Periodic Limb Movement Disorder Patients Research Articles

Nocturnal Hypoxia and Sleep Fragmentation May Drive Neurodegenerative Processes: The Compared Effects of Obstructive Sleep Apnea Syndrome and Periodic Limb Movement Disorder on Alzheimer's Disease Biomarkers.

Sleep disorders may cause dysregulation in cerebral glucose metabolism and synaptic functions, as well as alterations in cerebrospinal fluid (CSF) biomarker levels. This study aimed at measuring sleep, CSF Alzheimer's disease (AD) biomarkers, and cerebral glucose consumption in patients with obstructive sleep apnea syndrome (OSAS) and patients with periodic limb movement disorder (PLMD), compared to controls. OSAS and PLMD patients underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET), polysomnographic monitoring, and lumbar puncture to quantify CSF levels of amyloid-β42 (Aβ42), total tau, and phosphorylated tau. All patients were compared to controls, who were not affected by sleep or neurodegenerative disorders. Twenty OSAS patients, 12 PLMD patients, and 15 controls were included. Sleep quality and sleep structure were altered in both OSAS and PLMD patients when compared to controls. OSAS and PLMD patients showed lower CSF Aβ42 levels than controls. OSAS patients showed a significant increase in glucose uptake in a wide cluster of temporal-frontal areas and cerebellum, as well as a reduced glucose consumption in temporal-parietal regions compared to controls. PLMD patients showed increased brain glucose consumption in the left parahippocampal gyrus and left caudate than controls. Sleep dysregulation and nocturnal hypoxia present in OSAS patients, more than sleep fragmentation in PLMD patients, were associated with the alteration in CSF and 18F-FDG PET AD biomarkers, namely reduction of CSF Aβ42 levels and cerebral glucose metabolism dysregulation mainly in temporal areas, thus highlighting the possible role of sleep disorders in driving neurodegenerative processes typical of AD pathology.

Nocturnal eye movements in patients with idiopathic rapid eye movement sleep behaviour disorder and patients with Parkinson's disease.

Patients with idiopathic rapid-eye-movement (REM) sleep behaviour disorder (iRBD) have a high risk of converting into manifest α-synucleinopathies. Eye movements (EMs) are controlled by neurons in the lower brainstem, midbrain and frontal areas, and may be affected by the early neurodegenerative process seen in iRBD. Studies have reported impairment of the oculomotor function in patients with Parkinson's disease (PD) during wakefulness, but no studies have investigated EMs during sleep. We aimed to evaluate nocturnal EMs in iRBD and PD, hypothesizing that these patients present abnormal EM distribution during sleep. Twenty-eight patients with periodic limb movement disorder (PLMD), 24 iRBD, 23 PD without RBD (PDwoRBD), 29 PD and RBD (PDwRBD) and 24 controls were included. A validated EM detector automatically identified EM periods between lights off and on. The EM coverage was computed as the percentage of time containing EMs during stable wake after lights off, N1, N2, N3 and REM sleep. Between-group comparisons revealed that PDwRBD had significantly less EM coverage during wake and significantly higher EM coverage during N2 compared to controls and PLMD patients. PDwoRBD showed significantly less EM coverage during wake compared to controls and higher EM coverage during N2 compared to controls and PLMD. Finally, iRBD showed less coverage of EM during wake compared to controls. The same trend was observed between iRBD and controls in N2 but was not significant. The different profiles of EM coverage in iRBD and PD with/without RBD may mirror different stages of central nervous system involvement across neurodegenerative disease progression.

Validation of a new data-driven automated algorithm for muscular activity detection in REM sleep behavior disorder

BackgroundDocumentation of REM sleep without atonia is fundamental for REM sleep behavior disorder (RBD) diagnosis. The automated REM atonia index (RAI), Frandsen index (FRI) and Kempfner index (KEI) were proposed for this, but achieved moderate performances. New methodUsing sleep data from 27 healthy controls (C), 29 RBD patients and 36 patients with periodic limb movement disorder (PLMD), we developed and validated a new automated data-driven method for identifying movements in chin and tibialis electromyographic (EMG) signals. A probabilistic model of atonia from REM sleep of controls was defined and movements identified as EMG areas having low likelihood of being atonia. The percentages of movements and the median inter-movement distance during REM and non-REM (NREM) sleep were used for distinguishing C, RBD and PLMD by combining three optimized classifiers in a 5-fold cross-validation scheme. ResultsThe proposed method achieved average overall validation accuracies of 70.8% and 61.9% when REM and NREM, and only REM features were used, respectively. After removing apnea and arousal-related movements, they were 64.2% and 59.8%, respectively. Comparison with existing method(s)The proposed method outperformed RAI, FRI and KEI in identifying RBD patients and in particular achieved higher accuracy and specificity for classifying RBD. ConclusionsThe results show that i) the proposed method has higher performances than the previous ones in distinguishing C, RBD and PLMD patients, ii) removal of apnea and arousal-related movements is not required, and iii) RBD patients can be better identified when both REM and NREM muscular activities are considered.

Probabilistic Data-Driven Method for Limb Movement Detection during Sleep.

Periodic limb movement disorder (PLMD) is a sleep disorder characterized by repetitive limb movements (LM) during night. The gold standard for LM detection consists of visual analysis of tibialis left (TIBL) and right (TIBR) electromyographic (EMG) signals. Such analysis is subjective and time-consuming. We here propose a semi-supervised and data-driven approach for LM detection during sleep that was trained and tested on 27 healthy controls (C) and 36 PLMD patients. After preprocessing of the EMG signals, discrete wavelet transform (Daubechies 4 mother wavelet and down to 4th decomposition level) was applied. EMG was reconstructed for each set of detail coefficients, thus obtaining four signals (DI-D4). The pre-processed EMG and DI-D4 signals were divided in 3-s mini-epochs of which traditional EMG features were calculated. Based on the assumption of lack of movements in healthy controls during rapid eye movement (REM) sleep, we used the features during REM of a subgroup of C to build a non-parametric probabilistic model defining the resting EMG distribution. This model was then used to classify the remaining mini-epochs as either resting EMG or LM. The percentages of 3-s mini-epochs with LMs were calculated for each subject and used to distinguish the remaining C and PLMD with a support vector machine and 5-fold cross validation scheme. Results showed that C can be distinguished by PLMD with accuracy higher than 82% in the preprocessed EMG and DI-D3 signals.

Periodic leg movements during sleep in PLMD and RLS patients with and without pramipexole treatment

Objective Pharmacological treatment of restless legs syndrome (RLS) patients with pramipexole (PPX) is common and evidence based, whereas the effect of pramipexole on periodic leg movements (PLM) in periodic limb movement disorder (PLMD) patients is unknown. The aim of this study was to investigate the effect of pramipexole on sleep parameters and PLM indices in RLS and in PLMD patients.

Night-to-night variability of periodic leg movements during sleep in restless legs syndrome and periodic limb movement disorder: Comparison between the periodicity index and the PLMS index

The number of periodic leg movements during sleep (PLMS index) shows high night-to-night variability, requiring multiple nights for its reliable estimation. It is currently not known if this is also the case for the degree of periodicity of leg movements, quantified by the Periodicity index. To compare night-to-night variability of PLMS and Periodicity indices in patients with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD). Eighteen idiopathic RLS patients and 9 PLMD patients were recruited. Subjects underwent two consecutive full night polysomnographic studies. Polysomnographic recordings were scored and leg movement activity analyzed during sleep for the computation of the PLMS and Periodicity indices. In both patient groups, the Periodicity index showed a significantly lower degree of variability than that of PLMS index, being >6.5 times lower in RLS patients and 2 times lower in PLMD patients. These data support the use of the Periodicity index in the evaluation of PLMS in RLS and PLMD and indicate that this parameter seems to be more stable than the widely used PLMS index which has higher night-to-night variability.

Altered Cerebral Perfusion of Motor Cortex in Patients with Periodic Limb Movement Disorder

Address for correspondence Seung Bong Hong, MD, PhD Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea Tel: +82-2-3410-3592 Fax: +82-2-3410-0052 E-mail: ejoo@skku.edu eyuns@paran.com Objectives: The pathophysiology of sleep-related motor diseases and sleep dysfunction in movement disorders is widely unknown as yet. Functional brain imaging, in particular radioisotope techniques, is considered to be powerful tool to investigate pathomechanisms of periodic limb movement disorder (PLMD). Methods: We performed Tc-ethyl cysteinate dimer brain single-photon emission computed tomography in 25 drug-naive patients with PLMD and 23 age-and gender matched normal cotrols during wakefulness. For statistical parametric mapping analysis, single-photon emission computed tomography images were spatially normalized to the standard template and then smoothed using a 14-mm full width at half maximum Gaussian kernel. Results: Mean age of patients and normal controls was 48.6 years and over half of them were male. Most patients reported the sleep onset and maintenance insomnia due to repetitive leg jerks. Average duration of insomnia was 7.5 years. They denied the history of restless leg syndrome and there was no sleep disorders such as obstructive sleep apnea syndrome which was confirmed by polysomnography. Mean PLM during sleep index and movement arousal index were markedly increased to 45.3/hr and 7.5/hr, respectively. Their sleep quality was poorer than that of normal patients. In PLMD patients, cerebral blood flow was significantly increased in the bilateral precentral gyri as compared to normal controls. There was no brain region showing decreased perfusion in patients. Regional cerebral perfusion was not correlated to any polysomnography parameter including PLMS index or movement arousal index. Conclusions: Different perfusion pattern in bilateral primary motor cortices may provide the evidences of motor cortical impairment in patients with PLMD. J Korean Sleep Res Soc 2011;8:35-39

Periodic leg movements in sleep and periodic limb movement disorder: Prevalence, clinical significance and treatment

Periodic leg movements in sleep (PLMS) are a frequent finding in polysomnography. The prevalence of PLMS is estimated to be 4-11% in adults. In childhood, PLMS rarely occur although medical conditions like sleep apnea syndrome or neuropsychiatric disorders can lead to high rates of PLMS. In the elderly, PLMS are also common in subjects without sleep disturbances. In sleep studies, PLMS are found most frequently in restless legs syndrome (RLS) and often occur in narcolepsy, sleep apnea syndrome and REM sleep behavior disorder. Some patients with otherwise unexplained insomnia or hypersomnia reveal an elevated number of PLMS, a condition defined as periodic limb movement disorder (PLMD). PLMS were found also in various medical and neurological disorders that do not primarily affect sleep. A summary of these is presented. In sleep disorders related to dopaminergic dysfunction such as RLS, PLMS are considered to be a symptom of the disease. In other disorders like primary insomnia, the clinical relevance of PLMS is still being controversially discussed. Studies with findings both pro and contra are referred. To date, only a few studies have evaluated the efficacy of therapeutic substances in reducing PLMS in PLMD patients. Their results need to be confirmed in controlled randomized trials.

Periodic limb movement disorder and restless legs syndrome in dialysis patients

Sleep disturbances, in particular restless legs or limb movements, during the night are often reported by uremic patients. However, polysomnography (PSG) studies have never been carried out to confirm the actual occurrence of these disorders and the association with other objective and self-reported sleep-wake data. Forty-eight participants were subjected to a 2-day PSG. These data on sleep including periodic limb movements, which are associated with restless legs, were correlated with clinical observations, quality of sleep-wake and life questionnaires, and with biochemical and neurographical measures. Restless legs syndrome (RLS) was observed in 58.3% of the patients and periodic limb movement disorder (PLMD) occurred in 70.8% of the patients. PLMD was revealed polysomnographically in almost 90% of the RLS patients. Patients with both PLMD and RLS had significantly poorer sleep quality than those with neither disorder or with PLMD alone, both in terms of self-reported data and the PSG. Quality of life was significantly worse in patients with RLS and PLMD compared to those patients with neither disorder. PLMD patients also tended to have a lower quality of life. All other metabolic measures and the results of a nerve conduction test were not correlated with RLS and/or PLMD. There was a high prevalence of severe RLS and PLMD in the present sample of uraemia patients. Nearly all RLS patients had severe PLMD. RLS (in combination with PLMD) in dialysis is associated with poor sleep quality, insomnia complaints, depression and emotional distress. Our results suggest that PLMD per se is also clinically relevant.

Abnormal H-reflexes in periodic limb movement disorder; impact on understanding the pathophysiology of the disorder

Objective To get more insight in the pathophysiological basis of periodic limb movement disorder (PLMD) with or without restless legs syndrome (RLS), we investigated whether these patients have spontaneous changes in H-reflexes or show altered reflex patterns after (external) inhibition or excitation of the relevant spinal segment. Methods The ratio of the peak-to-peak values of the maximal soleus H-reflex and the maximal direct muscle potential (H/M ratio), H-reflex recruitment curves, vibratory inhibition and recovery curves of the soleus H-reflex in double stimulus experiments were measured in 9 PLMD patients and 11 controls. Results In comparison to controls the vibratory inhibition, predominantly reflecting pre-synaptic inhibitory action, was depressed in PLMD patients. The soleus H-reflex recovery curves showed increased late facilitation and depressed late inhibition, both reflecting diminished inhibition due to post-synaptic central activity. Conclusions Our data indicate diminished inhibition at spinal level in PLMD patients. This is probably due to altered function of the descending spinal tracts, peripheral influence or changes at the inter-neural circuitry at spinal level itself, or combinations of these 3 possibilities. Significance The results of this study give further insight in the pathophysiology of PLMD and RLS by stressing the importance of diminished central inhibition.

Different sleep characteristics in restless legs syndrome and periodic limb movement disorder

Objective: Periodic limb movements in sleep (PLMS) may or may not be associated with restless legs syndrome (RLS). The number of PLMS is commonly used to assess the clinical severity and sleep quality of patients with RLS. It is still unclear whether the sleep disorder of periodic limb movement disorder (PLMD) is different from the sleep disorder in RLS. Methods: We compared the polysomnograms (PSGs) of 27 prospectively recruited RLS patients and 26 retrospectively recruited age- and sex-matched PLMD patients without RLS symptoms. Results: The PLM index and the index of arousal-associated PLMS (PLMAI) were significantly higher in PLMD, whereas the index of EEG arousals not associated with any sleep-related event was significantly higher in RLS. In PLMD patients, the PLMI correlated negatively with the percentage of PLMS associated with an arousal, whereas this correlation was positive in RLS patients. Further, RLS patients spent significantly more time in wake-after-sleep onset, had more rapid eye movement sleep (REM) and less sleep stage I. Conclusions: We conclude that the sleep disorder in RLS differs from that in PLMD. Spontaneous, not PLM associated EEG arousals should be included in the assessment of the sleep structure of patients with RLS, particularly in studies concerned with drug-efficacy.

EEG mapping, psychometric, and polysomnographic studies in restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) patients as compared with normal controls

Objectives: Investigation of daytime brain function, psychopathology, and objective and subjective sleep and awakening quality in restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). Methods: Thirty-three RLS and 26 PLMD patients free of psychotropic drugs were studied as compared with age- and sex-matched normal controls, utilizing electroencephalographic (EEG) mapping and clinical evaluations by the Zung Self-Rating Depression (SDS) and Anxiety Scale (SAS), the Quality of Life Index, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale. In a subsample of 12 RLS patients, 12 PLMD patients, and 12 controls, objective and subjective sleep and awakening quality were evaluated in two sleep laboratory nights (adaptation and baseline night). Results: Scores of the PSQI, SDS, and SAS were found increased in both patient groups; RLS patients showed reduced quality of life, while in the PLMD group daytime sleepiness was increased. EEG mapping demonstrated findings characteristic of major depression in RLS patients and of generalized anxiety disorder in PLMD patients. Polysomnography showed a significant deterioration of sleep efficiency only for RLS patients, while nocturnal awakenings were increased in both patient groups. Concerning sleep architecture, both groups exhibited increased S1 and stage shifts and decreased S2, while only PLMD patients showed an increase in S4. The PLM/ h TST, the PLM/ h wake and the PLMS-arousal index were significantly increased in both patient groups as compared with controls. Subjective sleep and awakening quality and thymopsychic measures were deteriorated in RLS. Morning mental performance and fine motor activity were deteriorated in both groups, reaction time only in RLS, numerical memory and attention variability only in PLMD. Conclusion: EEG mapping revealed neurophysiological correlates of depression and anxiety in RLS and PLMD, respectively, which were confirmed by self-ratings of symptoms.

Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): Acute placebo-controlled sleep laboratory studies with clonazepam

Restless legs syndrome (RLS) — a common sensorimotor disorder — and periodic limb movement disorder (PLMD) are currently treated with substances of four classes: dopaminergic agents, which are considered the drugs of choice, benzodiazepines, opioids and anticonvulsants. As their effects on sleep variables differ considerably, the aim of the present placebo-controlled sleep laboratory study was to measure the acute effects of 1 mg clonazepam on objective and subjective sleep and awakening quality in ten RLS and 16 PLMD patients, utilizing polysomnography (PSG) and psychometry. Descriptive data analysis demonstrated at the confirmatory level concerning three target variables that — as compared with placebo — clonazepam significantly improved objective sleep efficiency and subjective sleep quality in both patient groups, but failed to reduce the index PLM/h of sleep. At the descriptive level, in PLMD clonazepam improved PLM during time in bed, REM and wakefulness and showed more significant changes in various sleep and awakening measures than in RLS patients, though there were no significant inter-group differences. In conclusion, in both PLMD and RLS clonazepam exhibited acute therapeutic efficacy regarding insomnia, which is quite different from the mode of action of dopamine agonists.

Sleep laboratory studies in periodic limb movement disorder (PLMD) patients as compared with normals and acute effects of ropinirole

Periodic limb movement disorder (PLMD) occurs in a variety of sleep disorders and can cause insomnia as well as hypersomnia with daytime somnolence. The aim of this study was to investigate 12 untreated PLMD patients as compared with 12 normal controls and to measure the acute effects of 0.5 mg ropinirole (Requip((R))) - a non-ergoline dopamine agonist - as compared with placebo. In three nights (adaptation, placebo, ropinirole night) objective and subjective sleep and awakening quality were evaluated. In the target variable 'periodic leg movements per hour of sleep' (PLM/(hTST)) PLMD patients showed an increased value of 42/h (normal 0-5/h) with a greater number of arousals due to periodic leg movements (PLM) in sleep. They further demonstrated an increased number of awakenings, sleep stage S1, S4, stage shifts and decreased S2, but there were no significant differences concerning total sleep time, sleep efficiency (SE), subjective sleep quality and morning measures of mood, drive and drowsiness. However, measures of attention variability, numerical memory, fine motor activity and reaction time performance were impaired. Ropinirole 0.5 mg was shown to significantly improve the index PLM/(hTST) by 64% and arousals due to PLM, increase spontaneous arousals, REM-latency, stage 2 and stage shifts and decrease SREM. In the morning attention variability was attenuated and numerical memory augmented. Thus, ropinirole improved some sleep architecture and early morning measures of performance but specifically all PLM variables, which suggests a dopaminergic pathogenesis in PLMD. Copyright 2001 John Wiley & Sons, Ltd.

Sleep laboratory studies in periodic limb movement disorder (PLMD) patients as compared with normals and acute effects of ropinirole

Periodic limb movement disorder (PLMD) occurs in a variety of sleep disorders and can cause insomnia as well as hypersomnia with daytime somnolence. The aim of this study was to investigate 12 untreated PLMD patients as compared with 12 normal controls and to measure the acute effects of 0.5 mg ropinirole (Requip®) – a non-ergoline dopamine agonist – as compared with placebo. In three nights (adaptation, placebo, ropinirole night) objective and subjective sleep and awakening quality were evaluated. In the target variable ‘periodic leg movements per hour of sleep’ (PLM/hTST) PLMD patients showed an increased value of 42/h (normal 0–5/h) with a greater number of arousals due to periodic leg movements (PLM) in sleep. They further demonstrated an increased number of awakenings, sleep stage S1, S4, stage shifts and decreased S2, but there were no significant differences concerning total sleep time, sleep efficiency (SE), subjective sleep quality and morning measures of mood, drive and drowsiness. However, measures of attention variability, numerical memory, fine motor activity and reaction time performance were impaired. Ropinirole 0.5 mg was shown to significantly improve the index PLM/hTST by 64% and arousals due to PLM, increase spontaneous arousals, REM-latency, stage 2 and stage shifts and decrease SREM. In the morning attention variability was attenuated and numerical memory augmented. Thus, ropinirole improved some sleep architecture and early morning measures of performance but specifically all PLM variables, which suggests a dopaminergic pathogenesis in PLMD. Copyright © 2001 John Wiley & Sons, Ltd.

Exogenous Melatonin in Periodic Limb Movement Disorder: An Open Clinical Trial and a Hypothesis

The etiology of Periodic Limb Movement Disorder (PLMD) as well as the precise role of melatonin in human physiology remains poorly understood. Inspired by a single case observation we performed the presented study in order to obtain first evidence for the hypothesis that exogenous melatonin would decrease PLM's and thereby improves symptoms of PLMD patients. N/A. N/A. Nine patients with first time diagnosis of PLMD without RLS were treated over a six-week period with 3 mg melatonin, taken between 10 and 11 p.m. N/A. Melatonin improved well-being in 7 of the 9 patients. Polysomnography, performed prior and at the end of melatonin treatment, demonstrated a significant reduction of investigated movement parameters, such as PLMs, PLM index, PLMs with arousals and PLM-arousal index. Actigraphy, measured over 14 nights prior and during the last 14 days of melatonin treatment, showed a significant reduction in movement rate and minutes with movements during Time in Bed. The temporal distribution of PLMs, as well as the coupling of PLMs with the phase position of circadian temperature curve, suggest an involvement of the circadian timing system in the pathophysiology of PLMD. Locomotor activity in animals clearly exhibits a circadian pattern and can be strongly influenced by exogenous melatonin. Results suggest a chronobiotic effect of exogenous melatonin in PLMD. More specifically, we hypothesize that the mode of action of melatonin in the presented PLMD patients might have been an increase of output-amplitude of the circadian timing system, thereby enhancing the circadian rhythmicity of locomotor activity with a reduction of sleep motor activity.