The functional brain connectome in isolated rapid eye movement sleep behavior disorder and Parkinson's disease.

BACKGROUND: Isolated rapid-eye-movement behavior disorder (iRBD) often precedes the development of alpha-synucleinopathies such as Parkinson's disease (PD). Magnetic resonance imaging (MRI) studies have revealed structural brain alterations in iRBD partially resembling those observed in PD. However, relatively little is known about whole-brain functional brain alterations in iRBD. Here, we characterize the functional brain connectome of iRBD compared with PD patients and healthy controls (HC) using resting-state functional MRI (rs-fMRI). METHODS: Eighteen iRBD subjects (67.3 ± 6.6 years), 18 subjects with PD (65.4 ± 5.8 years), and 39 age- and sex-matched HC (64.4 ± 9.2 years) underwent rs-fMRI at 3 T. We applied a graph theoretical approach to analyze the brain functional connectome at the global and regional levels. Data were analyzed using both frequentist and Bayesian statistics. RESULTS: Global connectivity was largely preserved in iRBD and PD individuals. In contrast, both disease groups displayed altered local connectivity mainly in the motor network, temporal cortical regions including the limbic system, and the visual system. There were some group specific alterations, and connectivity changes were pronounced in PD individuals. Overall, however, there was a good agreement of the connectome changes observed in both disease groups. CONCLUSIONS: This study provides evidence for widespread functional brain connectivity alterations in iRBD, including motor circuitry, despite normal motor function. Connectome alterations showed substantial resemblance with those observed in PD, underlining a close pathophysiological relationship of iRBD and PD.

Development of a Composite Score for the Clinical Assessment of Anti-IgLON5 Disease.

BACKGROUND AND OBJECTIVES: To develop a composite score to assess the severity of the multiple symptoms present in anti-IgLON5 disease. METHODS: The anti-IgLON5 disease composite score (ICS) was designed to evaluate 17 symptoms divided into 5 clinical domains (bulbar, sleep, movement disorders, cognition, and others). Each symptom was scored from 0 (absent/normal) to 3 or 6 (severe) depending on the contribution of the symptom to neurologic disability with a maximum ICS of 69. The ICS was tested in patients from 2 cohorts (Barcelona, Spain, and GENERATE, Germany) that included cases personally seen by the authors (internal) and patients whose ICS was obtained from information of questionnaires completed by the referring neurologists (external). Test-retest and interrater reliabilities of the ICS were assessed by the intraclass coefficient (ICC) and the correlation between the ICS and modified Rankin scale (mRS) with the nonparametric Spearman rank coefficient. The Wilcoxon signed rank test was used to compare the ICS at diagnosis of anti-IgLON5 disease and follow-up in a subset of patients with available clinical information. RESULTS: A total of 86 patients (46 from Barcelona cohort; 40 from GENERATE cohort) were included. The median ICS was 15 (range 2-31). The ICS was higher in the Barcelona cohort than in the German cohort (18 vs 12, p < 0.001), due to higher partial scores in sleep and movement disorder domains. There were no significant differences in the ICS between internal and external patients (15 vs 14, p = 0.96). The ICS correlated with the mRS score (r = 0.429, p < 0.001). Test-retest and interrater reliabilities were excellent with an ICC of 0.997 (95% CI 0.992-0.999) and 0.973 (95% CI 0.925-0.990), respectively. ICS was retested during follow-up in 27 patients, and it was similar to that at diagnosis in 10 clinically stable patients (median ICS at diagnosis 11.5 vs 11.5 at follow-up; p = 1), higher in 8 patients who worsened (12.5 vs 18; p = 0.012), and lower in 9 patients who improved after immunotherapy (14 vs 10; p = 0.007). DISCUSSION: The ICS is a valid method to assess the extension and severity of the different clinical manifestations of anti-IgLON5 disease.

HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement, and bulbar-associated dysfunction. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric HLA study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared to one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Effects of periodic breathing on sleep at high altitude: a randomized, placebo-controlled, crossover study using inspiratory CO2.

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo-controlled approach to prevent nPB by increasing inspiratory CO2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single-blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO2 , and CO2 concentration in the canopy (i.e. inspiratory CO2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%-2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%-80.8%) and 45.0% (24.5%-56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO2 reduced TST with nPB by an absolute 38.1% (28.1%-48.1%), the apnoea-hypopnoea index by 58.1/h (40.1-76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1-73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%-3.5%, P = 0.035). Increased inspiratory CO2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO2 effectively prevented hypoxia-induced nPB without affecting sleep macro-architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. KEY POINTS: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture. We developed a placebo-controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia. Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO2 fraction in a blinded manner. Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia. We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude.

Sleep features and long-term incident neurodegeneration: a polysomnographic study.

STUDY OBJECTIVES: Sleep is altered early in neurodegenerative diseases (NDDs) and may contribute to neurodegeneration. Long-term, large sample size studies assessing NDDs association with objective sleep measures are scant. We aimed to investigate whether video-polysomnography (v-PSG)-based sleep features are associated with long-term NDDs incidence. METHODS: Retrospective cohort study of patients referred 2004-2007 to the Sleep Disorders Unit, Neurology, Medical University Innsbruck, Austria. All patients ≥18 years undergoing v-PSG and without NDDs at baseline or within five years were included. Main outcome was NDDs diagnosis ≥five years after v-PSG. RESULTS: Of 1454 patients assessed for eligibility, 999 (68.7%) met inclusion criteria (68.3% men; median age 54.9 (IQR 33.9-62.7) years). Seventy-five patients (7.5%) developed NDDs and 924 (92.5%) remained disease-free after a median of 12.8 (IQR 9.9-14.6) years. After adjusting for demographic, sleep, and clinical covariates, one-percentage decrease in sleep efficiency, N3-, or REM-sleep was associated with 1.9%, 6.5%, or 5.2% increased risk of incident NDDs (HR 1.019, 1.065, 1.052). One-percentage decrease in wake within sleep period time represented a 2.2% reduced risk of incident NDDs (HR 0.978). Random-forest analysis identified wake, followed by N3 and REM sleep percentages, as the most important feature associated with NDDs diagnosis. Additionally, multiple sleep features combination improved discrimination of incident NDDs compared to individual sleep stages (concordance-index 0.72). CONCLUSIONS: These findings support contribution of sleep changes to NDDs pathogenesis and provide insights into the temporal window during which these differences are detectable, pointing to sleep as early NDDs marker and potential target of neuroprotective strategies.

Sleep disorders as both risk factors for, and a consequence of, stroke: A narrative review.

BACKGROUND AND PURPOSE: Sleep disorders are increasingly implicated as risk factors for stroke, as well as a determinant of stroke outcome. They can also occur secondary to the stroke itself. In this review, we describe the variety of different sleep disorders associated with stroke and analyze their effect on stroke risk and outcome. METHODS: A search term-based literature review ("sleep," "insomnia," "narcolepsy," "restless legs syndrome," "periodic limb movements during sleep," "excessive daytime sleepiness" AND "stroke" OR "cerebrovascular" in PubMed; "stroke" and "sleep" in ClinicalTrials.gov) was performed. English articles from 1990 to March 2023 were considered. RESULTS: Increasing evidence suggests that sleep disorders are risk factors for stroke. In addition, sleep disturbance has been reported in half of all stroke sufferers; specifically, an increase is not only sleep-related breathing disorders but also periodic limb movements during sleep, narcolepsy, rapid eye movement (REM) sleep behavior disorder, insomnia, sleep duration, and circadian rhythm sleep-wake disorders. Poststroke sleep disturbance has been associated with worse outcome. CONCLUSION: Sleep disorders are risk factors for stroke and associated with worse stroke outcome. They are also a common consequence of stroke. Recent guidelines suggest screening for sleep disorders after stroke. It is possible that treatment of sleep disorders could both reduce stroke risk and improve stroke outcome, although further data from clinical trials are required.

Analysis of inflammatory markers and tau deposits in an autopsy series of nine patients with anti-IgLON5 disease.

Anti-IgLON5 disease is a rare neurological, probably autoimmune, disorder associated in many cases with a specific tauopathy. Only a few post-mortem neuropathological studies have been reported so far. Little is known about the pathogenic mechanisms that result in neurodegeneration. We investigated the neuropathology of anti-IgLON5 disease and characterized cellular and humoral inflammation. We included nine cases (six of them previously published). Median age of patients was 71 years (53-82 years), the median disease duration was 6 years (0.5-13 years), and the female to male ratio was 5:4. Six cases with a median disease duration of 9 years presented a prominent tauopathy. Five of them had a classical anti-IgLON5-related brainstem tauopathy and another presented a prominent neuronal and glial 4-repeat tauopathy, consistent with progressive supranuclear palsy (PSP). Three cases with short disease duration (median 1.25 years) only showed a primary age-related neurofibrillary pathology. Inflammatory infiltrates of T and B cells were mild to moderate and did not significantly differ between anti-IgLON5 disease cases with or without tauopathy. In contrast, we found an extensive neuropil deposition of IgG4 in the tegmentum of the brainstem, olivary nucleus, and cerebellar cortex that was most prominent in two patients with short disease duration without the typical IgLON5-related tauopathy. The IgG4 deposits were particularly prominent in the cerebellar cortex and in these regions accompanied by mild IgG1 deposits. Activated complement deposition (C9neo) was absent. Our study indicates that IgLON5-related tau pathology occurs in later disease stages and may also present a PSP-phenotype with exclusively 4-repeat neuronal and glial tau pathology. The prominent deposition of anti-IgLON5 IgG4 at predilection sites for tau pathology suggests that anti-IgLON5 antibodies precede the tau pathology. Early start of immunotherapy might prevent irreversible neuronal damage and progression of the disease, at least in a subgroup of patients.

HLA in isolated REM sleep behavior disorder and Lewy body dementia.

Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27-1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95%CI = 1.12-1.41, p = 8.76e-05), 70Q (OR = 0.81, 95%CI = 0.72-0.91, p = 3.65e-04) and 71R (OR = 1.21, 95%CI = 1.08-1.35, p = 1.35e-03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.

A reliable automatic algorithm to score fragmentary myoclonus.

Excessive fragmentary myoclonus (EFM) is an incidental polysomnographic finding requiring documentation of ≥20 minutes of NREM sleep with ≥5 fragmentary myoclonus (FM) potentials per minute. Manual FM scoring is time-consuming and prone to inter-rater variability. This work aimed to validate an automatic algorithm to score FM in whole-night recordings. One expert scorer manually scored FM in the anterior tibialis muscles in 10 polysomnographies of as many subjects. The algorithm consisted of two steps. First, parameters of the automatic leg movement identification algorithm of the BrainRT software (OSG, Belgium) were modified to identify FM-like activity. Second, a post-processing algorithm was implemented to remove FM activity not meeting sufficient amplitude criteria. The parameter choice and the post-processing were optimised with leave-one-out cross-validation. Agreement with the human scorer was measured with Cohen's kappa (k) and correlation between manual and automatic FM indices in different sleep stages was evaluated. Agreement in identifying patients with EFM was computed. The algorithm showed substantial agreement (average k > 0.62) for all sleep stages, except for W, where a moderate agreement was observed (average k = 0.58). Nonetheless, the agreement between human scorer and the algorithm was similar to previously reported values of inter-rater variability for FM scoring. Correlation coefficients were over 0.96 for all sleep stages. Furthermore, the presence/absence of EFM was correctly identified in 80% of the subjects. In conclusion, this work presents a reliable algorithm for automatic scoring of FM and EFM. Future studies will apply it to objectively and consistently evaluate FM indices and the presence of EFM in large populations.

Improved automatic identification of isolated rapid eye movement sleep behavior disorder with a 3D time-of-flight camera.

BACKGROUND AND PURPOSE: Automatic 3D video analysis of the lower body during rapid eye movement (REM) sleep has been recently proposed as a novel tool for identifying people with isolated REM sleep behavior disorder (iRBD), but, so far, it has not been validated on unseen subjects. This study aims at validating this technology in a large cohort and at improving its performances by also including an analysis of movements in the head, hands and upper body. METHODS: Fifty-three people with iRBD and 128 people without RBD (of whom 89 had sleep disorders considered RBD differential diagnoses) were included in the study. An automatic algorithm identified movements from 3D videos during REM sleep in four regions of interest (ROIs): head, hands, upper body and lower body. The movements were divided into categories according to duration: short (0.1-2 s), medium (2-15 s) and long (15-300 s). For each ROI and duration range, features were obtained from the identified movements. Logistic regression models using as predictors the features from one single ROI or a combination of ROIs were trained and tested in a 10-runs 10-fold cross-validation scheme on the task of differentiating people with iRBD from people without RBD. RESULTS: The best differentiation was achieved using short movements in all four ROIs (test accuracy 0.866 ± 0.007, test F1 score = 0.783 ± 0.010). Single group analyses showed that people with iRBD were distinguished successfully from subjects with RBD differential diagnoses. CONCLUSIONS: Automatic 3D video analysis might be implemented in clinical routine as a supportive screening tool for identifying people with RBD.

Large muscle group movements during sleep in healthy people: normative values and correlation to sleep features.

STUDY OBJECTIVES: To investigate the frequency and characteristics of large muscle group movements (LMMs) during sleep in healthy adults. METHODS: LMMs were scored following the International Restless Legs Syndrome Study Group criteria in 100 healthy participants aged 19-77 years. A LMM was defined as a temporally overlapping increase in EMG activity and/or the occurrence of movement artifacts in at least two channels. LMM indices and durations in total sleep time (TST), NREM and REM sleep, and association with arousals, awakenings, and/or respiratory events were calculated. Correlations of LMMs indices and durations with sleep architecture, respiratory and motor events, and subjective sleep quality were investigated. RESULTS: Median LMMs index in TST was 6.8/h (interquartile range (IQR), 4.5-10.8/h), median mean duration 12.4 s (IQR 10.7-14.4 s). Mean LMMs duration was longer in NREM (median 12.7 s, IQR 11.1-15.2 s) versus REM sleep (median 10.3 s, IQR 8.0-13.5s), p < 0.001. LMMs associated with awakening increased with age (p = 0.029). LMMs indices in TST were higher in men than women (p = 0.018). LMMs indices correlated positively with N1 sleep percentage (ρ = 0.49, p < 0.001), arousal index (ρ = 0.40, p = 0.002), sleep stages shift index (ρ = 0.43, p < 0.001, apnea index (ρ = 0.36, p = 0.017), and video-visible movements indices (ρ = 0.45, p < 0.001), and negatively with N3 sleep (ρ = -0.38, p= 0.004) percentage. CONCLUSIONS: This is the first study providing normative data on LMMs frequency in healthy adults. LMMs are a ubiquitous phenomenon often associated with other events. Correlation with arousals and respiratory events suggests a potential clinical significance of LMMs in adults that awaits further investigation.

A prospective case-control study of excessive fragmentary myoclonus in the upper and lower extremities: Clinical characteristics and electrophysiological correlates.

BACKGROUND: Excessive fragmentary myoclonus (EFM) is an incidental finding in video-polysomnography (VPSG) and listed among "Sleep Related Movement Disorders - Isolated symptoms and normal variants" in the ICSD-3. We aimed to prospectively evaluate EFM in the upper and lower extremities in a large sleep laboratory cohort and to investigate clinical characteristics and peripheral nerve pathology in patients with and without EFM. METHODS: Two-hundred consecutive sleep laboratory patients with EFM according to ICSD-3 criteria were included and matched to 100 patients without EFM for age, sex and presence or absence of sleep-related breathing disorder. Patients additionally underwent peripheral neurophysiological work-up. RESULTS: In 31/200 (15.5%) patients EFM was present not only in the lower extremities, but also in the upper extremities. Patients with EFM had less REM sleep (%/SPT; median (IQR); 13.8 (9.1-18.2) vs. 17.1 (10.1-20.5); p = 0.008) and the PLMS-Index was higher in patients with EFM than in those without (16.2 vs. 8.8/h; p = 0.009). Polyneuropathy (PNP) and nerve root lesions L5 and S1 were more frequent in patients with than in those without EFM (31.5% vs. 21% and 5% vs. 0%; p = 0.003). CONCLUSIONS: In this large cohort we systematically investigated upper and lower extremities with surface electromyography during sleep and show that EFM is much more frequent in the lower extremities than in the upper extremities and corroborate the association of EFM with peripheral nerve pathology and PLMS.

Chronic Insomnia Disorder across Europe: Expert Opinion on Challenges and Opportunities to Improve Care.

One in ten adults in Europe have chronic insomnia, which is characterised by frequent and persistent difficulties initiating and/or maintaining sleep and daily functioning impairments. Regional differences in practices and access to healthcare services lead to variable clinical care across Europe. Typically, a patient with chronic insomnia (a) will usually present to a primary care physician; (b) will not be offered cognitive behavioural therapy for insomnia-the recommended first-line treatment; (c) will instead receive sleep hygiene recommendations and eventually pharmacotherapy to manage their long-term condition; and (d) will use medications such as GABA receptor agonists for longer than the approved duration. Available evidence suggests that patients in Europe have multiple unmet needs, and actions for clearer diagnosis of chronic insomnia and effective management of this condition are long overdue. In this article, we provide an update on the clinical management of chronic insomnia in Europe. Old and new treatments are summarised with information on indications, contraindications, precautions, warnings, and side effects. Challenges of treating chronic insomnia in European healthcare systems, considering patients' perspectives and preferences are presented and discussed. Finally, suggestions are provided-with healthcare providers and healthcare policy makers in mind-for strategies to achieve the optimal clinical management.

HLA in isolated REM sleep behavior disorder and Lewy body dementia.

Background and Objectives: Isolated/idiopathic REM sleep behavior disorder (iRBD) and Lewy body dementia (LBD) are synucleinopathies that have partial genetic overlap with Parkinson's disease (PD). Previous studies have shown that neuroinflammation plays a substantial role in these disorders. In PD, specific residues of the human leukocyte antigen ( HLA ) were suggested to be associated with a protective effect. This study examined whether the HLA locus plays a similar role in iRBD, LBD and PD. Methods: We performed HLA imputation on iRBD genotyping data (1,072 patients and 9,505 controls) and LBD whole-genome sequencing (2,604 patients and 4,032 controls) using the multi-ethnic HLA reference panel v2 from the Michigan Imputation Server. Using logistic regression, we tested the association of HLA alleles, amino acids and haplotypes with disease susceptibility. We included age, sex and the top 10 principal components as covariates. We also performed an omnibus test to examine which HLA residue positions explain the most variance. Results: In iRBD, HLA-DRB1 *11:01 was the only allele passing FDR correction (OR=1.57, 95% CI=1.27-1.93, p =2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR=1.26, 95%CI=1.12-1.41, p =8.76e-05), 70Q (OR=0.81, 95% CI=0.72-0.91, p =3.65e-04) and 71R (OR=1.21, 95% CI=1.08-1.35, p =1.35e-03). In HLA-DRB1 , position 71 ( p omnibus =0.00102) and 70 ( p omnibus =0.00125) were associated with iRBD. We found no association in LBD. Discussion: This study identified an association between HLA-DRB1 11:01 and iRBD, distinct from the previously reported association in PD. Therefore, the HLA locus may play different roles across synucleinopathies. Additional studies are required better to understand HLA's role in iRBD and LBD.

Anti-IgLON5 Disease with Isolated Hemichorea: A Case Report and Review of the Literature.

Background: Anti-IgLON5 disease is an autoimmune encephalopathy with sleep disturbances as a hallmark in the majority of reported cases. Additional clinical symptoms are heterogenous and include movement disorders, bulbar dysfunction, autonomic disorders, and neurocognitive impairment. Case: Here, we report the case of an 87-year-old woman presenting with isolated progressive hemichorea. An extensive diagnostic work-up revealed antibodies against IgLON5 in the serum. Neither history nor polysomnography (PSG) unveiled signs and features of sleep dysfunction typically reported in anti-IgLON5 disease. Literature Review: In an extensive literature review we identified twelve other studies reporting about patients with confirmed anti-IgLON5 disease and chorea as extrapyramidal movement disorder in their clinical phenotype. Subsequently, clinical characteristics of these patients were carefully evaluated. Conclusions: Our results support the diversity of clinical phenotypes in anti-IgLON5 disease, adding isolated hemichorea to the spectrum of presenting symptoms. As sleep-related disorders are often not the leading reason for consultation and only revealed by PSG examination, we suggest that screening for antibodies against IgLON5 should be considered in patients presenting with unexplained movement disorders, including isolated hemichorea.

Decline in spontaneous cervical artery dissection incidence during COVID-19 public health measures: Evidence for a role of upper respiratory infections in pathogenesis.

BACKGROUND: Upper respiratory infections have been suggested as a risk factor for spontaneous cervical artery dissection (sCeAD). If this is the case, public health measures implemented to contain the spread of SARS-CoV-2, which also reduced other communicable diseases such as influenza, might be associated with a reduction in cervical artery dissection incidence. AIMS: We determined the incidence of sCeAD before, during and after the COVID-19 pandemic, and the associated public health measures. METHODS: All patients suffering an sCeAD and seen in Innsbruck Austria, between January 2002 to December 2016 (pre-COVID comparators) and between January 2020 to August 2022 were recorded through two individual prospective cohort studies. We compared admission rates, demographic, and clinical characteristics of sCeAD patients in pre-COVID-19 and COVID-19 times. RESULTS: In total, 249 sCeAD patients were admitted prior to the COVID-19 pandemic compared to 20 during its course. Baseline characteristics of sCeAD subjects did not differ in subjects admitted during and prior to the pandemic. Following the introduction of public health measures for the pandemic, there was a marked decrease of sCeAD admissions from 16.5 per year to 6.3 per year (p = 0.012). Since the measures were ended the number of sCeAD admissions increased again. In contrast, the number of all ischemic stroke patients treated at the Medical University of Innsbruck did not alter during the pandemic. (N per year: 633 in 2015, 687 in 2017, 684 in 2019, 731 in 2020, and 717 in 2021). CONCLUSION: The incidence of sCeAD fell markedly during the pandemic and this may have resulted from the public health measures introduced and a subsequent reduction in upper respiratory infections. Our study provides indirect evidence for a role of infection in the pathogenesis of sCeAD. DATA ACCESS STATEMENT: Anonymized data not published within this article will be made available by request from any qualified investigator.

Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.

Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.

Automatic analysis of muscular activity in the flexor digitorum superficialis muscles: a fast screening method for rapid eye movement sleep without atonia.

STUDY OBJECTIVES: To identify a fast and reliable method for rapid eye movement (REM) sleep without atonia (RWA) quantification. METHODS: We analyzed 36 video-polysomnographies (v-PSGs) of isolated REM sleep behavior disorder (iRBD) patients and 35 controls' v-PSGs. Patients diagnosed with RBD had: i) RWA, quantified with a reference method, i.e. automatic and artifact-corrected 3-s Sleep Innsbruck Barcelona (SINBAR) index in REM sleep periods (RSPs, i.e. manually selected portions of REM sleep); and ii) v-PSG-documented RBD behaviors. We quantified RWA with other (semi)-automated methods requiring less human intervention than the reference one: the indices proposed by the SINBAR group (the 3-s and 30-s phasic flexor digitorum superficialis (FDS), phasic/"any"/tonic mentalis), and the REM atonia, short and long muscle activity indices (in mentalis/submentalis/FDS muscles). They were calculated in whole REM sleep (i.e. REM sleep scored following international guidelines), in RSPs, with and without manual artifact correction. Area under curves (AUC) discriminating iRBD from controls were computed. Using published cut-offs, the indices' sensitivity and specificity for iRBD identification were calculated. Apnea-hypopnea index in REM sleep (AHIREM) was considered in the analyses. RESULTS: RWA indices from FDS muscles alone had the highest AUCs and all of them had 100% sensitivity. Without manual RSP selection and artifact correction, the "30-s phasic FDS" and the "FDS long muscle activity" had the highest specificity (85%) with AHIREM < 15/h. RWA indices were less reliable when AHIREM≥15/h. CONCLUSIONS: If AHIREM<15/h, FDS muscular activity in whole REM sleep and without artifact correction is fast and reliable to rule out RWA.

Differentiation of central disorders of hypersomnolence with manual and artificial-intelligence-derived polysomnographic measures.

Differentiation of central disorders of hypersomnolence (DOH) is challenging but important for patient care. This study aimed to investigate whether biomarkers derived from sleep structure evaluated both by manual scoring as well as with artificial intelligence (AI) algorithms allow distinction of patients with different DOH. We included video-polysomnography data of 40 narcolepsy type 1 (NT1), 26 narcolepsy type 2 (NT2), 23 patients with idiopathic hypersomnia (IH) and 54 participants with subjective excessive daytime sleepiness (sEDS). Sleep experts manually scored sleep stages. A previously validated AI algorithm was employed to obtain automatic hypnograms and hypnodensity graphs (where each epoch is represented as a mixture of sleep stage probabilities). One-thousand-three features describing sleep architecture and instability were extracted from manual/automatic hypnogram and hypnodensity graphs. After feature selection, random forest classifiers were trained and tested in a 5-fold-cross-validation scheme to distinguish groups pairwise (NT1-vs-NT2, NT1-vs-IH, …) and single groups from the pooled remaining ones (NT1-vs-rest, NT2-vs-rest,…). The accuracy/F1-score values obtained in the test sets were: 0.74 ± 0.04/0.79 ± 0.05 (NT1-vs-NT2), 0.89 ± 0.09/0.91 ± 0.08 (NT1-vs-IH), 0.93 ± 0.06/0.91 ± 0.07 (NT1-vs-sEDS), 0.88 ± 0.04/0.80 ± 0.07 (NT1-vs-rest), 0.65 ± 0.10/0.70 ± 0.09 (NT2-vs-IH), 0.72 ± 0.12/0.60 ± 0.10 (NT2-vs-sEDS), 0.54 ± 0.19/0.38 ± 0.13 (NT2-vs-rest), 0.57 ± 0.11/0.35 ± 0.18 (IH-vs-sEDS), 0.71 ± 0.08/0.35 ± 0.10 (IH-vs-rest) and 0.76 ± 0.08/0.71 ± 0.13 (sEDS-vs-rest). The results confirm previous findings on sleep instability in patients with NT1 and show that combining manual and automatic AI-based sleep analysis could be useful for better distinction of NT2 from IH, but no precise sleep biomarker of NT2 or IH could be identified. Validation in a larger and multi-centric cohort is needed to confirm these findings.