A 9-year-old female with iron deficiency has severe periodic limb movements while taking mirtazapine for insomnia.

Mirtazapine is a Food and Drug Administration-approved atypical antidepressant used off-label for insomnia. Mirtazapine has been associated with movement disorders in adults. A 9-year-old female was seen in the sleep clinic for symptoms of insomnia, nocturnal awakenings, restless sleep, and growing pains. Mirtazapine was started prior to presentation for severe insomnia. A sleep study showed frequent repetitive leg movements prior to sleep onset as well as significant periodic limb movement disorder with a periodic limb movement index of 25.1/hour. The child was found to have a ferritin level of 23 ng/mL and an iron saturation of 10%. There were concerns that the presence of iron deficiency along with the use of mirtazapine may have contributed to the elevated periodic limb movement index. After starting iron therapy to treat the child's iron deficiency, mirtazapine was weaned off, with further clinical improvements in sleep quality reported. A follow-up sleep study showed a resolution of her periodic limb movement disorder with a periodic limb movement index of 1.4/hour. This is the first pediatric case to describe a sleep-related movement disorder associated with the use of mirtazapine and polysomnographic data to support resolution after discontinuation of mirtazapine along with iron therapy. CITATION: Hawkins M. A 9-year-old female with iron deficiency has severe periodic limb movements while taking mirtazapine for insomnia. J Clin Sleep Med. 2023;19(7):1369-1373.

Leg movements during sleep in children treated with serotonergic antidepressants.

STUDY OBJECTIVES: To evaluate leg movements during sleep (LMS) in children taking serotonergic antidepressants, compared to those of children with restless legs syndrome (RLS) and controls, and to assess the time structure of intermovement intervals (IMI). METHODS: Twenty-three children (12 girls, mean age 14.1 years) on antidepressants and with a total LMS index ≥ 15/h, 21 drug-naïve RLS children (11 girls, mean age 13.6 years) also with total LMS index ≥ 15/h, and 35 control children (17 girls, mean age 14.3 years) were recruited. LMS were scored and a series of parameters was calculated, along with the analysis of their time structure. RESULTS: Children taking antidepressants showed higher total and periodic LMS (PLMS) indexes than both controls and RLS children, as well as higher short-interval and isolated LMS indexes than controls. LMS periodicity was highest in children on antidepressants. In children taking antidepressants, a well-defined PLMS IMI peak corresponding to approximately 10-60 s, with a maximum at approximately 20 s was present, which was much less evident in RLS patients and absent in controls. A progressive decrease of PLMS during the night and more frequent arousals were found in children on antidepressants and with RLS. CONCLUSIONS: Children taking serotonergic antidepressants show higher periodicity LMS than children with RLS or controls and have a higher number of PLMS through the night. Antidepressant-associated PLMS in children seem to have features similar to PLMS of adults with RLS. Whether this is a marker of an increased risk to develop RLS later in life needs to be determined.

Actimetry-Documented Persistent Periodic Limb Movements During EEG-Confirmed Deep General Anesthesia: A Case Report.

Motor activity during general anesthesia (GA) without neuromuscular blockade is often interpreted as reflecting insufficient anesthesia. Here we present the case of an octogenarian undergoing deep sclerectomy with opioid-sparing electroencephalography (EEG)-guided anesthesia. Periodic leg movements (PLM) appeared during ongoing surgery while the patient's raw EEG displayed a pattern of deep anesthesia, evidenced by burst suppression. Recognizing PLM in the context of opioid-sparing GA is of importance for anesthesiologists, as deep anesthesia is not necessarily associated with a decrease in motor activity.

Respiratory-Related Leg Movements of Sleep Are Associated With Serotonergic Antidepressants But Not Bupropion.

STUDY OBJECTIVES: Respiratory-related leg movements (RRLMs) may contribute to the cardiovascular risk associated with obstructive sleep apnea (OSA). Selective serotonin reuptake inhibitors (SSRIs), but not bupropion, increase periodic leg movements in sleep. This study examines whether patients with OSA using SSRIs have more RRLMs than those taking bupropion or no antidepressant. METHODS: Patients with an apnea-hypopnea index (AHI) of at least 10 events/h during a full-night diagnostic study or split-night study, who were taking bupropion (n = 32), an SSRI (n = 31), or no antidepressant (n = 31), were selected from a database of prestudy questionnaires. RRLMs were scored according to World Association of Sleep Medicine 2016 standards. RESULTS: Patients using SSRIs had significantly greater overall RRLM% (defined as the percentage of respiratory events associated with a leg movement, including apneas, hypopneas, and respiratory effort-related arousals), RRLM index, and periodic limb movement index relative to patients using bupropion and control patients. The difference between the RRLM% in the SSRI and bupropion groups was limited to patients undergoing split-night studies, and that of the SSRI and control groups was limited to patients undergoing full-night diagnostic studies. CONCLUSIONS: The greater number of RRLMs and PLMs in the SSRI group may contribute to treatment-emergent insomnia often seen with SSRI use. Fragmented sleep and elevated autonomic nervous system activation associated with increased RRLMs in patients with OSA taking SSRIs might also limit the tolerability of antidepressant treatment, as well as increase the risk for cardiovascular disease.

Sertraline and periodic limb movements during sleep: an 8-week open-label study in depressed patients with insomnia.

BACKGROUND: Previous studies have reported that selective serotonin reuptake inhibitors (SSRIs) might induce or exacerbate periodic limb movements during sleep (PLMS). However, most of these studies were retrospective and cross-sectional studies with small sample sizes on a selective SSRI, fluoxetine. Because different SSRIs have different pharmacologic profiles, it was not certain if other SSRIs also might lead to PLMS. METHODS: Data were taken from an open-label 8-week trial of sertraline in depressive patients with insomnia (n=31). Depressed patients were administered sertraline 50mg at 8:00am on the first day, and the dosage was subsequently titrated up to a maximum of 200mg daily during the 8-week trial. All participants were tested by repeated polysomnography (PSG) (baseline, first day, 14th day, 28th day, and 56th day). Periodic leg movements (PLM) were visually counted and the PLM index (PLMI) was calculated. PLMS was defined as PLMI ⩾5, and significant PLMS was defined as PLMI ⩾15. RESULTS: Compared with baseline (PLMI, 3.6±1.5), all PLMI indices increased on the immediate administration of sertraline on the first day (PLMI, 5.1±3.9). From the 14th day onward, PLMI became stable and significantly higher than baseline and the first day (8.7±3.1 on the 14th day, 8.3±3.7 on the 28th day, and 8.5±3.6 on the 56th day; F[11.81]; P=.003). The clinical responses and PSG characteristics continuously improved during the 8-week trial. The PLMS group (PLMI ⩾5) had a higher arousal index (AI) than the non-PLMS group on the 14th day (9.4±5.5 vs 5.2±3.7; t test, 4.22; P=.03) and the 56th day (8.1±5.5 vs 4.3±3.7; z score, 3.11; P=.04); albeit, there was no significant clinical disturbances in the PLMS group. CONCLUSIONS: PLMS were increased during sertraline treatment, but only a few of the PLMS reached the significant level. This effect of sertraline on PLMS might be dosage dependent. Although the sertraline-induced PLMS did not seem to cause significant clinical disturbance, the PLMS group (PLMI ⩾5) had a higher AI than the non-PLMS group. Thus clinicians should pay more attention to PLMS during SSRI antidepressant treatment.

Mirtazapine provokes periodic leg movements during sleep in young healthy men.

STUDY OBJECTIVES: Recent evidence suggests that certain antidepressants are associated with an increase of periodic leg movements (PLMS) that may disturb sleep. So far, this has been shown in patients clinically treated for depression and in cross-sectional studies for various substances, but not mirtazapine. It is unclear whether antidepressants induce the new onset of PLMS or only increase preexisting PLMS, and whether this is a general property of the antidepressant or only seen in depressed patients. We report here the effect of mirtazapine on PLMS in young healthy men. DESIGN: Open-labeled clinical trial (NCT00878540) including a 3-week preparatory phase with standardized food, physical activity, and sleep-wake behavior, and a 10-day experimental inpatient phase with an adaptation day, 2 baseline days, and 7 days with mirtazapine. SETTING: Research institute. PARTICIPANTS: Twelve healthy young (20-25 years) men. INTERVENTIONS: Seven days of nightly intake (22:00) of 30 mg mirtazapine. MEASUREMENTS AND RESULTS: Sleep was recorded on 2 drug-free baseline nights, the first 2 drug nights, and the last 2 drug nights. Eight of the 12 subjects showed increased PLMS after the first dose of mirtazapine. Frequency of PLMS was highest on the first drug night and attenuated over the course of the next 6 days. Three subjects reported transient restless legs symptoms. CONCLUSIONS: Mirtazapine provoked PLMS in 67% of young healthy males. The effect was most pronounced in the first days. The possible role of serotonergic, noradrenergic and histaminergic mechanisms in mirtazapine-induced PLMS is discussed.

PLMD-like nocturnal movements with mirtazapine.

Mirtazapine is a commonly prescribed antidepressant with sedative properties. We report a case of nocturnal involuntary limb movements developing in an opioid-dependent young man after starting mirtazapine. The involuntary repetitive bilateral leg movements during initial phase of sleep began when mirtazapine was initiated. They continued for 4 days till mirtazapine was stopped and did not recur subsequently. The role of mirtazapine should be considered when a patient on this drug complains of leg movement during early phase of sleep.

Age, drugs, or disease: what alters the macrostructure of sleep in Parkinson's disease?

OBJECTIVE: To describe the alterations in the macrostructure of sleep in a large cohort of sleep-disturbed patients with Parkinson's disease (PD) and investigate influencing factors. METHODS: A cohort of sleep-disturbed but otherwise unselected PD patients (n=351) was investigated with video-supported polysomnography. We analyzed the influence of age, disease duration, disease severity, and dopaminergic medication on subjective sleep perception, sleep efficiency, the amount of slow wave sleep, awakenings, periodic leg movements in sleep (PLMS), and REM sleep behavior disorder (RBD). RESULTS: Sleep efficiency and slow wave sleep decreased with age (p=0.003 and p=0.041, respectively). The number of awakenings and the frequency of RBD increased with age (p=0.028 and p=0.006, respectively). Higher Hoehn & Yahr stages were associated with more PLMS (p=0.017). A higher daily dose of levodopa corresponded to more RBD (p<0.001). Neither disease duration nor levodopa dosage had any influence on sleep efficiency, slow wave sleep, awakenings, or PLMS. Dopamine agonists increased awakenings (p<0.001) and lowered PLMS (p<0.001). Subjective sleep perception was not influenced by any of the factors analyzed. The only path model that could be replicated identified disease severity and dopamine agonists as interdependent factors influencing awakenings and PLMS. CONCLUSION: Age leads to less sleep and a higher risk for RBD, and disease severity increases motor phenomena such as PLMS; dopamine agonists reduce PLMS but increase awakenings. No single factor analyzed influenced subjective sleep perception in this cohort of sleep disturbed PD patients.

Selective serotonin reuptake inhibitors and periodic limb movements of sleep.

Serotonin reuptake inhibitors may induce periodic limb movements of sleep in adults. We undertook a retrospective review of polysomnography data of 1,023 children acquired at our institution over 1 year to assess whether children receiving serotonin reuptake inhibitors have a higher risk of periodic limb movements of sleep than children that are not treated with these medications. Periodic limb movements of sleep were found in 13 (31.7%) of 41 children receiving serotonin reuptake inhibitors and in 77 (7.8%) of 982 children not receiving serotonin reuptake inhibitors (odds ratio 5.45). Furthermore, the median periodic limb movement index in patients receiving serotonin reuptake inhibitors was significantly higher than patients not receiving serotonin reuptake inhibitors (11.2 and 6.5 respectively; P < 0.05). Children receiving serotonin reuptake inhibitors are at risk of periodic limb movements of sleep. Appropriate clinical judgment and medical management may result in better control of periodic limb movements of sleep and improved quality of life in these patients.

Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis.

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.

A patient with epilepsy and new onset of nocturnal symptoms.

A patient with a 14-year history of complex partial seizures presented with new onset of nocturnal symptoms consisting of hallucinations, vivid dreams, and gross motor activity. These episodes were not consistent with his previous seizures, which had consisted of a foul smell, automatisms, and an altered stage of consciousness. Prior to this presentation, the patient had been seizure-free for 3 years while taking antiepileptic medications.

Restless legs syndrome and periodic limb movements during sleep probably associated with olanzapine.

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, periodic limb movements, and psychopharmacology]. / Restless-legs-Syndrom, periodische Gliedmassenbewegungen im Schlaf und Psychopharmakologie.

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.

Tacrolimus-related nocturnal myoclonus of the lower limbs in elderly patients with rheumatoid arthritis.

Tacrolimus is an effective and well-tolerated treatment for rheumatoid arthritis (RA). We report three cases of strictly sleep-associated myoclonus in RA patients treated with tacrolimus. Although the high-dosage administration of tacrolimus in transplantation is known to cause diverse neurotoxic adverse effects, including myoclonus, no previous cases of myoclonus in RA, especially in association with sleep, have been reported. We suggest that this is not a rare adverse effect, particularly in elderly RA patients.