Molecular portrait of chronic joint diseases: Defining endotypes toward personalized medicine.

Joint diseases affect hundreds of millions of people worldwide, and their prevalence is constantly increasing. To date, despite recent advances in the development of therapeutic options for most rheumatic conditions, a significant proportion of patients still lack efficient disease management, considerably impacting their quality of life. Through the spectrum of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA) as quintessential and common rheumatic diseases, this review first provides an overview of their epidemiological and clinical features before exploring how the better definition of clinical phenotypes has helped their clinical management. It then discusses the recent progress in understanding the diversity of endotypes underlying disease phenotypes. Finally, this review highlights the current challenges of implementing molecular endotypes towards the personalized management of RA, PsA and OA patients in the future

A Narrative Review of the Lesser Known Medications for Treatment of Restless Legs Syndrome and Pathogenetic Implications for Their Use

Background: There are several well-known treatments for Restless Legs Syndrome (RLS), including dopamine agonists (pramipexole, ropinirole, rotigotine), anticonvulsants (gabapentin and its analogs, pregabalin), oral or intravenous iron, opioids and benzodiazepines. However, in clinical practice, treatment is sometimes limited due to incomplete response or side effects and it is necessary to be aware of other treatment options for RLS, which is the purpose of this review. Methods: We performed a narrative review detailing all of the lesser known pharmacological treatment literature on RLS. The review purposefully excludes well-established, well-known treatments for RLS which are widely accepted as treatments for RLS in evidence-based reviews. We also have emphasized the pathogenetic implications for RLS of the successful use of these lesser known agents. Results: Alternative pharmacological agents include clonidine which reduces adrenergic transmission, adenosinergic agents such as dipyridamole, glutamate AMPA receptor blocking agents such as perampanel, glutamate NMDA receptor blocking agents such as amantadine and ketamine, various anticonvulsants (carbamazepine/oxcarbazepine, lamotrigine, topiramate, valproic acid, levetiracetam), anti-inflammatory agents such as steroids, as well as cannabis. Bupropion is also a good choice for the treatment of co-existent depression in RLS because of its pro-dopaminergic properties. Discussion: Clinicians should first follow evidence-based review recommendations for the treatment of RLS but when the clinical response is either incomplete or side effects are intolerable other options can be considered. We neither recommend nor discourage the use of these options, but leave it up to the clinician to make their own choices based upon the benefit and side effect profiles of each medication

Focus on the complex interconnection between cancer, narcolepsy and other neurodegenerative diseases: A possible case of orexin-dependent inverse comorbidity

Conditions such as Alzheimer’s (AD) and Parkinson’s diseases (PD) are less prevalent in cancer survivors and, overall, cancer is less prevalent in subjects with these neurodegenerative disorders. This seems to suggest that a propensity towards one type of disease may decrease the risk of the other. In addition to epidemiologic data, there is also evidence of a complex biological interconnection, with genes, proteins, and pathways often showing opposite dysregulation in cancer and neurodegenerative diseases. In this narrative review, we focus on the possible role played by orexin signaling, which is altered in patients with narcolepsy type 1 and in those with AD and PD, and which has been linked to β-amyloid brain levels and inflammation in mouse models and to cancer in cell lines. Taken together, these lines of evidence depict a possible case of inverse comorbidity between cancer and neurodegenerative disorders, with a role played by orexins. These considerations suggest a therapeutic potential of orexin modulation in diverse pathologies such as narcolepsy, neurodegenerative disorders, and cancer

Nocturnal Hypermotor Activity during Apnea-Related Arousals

We present a case of a 50-year-old patient who exhibits nocturnal hypermotor activity occurring exclusively during apnea-related arousals consisting of repetitive lower extremity hip-flapping. This movement is unusual and reflects a new form of lower extremity movement associated with apnea-related arousals. CITATION: Hoque R, DelRosso LM. Nocturnal hypermotor activity during apnea-related arousals. J Clin Sleep Med 2016;12(9):1305–1307

Heart rate variability during sleep in children and adolescents with restless sleep disorder: a comparison with restless legs syndrome and normal controls

Study Objectives: Restless sleep disorder (RSD) has recently been characterized clinically and polysomnographically in children and differentiated from restless legs syndrome (RLS). Heart rate variability is a reliable method to quantify autonomic changes during sleep. The aim of this study was to characterize heart rate variability in children with RSD, RLS, and individuals without these disorders, with the hypothesis that children with RSD have a shift toward sympathetic predominance during sleep. Methods: We analyzed polysomnographic recordings from 32 children who fulfilled RSD diagnostic criteria (19 boys and 13 girls), 32 children with RLS (20 boys and 12 girls), and 33 individuals without disorders (17 boys and 16 girls). Four electrocardiographic epochs were chosen, 1 for each stage, and were analyzed for automatic detection of R waves. Time domain and frequency domain heart rate variability parameters were obtained and analyzed. Results: In terms of time domain, only the standard deviation of the average interval between successive R waves during stage N3 was slightly but significantly higher in patients with RSD than in patients with RLS. In terms of frequency domain, in patients with RSD, the very-low-frequency and low-frequency bands were increased (vs patients with RLS and individuals without disorders, respectively), whereas low-frequency/high-frequency ratio tended to be increased in both patients with RSD and with RLS. In rapid eye movement sleep, low-frequency/high-frequency ratio was increased in both patients with RSD and with RLS. The low-frequency/high-frequency ratio increased in patients with RLS during quiet wakefulness preceding sleep. Conclusions: Children with RSD have increased sympathetic activation during sleep, particularly N3 and rapid eye movement sleep, compared with individuals without disorders but, as expected, not during wakefulness. Differently, children with RLS have sympathetic activation during relaxed wakefulness preceding sleep and during sleep

Restless sleep disorder in children. A pilot study on a tentative new diagnostic category

A group of children with "restless sleep" who do not fit the criteria for any other sleep disorder but with daytime impairment are studied to identify restless sleep disorder (RSD) clinically and polysomnographically and to differentiate it from other sleep disorders of childhood

Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations

After a detailed description of orexins and their roles in sleep and other medical disorders, we discuss here the current clinical evidence on the effects of dual (DORAs) or selective (SORAs) orexin receptor antagonists on insomnia with the aim to provide recommendations for their further assessment in a context of personalized and precision medicine. In the last decade, many trials have been conducted with orexin receptor antagonists, which represent an innovative and valid therapeutic option based on the multiple mechanisms of action of orexins on different biological circuits, both centrally and peripherally, and their role in a wide range of medical conditions which are often associated with insomnia. A very interesting aspect of this new category of drugs is that they have limited abuse liability and their discontinuation does not seem associated with significant rebound effects. Further studies on the efficacy of DORAs are required, especially on children and adolescents and in particular conditions, such as menopause. Which DORA is most suitable for each patient, based on comorbidities and/or concomitant treatments, should be the focus of further careful research. On the contrary, studies on SORAs, some of which seem to be appropriate also in insomnia in patients with psychiatric diseases, are still at an early stage and, therefore, do not allow to draw definite conclusions

Characterization of Sleep Spindle Index in Patients with Narcolepsy and Idiopathic Hypersomnia

This is a retrospective review of PSG data from 8 narcolepsy patients and 8 idiopathic hypersomnia (IH) patients, evaluating electrophysiologic differences between these two central hypersomnias. Spindles were identified according to the AASM Manual for the Scoring of Sleep and Associated Events; and counted per epoch in the first 50 epochs of N2 sleep and the last 50 epochs of N2 sleep in each patient's PSG. Spindle count data (mean ± standard deviation) per 30 second-epoch (spindle index) in the 8 narcolepsy patients was as follows: 0.37 ± 0.73 for the first 50 epochs of N2; 0.65 ± 1.09 for the last 50 epochs of N2; and 0.51 ± 0.93 for all 100 epochs of N2. Spindle index data in the 8 IH patients was as follows: 2.31 ± 2.23 for the first 50 epochs of N2; 2.84 ± 2.43 for the last 50 epochs of N2; and 2.57 ± 2.35 for all 100 epochs of N2. Intergroup differences in spindle count in the first 50 N2 epochs, the last 50 N2 epochs, and all 100 epochs of scored N2 were significant ( < 0.01) as were the intragroup differences between the first 50 N2 epochs and the last 50 N2 epochs