Treatment of Sleep-Related Movement Disorders

By | March 29, 2012

Sleep-related movement disorders represent a newly established category of sleep disorders in the new International Classification of Sleep Disorders, second edition (ICSD-2), recently published. This category includes restless legs syndrome (restless legs syndrome), periodic limb movement disorder (periodic limb movement disorder), sleep-related leg cramps, sleep-related bruxism, sleep-related rhythmic movement disorders (RMDs), sleep-related movement disorder due to a drug or substance, and sleep-related movement disorder due to a medical condition; finally sleep-related movement disorder, unspecified when the disturbance does not fit into any of the above disorders. Some of these entities were previously categorized within the parasomnias or the wake-sleep transition disorders. Mostly, they involve simple, stereotyped movements during sleep or at the transition between waking and sleeping. Restless legs syndrome is a more complex disease with sensory disturbances occurring at rest and in the evening, and in which the motor accompaniment is mainly represented by the periodic limb movements in sleep (periodic limb movements in sleep). All of these sleep-related movement disorders may cause fragmented sleep, insomnia, and / or excessive daytime sleepiness (excessive daytime sleepiness).

Management of Restless Legs Syndrome

Management of Periodic Limb Movement Disorder

Management of Rhythmic Movement Disorder

Management of Sleep-Related Bruxism

Management of Sleep-Related Leg Cramps

Management of Alternating Leg Muscle Activation (Hypnagogic Foot Tremor; Rhythmic Feet Movements While Falling Asleep)

Hypnagogic foot tremor is a sleep-related movement disorder originally described by Broughton as rhythmic foot / leg movements during sleep or at the wake-sleep transition. Recently, alternating leg muscle activation and rhythmic feet movements while falling asleep have been reported, but the relations between these latter entities and the hypnagogic foot tremor of Broughton are still unclear. All may indeed represent normal variants of sleep and as such they are classified in the ICSD-2 section VII: isolated symptoms, apparently normal variants, and unresolved issues. rhythmic feet movements occurred in 7.5% of polysomnographic recordings in a sleep disorder center as single, short series of leg muscle bursts with a duration of between 10 and 15 seconds especially during pre-hypnic wakefulness and light sleep. rhythmic feet movements did not have any major sleep-disturbing effect in any of the affected subjects, and it was therefore concluded that rhythmic feet movements could be considered a quasi-physiological phenomenon. However, in more severe forms of rhythmic feet movements with evidence of a sleep-disturbing effect, rhythmic feet movements was considered abnormal, but no indication was given concerning management. Alternating leg muscle activation was described by Chervin et al. as a quickly alternating pattern of anterior tibialis activation in 16 patients examined for sleep-disordered breathing and also showing periodic limb movements in sleep. Brief activations of the tibialis anterior in one leg alternated with similar activation in the other leg, with a frequency of about 1 to 2 Hz. Remarkably, 12 of the 16 patients were undergoing treatment with antidepressants, suggesting a pharmacological effect. Alternating leg muscle activation has been reported in restless legs syndrome, and Cosentino et al. described a patient with alternating leg muscle activation associated with insomnia and daytime sleepiness, in whom pramipexole was effective in curtailing the leg movements and in improving insomnia and excessive daytime sleepiness. This suggested that alternating leg muscle activation may be related to dysfunction in dopaminergic systems.

Future Research

Studies of restless legs syndrome treatment have been particularly robust and include some with the highest evidentiary quality. Nevertheless, there has been a substantial imbalance in the treatment areas investigated. First, studies have concentrated on treatments of daily restless legs syndrome and have not provided much evidence for on-demand treatment of intermittent restless legs syndrome. Second, almost all large-scale trials have employed dopamine agonists as treatment. While there is evidence for other drug classes, this is generally of lower quality. The efficacy and safety of anticonvulsants, opioids, and sedative-hypnotics as well as iron supplements and infusions needs much more investigation. Recent investigations of a gabapentin prodrug that have not yet been published begin to reduce this lack. Third, there are limited studies of special populations (children, pregnant women, patiens with kidney failure) who may also have clinically significant restless legs syndrome. Fourth, there have been few comparative trials or studies looking into combination treatment. Fifth, nonpharmacological, adjunctive, and complementary or alternative medicine treatments have received scant investigation. Sixth, the almost complete reliance on oral medications has just begun to subside with the studies of the rotigotine patch. Other formulations also need to be investigated.

The study of restless legs syndrome treatments has clearly benefited from the development of diagnostic standards and a severity scale. However, the diagnostic standards can fail in specific cases, and the total reliance on subjective report is a weakness of the diagnosis. Similarly, the severity scale (International restless legs syndrome Rating Scale, IRLS), which has often been a primary outcome variable of studies, has been critiqued for failure to include key elements as well as deficiencies in its structure that may promote greater placebo effects. A focus on the periodic limb movement frequently found in restless legs syndrome may enhance diagnosis and assessment, but eliminates those who do not have increased periodic limb movement and may only modestly reflect the impact of the illness on individuals. In the future, it can be hoped that better assessment tools may be developed. Potential tools include sleep and wake diaries, with potential for use of electronic ones, the suggested immobilization test, and actigraphy to record both sleep and periodic limb movement.

A rather immediate question is how important augmentation is as a consequence of dopaminergic treatment. Several series suggest that this is a frequent, but manageable complication of dopamine agonist treatment, but these studies have been limited to several years, while restless legs syndrome may require long-term management. It seems well established that levodopa is more likely to cause augmentation than the agonists, but whether this is due to half-life remains unclear. There is also need for better instruments for detecting and assessing augmentation: the current state of the art requires an expert panel to review individual cases. An objective measure of augmentation would be particularly welcome. This may be particularly important for those drugs with very long half-life (cabergoline) or continuous release (rotigotine), which provide round the clock treatment. It may also be important to determine the distinctions between augmentation, tolerance, and disease progression.

Recent genetic studies have suggested new paths for understanding restless legs syndrome pathophysiology and underscore the close connection between restless legs syndrome and periodic limb movement. The full implications of these studies may lead to new and rational therapeutic approaches, going beyond the current medications that have in general been discovered serendipitously and based on clinical considerations. The future of treatment of periodic limb movement disorder, on the other hand, may depend on the resolution of serious issues about the clinical significance of these movements. Like many of the other sleep-related movement disorders, it may be only the rare patient who has a clinically significant condition: this is based on the understanding that periodic limb movement disorder can only be diagnosed when another sleep disorder does not account for its symptoms, including restless legs syndrome. On the other hand, if periodic limb movement disorder does turn out to be a “forme fruste” of restless legs syndrome, it may turn out that treatment is clinically justified. Some recent studies suggest that, beyond psychiatric impairment, restless legs syndrome may be an important risk factor for cardiovascular disease. Since a potential mechanism may be the autonomic arousal associated with periodic limb movements in sleep, this may provide a rationale for treating both restless legs syndrome and periodic limb movement disorder to reduce future risk of cardiovascular disease.

The other sleep-related movement disorders, rhythmic movement disorder, sleep bruxism, and nocturnal cramps are far behind restless legs syndrome in therapeutic investigation. As specific reviews suggest, the major need may be for better designed, controlled trials. Definitions of clinical significance, specific diagnostic criteria, and a consensus on how to evaluate improvement are needed to advance the field beyond the current reliance, for the most part, on case reports and small clinical series. The field might benefit if there were better demonstration that these conditions are clinically significant and that there is a substantial unmet need for treatment. The importance of alternating leg muscle activation or HFT seems to be marginal and these phenomena may merely be part of the rhythmic movement disorder spectrum. It seems less likely that good evidentiary studies can be expected.

Conclusions

The best-studied sleep-related movement disorder, restless legs syndrome, has seen significant advances in treatment, with specific reliance on the dopaminergics, especially dopamine agonists. The agonists represent all the regulatory approved agents and are first-line treatment. However, to provide relief to all patients, better tools, different agents, alternate formulations, and studies in specific populations are needed. The future of treatment of periodic limb movement or periodic limb movement disorder seems more highly tied than in the past to developments concerning the relation between restless legs syndrome and periodic limb movement and their perhaps mutual risk for subsequent medical problems.

The other sleep-related movement disorders remain at a much earlier stage of development. In most cases, there is no clearly established treatment that can be unequivocally endorsed as both safe and effective. Whether there can be better studies to delineate effective treatments may depend on the clinical significance of these conditions and the efficacy of tools to diagnose them and evaluate their treatment response.