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Restless leg syndrome (RLS) is a major healthcare burden with increasing prevalence. It has been demonstrated that periodic limb movements (PLM) can occur as an isolated phenomenon, but they are often associated with this syndrome and are the only symptom of this disorder that can be measured electrophysiologically. The aim of this study was to examine the sleep-wake behavior and the presence of limb movement in a rat model of RLS induced by lesioning the A11 dopaminergic nuclei with the neurotoxin 6-hydroxydopamine (6-OHDA). Rats were implanted with electrodes for electrocorticography and electromyography. Sleep recordings were monitored during light/dark periods lasting 12 hours each and were evaluated on days 7, 15, and 28 after injection of the drug or phosphate-buffered saline (PBS). A control group that did not receive any injection was also included. Wakefulness percentages were generated for 4-hour segments of the dark period, yielding the following 3 bins: 7 PM to 11 PM, 11 PM to 3 AM, and 3 PM to 7 PM. Additionally, slow wave sleep, paradoxical sleep, wakefulness, and limb movements were evaluated over the entire 12 hours of the light/dark cycle. All A11-lesioned rats exhibited an increased percentage of wakefulness during the last block of the dark period, as would be expected for an animal model of this syndrome. In addition, at all time points after lesioning, these animals presented increased frequencies of limb movement during both the light and the dark periods. These alterations were reversed by the acute administration of the dopaminergic agonist pramipexole. This animal model strengthens the notion that 6-OHDA-induced A11 lesions can be a valid animal model for RLS and PLM., (Copyright © 2011 Movement Disorder Society.)

Background: Pharmacologically induced/exacerbated restless legs syndrome (RLS), periodic limb movements in sleep (PLMS), and REM behavior disorder/REM sleep without atonia (RSWA) are increasingly recognized in clinical sleep medicine. A scoring system to evaluate the literature was created and implemented. The aim was to identify the evidence with the least amount of confound, allowing for more reliable determinations of iatrogenic etiology., Methods: Points were provided for the following criteria: manuscript type (abstract, peer-reviewed paper); population size studied (large retrospective study, small case series, case report); explicitly stated dosage timing; identification of peak symptoms related to time of medication administration (i.e., medication was ingested in the evening or at bedtime); initiation of a treatment plan; symptoms subsided or ceased with decreased dosage or drug discontinuation (for RLS articles only); negative personal history for RLS prior to use of the medication; exclusion of tobacco/alcohol/excessive caffeine use; exclusion of sleep disordered breathing by polysomnography (PSG); and PSG documentation of presence or absence of PLMS. For RLS and PLMS articles were also given points for the following criteria: each 2003 National Institutes of Health (NIH) RLS criteria met; exclusion of low serum ferritin; and exclusion of peripheral neuropathy by neurological examination., Results: Thirty-two articles on drug-induced RLS, 6 articles on drug-induced PLMS, and 15 articles on drug-induced RBD/ RSWA were analyzed., Conclusion: Based on scores < or = 10 and trials of medication reduction/cessation, the strongest evidence available for drug induced RLS are for the following drugs: escitalopram; fluoxetine; L-dopa/carbidopa and pergolide; L-thyroxine; mianserin; mirtazapine; olanzapine; and tramadol. Since none of the PLMS articles assessed PLMI in trials of medication reduction/cessation, the strongest evidence based on scores > or = 10 are for the following drugs: bupropion, citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine. Based on scores > or = 10 and/or trials of medication cessation, the strongest evidence for drug induced RBD/ RSWA is for the following drugs: clomipramine, selegiline, and phenelzine.

We report five cases of restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS) that were probably associated with olanzapine. The first patient showed a good response to olanzapine, but the RLS symptoms associated with olanzapine resulted in poor long-term compliance, eventually leading to frequent relapse of psychotic symptoms. The second patient exhibited sudden PLMS following olanzapine injection. The third patient had been suffering from serious akathisia while on risperidone, and was cured after switching to olanzapine, but thereafter the patient suffered from RLS at nighttime. The fourth patient showed RLS symptoms that were initially caused by a 20-mg daily olanzapine dosage and were later mitigated when olanzapine was reduced and ropinirole was administered. The fifth patient exhibited paraesthesia and agitation caused by olanzapine that was misdiagnosed as psychotic agitation. Increasing the olanzapine dosage severely aggravated the symptoms of RLS. Antipsychotic-induced RLS and PLMS are not well-recognized side effects of antipsychotics, with the symptoms often misdiagnosed as psychotic agitation. These cases also suggest that the occurrence of RLS can cause noncompliance with antipsychotics in psychiatric patients, and thus aggravate their psychotic symptoms.

Restless legs syndrome (RLS) and the often associated periodic limb movement disorder in sleep (PLMD) frequently occur in the general population as a primary disorder. In addition to organic disease, secondary forms are caused by psychotropic medication. Several antidepressants, antipsychotics, lithium, and opioid withdrawal have been shown to induce or exacerbate RLS and PLMD, while several antiepileptics used as mood stabilizers and some benzodiazepines demonstrate therapeutic potential for treating RLS/PLMD. Systematic or controlled studies for evaluating these side effects still do not exist. Among the antidepressants at higher risk of inducing this disorder are selective serotonin reuptake inhibitors, venlafaxine, and some tetracyclic antidepressants. Under medication with some tricyclic substances, periodic limb movements were observed more often. For some antidepressants with differing transmitter profiles such as bupropion RLS/PLMD ameliorating effects or at least neutral effects (Trazodon, Nortriptylin) have been described in small studies. In case of continued of or newly occurring insomnia a thorough history should be taken to identify a possible RLS/PLMD as an intolerable side effect of treatment. A change in medications should be considered if clinically feasible. In case of RLS/PLMD occurring in psychotic patients switching the antipsychotic and additionally using a second line medication such as antiepileptics or a benzodiazepine should be considered.

Periodic leg movements in sleep (PLMS) unrelated to restless legs syndrome (RLS) are a polysomnographic finding with a controversial clinical value. We describe a patient with isolated periodic leg movements in sleep (without any awake or sleep complaints), who developed severe diurnal RLS symptoms a few months after starting dopaminergic treatment, a phenomenon mimicking augmentation. The diurnal RLS symptoms disappeared after withdrawal of the dopaminergic drugs. Serum ferritin levels were relatively low (31-61 mcg/l; normal: 30-400 mcg/l). Since low levels of ferritin have been implicated in the genesis of RLS, and augmentation is a phenomenon associated with RLS, our findings here suggest that asymptomatic PLMS may have pathogenic mechanisms similar to RLS. Isolated PLMS and RLS could be, at least in some cases, different clinical forms of the same disorder. The conjunction of dopaminergic treatment with low ferritin levels may expose a patient with isolated PLMS to the development of RLS. Discontinuation of dopaminergic drugs in patients with isolated PLMS who develop RLS during the course of the treatment would be a reasonable recommendation.