Publications by authors named "Joan Santamaria"

155 Publications

Video-polysomnography procedures for diagnosis of rapid eye movement sleep behavior disorder (RBD) and the identification of its prodromal stages: Guidelines from the International RBD Study Group.

Sleep 2021 Oct 25. Epub 2021 Oct 25.

Department of Neurology, Medical University of Innsbruck, Austria.

Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible.
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http://dx.doi.org/10.1093/sleep/zsab257DOI Listing
October 2021

Abnormal sleep behavior caused by hypoglycemia.

Sleep Med 2021 09 24;85:268-270. Epub 2021 Jul 24.

Neurology Service, Hospital Clínic of Barcelona, Spain.

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http://dx.doi.org/10.1016/j.sleep.2021.07.029DOI Listing
September 2021

Ambulatory circadian monitoring in sleep disordered breathing patients and CPAP treatment.

Sci Rep 2021 07 19;11(1):14711. Epub 2021 Jul 19.

Chronobiology Lab, Department of Physiology, College of Biology, University of Murcia, Mare Nostrum Campus. IUIE. IMIB - Arrixaca, 30100, Espinardo, Murcia, Spain.

Our aim was to evaluate the circadian rhythm of motor activity, body position and integrated variable TAP (composed by wrist Temperature, motor Activity and body Position) in Sleep Disordered Breathing (SDB), its relation to SDB severity and the effect of continuous positive airway pressure (CPAP) on these circadian rhythms. To do this, we monitored motor activity and body position rhythms of 78 SDB patients (53.3 ± 1.2 years old, 26.9% women) and 32 healthy subjects (51.4 ± 3.2 years old, 43.8% women) for 1 week. On the last day of that week, SDB patients underwent a polysomnography followed by a Maintenance of Wakefulness Test, Multiple Sleep Latency Test and Sustained Attention to Response Task protocol. A subgroup of 18 moderate to severe SDB patients was treated with CPAP and monitored again after 3 months under treatment. A non-parametrical analysis was performed to characterize the circadian patterns to assess differences between groups and associations between sleep and circadian parameters. Circadian variables were altered in SDB, exhibiting a direct relationship to SDB severity. The motor activity pattern showed a clear improvement with CPAP treatment. Thus, circadian ambulatory monitoring, including the integrated variable TAP, could be used to evaluate the circadian alterations caused by SDB and activity pattern to monitor the effect of CPAP treatment.
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http://dx.doi.org/10.1038/s41598-021-94315-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290024PMC
July 2021

Characterization of sleep in six patients with pantothenate kinase-associated neurodegeneration.

Sleep Med 2021 08 27;84:389-396. Epub 2021 Jun 27.

Parkinson's Disease and Movement Disorders Unit, Neurology Department, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain; Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII), Barcelona, Catalonia, Spain; European Reference Network for Rare Neurological Diseases - Project ID No 739510, Spain. Electronic address:

Background: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare neurologic disorder included in the group of neurodegeneration with brain iron accumulation diseases (NBIA). Information regarding sleep in patients with PKAN is limited.

Objectives: To describe the clinical and polysomnographic characteristics of sleep in six patients with genetically confirmed PKAN.

Methods: The evaluation included a clinical interview, sleep questionnaires -Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS)- and a video-polysomnography (VPSG). In addition to standard sleep measures we manually quantified sleep spindle density in stage N2 and rapid eye movements in REM sleep comparing the results with matched controls. Quantification of EMG activity in REM sleep was performed following standard criteria.

Results: All the patients reported at least one sleep complaint, most commonly sleep fragmentation (4/6) and sleep onset insomnia (3/6). ESS and PSQI were abnormal in 3/6 and 4/6, respectively. VPSG showed in 4/6 decreased ocular movements during REM sleep, an increase in sleep spindles in 3/6 (all of them with deep brain pallidal stimulation), an absence of slow wave sleep in 2 and undifferentiated NREM sleep and delayed sleep phase in one. Three patients had an abnormal sleep apnea/hypopnea index, and 2 periodic limb movements of sleep. REM sleep muscular atonia was preserved in all.

Conclusions: Sleep disorders are common in patients with PKAN. Although our sample is small and heterogeneous, with different symptomatic treatments possibly influencing the results, it suggests that evaluation of sleep should be considered in their management.
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http://dx.doi.org/10.1016/j.sleep.2021.06.019DOI Listing
August 2021

European guideline and expert statements on the management of narcolepsy in adults and children.

Eur J Neurol 2021 09 25;28(9):2815-2830. Epub 2021 Jun 25.

Sleep Wake Centre SEIN, Heemstede, The Netherlands.

Background And Aim: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children.

Methods: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach.

Results: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions.

Conclusion: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.
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http://dx.doi.org/10.1111/ene.14888DOI Listing
September 2021

European guideline and expert statements on the management of narcolepsy in adults and children.

J Sleep Res 2021 Jun 25:e13387. Epub 2021 Jun 25.

Sleep Wake Centre SEIN, Heemstede, The Netherlands.

Background And Purpose: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children.

Methods: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach.

Results: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions.

Conclusion: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.
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http://dx.doi.org/10.1111/jsr.13387DOI Listing
June 2021

Serum metabolic biomarkers for synucleinopathy conversion in isolated REM sleep behavior disorder.

NPJ Parkinsons Dis 2021 May 13;7(1):40. Epub 2021 May 13.

Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain.

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of Lewy-type synucleinopathies (LTS), which can present either with an initial predominant parkinsonism (Parkinson's disease (PD)) or dementia (dementia with Lewy bodies (DLB)). To provide insights into the underlying pathogenic mechanisms, the lipoprotein and protein glycosylation profile of 82 iRBD patients, collected before and/or after their conversion to an overt LTS, and 29 matched control serum samples were assessed by nuclear magnetic resonance (NMR) spectroscopy. Data were statistically analyzed to identify altered metabolites and construct predictive models. Univariant analysis detected no differences between iRBD patients with an LTS compared to controls. However, significant differences were found when the analysis distinguished between iRBD patients that manifested initially predominant parkinsonism (pre-PD) or dementia (pre-DLB). Significant differences were also found in the analysis of paired iRBD samples pre- and post-LTS diagnosis. Predictive models were built and distinguished between controls and pre-DLB patients, and between pre-DLB and pre-PD patients. This allowed a prediction of the possible future clinical outcome of iRBD patients. We provide evidence of altered lipoprotein and glycosylation profiles in subgroups of iRBD patients. Our results indicate that metabolic alterations and inflammation are involved in iRBD pathophysiology, and suggest biological differences underlying the progression of LTS in iRBD patients. Our data also indicate that profiling of serum samples by NMR may be a useful tool for identifying short-term high-risk iRBD patients for conversion to parkinsonism or dementia.
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http://dx.doi.org/10.1038/s41531-021-00184-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119407PMC
May 2021

Impaired cerebral microcirculation in isolated REM sleep behaviour disorder.

Brain 2021 06;144(5):1498-1508

Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark.

During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism.
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http://dx.doi.org/10.1093/brain/awab054DOI Listing
June 2021

Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder.

Brain 2021 05;144(4):1118-1126

Department of Neurosciences, Biomedicine and Movement Sciences University of Verona, Verona, Italy.

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P < 0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P < 0.001). We provide evidence that the α-synuclein RT-QuIC assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt α-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity.
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http://dx.doi.org/10.1093/brain/awab005DOI Listing
May 2021

Persistence of Facio-Skeletal Myorhythmia During Sleep in anti-IgLON5 Disease.

Mov Disord Clin Pract 2021 Apr 25;8(3):460-463. Epub 2021 Feb 25.

IRCCS Istituto delle Scienze Neurologiche di Bologna UOC Clinica Neurologica Rete Metropolitana NEUROMET Bologna Italy.

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http://dx.doi.org/10.1002/mdc3.13159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015885PMC
April 2021

Rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia are more frequent in advanced versus early Parkinson's disease.

Sleep 2021 Sep;44(9)

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.

Study Objectives: To evaluate macro sleep architecture and characterize rapid eye movement (REM) sleep without atonia (RWA) by using the SINBAR excessive electromyographic (EMG) montage including mentalis and upper extremity muscles in early and advanced Parkinson's disease (PD).

Methods: We recruited 30 patients with early- and advanced-stage of PD according to Movement Disorder Society (MDS) Clinical Diagnostic Criteria. Participants were classified as early-stage PD if they were treatment-naïve or had no motor complications and had been diagnosed with PD within the previous 6 years. Advanced PD was defined as a disease duration equal to or >6 years with or without motor complications.

Results: There was significantly shorter REM sleep latency in early as compared to the advanced stage of PD. We found that the sleep Innsbruck Barcelona (SINBAR) EMG index and tonic EMG activity of the mentalis muscle in advanced-stage PD were significantly higher than in early-stage PD with a trend in phasic EMG activity of the flexor digitorum superficialis muscles. The SINBAR EMG index, tonic and any EMG activity of the mentalis muscle, and phasic EMG activity of flexor digitorum superficialis muscles significantly correlated with disease duration.

Conclusions: This study analyzed RWA using the SINBAR EMG montage in early- and advanced-stage of PD and showed higher RWA in mentalis and flexor digitorum superficialis muscles and SINBAR EMG index in advanced-PD patients compared to patients in the early stage. Also, polysomnography-confirmed REM sleep behavior disorder was more common in advanced versus early-stage patients. Our findings suggest that RWA worsens or is more intense or more frequent with disease progression.
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http://dx.doi.org/10.1093/sleep/zsab067DOI Listing
September 2021

Nelotanserin as symptomatic treatment for rapid eye movement sleep behavior disorder: a double-blind randomized study using video analysis in patients with dementia with Lewy bodies or Parkinson's disease dementia.

Sleep Med 2021 05 25;81:180-187. Epub 2021 Feb 25.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Study Objectives: Rapid eye movement sleep behavior disorder (RBD) is frequent in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), and poses a risk of injury to patients and their bed partners. We assessed the efficacy of nelotanserin, a selective 5-HT (2A) inverse agonist, for symptomatic treatment of RBD using systematic video analysis.

Methods: This was a phase 2 multicenter study in DLB or PDD with video polysomnography (vPSG)-confirmed RBD. After a single-blind placebo run-in period, patients meeting eligibility criteria entered a 4-week double-blind treatment period (1:1 ratio with nelotanserin 80 mg/placebo). Whole-night vPSG was conducted during the run-in and at the end of the treatment period. Videos of all rapid eye movement (REM) sleep periods were analysed for RBD behaviors (movements and vocalizations) using the Innsbruck classification system by two of the central reviewers, and a third reviewer adjudicated ambiguous cases.

Results: 34 patients (N = 26 DLB, N = 8 PDD; 85.3% men; mean age 71.3 ± 6.36 years) were included in the analyses. Two (5.9%) patients were excluded due to protocol deviation in treatment compliance. Systematic video analysis demonstrated no difference between nelotanserin and placebo in RBD behaviors. Bland-Altman plot showed high interrater reliability.

Conclusions: Despite negative results, this is the first randomized, placebo-controlled study on symptomatic RBD treatment using objective outcome measures based on systematic video analysis. This study provides a new method for outcome research in RBD and proves that movement analysis is a feasible and meaningful outcome for studies evaluating changes in RBD severity.

Clinical Trial Information: ClinicalTrials.gov. NCT Number NCT02708186. https://clinicaltrials.gov/ct2/show/NCT02708186.
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http://dx.doi.org/10.1016/j.sleep.2021.02.038DOI Listing
May 2021

Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder.

Proc Natl Acad Sci U S A 2021 03;118(10)

Department of Biomedicine and Danish Research Institute of Translational Neuroscience (DANDRITE), Aarhus University, 8000 Aarhus, Denmark;

Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by C-PK11195 PET and negatively correlated with putaminal F-DOPA uptake; the opposite was seen for the percentage of CD163 myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.
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http://dx.doi.org/10.1073/pnas.2020858118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958435PMC
March 2021

Insights into the Use of Peripherally Acting μ-Opioid Receptor Antagonists (PAMORAs) in Oncologic Patients: from Scientific Evidence to Real Clinical Practice.

Curr Treat Options Oncol 2021 02 26;22(3):26. Epub 2021 Feb 26.

Medical Oncology, Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga, Spain.

Opinion Statement: Management of chronic pain is crucial to improve the quality of life of cancer and palliative care patients. Opioid-based treatments used to control pain can be prolonged over time. Unfortunately, constipation is one of the most disturbing adverse effects of long-term use of opioids. Opioid-induced constipation (OIC) occurs when opioids bind to the specific receptors present in the gastrointestinal (GI) tract, and can affect any patients receiving chronic opioid therapy, including cancer patients. The limited efficacy of laxatives to treat OIC symptoms prompted the search for new therapeutic strategies. Peripherally acting μ-opioid receptor antagonists (PAMORAs) have recently emerged as new effective drugs for OIC management due to their specific binding to enteric μ-receptors. Little information is available on the use of PAMORAs in real-life practice for OIC treatment in cancer patients. In this paper, a panel of experts specializing in cancer and palliative care pools their clinical experience with PAMORAs in cancer patients presenting OIC and highlights the importance of timing and choice of therapy in achieving prompt OIC management and benefitting patients.
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http://dx.doi.org/10.1007/s11864-021-00816-5DOI Listing
February 2021

Detection of α-synuclein in CSF by RT-QuIC in patients with isolated rapid-eye-movement sleep behaviour disorder: a longitudinal observational study.

Lancet Neurol 2021 03;20(3):203-212

National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the α-synucleinopathies Parkinson's disease and dementia with Lewy bodies. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has high sensitivity and specificity for the detection of misfolded α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect α-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal α-synucleinopathy.

Methods: In this longitudinal observational study, CSF samples were obtained by lumbar puncture from patients with video polysomnography-confirmed IRBD recruited at a specialised sleep disorders centre in Barcelona, Spain, and from controls free of neurological disease. CSF samples were stored until analysed using RT-QuIC. After lumbar puncture, participants were assessed clinically for neurological status every 3-12 months. Rates of neurological disease-free survival were estimated using the Kaplan-Meier method. Disease-free survival rates were assessed from the date of lumbar puncture to the date of diagnosis of any neurodegenerative disease, or to the last follow-up visit for censored observations.

Findings: 52 patients with IRBD and 40 healthy controls matched for age (p=0·20), sex (p=0·15), and duration of follow-up (p=0·27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF α-synuclein RT-QuIC assay was positive in 47 (90%) patients with IRBD and in four (10%) controls, resulting in a sensitivity of 90·4% (95% CI 79·4-95·8) and a specificity of 90·0% (95% CI 76·9-96·0). Mean follow-up from lumbar puncture until the end of the study (July 31, 2020) was 7·1 years (SD 2·8) in patients with IRBD and 7·7 years (2·9) in controls. During follow-up, 32 (62%) patients were diagnosed with Parkinson's disease or dementia with Lewy bodies a mean 3·4 years (SD 2·6) after lumbar puncture, of whom 31 (97%) were α-synuclein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were α-synuclein negative had lower risk for developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were α-synuclein positive (log-rank test p=0·028; hazard ratio 0·143, 95% CI 0·019-1·063). During follow-up, none of the controls developed an α-synucleinopathy. Kaplan-Meier analysis showed that participants who were α-synuclein negative (ie, five patients with IRBD plus 36 controls) had lower risk of developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8 and 10 years after lumbar puncture than participants who were α-synuclein positive (ie, 47 patients with IRBD plus four controls; log-rank test p<0·0001; hazard ratio 0·024, 95% CI 0·003-0·177).

Interpretation: In patients with IRBD, RT-QuIC detects misfolded α-synuclein in the CSF with both sensitivity and specificity of 90%, and α-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson's disease or dementia with Lewy bodies. Detection of α-synuclein in the CSF represents a potential prodromal marker of Parkinson's disease and dementia with Lewy bodies. If these findings are replicated in additional cohorts, detection of CSF α-synuclein by RT-QuIC could be used to enrich IRBD cohorts in neuroprotective trials, particularly when assessing interventions that target α-synuclein.

Funding: Department of Health and Social Care Policy Research Programme, the Scottish Government, and the Weston Brain Institute.
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http://dx.doi.org/10.1016/S1474-4422(20)30449-XDOI Listing
March 2021

Did inspector Kurt Wallander develop dementia with Lewy bodies?

Sleep Med 2021 02 4;78:36-37. Epub 2020 Dec 4.

Sleep Disorders Center, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Barcelona, Spain.

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http://dx.doi.org/10.1016/j.sleep.2020.11.032DOI Listing
February 2021

Sleep disorders in autoimmune encephalitis.

Lancet Neurol 2020 12;19(12):1010-1022

Department of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain.

Sleep disorders in people with autoimmune encephalitis have received little attention, probably overshadowed by the presence of other neurological and psychiatric symptoms in this group of conditions. However, sleep disorders are frequent, often severe, and usually persist beyond the acute disease stage, interfering with patients' recovery and quality of life. Because autoimmune encephalitis can affect any brain network involved in sleep initiation and regulation, all types of sleep disorders can occur, with varying distinct associations, frequency, and intensity. Anti-IgLON5 and anti-NMDA receptor encephalitis exemplify two diseases in which sleep disorders are prominent. In anti-IgLON5 disease, sleep disorders were the core symptoms that led to the description of this disease, whereas in anti-NMDA receptor encephalitis, sleep disorders vary according to the disease stage along with other neuropsychiatric symptoms. Comprehensive, systematic, multicentre studies are needed to characterise sleep disorders and their mechanisms in autoimmune encephalitis.
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http://dx.doi.org/10.1016/S1474-4422(20)30341-0DOI Listing
December 2020

Cortical cholinergic dysfunction correlates with microglial activation in the substantia innominata in REM sleep behavior disorder.

Parkinsonism Relat Disord 2020 12 8;81:89-93. Epub 2020 Oct 8.

Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Denmark; Translational and Clinical Research Institute, Newcastle University, United Kingdom. Electronic address:

Introduction: In vivo PET studies in patients with isolated REM sleep behavior disorder (iRBD) have shown presence of neuroinflammation (microglial activation) in the substantia nigra, and reduced cortical acetylcholinesterase activity, suggestive of cholinergic dysfunction, that was more widespread in patients with poorer cognitive performances. This study aimed to explore whether reduced cortical acetylcholinesterase activity in iRBD is linked to microglial activation in the substantia innominata (SI), the major source of cholinergic input to the cortex.

Methods: We used C(R)-PK11195 and C-Donepezil PET to assess levels of activated microglia and cholinergic function, respectively, in 19 iRBD patients. C(R)-PK11195 binding potential (BP) and C-Donepezil distribution volume ratio (DVR) values were correlated using the Pearson statistic.

Results: We found that a lower cortical C-Donepezil DVR correlated with a higher C(R)-PK11195 BP in the SI (r = -0.48, p = 0.04). At a voxel level, the strongest negative correlations were found in the frontal and temporal lobes.

Conclusion: Our results suggest that reduced cortical acetylcholinesterase activity observed in our iRBD patients could be linked to the occurrence of neuroinflammation in the SI. Early modulation of microglial activation might therefore preserve cortical cholinergic functions in these patients.
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http://dx.doi.org/10.1016/j.parkreldis.2020.10.014DOI Listing
December 2020

Magnetic resonance imaging abnormalities as a marker of multiple system atrophy in isolated rapid eye movement sleep behavior disorder.

Sleep 2021 01;44(1)

Center for Sleep Disorders, Neurology Service, Universitat de Barcelona, IDIBAPS, CIBERNED:CB06/05/0018-ISCIII, Hospital Clínic de Barcelona, Barcelona, Spain.

Study Objectives: Patients with isolated rapid eye movement (REM) sleep behavior disorder (IRBD) develop Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). Magnetic resonance imaging (MRI) is abnormal in MSA showing abnormalities in the putamen, cerebellum, and brainstem. Our objective was to evaluate the usefulness of MRI to detect MRI abnormalities in IRBD and predict development of MSA and not PD and DLB.

Methods: In IRBD patients that eventually developed PD, DLB, and MSA, we looked for the specific structural MRI abnormalities described in manifest MSA (e.g. hot cross-bun sign, putaminal rim, and cerebellar atrophy). We compared the frequency of these MRI changes among groups of converters (PD, DLB, and MSA) and analyzed their ability to predict development of MSA. The clinical and radiological features of the IRBD patients that eventually converted to MSA are described in detail.

Results: A total of 61 IRBD patients who underwent MRI phenoconverted to PD (n = 30), DLB (n = 26), and MSA (n = 5) after a median follow-up of 2.4 years from neuroimaging. MRI changes typical of MSA were found in four of the five (80%) patients who converted to MSA and in three of the 56 (5.4%) patients who developed PD or DLB. MRI changes of MSA had sensitivity of 80.0%, specificity of 94.6%, positive likelihood ratio of 14.9 (95% CI 4.6-48.8), and negative likelihood ratio of 0.2 (95% CI 0.04-1.2) to predict MSA.

Conclusions: In IRBD, conventional brain MRI is helpful to predict conversion to MSA. The specific MRI abnormalities of manifest MSA may be detected in its premotor stage.
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http://dx.doi.org/10.1093/sleep/zsaa089DOI Listing
January 2021

Significance of hyposmia in isolated REM sleep behavior disorder.

J Neurol 2021 Mar 23;268(3):963-966. Epub 2020 Sep 23.

Otorhinolaryngology Service, Hospital Clínic de Barcelona, Universitat de Barcelona, IDIBAPS, CIBER Enfermedades Respiratorias, Bunyola, Spain.

Objective: To determine if hyposmia in isolated REM sleep behavior disorder (IRBD) predicts short-term conversion to any α-synucleinopathy and declines with time.

Methods: Olfaction was tested using the University of Pennsylvania Smell Identification Test (UPSIT-40) in 140 consecutive patients with polysomnography-confirmed IRBD and in 77 matched controls. Patients were followed-up during 5.6 ± 3.9 (range 0.2-13) years. Twenty-one patients underwent serial UPSIT-40 evaluations at 1-3 and 4-6 years after baseline.

Results: UPSIT-40 score was lower in patients than in controls (20.2 ± 6.5 vs. 28.6 ± 5.0; p < 0.001). Hyposmia (UPSIT-40 score < 19 points) occurred in 42.9% patients. Forty-three (30.7%) patients developed Parkinson disease (PD = 27), dementia with Lewy bodies (DLB = 13) and multiple system atrophy (MSA = 3). Kaplan-Meier analysis showed that hyposmics had higher risk than normosmics to develop a synucleinopathy at the short term (p = 0.030). UPSIT-40 score was similar between patients who developed PD and DLB (p = 0.136). Normal smell occurred in all three (100%) IRBD patients who developed MSA, 12 of 27 (44%) who developed PD, and 4 of 13 (31%) that developed DLB. Serial UPSIT-40 evaluations showed no changes with time (p = 0.518).

Conclusion: In IRBD, hyposmia is a short-term risk for synucleinopathies but cannot distinguish underlying PD from DLB. Normosmia not only occurs in latent MSA but also in latent PD and DLB. In future IRBD neuroprotective trails, individuals at entry could be enriched for hyposmia, whereas serial evaluation of smell would not be useful to monitor the efficacy of a therapeutic intervention.
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http://dx.doi.org/10.1007/s00415-020-10229-3DOI Listing
March 2021

Standard procedures for the diagnostic pathway of sleep-related epilepsies and comorbid sleep disorders: A European Academy of Neurology, European Sleep Research Society and International League against Epilepsy-Europe consensus review.

J Sleep Res 2020 12 21;29(6):e13184. Epub 2020 Sep 21.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Bologna, Italy.

Background: Some epilepsy syndromes (sleep-related epilepsies [SRE]) have a strong link with sleep. Comorbid sleep disorders are common in patients with SRE and can exert a negative impact on seizure control and quality of life.

Purposes: To define the standard procedures for the diagnostic pathway of patients with possible SRE (scenario 1) and the general management of patients with SRE and comorbidity with sleep disorders (scenario 2).

Methods: The project was conducted under the auspices of the European Academy of Neurology (EAN), the European Sleep Research Society (ESRS) and the International League against Epilepsy (ILAE) Europe. The framework of the document entailed the following phases: conception of the clinical scenarios; literature review; statements regarding the standard procedures. For literature search a step-wise approach starting from systematic reviews to primary studies was applied. Published studies were identified from the National Library of Medicine's MEDLINE database and Cochrane Library.

Results: Scenario 1: despite a low quality of evidence, recommendations on anamnestic evaluation, tools for capturing the event at home or in the laboratory are provided for specific SRE. Scenario 2: Early diagnosis and treatment of sleep disorders (especially respiratory disorders) in patients with SRE are likely to be beneficial for seizures control.

Conclusions: Definitive procedures for evaluating patients with SRE are lacking. We provide advice that could be of help for standardising and improving the diagnostic approach of specific SRE. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined.
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http://dx.doi.org/10.1111/jsr.13184DOI Listing
December 2020

Stridor during sleep: description of 81 consecutive cases diagnosed in a tertiary sleep disorders center.

Sleep 2021 03;44(3)

Otorhinolaryngology Service, Hospital Clínic de Barcelona, Universitat de Barcelona, CIBER Enfermedades Respiratorias, Bunyola, Spain.

Study Objectives: To describe the characteristics of stridor during sleep (SDS) in a series of adults identified by video-polysomnography (V-PSG).

Methods: Retrospective clinical, V-PSG, laryngoscopic, and therapeutic data of patients diagnosed with SDS in a tertiary referral sleep disorders center between 1997 and 2017.

Results: A total of 81 patients were identified (56.8% males, age 61.8 ± 11.2 years). Related etiologies were multiple system atrophy (MSA), amyotrophic lateral sclerosis, spinocerebellar ataxia type 1, anti-IgLON5 disease, fatal familial insomnia, brainstem structural lesions, vagus nerve stimulation, recurrent laryngeal nerve injury, the effect of radiotherapy on the vocal cords, cervical osteophytes, and others. Stridor during wakefulness coexisted in 13 (16%) patients and in MSA was only seen in the parkinsonian form. Laryngoscopy during wakefulness in 72 (88.9%) subjects documented vocal cord abductor impairment in 65 (90.3%) and extrinsic lesions narrowing the glottis in 2 (2.4%). The mean apnea-hypopnea index (AHI) was 21.4 ± 18.6 and CT90 was 11.5 ± 19.1. Obstructive AHI > 10 occurred in 52 (64.2%) patients and central apnea index >10 in 2 (2.4%). CPAP abolished SDS, obstructive apneic events and oxyhemoglobin desaturations in 58 of 60 (96.7%) titrated patients with optimal pressure of 9.0 ± 2.3 cm H20. Tracheostomy in 19 (23.4%) and cordotomy in 3 (3.7%) subjects also eliminated SDS.

Conclusions: SDS in adults is linked to conditions that damage the brainstem, recurrent laryngeal nerve, and vocal cords. V-PSG frequently detects obstructive sleep apnea and laryngoscopy usually shows vocal cord abductor dysfunction. CPAP, tracheostomy, and laryngeal surgery abolish SDS.
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http://dx.doi.org/10.1093/sleep/zsaa191DOI Listing
March 2021

New 2013 incidence peak in childhood narcolepsy: more than vaccination?

Sleep 2021 02;44(2)

Center for Sleep Medicine, Sleep Research and Epileptology, Clinic Barmelweid AG, Barmelweid, Switzerland.

Increased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009-2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the NT1 incidence increase and the H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus itself to be linked to the increased NT1 incidence. Using robust data-driven modeling approaches, that is, locally estimated scatterplot smoothing methods, we analyzed the number of de novo NT1 cases (n = 508) in the last two decades using the European Narcolepsy Network database. We confirmed the peak of NT1 incidence in 2010, that is, 2.54-fold (95% confidence interval [CI]: [2.11, 3.19]) increase in NT1 onset following 2009-2010 pH1N1. This peak in 2010 was found in both childhood NT1 (2.75-fold increase, 95% CI: [1.95, 4.69]) and adulthood NT1 (2.43-fold increase, 95% CI: [2.05, 2.97]). In addition, we identified a new peak in 2013 that is age-specific for children/adolescents (i.e. 2.09-fold increase, 95% CI: [1.52, 3.32]). Most of these children/adolescents were HLA DQB1*06:02 positive and showed a subacute disease onset consistent with an immune-mediated type of narcolepsy. The new 2013 incidence peak is likely not related to Pandemrix as it was not used after 2010. Our results suggest that the increased NT1 incidence after 2009-2010 pH1N1 is not unique and our study provides an opportunity to develop new hypotheses, for example, considering other (influenza) viruses or epidemiological events to further investigate the pathophysiology of immune-mediated narcolepsy.
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http://dx.doi.org/10.1093/sleep/zsaa172DOI Listing
February 2021

Take Care.

Curr Treat Options Neurol 2020 6;22(10):32. Epub 2020 Aug 6.

Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

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http://dx.doi.org/10.1007/s11940-020-00637-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406693PMC
August 2020

Prodromal Parkinson disease in patients with idiopathic hyposmia.

J Neurol 2020 Dec 16;267(12):3673-3682. Epub 2020 Jul 16.

Rhinology Unit and Smell and Taste Clinic, Otorhinolaryngology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, IDIBAPS, CIBERES, Barcelona, Catalonia, Spain.

Background: Idiopathic hyposmia (IH) is a prodromal marker of Parkinson disease (PD). However, IH is common in the general population and only a minority will develop PD. Identification of individuals with IH at prodromal stage of PD would serve to select them to implement neuroprotective agents, when available.

Objective: To identify prodromal PD in IH patients using the Movement Disorders Society (MDS) research criteria for prodromal PD.

Methods: We applied the MDS research criteria for prodromal PD to 25 consecutive patients older than 50 years who were self-referred for smell loss and had IH, and to 18 controls. A number of risk and prodromal PD markers were assessed in all participants including REM sleep behavior disorder (RBD) by video-polysomnography and nigrostriatal dopaminergic dysfunction by DAT-SPECT. After follow-up of 4.7 ± 2.2 years, participants were re-assessed to look for incident PD.

Results: Prodromal PD probability was higher in patients than in controls (19.45 ± 34.9% versus 1.74 ± 4.48%; p = 0.019). Four (16%) patients met the criteria of prodromal PD surpassing 80% probability (99.8%, 99.5%, 88.3%, 86.4%). Three (12%) patients had RBD and four (16%) abnormal DAT-SPECT. At the end of follow-up, one (4%) IH patient who had RBD and baseline prodromal PD probability of 86.4% developed PD, while all controls remained disease free.

Conclusions: Prodromal PD is infrequent among IH patients. MDS research criteria for prodromal PD are useful to identify a subgroup of IH patients at high risk of PD when RBD is assessed by video-polysomnography and nigrostriatal dopamine deficiency with DAT-SPECT.
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http://dx.doi.org/10.1007/s00415-020-10048-6DOI Listing
December 2020

Sleep disorders in anti-NMDAR encephalitis.

Neurology 2020 08 23;95(6):e671-e684. Epub 2020 Jun 23.

From Clinical and Experimental Neuroimmunology (H.A., A.M.-L., E.M.-H., T.A., M.R.-J., D.E., F.G., G.S., J.C.-F., A.C., J.D., J.S.), Institut d'Investigació Biomèdica August Pi i Sunyer; Departments of Neurology (A.M.-L., E.M.-H., D.E., N.M., J.D., J.S.) and Child and Adolescent Psychiatry and Psychology (T.A., G.S., J.C.-F.), Hospital Clinic, and Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Déu Children's Hospital, University of Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (J.D.), Barcelona, Spain.

Objective: To describe the sleep disorders in anti-NMDA receptor encephalitis (anti-NMDARe).

Methods: Patients recovering from anti-NMDARe were invited to participate in a prospective observational single-center study including comprehensive clinical, video-polysomnography (V-PSG) sleep assessment, and neuropsychological evaluation. Age- and sex-matched healthy participants served as controls.

Results: Eighteen patients (89% female, median age 26 years, interquartile range [IQR] 21-29 years) and 21 controls (81% female, median age 23 years, IQR 18-26 years) were included. In the acute stage, 16 (89%) patients reported insomnia and 2 hypersomnia; nightmares occurred in 7. After the acute stage, 14 (78%) had hypersomnia. At study admission (median 183 days after disease onset, IQR 110-242 days), 8 patients still had hypersomnia, 1 had insomnia, and 9 had normal sleep duration. Patients had more daytime sleepiness than controls (higher Barcelona Sleepiness Index, = 0.02, and Epworth Sleepiness Score, = 0.04). On V-PSG, sleep efficiency was similar in both groups, but patients more frequently had multiple and longer confusional arousals in non-REM (NREM) sleep (videos provided). In addition, 13 (72%) patients had cognitive deficits; 12 (67%) had psychological, social, or occupational disability; and 33% had depression or mania. Compared with controls, patients had a higher body mass index (median 23.5 [IQR 22.3-30.2] vs 20.5 [19.1-21.1] kg/m; = 0.007). Between disease onset and last follow-up, 14 (78%) patients developed hyperphagia, and 6 (33%) developed hypersexuality (2 requiring hospitalization), all associated with sleep dysfunction.

Conclusions: Sleep disturbances are frequent in anti-NMDARe. They show a temporal pattern (predominantly insomnia at onset; hypersomnia during recovery), are associated with behavioral and cognitive changes, and can occur with confusional arousals during NREM sleep.
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http://dx.doi.org/10.1212/WNL.0000000000009987DOI Listing
August 2020

Cervical spinal cord injury by a low-impact trauma as an unnoticed cause of cardiorespiratory arrest.

Eur Heart J Case Rep 2020 Apr 10;4(2):1-6. Epub 2020 Mar 10.

Neurology Department, Hospital Clínic de Barcelona, Centros de Investigación Biomédica en Red de enfermedades neurodegenerativas (CIBERNED), C/Villarroel 170, Barcelona 0008036, Spain.

Background: Cardiorespiratory arrest (CA) secondary to traumatic cervical spinal cord injury can occur in minor accidents with low-impact trauma and may be overlooked as the cause of CA in patients admitted in the coronary care unit.

Case Summary: We present two patients admitted to the coronary care unit because of suspected CA of cardiac origin. Both patients were found in CA with asystole, one after collapsing in a shopping mall and falling down a few steps and the other in the street next to his bicycle. They underwent early pharmacologically induced coma and hypothermia precluding neurological examination. Both patients remained in coma after rewarming, with preserved brainstem reflexes but absent motor response to pain. One patient had post-anoxic myoclonus in the face without limb involvement. In both patients, median nerve somatosensory evoked potentials demonstrated bilateral absence of thalamocortical N19 responses and abnormal cervicomedullary junction potentials (N13 wave). Extensive diagnostic work-up did not find a cardiac cause of the CA, pulmonary thromboembolism, or intracranial haemorrhage. In both patients, cervical spinal cord injury was diagnosed incidentally 5 and 6 days after CA, when a brain magnetic resonance imaging performed to assess post-anoxic brain injuries detected spinal cord hyperintensities with fracture and luxation of the odontoid. Both patients died 11 and 8 days after CA.

Discussion: Low-impact traumatic cervical spinal cord injury should be considered in the diagnostic work-up of patients with CA of unknown cause.
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http://dx.doi.org/10.1093/ehjcr/ytaa044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180526PMC
April 2020

Diagnosis of central disorders of hypersomnolence: A reappraisal by European experts.

Sleep Med Rev 2020 08 23;52:101306. Epub 2020 Mar 23.

Sleep-Wake Disorders Center, National Reference Network for Narcolepsy, Department of Neurology, Gui-de-Chauliac Hospital, INSERM, U1061, University of Montpellier, CHU Montpellier, France. Electronic address:

The aim of this European initiative is to facilitate a structured discussion to improve the next edition of the International Classification of Sleep Disorders (ICSD), particularly the chapter on central disorders of hypersomnolence. The ultimate goal for a sleep disorders classification is to be based on the underlying neurobiological causes of the disorders with clear implication for treatment or, ideally, prevention and or healing. The current ICSD classification, published in 2014, inevitably has important shortcomings, largely reflecting the lack of knowledge about the precise neurobiological mechanisms underlying the majority of sleep disorders we currently delineate. Despite a clear rationale for the present structure, there remain important limitations that make it difficult to apply in routine clinical practice. Moreover, there are indications that the current structure may even prevent us from gaining relevant new knowledge to better understand certain sleep disorders and their neurobiological causes. We suggest the creation of a new consistent, complaint driven, hierarchical classification for central disorders of hypersomnolence; containing levels of certainty, and giving diagnostic tests, particularly the MSLT, a weighting based on its specificity and sensitivity in the diagnostic context. We propose and define three diagnostic categories (with levels of certainty): 1/"Narcolepsy" 2/"Idiopathic hypersomnia", 3/"Idiopathic excessive sleepiness" (with subtypes).
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http://dx.doi.org/10.1016/j.smrv.2020.101306DOI Listing
August 2020

Left-hemispheric predominance of nigrostriatal deficit in isolated REM sleep behavior disorder.

Neurology 2020 04 11;94(15):e1605-e1613. Epub 2020 Mar 11.

From the Sleep Disorders Center (A.I., M.S., D.V., C.G., D.R., J.S.) and Movement Disorders Unit (E.T.), Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain; Department of Neurology (A.S., H.S., E.H., K.S., B.H., W.P.), Medical University Innsbruck, Austria; Biomedical Research Networking Center of Bioengineering, Biomaterials and Nanomedicine (A.N.-B., J.P.); and Nuclear Medicine Service (J.P., F.L.), Hospital Clinic Barcelona, IDIBAPS, Barcelona, Spain.

Objective: Unilateral onset of parkinsonism due to nigrostriatal damage of the contralateral hemisphere is frequent in Parkinson disease (PD). There is evidence for a left-hemispheric bias of motor asymmetry in right-handed patients with PD indicating a hemispheric dominance. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of PD and other synucleinopathies. To test the hypothesis that right-handed patients with IRBD exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction, we evaluated this aspect using neuroimaging instruments.

Methods: In 167 right-handed patients with IRBD without parkinsonism, we evaluated in each hemisphere the integrity of the striatal dopaminergic terminals by dopamine transporter (DAT)-SPECT and the substantia nigra echogenicity by transcranial sonography.

Results: DAT-SPECT showed lower specific binding ratio (SBR) in the left striatum and left caudate nucleus than in the right striatum and right caudate nucleus. The percentage of patients with lower SBR was greater in the left striatum and left caudate nucleus than in the right striatum and right caudate nucleus. In those who developed a synucleinopathy in <5 years from DAT-SPECT, there was a lower SBR in the left putamen and left caudate nucleus than in the right putamen and right caudate nucleus. Substantia nigra echogenic size was greater in the left than in the right side in patients with hyperechogenicity and among individuals who phenoconverted in <5 years from transcranial sonography.

Conclusion: Right-handed patients with IRBD exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction. In premotor PD, the neurodegenerative process begins asymmetrically, initially impairing the nigrostriatal system of the dominant hemisphere.
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http://dx.doi.org/10.1212/WNL.0000000000009246DOI Listing
April 2020

Lack of Asymmetry of Nigrostriatal Dopaminergic Function in Healthy Subjects.

Mov Disord 2020 06 6;35(6):1072-1076. Epub 2020 Mar 6.

Center for Sleep Disorders, Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain.

Objective: In right-handed patients with Parkinson's disease (PD) or isolated rapid eye movement sleep behavior disorder, dopamine transporter (DAT) [(123)I]β-carboxymethyoxy-3-β-(4-iodophenyl) tropane single photon emission computed tomography (SPECT) shows predominant nigrostriatal deficit in the left striatum. This suggests that in PD patients, the nigrostriatal system of the dominant hemisphere is more susceptible to disease-related dysfunction. To confirm this hypothesis, we investigated whether the nigrostriatal function is symmetric in healthy controls and in patients with PD.

Methods: In 113 right-handed healthy controls and 279 right-handed early-PD patients, we examined the striatal dopaminergic terminals function in each hemisphere using DAT-SPECT.

Results: In the controls, DAT-SPECT showed symmetric specific binding ratios in the putamen and caudate nucleus of each hemisphere. In patients with PD, the specific binding ratio was lower in the left than in the right putamen.

Conclusions: Right-handed healthy controls have symmetric nigrostriatal dopaminergic function. The left hemispheric predominance of nigrostriatal deficit seen in right-handed premotor and manifest PD represents an early pathological feature of the disease. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28019DOI Listing
June 2020
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