Maria Livia Fantini

Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder

Objective: Idiopathic REM sleep behavior disorder (RBD) is a potential preclinical marker for the development of neurodegenerative diseases, particularly Parkinson disease (PD) and Lewy body dementia. However, the long-term risk of developing neurodegeneration in patients with idiopathic RBD has not been established. Obtaining an accurate picture of this risk is essential for counseling patients and for development of potential neuroprotective therapies. Methods: We conducted a follow-up study of all patients seen at the sleep disorders laboratory at the Hôpital du Sacré Coeur with a diagnosis of idiopathic RBD. Diagnoses of parkinsonism and dementia were defined according to standard criteria. Survival curves were constructed to estimate the 5-, 10-, and 12-year risk of developing neurodegenerative disease. Results: Of 113 patients, 93 (82%) met inclusion criteria. The mean age of participants was 65.4 years and 75 patients (80.4%) were men. Over the follow-up period, 26/93 patients developed a neurodegenerative disorder. A total of 14 patients developed PD, 7 developed Lewy body dementia, 4 developed dementia that met clinical criteria for AD, and 1 developed multiple system atrophy. The estimated 5-year risk of neurodegenerative disease was 17.7%, the 10-year risk was 40.6%, and the 12-year risk was 52.4%. Conclusions: Although we have found a slightly lower risk than other reports, the risk of developing neurodegenerative disease in idiopathic REM sleep behavior disorder is substantial, with the majority of patients developing Parkinson disease and Lewy body dementia.

REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease

Objective To determine the frequency of REM sleep behavior disorder (RBD) among patients with PD using both history and polysomnography (PSG) recordings and to further study REM sleep muscle atonia in PD. Background The reported occurrence of RBD in PD varies from 15 to 47%. However, no study has estimated the frequency of RBD using PSG recordings or analyzed in detail the characteristics of REM sleep muscle atonia in a large group of unselected patients with PD. Methods Consecutive patients with PD (n = 33) and healthy control subjects (n = 16) were studied. Each subject underwent a structured clinical interview and PSG recording. REM sleep was scored using a method that allows the scoring of REM sleep without atonia. Results One third of patients with PD met the diagnostic criteria of RBD based on PSG recordings. Only one half of these cases would have been detected by history. Nineteen (58%) of 33 patients with PD but only 1 of 16 control subjects had REM sleep without atonia. Of these 19 patients with PD, 8 (42%) did not present with behavioral manifestations of RBD, and their cases may represent preclinical forms of RBD associated with PD. Moreover, the percentage of time spent with muscle atonia during REM sleep was lower among patients with PD than among healthy control subjects (60.1% vs 93.2%;p = 0.003). ConclusionsRBD and REM sleep without atonia are frequent in PD as shown by PSG recordings.

Periodic leg movements in REM sleep behavior disorder and related autonomic and EEG activation

Objective: To assess the frequency of periodic leg movements (PLM) in idiopathic REM sleep behavior disorder (RBD) and to analyze their polysomnographic characteristics and associated autonomic and cortical activation. Background: PLM during sleep (PLMS) and wakefulness (PLMW) are typical features of restless legs syndrome (RLS), but are also frequently observed in patients with RBD. Methods: Forty patients with idiopathic RBD underwent one night of polysomnographic recording to assess PLMS frequency. PLM features, PLMS-related cardiac activation during stage 2 sleep, and EEG changes were analyzed in 15 of these patients with RBD. Results were compared with similar data obtained in 15 sex- and age-matched patients with primary RLS. Results: Twenty-eight (70%) of 40 patients with RBD showed a PLMS index greater than 10. No between-group differences were found in sleep architecture or indexes of PLMW and PLMS during non-REM sleep, but a trend for a higher PLMS index during REM sleep was found in patients with RBD. PLM mean duration and interval in the two conditions were similar. A transient tachycardia followed by a bradycardia was observed in close association with every PLMS in both groups, but the amplitude of the cardiac activation was significantly reduced in patients with RBD. In addition, significantly fewer PLMS were associated with microarousal in this condition. Conclusions: Periodic leg movements are very common in idiopathic RBD, occurring in all stages of sleep, especially during REM sleep. In idiopathic RBD, the reduction of cardiac and EEG activation associated with PLMS suggests the presence of an impaired autonomic and cortical reactivity to internal stimuli.

The effects of pramipexole in REM sleep behavior disorder

The authors evaluated the effects of pramipexole, a dopaminergic D2-D3 receptor agonist, on eight patients with idiopathic REM sleep behavior disorder. Five patients reported a sustained reduction in the frequency or intensity of sleep motor behaviors, which was confirmed by video recording, although no change was observed for the percentage of phasic EMG activity during REM sleep. Surprisingly, a decrease in the percentage of time spent with REM sleep muscle atonia was observed with treatment. The treatment did not modify the indexes of periodic leg movements.

Polysomnographic diagnosis of idiopathic REM sleep behavior disorder

The presence of either excessive tonic chin EMG activity during REM sleep, or excessive phasic submental or limb EMG twitching is required to diagnose REM sleep behavior disorder (RBD). The aim was to identify cut‐off values and to assess the sensitivity and specificity of these values taken separately or combined to diagnose idiopathic RBD patients. Eighty patients presenting with a clinical diagnosis of idiopathic RBD and 80 age‐ and gender‐matched normal controls were studied in the sleep laboratory. Receiver operating characteristic curves were drawn to find optimal cut‐off values for three REM sleep EMG parameters. Tonic and phasic EMG activity were measured in the chin, but not in the limbs. Videos were examined during the recording but were not systematically reviewed by the authors. Total correct classification of 81.9% was found for tonic chin EMG density ≥30%; 83.8% for phasic chin EMG density ≥15% and 75.6% for ≥24 leg movements per hour of REM sleep. Five patients did not fulfill any of these three polysomnographic (PSG) criteria. Conversely, one subject of the control group met the PSG criteria for RBD. This study estimates the diagnostic value of a visual scoring method for the diagnosis of idiopathic RBD and establishes cut‐off values to be used in clinical and research set‐ups. For the five RBD patients who did not show chin EMG abnormalities, it cannot be excluded that they had increased phasic EMG activity in the upper limbs and presented visible motor activity.

Slowing of electroencephalogram in rapid eye movement sleep behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by a loss of atonia and an increase in phasic muscle activity during REM sleep, leading to complex nocturnal motor behaviors. Brainstem structures responsible for the pathogenesis of RBD are also implicated in cortical activation. To verify the hypothesis that electroencephalogram (EEG) activation will be impaired in RBD, we performed quantitative analyses of waking and REM sleep EEG in 15 idiopathic RBD patients and 15 age‐ and gender‐matched healthy subjects. During wakefulness, RBD patients showed a considerably higher θ power in frontal, temporal, and occipital regions with a lower β power in the occipital region. The dominant occipital frequency was significantly lower in RBD. During REM sleep, β power in the occipital region was lower in RBD. This study shows for the first time an impaired cortical activation during both wakefulness and REM sleep in idiopathic RBD, despite an absence of changes on sleep architecture compared with controls. EEG slowing in these patients may represent an early sign of central nervous system dysfunction, perhaps paralleled by subclinical cognitive deficits. The topographical distribution of EEG slowing and possible pathophysiological mechanisms are discussed in light of the known association between RBD and neurodegenerative disorders. Ann Neurol 2003;53:774–780

Circadian rhythm of restless legs syndrome: Relationship with biological markers

Recently, it was suggested that the intensity of restless legs syndrome (RLS) symptoms may be modulated by a circadian factor. The objective of this study was to evaluate, during a 28‐hour modified constant routine, the nycthemeral or circadian variations in subjective leg discomfort and periodic leg movements (PLMs) and to parallel these changes with those of subjective vigilance, core body temperature, and salivary melatonin. Seven patients with primary RLS and seven healthy subjects matched for sex and age entered this study. Although the symptoms were more severe in patients than in controls, a significant circadian variation in leg discomfort and PLM (p < 0.01) was found for both groups. In both groups, the profiles of leg discomfort and PLM were significantly correlated with those of subjective vigilance, core body temperature, and salivary melatonin. However, among these variables, the changes in melatonin secretion were the only ones that preceded the increase in sensory and motor symptoms in RLS patients. This result and those of others studies showing that melatonin exerts an inhibitory effect on central dopamine secretion suggest that melatonin might be implicated in the worsening of RLS symptoms in the evening and during the night.

Idiopathic REM sleep behavior disorder Toward a better nosologic definition

REM sleep behavior disorder (RBD) is a parasomnia characterized by a lack of motor inhibition during REM sleep leading to potentially harmful dream-enacting behaviors. RBD affects mainly older men and its prevalence in the general population is estimated to be around 0.5%. RBD may be idiopathic or associated with other neurologic disorders. A strong association between RBD and alpha-synucleinopathies has been recently observed, with the parasomnia often heralding the clinical onset of the neurodegenerative disease. The idiopathic form accounts for up to 60% of the cases reported in the three largest series of patients with RBD. Small clinical follow-up studies revealed that a proportion of these patients will eventually develop a parkinsonian syndrome or a dementia of Lewy bodies type in the years following the RBD diagnosis, while some patients will never show other neurologic signs within several decades from the RBD onset. Recent studies have looked at neurophysiologic and neuropsychological functions in idiopathic RBD and have found evidences of CNS dysfunction during both wakefulness and sleep. An impairment of the cortical activity, specific neuropsychological deficits, and signs of autonomic dysfunction have been observed in a variable proportion of these patients, challenging the concept of idiopathic RBD. Identifying subjects with a high risk of developing a neurodegenerative process may be crucial in order to develop early intervention strategies.

Olfactory deficit in idiopathic rapid eye movements sleep behavior disorder.

INTRODUCTION REM sleep behavior disorder (RBD) is a parasomnia characterized by a loss of atonia and an increased phasic muscle activity during REM sleep. Idiopathic RBD frequently herald an alpha-synucleinopathy, including such as Parkinsons disease (PD) and dementia with Lewy Body (DLB). Pathological changes in the anterior olfactory nucleus and olfactory loss occur very early in the course of PD and DLB. The aim of the study was to assess olfactory function in a large group of idiopathic RBD patients. METHODS Fifty-four consecutive polysomnographically-confirmed iRBD patients (44 men, 10 women; mean age: 69.2+/-8.3 years; mean Unified Parkinsons Disease Rating Scale Part III (UPDRS-III) score: 4.9+/-4.3) and 54 age and gender-matched control subjects underwent the Brief University of Pennsylvania Smell Identification Test (B-SIT). RESULTS A marked olfactory impairment was observed in the RBD group (mean B-SIT score: 7.1+/-2.5 versus 9.4+/-1.8; p < 0.0001), with 33 (61.1%) RBD patients versus 9 (16.6%) controls showing abnormal olfactory function (p < 0.0001). No correlation was found between the degree of olfactory loss and either duration of RBD symptoms or UPDRS-III score. Deficit in recognize paint thinner odorant showed the highest positive predictive value (0.95) for identifying idiopathic RBD. CONCLUSIONS The olfactory deficit found in most idiopathic RBD patients shares similarities with that described in PD and may be a sign of a widespread neurodegenerative process. Its detection may help in identifying subjects at higher risk of developing an alpha-synucleinopathy-mediated neurodegeneration.

Association between waking EEG slowing and REM sleep behavior disorder in PD without dementia

Objective: To compare nondemented patients with Parkinson’s disease (PD) with and without REM sleep behavior disorder (RBD) to healthy controls on quantitative EEG characteristics for both wakefulness and REM sleep. Methods: Fifteen patients with PD (7 patients with polysomnographic-confirmed RBD [PD-RBD] and 8 patients without RBD [PD-NRBD]) and 15 healthy control subjects were studied. Each subject underwent a quantitative EEG analysis of both wakefulness and REM sleep. Results: During wakefulness, patients with PD-RBD showed a higher theta power in frontal, parietal, temporal, and occipital regions in comparison to patients with PD-NRBD and control subjects. Moreover, a slowing of the dominant occipital frequency was observed only in patients with PD-RBD (p < 0.02). Patients with PD-NRBD did not present any slowing of the EEG. No between-group difference in quantitative REM sleep EEG was observed. Conclusions: This study demonstrates that the EEG slowing reported during wakefulness in nondemented patients with PD is strongly related to the presence of RBD.