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

Tourette disorder and sleep.

Healthy sleep is of utmost importance for growth, development, and overall health. Strong evidence shows that sleep is affected negatively in patients and particularly children with Tourette Disorder (TD). There is also a frequent association of TD with Attention Deficit Hyperactivity Disorder (ADHD) which alone has negative effects on sleep and cumulatively worsens the associated sleep findings. The most consistent polysomnographic findings in patients with TD is decreased total sleep time, lower sleep efficiency and an elevated arousal index. Polysomnography studies have confirmed the presence of movements and persistence of tics during both Rapid Eye Movement (REM) and NREM sleep [1]. In general Patients with TD are found to have an increased incidence of sleep onset and sleep maintenance insomnia. Some studies have shown increased incidence of parasomnias (including sleepwalking, sleep talking and night terrors), but this may be confounded by the increased underlying sleep disruptions seen in TD. The hypersomnolence found in patients with TD is also suggested to be secondary to the underlying TD sleep disruption. There is not a significant association with sleep disordered breathing or circadian rhythm disorders and TD. Treatment of underlying TD is important for the improvement of sleep related TD manifestations and is outlined in this review

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

Severe Obstructive Sleep Apnea in a Child With Goldenhar Syndrome and Nasal Obstruction.

A 4-year-old boy with Goldenhar syndrome and severe obstructive sleep apnea does not tolerate nasal continuous positive airway pressure. Evaluation with imaging showed nasal obstruction with an inverted tooth. This case illustrates the importance of personalized evaluation and treatment plan in a child with Goldenhar syndrome

When Sleeping With Eyes Closed Is Optional.

DelRosso LM, Lehnert D, Chen ML.When sleeping with eyes closed is optional. J Clin Sleep Med. 2019;15(10):1551–1553

Characterization of REM sleep without atonia in patients with narcolepsy and idiopathic hypersomnia using AASM scoring manual criteria.

INTRODUCTION: The AASM Manual for the Scoring of Sleep and Associated Events (Manual) has provided standardized definitions for tonic and phasic REM sleep without atonia (RSWA). This study used Manual criteria to characterize REM sleep in patients with narcolepsy and idiopathic hypersomnia (IH). METHODS: A retrospective review of PSG data from ICSD-2 defined patients with narcolepsy or IH, performed by two board certified sleep medicine physicians. Data compiled included REM sleep epochs and the presence in REM sleep of epochs scored as sustained muscle activity (tonic), and excessive transient muscle activity (phasic) as defined by Manual criteria. RESULTS: PSG data from 8 narcolepsy patients (mean age: 27.5 years; age range: 11-55) showed mean ± standard deviation values for: total REM sleep epochs 205 ± 46.1; RSWA/ phasic epochs 56.1 ± 25.4; and RSWA/tonic epochs 15.0 ± 10.7. PSG data from 8 IH patients (mean age: 33.1 years; age range: 20-57) showed mean ± standard deviation values of total REM sleep epochs 163.8 ± 67.9; RSWA/phasic epochs 6.2 ± 3.5; and RSWA/tonic epochs 0.2 ± 0.4. Comparison revealed intergroup differences in phasic REM sleep (p < 0.01) and tonic REM sleep (p < 0.01) were significantly increased in narcoleptics compared to IH. CONCLUSION: Our retrospective analysis showed that RSWA phasic activity and RSWA tonic activity are significantly increased in patients meeting ICSD-2 criteria for narcolepsy compared to patients meeting ICSD-2 criteria for IH. This robust difference, with further validation, could be useful as electrophysiological criteria differentiating the two disorders and understanding the physiological differences

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

Two-year-old with post-surgical hypoglossal nerve injury and obstructive sleep apnea.

BACKGROUND: Airway patency in both children and adults depends on the tonic and phasic activation of muscles of the tongue and pharynx supplied by the hypoglossal nerve arising at the medullary level. METHODS/PATIENT: We report a case of a 2-year-old who after resection of fourth ventricle anaplastic ependymoma developed severe sleep disordered breathing and tongue fasciculation. RESULTS: Polysomnography showed severe obstructive sleep apnea with oxygen desaturation to 33%. Magnetic resonance imaging of the brain showed post-surgical effacement of the dorsal lateral medulla. CONCLUSIONS: We postulate that damage to the hypoglossal nerve at the level of the medulla contributed to the patients severe obstructive sleep apnea. Patient was treated with tracheostomy

Actigraphy evaluation before and after intravenous ferric carboxymaltose in 3 children with restless sleep disorder.

UNLABELLED: Restless sleep disorder has been described in the literature as a disorder affecting children and presenting with large muscle movements during sleep with an index of 5 events/h or more, leading to daytime impairment including sleepiness or behavioral problems. Children with restless sleep disorder have been found to have low ferritin levels. Studies with iron supplementation both oral or intravenous have been shown effective in clinically improving both nighttime and daytime symptoms. However objective data of the improvement is lacking. Repeating polysomnography is expensive, and alternative methods of assessing large muscle movements are needed. In this small case series we present actigraphy results in 3 children with restless sleep disorder collected for 1 week, a week before and 8 weeks after intravenous iron supplementation. Although actigraphy parameters were not highly consistent between our 3 patients, improvement in symptoms tend to parallel sleep parameters in actigraphy. CITATION: Chu ZYB, DelRosso LM, Mogavero MP, Ferri R. Actigraphy evaluation before and after intravenous ferric carboxymaltose in 3 children with restless sleep disorder. J Clin Sleep Med. 2023;19(3):633-637

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