Rethinking clinical trials in restless legs syndrome: A roadmap.

The number of large clinical trials of restless legs syndrome (RLS) have decreased in recent years, this coincides with reduced interest in developing and testing novel pharmaceuticals. Therefore, the International Restless Legs Syndrome Study Group (IRLSSG) formed a task force of global experts to examine the causes of these trends and make recommendations to facilitate new clinical trials. In our article, we delve into potential complications linked to the diagnostic definition of RLS, identify subpopulations necessitating more attention, and highlight issues pertaining to endpoints and study frameworks. In particular, we recommend developing alternative scoring methods for more accurate RLS diagnosis, thereby improving clinical trial specificity. Furthermore, enhancing the precision of endpoints will increase study effect sizes and mitigate study costs. Suggestions to achieve this include developing online, real-time sleep diaries with high-frequency sampling of nightly sleep latency and the use of PLMs as surrogate markers. Furthermore, to reduce the placebo response, strategies should be adopted that include placebo run-in periods. As RLS is frequently a chronic condition, priority should be given to long-term studies, using a randomized, placebo-controlled, withdrawal design. Lastly, new populations should be investigated to develop targeted treatments such as mild RLS, pregnancy, hemodialysis, or iron-deficient anemia.

HLA dependency and possible clinical relevance of intrathecally synthesized anti-IgLON5 IgG4 in anti-IgLON5 disease.

Background: Anti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance. Methods: IgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method. Results: The median age at onset was 66 years (range: 54-75), disease duration 10 years (range: 15-156 months), and follow-up 25 months (range: 0-83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab. Conclusion: Our findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease.

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

Effect of positive airway pressure treatment on excessive fragmentary myoclonus in 100 sleep-related breathing disorder patients.

STUDY OBJECTIVES: Excessive fragmentary myoclonus (EFM) is a frequent finding in patients undergoing video-polysomnography (VPSG). We aimed to evaluate the potential effect of sleep-related breathing disorder's treatment with positive airway pressure (PAP) therapy on EFM. METHODS: One hundred consecutive patients with EFM and sleep-related breathing disorder subsequently treated with PAP at the sleep lab of the Medical University of Innsbruck, Department of Neurology, Austria, were included. Each patient underwent two nights of VPSG: the first night without and the second night with PAP therapy. Fragmentary myoclonus was automatically scored with validated software, and fragmentary myoclonus index (FMI) and minutes of non-rapid eye movement (NREM) sleep with EFM (minNREM+EFM) were calculated. RESULTS: Under PAP therapy there was a significant decrease in the minNREM+EFM - 60.5 (9.5-161.8) at baseline vs. 37.5 (6.3-168.8) minutes under PAP, p = 0.025. No significant differences were observed for FMI between the two nights. Sleep variables, sleep diagnoses, comorbidities, and medication did not influence FMI or the minNREM+EFM. CONCLUSIONS: The initiation of PAP treatment led to a significant reduction of minNREM+EFM, but not of FMI. The results suggest that PAP therapy might influence the distribution of FM potentials.

Genetic Determined Iron Starvation Signature in Friedreich's Ataxia.

BACKGROUND: Early studies in cellular models suggested an iron accumulation in Friedreich's ataxia (FA), yet findings from patients are lacking. OBJECTIVES: The objective is to characterize systemic iron metabolism, body iron storages, and intracellular iron regulation in FA patients. METHODS: In FA patients and matched healthy controls, we assessed serum iron parameters, regulatory hormones as well as the expression of regulatory proteins and iron distribution in peripheral blood mononuclear cells (PBMCs). We applied magnetic resonance imaging with R2*-relaxometry to quantify iron storages in the liver, spleen, and pancreas. Across all evaluations, we assessed the influence of the genetic severity as expressed by the length of the shorter GAA-expansion (GAA1). RESULTS: We recruited 40 FA patients (19 women). Compared to controls, FA patients displayed lower serum iron and transferrin saturation. Serum ferritin, hepcidin, mean corpuscular hemoglobin and mean corpuscular volume in FA inversely correlated with the GAA1-repeat length, indicating iron deficiency and restricted availability for erythropoiesis with increasing genetic severity. R2*-relaxometry revealed a reduction of splenic and hepatic iron stores in FA. Liver and spleen R2* values inversely correlated with the GAA1-repeat length. FA PBMCs displayed downregulation of ferritin and upregulation of transferrin receptor and divalent metal transporter-1 mRNA, particularly in patients with >500 GAA1-repeats. In FA PBMCs, intracellular iron was not increased, but shifted toward mitochondria. CONCLUSIONS: We provide evidence for a previously unrecognized iron starvation signature at systemic and cellular levels in FA patients, which is related to the underlying genetic severity. These findings challenge the use of systemic iron lowering therapies in FA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effects of periodic breathing on sleep at high altitude: a randomized, placebo-controlled, crossover study using inspiratory CO2.

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo-controlled approach to prevent nPB by increasing inspiratory CO2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single-blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO2 , and CO2 concentration in the canopy (i.e. inspiratory CO2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%-2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%-80.8%) and 45.0% (24.5%-56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO2 reduced TST with nPB by an absolute 38.1% (28.1%-48.1%), the apnoea-hypopnoea index by 58.1/h (40.1-76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1-73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%-3.5%, P = 0.035). Increased inspiratory CO2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO2 effectively prevented hypoxia-induced nPB without affecting sleep macro-architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. KEY POINTS: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture. We developed a placebo-controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia. Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO2 fraction in a blinded manner. Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia. We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude.

Clinical neurophysiology of REM parasomnias: Diagnostic aspects and insights into pathophysiology.

Parasomnias are due to a transient unstable state dissociation during entry into sleep, within sleep, or during arousal from sleep, and manifest with abnormal sleep related behaviors, perceptions, emotions, dreams, and autonomic nervous system activity. Rapid eye movement (REM) parasomnias include REM sleep behavior disorder (RBD), isolated recurrent sleep paralysis and nightmare disorder. Neurophysiology is key for diagnosing these disorders and provides insights into their pathophysiology. RBD is very well characterized from a neurophysiological point of view, also thank to the fact that polysomnography is needed for the diagnosis. Diagnostic criteria are provided by the American Academy of Sleep Medicine and video-polysomnography guidelines for the diagnosis by the International REM Sleep Behavior Disorder Study Group. Differences between the two sets of criteria are presented and discussed. Availability of polysomnography in RBD provides data on sleep electroencephalography (EEG), electrooculography (EOG) and electromyography (EMG). Sleep EEG in RBD shows e.g. changes in delta and theta power, in sleep spindles and K complexes. EMG during REM sleep is essential for RBD diagnosis and is an important neurodegeneration biomarker. RBD patients present alterations also in wake EEG, autonomic function, evoked potentials, and transcranial magnetic stimulation. Clinical neurophysiological data on recurrent isolated sleep paralysis and nightmare disorder are scant. The few available data provide insights into the pathophysiology of these disorders, demonstrating a state dissociation in recurrent isolated sleep paralysis and suggesting alterations in sleep macro- and microstructure as well as autonomic changes in nightmare disorder.