nightmares (13.3%) and possible RBD (2.3%). Eighty percent demonstrated SLEEP+, having at least one sleep disorder. Independent risk factors for sleep disorders were advanced age (P<0.001), excessive alcohol intake (P<0.04), cigarette smoking (P<0.006), polyneuropathy (P<0.05) and dialysis shift in the morning (P<0.001). CONCLUSIONS: The questionnaire showed a high presence of sleep disruption in dialytic populations. Awareness by Italian nephrologists regarding sleep disruption seems to be insufficient. Our data might help nephrologists to deal with uraemic patients with possible sleep disorders. Concerning the high prevalence of possible narcolepsy, further studies using polysomnographic records are necessary to confirm our results.

Restless legs syndrome in end-stage renal disease.

BACKGROUND AND PURPOSE: Patients undergoing dialysis therapy due to end-stage renal disease (ESRD) present a high prevalence of sleep disorders, including restless legs syndrome (RLS). However, the known data generally have been obtained from relatively small patient samples, coming from single or very few dialysis units. Moreover, some data were collected prior to the recent improvements in dialysis techniques, pharmacological therapies and to the establishment of internationally recognised diagnostic criteria for RLS. PATIENTS AND METHODS: In order to study the incidence of the different sleep disorders, and of RLS in particular, in a large population of dialysis patients, a questionnaire was administered to all the patients in dialysis units of the 'Triveneto' area (Italy) who agreed to participate. The first part of the questionnaire included questions about demographic data, general medical history, history of renal disease, dialytic treatment and pharmacological therapy. The second part, which was self-administered, explored the patient's complaints about sleep, the presence of the minimal International Restless Legs Syndrome Study Group (IRLSSG) criteria for the diagnosis of RLS, the Epworth Sleepiness Scale and questions particularly related to somnolence. Patients whose responses indicated a diagnosis of RLS according to the IRLSSG criteria were requested to answer the 10 questions of the IRLSSG Severity Scale. The same group of patients was compared to those who did not fulfil any of the four minimal criteria for RLS. Statistical analysis was performed by using ANOVA and non-parametric tests. Whenever possible, data were compared with the database of the Veneto Dialysis Register. The first 601 consecutive questionnaires that we were able to analyse are presented in this paper. RESULTS: Applying the IRLSSG criteria for the diagnosis, the percentage of RLS patients in our sample was 21.5%, with a score of 20.5+/-8.7 on the IRLSSG Severity Scale. Comparing patients who are definitely affected by RLS (n=127) with unaffected patients (n=280), we found that the two groups did not differ as to age, sex, weight, body mass index (BMI), and intake of nicotine, alcohol and caffeine. Similarly, the two groups did not differ as to the etiology of ESRD, type of dialysis or percentage of previous transplantations; however, the period of dialysis dependence was significantly lower in the group negative for RLS. The use of drugs did not differ in the two groups, except for lower intake of phosphorus binders and antihypertensive drugs among RLS patients. No patient was receiving specific treatment for RLS. RLS patients reported more fragmented, less restful nightly sleep and more daytime somnolence, more often presented symptoms of other sleep disorders and were more affected by anxiety or depression. CONCLUSIONS: The high prevalence of RLS and other sleep disorders among uremics requires careful investigation of nocturnal sleep; although often underdiagnosed, correct identification of these disorders can lead to better therapy and improvement of clinical conditions and quality of life. Sleep fragmentation and sleep deprivation caused by RLS may contribute to the cardiovascular complications and infections, often with bad prognosis in dialysis patients.