Ambra Stefani

Loss of dorsolateral nigral hyperintensity on 3.0 tesla susceptibility-weighted imaging in idiopathic rapid eye movement sleep behavior disorder

We assessed loss of dorsolateral nigral hyperintensity (DNH) on high‐field susceptibility‐weighted imaging (SWI), a novel magnetic resonance imaging marker for Parkinsons disease (PD), in 15 subjects with idiopathic rapid eye movement sleep behavior disorder (iRBD) and compared findings to 42 healthy controls (HCs) and 104 PD patients. We found loss of DNH in at least two thirds of iRBD subjects, which approaches the rate observed in PD and is in contrast to findings in HCs. We propose that absence of DNH on high‐field SWI could identify prodromal degenerative parkinsonism in iRBD. Ann Neurol 2016;79:1026–1030

Idiopathic REM sleep behaviour disorder and neurodegeneration — an update

So-called idiopathic rapid eye movement (REM) sleep behaviour disorder (RBD), formerly seen as a rare parasomnia, is now recognized as the prodromal stage of an α-synucleinopathy. Given the very high risk that patients with idiopathic RBD have of developing α-synucleinopathies, such as Parkinson disease (PD), PD dementia, dementia with Lewy bodies or multiple system atrophy, and the outstandingly high specificity and very long interval between the onset of idiopathic RBD and the clinical manifestations of α-synucleinopathies, the prodromal phase of this disorder represents a unique opportunity for potentially disease-modifying intervention. This Review provides an update on classic and novel biomarkers of α-synuclein-related neurodegeneration in patients with idiopathic RBD, focusing on advances in imaging and neurophysiological, cognitive, autonomic, tissue-specific and other biomarkers. We discuss the strengths, potential weaknesses and suitability of these biomarkers for identifying RBD and neurodegeneration, with an emphasis on predicting progression to overt α-synucleinopathy. The role of video polysomnography in providing quantifiable and potentially treatment-responsive biomarkers of neurodegeneration is highlighted. In light of all these advances, and the now understood role of idiopathic RBD as an early manifestation of α-synuclein disease, we call for idiopathic RBD to be reconceptualized as isolated RBD.

Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

Summary Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10−8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85–1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. Funding Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München–Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder

To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic rapid eye movement sleep behavior disorder (IRBD) patients at risk for short‐term development of clinically defined synucleinopathy.

Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic REM sleep behavior disorder

To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic rapid eye movement sleep behavior disorder (IRBD) patients at risk for short‐term development of clinically defined synucleinopathy.

A Prospective Video-Polysomnographic Analysis of Movements during Physiological Sleep in 100 Healthy Sleepers.

STUDY OBJECTIVES Video-polysomnography (v-PSG) is the gold standard for the diagnosis of sleep disorders. Quantitative assessment of type and distribution of physiological movements during sleep for the differentiation between physiological and pathological motor activity is lacking. We performed a systematic and detailed analysis of movements during physiological sleep using v-PSG technology. DESIGN Prospective v-PSG investigation. SETTING Academic referral center sleep laboratory. PARTICIPANTS One hundred healthy sleepers aged 19-77 years recruited from a representative population sample after a two-step screening. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS All subjects underwent v-PSG. In all cases where electromyographic activity > 100 msec duration was visible during sleep in the mentalis, submentalis, flexor digitorum superficialis, or anterior tibialis muscles, the time-synchronized video was analyzed. Visible movements were classified according to movement type and topography, and movement rates were computed for the different sleep stages. A total of 9,790 movements (median 10.2/h, IQR 4.6-16.2) were analyzed: 99.7% were elementary, 0.3% complex. Movement indices were higher in men than women (men: median 13/h, interquartile range 7.1-29.3, women: median 7.9/h, interquartile range 3.4-14.5; P = 0.006). The majority of movements involved the extremities (87.9%) and were classified as focal (53.3%), distal (79.6%), and unilateral (71.5%); 15.3% of movements were associated with arousals. REM-related movements (median 0.8 sec, IQR 0.5-1.2) were shorter than NREM-related movements (median 1.1 sec, IQR 0.8-1.6; P = 0.001). Moreover, REM-related movements were predominantly myocloniform (86.6%), whereas NREM-related movements were more often non-myocloniform (59.1%, P < 0.001). CONCLUSION Minor movements are frequent during physiological sleep, and are associated with low arousal rates. REM-related movements were predominantly myocloniform and shorter than NREM movements, indicating different influences on motor control during both sleep states.

Augmentation and impulsive behaviors in restless legs syndrome Coexistence or association

Objectives: To assess the frequency of impulse control disorders (ICDs) in patients with restless legs syndrome (RLS) with and without augmentation under dopaminergic therapy in a case-control study. Augmentation and ICDs are both serious complications of dopaminergic treatment of RLS but little is known about possible associations between these drug-induced disorders. Methods: In total, 58 patients with idiopathic RLS diagnosed according to the International Restless Legs Syndrome Study Group criteria were recruited. Of these, 35 patients had augmentation. The frequency of ICD symptoms was assessed using semi-structural interviews. Results: Demographic variables did not differ between patients with RLS with and without augmentation but those with augmentation took higher dopaminergic medication than patients without augmentation. Twenty-three patients with RLS (39.7%) had ICD symptoms, with 12 patients (20.7%) having definitive ICDs. Patients with augmentation had an increased risk of expressing ICD symptoms (p = 0.007, odds ratio 5.64, 95% confidence interval 1.59–20.02). Conclusions: Patients with RLS with augmentation have an almost 6-fold increased risk of exhibiting ICD symptoms. This implies that augmentation and ICDs are related and may share a common pathophysiology. Moreover, our results have clinical implications, suggesting that patients with RLS with augmentation should be screened for ICD symptoms.

Natural course of restless legs syndrome/Willis–Ekbom disease: long-term observation of a large clinical cohort

OBJECTIVE Although restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is a common neurological disorder, data on the long-term course and management of the disease are scarce. The aim of the current study was to extend the knowledge on the long-term clinical course and treatment outcome of RLS/WED. METHODS In this retrospective analysis, we performed a chart review of consecutive visits of 160 patients with definite RLS/WED from the RLS/WED database of the Innsbruck Medical University. RESULTS A total of 160 patients (58.8% female, aged 58.9 years, range 21.5-86.8 years) met inclusion criteria of two or more visits during a follow-up of at least five years. The duration of the observational period was 8.1 ± 2.9 years. During the observational period, the percentage of treated patients increased (first vs last visit: 67.5% vs 77.5%). Of the patients, 59.4% had one or more switches of medication. Overall the RLS/WED severity, evaluated using a combined severity score (CSS) ranging from 1 to 5, decreased between the first and last visits (median [range], first visit: 3 [1-5] vs last visit 2.5 [1-5]; p <0.001). Symptoms improved in 55.0% of patients, worsened in 10.6%, and remained unchanged in 34.4% during the observational period. Augmentation of RLS/WED occurred in 42 patients (13/42 as the presenting cause; 29/42 occurring during treatment after 4.1 years). The annual rate of augmentation for subjects on dopaminergic medication was 8.1%. CONCLUSIONS Our data suggest that, with the possibility of regular treatment adjustments, RLS/WED remains treatable in the majority of patients over years. Nevertheless, in this study, despite the overall decreased severity, RLS symptoms remained unchanged or worsened in 45% of the patients during the observational period.

Restless legs syndrome and periodic leg movements in patients with movement disorders: Specific considerations

Restless legs syndrome is a frequent neurological disorder with potentially serious and highly distressing treatment complications. The role and potential implications of periodic leg movements during sleep range from being a genetic risk marker for restless legs syndrome to being a cardiovascular risk factor. The diagnosis of restless legs syndrome in patients with daytime movement disorders is challenging and restless legs syndrome needs to be differentiated from other sleep‐related movement disorders. This article provides an update on the diagnosis of restless legs syndrome as an independent disorder and the role of periodic leg movements and reviews the association of restless legs syndrome with Parkinsons disease and other movement disorders.

Peripheral nerve function in patients with excessive fragmentary myoclonus during sleep.

OBJECTIVES Excessive fragmentary myoclonus is a frequent incidental finding in patients undergoing polysomnography for other reasons. The aim of this study was to evaluate whether electrophysiological examination in patients with excessive fragmentary myoclonus during sleep according to American Academy of Sleep Medicine (AASM) criteria shows findings of peripheral nerve dysfunction. METHODS Ninety-eight of 100 patients with excessive fragmentary myoclonus detected as an incidental finding during routine polysomnography underwent electrophysiological workup. Motor nerve conduction studies of the right peroneal and tibial nerves, F-wave recordings of the tibial nerve, antidromic sensory nerve conduction studies of the left sural nerve and needle electromyography of the right tibialis anterior muscle were performed and classified as normal, peripheral neuropathy, lumbar 5 (L5) nerve root lesion, or benign fasciculations. RESULTS Fifty percent (49 out of 98) presented with electrophysiological abnormalities, most frequently polyneuropathy (32 out of 49, 65.3%), followed by L5 nerve root lesions (13 out of 49, 26.5%) and benign fasciculations (4 out of 49, 8.2%). Patients with electrophysiological abnormalities were older than those without. CONCLUSIONS The high prevalence of abnormal neurophysiological findings in patients with excessive fragmentary myoclonus during polysomnography suggests that excessive fragmentary myoclonus during sleep according to AASM criteria is not primarily a sleep-related phenomenon, but only persists during sleep and points to peripheral nerve pathology at least in part of the cases. Patients with incidental EFM during polysomnography should undergo electrophysiological workup for peripheral nerve pathology.