Current treatment options for restless legs syndrome

Restless legs syndrome (RLS) is a common but often underdiagnosed neurological disorder characterised by an imperative desire to move the extremities associated with paraesthesias, motor restlessness, worsening of symptoms at rest in the evening or at night and, as a consequence, sleep disturbances particulary. Additionally, most patients with RLS have periodic limb movements during sleep and relaxed wakefulness. The aetiology of RLS remains unknown. Treatment of RLS is generally symptomatic, a causal therapy is possible only in the secondary forms. Dopaminergic agents including levodopa and dopamine agonists such as pergolide, pramipexole, cabergoline and ropinirole are regarded as the treatment of choice for idiopathic RLS, however, the development of augmentation of symptoms, especially under levodopa therapy, may be a major problem. Except in special circumstances, opioids and anticonvulsants such as gabapentin or benzodiazepines, are regarded as second-line treatment. In secondary RLS, the underlying illness should first be treated, although dopaminergic drugs may also be helpful.     

Real-world Outcomes,Treatment Patterns and T790M Testing Rates in Non-small Cell Lung Cancer Patients Treated with First-line First- or Second-generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors from the Slovenian Cohort of the REFLECT Study

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective treatments for EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). However, routine clinical practice is different between countries/institutions.Patients and methodsThe REFLECT study ({"type":"clinical-trial","attrs":{"text":"NCT04031898","term_id":"NCT04031898"}}NCT04031898) is a retrospective medical chart review that explored real-life treatment and outcomes of EGFRm NSCLC patients receiving first-line (1L) first-/second-generation (1G/2G) EGFR TKIs in 8 countries. This study included adult patients with documented advanced/metastatic EGFRm NSCLC with 1L 1G/2G EGFR TKIs initiated between Jan 2015 – Jun 2018. We reviewed data on clinical characteristics, treatments, EGFR/T790M testing patterns, and survival outcomes. Here, we report data from 120 medical charts in 3 study sites from Slovenia.ResultsThe Slovenian cohort (median age 70 years, 74% females) received 37% erlotinib, 32% afatinib, 31% gefitinib. At the time of data collection, 94 (78%) discontinuations of 1L TKI, and 89 (74%) progression events on 1L treatment were reported. Among patients progressing on 1L, 73 (82%) were tested for T790M mutation yielding 50 (68%) positive results, and 62 (85%) received 2L treatment. 82% of patients received osimertinib. Attrition rate between 1L and 2L was 10%. The median (95% CI) real-world progression free survival on 1L EGFR TKIs was 15.6 (12.6, 19.2) months; median overall survival (95% CI) was 28.9 (25.0, 34.3) months.ConclusionsThis real-world study provides valuable information about 1G/2G EGFR TKIs treatment outcomes and attrition rates in Slovenian EGFRm NSCLC patients. The reduced attrition rate and improved survival outcomes emphasize the importance of 1L treatment decision.Key words: real-world study, non-small cell lung cancer, epidermal growth factor receptor, T790M testing, attrition     

Indications for performing polysomnography in the diagnosis and treatment of restless legs syndrome

Summary Restless legs syndrome (RLS) is diagnosed clinically by evaluating the patient's complaints. Diagnostic criteria based on the clinical symptoms were defined by the International Restless Legs Syndrome Study Group. Laboratory and/or neurophysiological assessments can differentiate a primary (idiopathic) RLS from a secondary (associated with an other disease) RLS. Some differential diagnostic and therapeutic issues may, however, require polysomnographic assessment. An investigation in the sleep laboratory should be considered in the following cases: 1) in patients with "atypical" RLS symptoms to support the diagnosis, before pharmacological treatment is begun; 2) in patients on sufficient dopaminergic treatment but still suffering from sleep disturbance, in order to exclude other sleep-related disorders; 3) in patients with mild RLS but marked daytime sleepiness as the main symptom; 4) to support the diagnosis in young patients with severe RLS before dopaminergic treatment is begun or in patients with severe RLS before the start of a treatment with opiates; 5) in patients with RLS and sleep-related respiratory disorders; 6) and finally in patients who are involved in a formal expert's opinion report. Further indications may exist in exceptional cases. A recommendation for performing polysomnography should be always made by a clinician experienced in the diagnosis and treatment of sleep disorders.     

Deficient alpha-1-antitrypsin phenotypes and persistent airflow limitation in severe asthma

BACKGROUND: Persistent airflow limitation is common among patients with severe asthma, but its pathogenesis has not been fully clarified. Severe alpha-1-antitrypsin (AAT) deficiency is a risk factor of chronic airflow limitation and emphysema, and partially deficient phenotypes have been associated with an accelerated decline in lung function. We hypothesized that partial deficiency of AAT (non-PiM AAT phenotype) is a risk factor of persistent airflow limitation in asthma. METHODS: In 122 patients with severe asthma (86 females; age (median (range)): 44.0 yr (18-75)) postbronchodilator FEV1 and FEV1/VC were measured and the AAT phenotype was determined. Persistent airflow limitation was defined as postbronchodilator FEV1 or FEV1/VC < 75% pred. with TLC > 75% pred. RESULTS: Six patients (4.9%) had a non-PiM phenotype (1 MF, 3 MS, 1 MZ and 1 SZ). Of the 58 patients with persistent airflow limitation only 1 patient (1.7%) had a non-PiM phenotype vs. 7.8% among the patients without persistent airflow limitation (P = 0.21). Postbronchodilator FEV1/VC (% pred.) was higher in the non-PiM patients than in the PiM patients (P = 0.02), the other lung function parameters were not different. Linear regression analysis showed no association between AAT phenotype and FEV1% predicted (P = 0.26). CONCLUSIONS: AAT heterozygoty does not seem to be an important risk factor of persistent airflow limitation in patients with asthma. Although confirmation by longitudinal follow-up studies with larger sample sizes is needed, these results suggest that routine assessment of the AAT phenotype is not indicated in asthmatic patients even if they exhibit fixed airflow limitation.     

PAR1-type thrombin receptor stimulates migration and matrix adhesion of human colon carcinoma cells by a PKCepsilon-dependent mechanism

The proteinase-activated receptor1 (PAR1) was characterized as a functional receptor for thrombin in cells from different tumor entities. In colon carcinoma, its function has to be defined. In this study we demonstrate that the PAR1-selective agonist peptide TFLLRN induced activation of protein kinase C isoenzymes alpha and epsilon in human HT-29 colon carcinoma cells expressing PAR1 endogeneously. On the cellular level, TFLLRN and thrombin prompted HT-29 cell migration and matrix adhesion by a PKCepsilon-dependent mechanism as concluded because of the inhibition of PAR1-mediated effects by the PKC inhibitor bisindolylmaleimide I and the PKCepsilon translocation inhibitory peptide EAVSLKPT but not by the PKC inhibitor G? 6976. In addition, blockade of PAR1 by RWJ 56110, a selective PAR1 antagonist, fully abolished the effect of thrombin on HT-29 cell migration and adhesion. Therefore, PAR1 seems to be the responsible receptor for thrombin-induced migration and adhesion of human colon carcinoma cells including PKCepsilon as an essential signal transducer.     

Quantification of mitral regurgitation during percutaneous mitral valve repair: added value of simultaneous hemodynamic and 3D echocardiographic assessment

The objective of this study was to investigate the usefulness of intraprocedural hemodynamic monitoring for MR evaluation during pMRV. Assessment of mitral regurgitation (MR) during percutaneous mitral valve repair (pMVR) procedure is challenging. 3D color Doppler allows exact quantification of MR, but is technically demanding. Sixty patients with moderate to severe MR (14 with structural and 46 functional MR) were included in the study. Intraprocedural pressure curves were continuously obtained in the left atrium (LA) and left ventricle (LV). Transesophageal echocardiography was performed using 3D color Doppler derived mean vena contracta area (VCA_mean) and mitral regurgitation volume (RegVol) to quantify MR severity before and after each clip implantation. In the entire patient group, strongest correlations were observed firstly between VCA and the raise of the ascending limb of the left atrial V pressure wave (V_ascend; r?=?0.58, p?<?0.001) and secondly between the difference of peak V wave pressure and mean LA pressure divided by systolic LV pressure [(V_peak???LA_mean)???LV_systole; r?=?0.53, p?<?0.001]. In patients with structural MR, the highest area under the ROC curve for prediction of mild MR (VCA_mean < 0.2 cm² and RegVol?<?30 ml) after clip implantation was found for V_ascend (AUC 0.89, p?<?0.001) whereas in functional MR calculation of (V_peak???LA_mean)???LV_systole showed the highest predictive value (AUC 0.69, p?=?0.003). Invasive pressure monitoring can give a direct feedback with regard to the success of clip placement during pMVR.     

Heart rate increase in otherwise subclinical seizures is different in temporal versus extratemporal seizure onset: support for temporal lobe autonomic influence.

Ictal heart rate was investigated in otherwise subclinical epileptic seizures to test the hypothesis as to whether ictal tachycardia is physiological and not a physical or psychological stress response. In addition, we aimed to evaluate the localizing significance of pure ictal tachycardia. We included 21 epilepsy patients, who showed an ictal EEG seizure pattern during 22, otherwise subclinical seizures. All patients underwent ictal video-EEG recordings to evaluate the possibility of resective epilepsy surgery. The changes in heart rate in these patients were investigated in order to determine their relationship to localization and duration of EEG seizure patterns. Ictal tachycardia was observed in 41% of the otherwise subclinical seizures (nine out of 22), and significantly more often in seizures arising from the temporal lobe than from extratemporal regions (62% versus 11%, p < 0.0018). The seizure duration as defined by EEG was significantly positively correlated with an increase of heart rate (p = 0.043). Ictal heart rate can increase as a result of epileptic activation of autonomic cortex, reflecting a temporal lobe autonomic influence. Thus, measurement of heart rate should be included in the evaluation of otherwise subclinical epileptic seizures, because of its localizing value.     

Disease course, frequency of relapses and survival of patients with juvenile or adult dermatomyositis

INTRODUCTION: The idiopathic inflammatory myopathies are systemic autoimmune diseases characterized by chronic muscle inflammation resulting progressive weakness and frequent involvement of internal organs, mainly the pulmonary, gastrointestinal and cardiac systems. OBJECTIVE: To present clinical characteristics, disease course, frequency of relapses and survival of 79 patients with juvenile or adult dermatomyositis. METHODS: A national registry of patients with juvenile dermatomyositis was elaborated by the authors in Hungary. The authors summarize data of the register such as signs and symptoms, disease course, frequency of relapses and survival of patients with juvenile dermatomyositis. Analysis was performed using data of 44 patients diagnosed between 1976 and 2004 according to Bohan and Peter's criteria. Survival probability was calculated by Kaplan-Meier method. Data of patients with juvenile dermatomyositis were compared with data of 35 patients with adult dermatomyositis. RESULTS: In view of the disease course, the authors found that more than the half of patients have monophasic disease, while one third of them suffered from polycyclic disease. The risk of the relapse was found to be higher during the first year after the remission. None of the juvenile patients died. Among adult patients, 4 disease-specific deaths occurred. DISCUSSION: There was no correlation between relapse free survival and initial therapeutic regimen. Many of the patients had polycyclic or chronic disease. As relapses can occur after a prolonged disease-free interval, patients should be followed up for at least 2 years. Despite favourable survival probability, further investigations are needed to assess functional outcome.