Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review.

PURPOSE OF REVIEW: Sleep disturbances are amongst most frequent non-motor symptoms of Parkinson's Disease (PD), and they are similarly frequently reported in other alpha-syncleinopathies, such as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). More recently, the orexin system has been implicated in control of arousal based on salient environmental set points, and its dysregulation in sleep issues in alpha-synucleinopathies suggested by the findings from the translational animal models. However, its role in the patients with alpha-synucleinopathies remains unclear. We thus set to systematically review, and to critically assess, contemporary evidence on the association of the orexinergic system and sleep disturbances in alpha-synucleinopathies. In this systematic review, studies investigating orexin and sleep in alpha-synucleinopathies (Rapid Eye Movement (REM) Behaviour Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) were identified using electronic database searches of PubMed, Web of Science and PsychINFO using MeSH terms, keywords, and title words such as "Alpha-synucleinopathies" AND "Orexin" AND "Sleep Disturbances". RECENT FINDINGS: 17 studies were included in this systemic review, of which 2 studies on RBD, 10 on PD, 4 on DLB, and 1 on MSA patients. Taken together, RBD and PD studies suggest a potential adaptive increase in orexin levels in early stages of the neurodegenerative process, with reduced levels more often reported for later, more advanced stages of illness. To date, no differences in orexin levels were demonstrated between MSA patients and healthy controls. There is a dearth of studies on the role of orexin levels in alpha-synucleinopathies. Moreover, significant methodologic limitations in the current body of work, including use of non-standardised research protocols and lack of prospective, multi-centre studies, disallow for any finite conclusion in regards to underlying pathomechanisms. Nonetheless, a picture of a complex, multifaceted relationship between the dysregulation of the orexinergic pathway and sleep disturbances in alpha-synucleinopathies is emerging. Hence, future studies disentangling orexinergic pathomechanisms of alpha-syncleinopathies are urgently needed to obtain a more comprehensive account of the role of orexinergic pathway in alpha-synucleinopathies. Pharmacological manipulations of orexins may have multiple therapeutic applications in treatment strategies, disease diagnosis, and might be effective for treating both motor and non-motor symptoms.

Unraveling sleep respiratory dysfunction in amyotrophic lateral sclerosis: Beyond the apnea-hypopnea index and sleep-related hypoxia.

The timely introduction of non-invasive ventilation (NIV) is extremely relevant in the multidisciplinary management of patients affected by amyotrophic lateral sclerosis (ALS) and is based on the proper identification of red flags for early diaphragmatic exhaustion. Polygraphic sleep recording may provide insightful information on the ongoing respiratory impairment; in particular, atypical breathing patterns need to be recognized, as the application of current guidelines for sleep-related hypoxemia or sleep apnea may be insufficient for detecting early signs of diaphragmatic fatigue. We report the case of a 51-year-old man affected by ALS who was asymptomatic for breathing impairment, but whose nocturnal polysomnographic recording, despite not significant for obstructive sleep apnea nor for conventional hypoventilatory patterns, strongly suggested initial respiratory failure, as lately confirmed by the pulmonary follow-up. We discuss the advantages of including sleep recording in the clinical work-up of patients affected by ALS.

Periodic discharges and status epilepticus: A critical reappraisal.

OBJECTIVE: Periodic Discharges (PDs) in Status Epilepticus (SE) are historically related to negative outcome, and the Epidemiology-based Mortality Score in SE (EMSE) identifies PDs as an EEG feature associated with unfavorable prognosis. However, supportive evidence is conflicting. This study aims to evaluate the prognostic significance of interictal PDs during and following SE. METHODS: All 2020-2023 non-hypoxic-ischemic SE patients with available EEG during SE were retrospectively assessed. Interictal PDs during SE (SE-PDs) and PDs occurring 24-72 h after SE resolution (post-SE-PDs) were examined. In-hospital death was defined as the primary outcome. RESULTS: 189 SE patients were finally included. SE-PDs were not related to outcome, while post-SE-PDs were related to poor prognosis confirmed after multiple regression analysis. EMSE global AUC was 0.751 (95%CI:0.680-0.823) and for EMSE-64 cutoff sensitivity was 0.85, specificity 0.52, accuracy 63%. We recalculated EMSE score including only post-SE-PDs. Modified EMSE (mEMSE) global AUC was 0.803 (95%CI:0.734-0.872) and for mEMSE-64 cutoff sensitivity was 0.84, specificity 0.68, accuracy 73%. CONCLUSION: Interictal PDs during SE were not related to outcome whereas PDs persisting or appearing > 24 h after SE resolution were strongly associated to unfavorable prognosis. EMSE performed well in our cohort but considering only post-SE-PDs raised specificity and accuracy for mEMSE64 cutoff. SIGNIFICANCE: This study supports the utility of differentiating between interictal PDs during and after SE for prognostic assessment.

How can sleep disorders affect our reaction towards external stressors: a lesson from the COVID-19 outbreak.

BACKGROUND: The COVID-19 outbreak produced extensive psychological consequences, especially among vulnerable populations. Sleep was identified as one of the most common "indirect targets" of the pandemia, with up to 74.8% of patients surviving from COVID-19 complaining of new-onset sleep disorders. However, so far, the clinic-psychological impact of the outbreak in patients affected by pre-existing sleep disorders has not been examined in details. MATERIALS AND METHODS: In the present study, we aim to assess the effect of the COVID-19 outbreak in a cohort of 190 adult patients affected by sleep disorders, compared to 265 age and sex-matched healthy sleepers. The assessment was implemented throughout the use of ad hoc anamnestic questions, exploration of dream content, and validated questionnaires, aiming to capture the broad range of the neuropsychological nuances of the COVID-19 impact. RESULTS: Subjects with pre-existent sleep disorders faced a more severe impact in terms of sleep quality and amount compared to healthy sleepers, presenting longer sleep latency, reduced sleep efficacy, and greater use of hypnotics and medications. On the other hand, healthy sleepers experienced deeper variation in sleeping habits, sleep duration, and greater impact on dream activity in terms of content, emotionality, and presence of recurrent dreams. Finally, in our sample, being female represents an important aggravating factor in the pandemic experience, both in terms of sleep deterioration and with respect to physical and mental health. For instance, females indeed presented the highest scores of Pittsburgh Sleep Quality Index (PSQI) both in cases and control groups (respectively 10 ± 3.8 vs 7.3 ± 3.9 in cases and 6.6 ± 3.6 vs 6.0 ± 3.4 in controls, p-value < 0.001). CONCLUSION: Pre-existent sleep disorders and the female sex might represent risk factors increasing the clinic-psychological burden in dramatic scenarios, such as the COVID-19 pandemia, requiring dedicated attention from clinicians.

Imaging biomarkers of sleep-related hypermotor epilepsy and sudden unexpected death in epilepsy: a review.

In recent years, imaging has emerged as a promising source of several intriguing biomarkers in epilepsy, due to the impressive growth of imaging technology, supported by methodological advances and integrations of post-processing techniques. Bearing in mind the mutually influencing connection between sleep and epilepsy, we focused on sleep-related hypermotor epilepsy (SHE) and sudden unexpected death in epilepsy (SUDEP), aiming to make order and clarify possible clinical utility of emerging multimodal imaging biomarkers of these two epilepsy-related entities commonly occurring during sleep. Regarding SHE, advanced structural techniques might soon emerge as a promising source of diagnostic and predictive biomarkers, tailoring a targeted therapeutic (surgical) approach for MRI-negative subjects. Functional and metabolic imaging may instead unveil SHE's extensive and night-related altered brain networks, providing insights into distinctions and similarities with non-epileptic sleep phenomena, such as parasomnias. SUDEP is considered a storm that strikes without warning signals, but objective subtle structural and functional alterations in autonomic, cardiorespiratory, and arousal centers are present in patients eventually experiencing SUDEP. These alterations could be seen both as susceptibility and diagnostic biomarkers of the underlying pathological ongoing loop ultimately ending in death. Finally, given that SHE and SUDEP are rare phenomena, most evidence on the topic is derived from small single-center experiences with scarcely comparable results, hampering the possibility of performing any meta-analytic approach. Multicenter, longitudinal, well-designed studies are strongly encouraged.

Prognostic value of Salzburg nonconvulsive status epilepticus criteria: The SACE score.

OBJECTIVE: This study was undertaken to investigate the association between the Salzburg nonconvulsive status epilepticus (NCSE) criteria and in-hospital outcome, to determine the predictive accuracy of the Status Epilepticus Severity Score (STESS), modified STESS (mSTESS), Epidemiology-Based Mortality Score in Status Epilepticus (EMSE), and END-IT (encephalitis, NCSE, diazepam resistance, imaging features, and tracheal intubation) in NCSE patients, and to develop a new prognostic score specifically designed for NCSE patients. METHODS: Clinical and electroencephalographic (EEG) data of adult patients treated for NCSE from 2020 to 2023 were retrospectively assessed. Age, sex, modified Rankin Scale at admission, comorbidities, history of seizures, etiology, status epilepticus type, and outcome were collected from the patients' digital charts. EEG data were assessed and categorized applying the Salzburg NCSE criteria. In-hospital death was defined as the primary outcome. RESULTS: A total of 116 NCSE patients were included. Multivariable logistic regression revealed that Salzburg NCSE criterion A2 (ictal morphological, spatial, and temporal evolution) was associated with in-hospital survival. The best STESS cutoff was ≥4 (sensitivity = .62, specificity = .69, accuracy = 67%). mSTESS ≥ 5 reached a sensitivity of .68, a specificity of .57, and an overall accuracy of 60%, EMSE ≥ 64 a sensitivity of .82, a specificity of .39, and an overall accuracy of 52%, and END-IT ≥ 3 a sensitivity of .65, a specificity of .44, and an overall accuracy of 50%. Through a hypothesis-generating approach, we developed the SACE score, which integrates EEG features (criterion A2) with patient age (with a 75-year cutoff), history of seizures, and level of consciousness. With a cutoff of ≥3, it had a sensitivity of .77, a specificity of .74, and an overall accuracy of 76%, performing better than other prognostic scores. SIGNIFICANCE: We developed a new user-friendly scoring system, the SACE score, which integrates EEG features with other established outcome-related variables assessable in early stages, to assist neurologists and neurointensivists in making more tailored prognostic decisions for NCSE patients.

Predicting amyloid-PET status in a memory clinic: The role of the novel antero-posterior index and visual rating scales.

INTRODUCTION: Visual rating scales are increasingly utilized in clinical practice to assess atrophy in crucial brain regions among patients with cognitive disorders. However, their capacity to predict Alzheimer's disease (AD)-related pathology remains unexplored, particularly within a heterogeneous memory clinic population. This study aims to assess the accuracy of a novel visual rating assessment, the antero-posterior index (API) scale, in predicting amyloid-PET status. Furthermore, the study seeks to determine the optimal cohort-based cutoffs for the medial temporal atrophy (MTA) and parietal atrophy (PA) scales and to integrate the main visual rating scores into a predictive model. METHODS: We conducted a retrospective analysis of brain MRI and high-resolution TC scans from 153 patients with cognitive disorders who had undergone amyloid-PET assessments due to suspected AD pathology in a real-world memory clinic setting. RESULTS: The API scale (cutoff ≥1) exhibited the highest accuracy (AUC = 0.721) among the visual rating scales. The combination of the cohort-based MTA and PA threshold with the API yielded favorable accuracy (AUC = 0.787). Analyzing a cohort of MCI/Mild dementia patients below 75 years of age, the API scale and the predictive model improved their accuracy (AUC = 0.741 and 0.813, respectively), achieving excellent results in the early-onset population (AUC = 0.857 and 0.949, respectively). CONCLUSION: Our study emphasizes the significance of visual rating scales in predicting amyloid-PET positivity within a real-world memory clinic. Implementing the novel API scale, alongside our cohort-based MTA and PA thresholds, has the potential to substantially enhance diagnostic accuracy.

Sleep Pathologies and Eating Disorders: A Crossroad for Neurology, Psychiatry and Nutrition.

The intricate connection between eating behaviors and sleep habits is often overlooked in clinical practice, despite their profound interdependence. Sleep plays a key role in modulating psychological, hormonal and metabolic balance and exerting an influence on food choices. Conversely, various eating disorders may affect sleep continuity, sometimes promoting the development of sleep pathologies. Neurologists, nutritionists and psychiatrists tend to focus on these issues separately, resulting in a failure to recognize the full extent of the clinical conditions. This detrimental separation can lead to underestimation, misdiagnosis and inappropriate therapeutic interventions. In this review, we aim to provide a comprehensive understanding of the tangled relationship between sleep, sleep pathologies and eating disorders, by incorporating the perspective of sleep experts, psychologists and psychiatrists. Our goal is to identify a practical crossroad integrating the expertise of all the involved specialists.

Criticality of neuronal avalanches in human sleep and their relationship with sleep macro- and micro-architecture.

Sleep plays a key role in preserving brain function, keeping brain networks in a state that ensures optimal computation. Empirical evidence indicates that this state is consistent with criticality, where scale-free neuronal avalanches emerge. However, the connection between sleep architecture and brain tuning to criticality remains poorly understood. Here, we characterize the critical behavior of avalanches and study their relationship with sleep macro- and micro-architectures, in particular, the cyclic alternating pattern (CAP). We show that avalanches exhibit robust scaling behaviors, with exponents obeying scaling relations consistent with the mean-field directed percolation universality class. We demonstrate that avalanche dynamics is modulated by the NREM-REM cycles and that, within NREM sleep, avalanche occurrence correlates with CAP activation phases-indicating a potential link between CAP and brain tuning to criticality. The results open new perspectives on the collective dynamics underlying CAP function, and on the relationship between sleep architecture, avalanches, and self-organization to criticality.

Visuo-spatial imagery in dreams of congenitally and early blind: a systematic review.

Background: The presence of visual imagery in dreams of congenitally blind people has long been a matter of substantial controversy. We set to systematically review body of published work on the presence and nature of oneiric visuo-spatial impressions in congenitally and early blind subjects across different areas of research, from experimental psychology, functional neuroimaging, sensory substitution, and sleep research. Methods: Relevant studies were identified using the following databases: EMBASE, MEDLINE and PsychINFO. Results: Studies using diverse imaging techniques and sensory substitution devices broadly suggest that the "blind" occipital cortex may be able to integrate non-visual sensory inputs, and thus possibly also generate visuo-spatial impressions. Visual impressions have also been reported by blind subjects who had near-death or out-of-body experiences. Conclusion: Deciphering the mechanistic nature of these visual impression could open new possibility in utilization of neuroplasticity and its potential role for treatment of neurodisability.

The Contribution of Sleep Texture in the Characterization of Sleep Apnea.

Obstructive sleep apnea (OSA) is multi-faceted world-wide-distributed disorder exerting deep effects on the sleeping brain. In the latest years, strong efforts have been dedicated to finding novel measures assessing the real impact and severity of the pathology, traditionally trivialized by the simplistic apnea/hypopnea index. Due to the unavoidable connection between OSA and sleep, we reviewed the key aspects linking the breathing disorder with sleep pathophysiology, focusing on the role of cyclic alternating pattern (CAP). Sleep structure, reflecting the degree of apnea-induced sleep instability, may provide topical information to stratify OSA severity and foresee some of its dangerous consequences such as excessive daytime sleepiness and cognitive deterioration. Machine learning approaches may reinforce our understanding of this complex multi-level pathology, supporting patients' phenotypization and easing in a more tailored approach for sleep apnea.

Non-alcoholic Wernicke's Encephalopathy mimicking neuromyelitis optica spectrum disorder in a young woman: a case report and literature review.

Wernicke's encephalopathy is an under-recognized life-threatening disease caused by thiamine (vitamin B1) deficiency. It has historically been related to chronic alcoholic intake but other causes of malnutrition, such as invasive gastric surgery and hyperemesis, have been linked to the onset of this illness over the years, often presenting with atypical clinical manifestations.  Herein we report a case of a young obese woman affected by non-alcoholic Wernicke's Encephalopathy following a minimally invasive gastrointestinal surgery. She showed an unusual clinical profile characterized by prominent subacute neuro-ophthalmological involvement which combined to her juvenile age, overweight condition and brain lesions, have made diagnosis challenging due to similarities with Neuromyelitis Optica Spectrum Disorder.   Our case underscores the relevance of prompt diagnosis in order to prevent the development of irreversible neuropathological changes and to avoid the use of a long-term immunosuppressive treatment.

Volumetric hippocampal changes in glioblastoma: a biomarker for neuroplasticity?

PURPOSE: The pleiotropic effect of gliomas on the development of cognitive disorders and structural brain changes has garnered increasing interest in recent years. While it is widely accepted that multimodal therapies for brain cancer can foster cognitive impairment, the direct effect of gliomas on critical cognitive areas before anti-tumor therapies is still controversial. In this study, we focused on the effect of IDH1 wild-type glioblastoma on the human hippocampus volume. METHODS: We carried out a case-control study using voxel-based morphometry assessment, analyzed with the Computational Anatomy Toolbox software. Glioblastoma diagnosis was performed according to the latest 2021 WHO classification. Due to stringent inclusion criteria, 15 patients affected by IDH1 wild type glioblastoma were included and compared to 19 age-matched controls. RESULTS: We observed a statistically significant increase in the absolute mean hippocampal volume (p = 0.017), as well as in the ipsilateral (compared to the lesion, p = 0.027) and the contralateral hippocampal volumes (p = 0.014) in the group of patients. When the data were normalized per total intracranial volume, we confirmed a statistically significant increase only in the contralateral hippocampal volume (p = 0.042). CONCLUSIONS: To the best of our knowledge, this is the first study to explore hippocampal volumetric changes in a cohort of adult patients affected by IDH1 wild-type glioblastoma, according to the latest WHO classification. We demonstrated an adaptive volumetric response of the hippocampus, which was more pronounced on the side contralateral to the lesion, suggesting substantial integrity and resilience of the medial temporal structures before the initiation of multimodal treatments.

Epileptiform patterns predicting unfavorable outcome in postanoxic patients: A matter of time?

OBJECTIVE: Historically, epileptiform malignant EEG patterns (EMPs) have been considered to anticipate an unfavorable outcome, but an increasing amount of evidence suggests that they are not always or invariably associated with poor prognosis. We evaluated the prognostic significance of an EMP onset in two different timeframes in comatose patients after cardiac arrest (CA): early-EMPs and late-EMPs, respectively. METHODS: We included all comatose post-CA survivors admitted to our intensive care unit (ICU) between 2016 and 2018 who underwent at least two 30-minute EEGs, collected at T0 (12-36 h after CA) and T1 (36-72 h after CA). All EEGs recordings were re-analyzed following the 2021 ACNS terminology by two senior EEG specialists, blinded to outcome. Malignant EEGs with abundant sporadic spikes/sharp waves, rhythmic and periodic patterns, or electrographic seizure/status epilepticus, were included in the EMP definition. The primary outcome was the cerebral performance category (CPC) score at 6 months, dichotomized as good (CPC 1-2) or poor (CPC 3-5) outcome. RESULTS: A total of 58 patients and 116 EEG recording were included in the study. Poor outcome was seen in 28 (48%) patients. In contrast to late-EMPs, early-EMPs were associated with a poor outcome (p = 0.037), persisting after multiple regression analysis. Moreover, a multivariate binomial model coupling the timing of EMP onset with other EEG predictors such as T1 reactivity and T1 normal voltage background can predict outcome in the presence of an otherwise non-specific malignant EEG pattern with quite high specificity (82%) and moderate sensitivity (77%). CONCLUSIONS: The prognostic significance of EMPs seems strongly time-dependent and only their early-onset may be associated with an unfavorable outcome. The time of onset of EMP combined with other EEG features could aid in defining prognosis in patients with intermediate EEG patterns.

Anti-Gad 65 encephalitis with rapidly progressive temporal atrophy reveals the involvement of the temporal lobe in the neuroanatomical basis of palilalia.

Palilalia is an acquired speech disorder characterized by the reiteration of words or sentences, historically divided in two main subtypes: "palilalie heterolalique" and "palilalie homolalique". In the former, the reiteration is characterized by rate increase and volume decrease, while in the latter these features remain unaltered. While the "heterolalique" subtype has been mainly observed in the context of basal ganglia diseases, the neuroanatomical basis of the "homolalique" subtype has never been completely clarified. Here we report the case of an 81 years-old woman who developed an extremely repetitive and perseverative language with "homolalique" subtype features and a rapidly progressive course with severe bitemporal atrophy, as a consequence of anti-glutamic acid decarboxylase 65 (GAD 65) antibodies encephalitis. To the best of our knowledge, this is the first report of palilalia in the context of anti-GAD 65 encephalitis. Through the support of voxel-based morphometry and hippocampal subfields analysis, this case study provides a fascinating way of understanding the networks responsible for palilalia, shedding some light on the critical role of temporal areas in the onset of this rare language disorder.

Heart rate variability and cognitive performance in adults with cardiovascular risk.

Background: Heart rate variability (HRV), a measure of autonomic function, has been associated with both cardiovascular disease and cognitive dysfunction. In turn, cardiovascular risk has been linked to an increased risk of dementia onset. However, whether autonomic dysfunction may represent an early marker of cognitive decline in individuals with high cardiovascular risk is still an open issue. Methods: We performed a complete 24-hour HRV analysis in 50 middle-aged and elderly subjects with cardiovascular risk as assessed with the European Society of Cardiology Systematic Coronary Risk Evaluation (ESC SCORE). Cognitive performance was evaluated by Montreal Cognitive Assessment (MoCA), Free and Cued Selective Reminding Test (FCSRT) and Stroop Color and Word Test. Stepwise regression was used to identify significant associations between 24-hour ambulatory ECGs parameters and cognitive performances. Results: There were 30 women and 20 men with mean age of 64.9 years (range 51-77) and the mean ESC SCORE was 6%. Four subjects were diagnosed with mild cognitive impairment. Associations were found between measures of HRV and measures of cognition. Ultra-low frequency (ULF) band power of HRV significantly correlated with MoCA (r = 0.424, p = 0.003), also after adjustment for demographics and education. A significant association was also found between the ESC SCORE and ULF band power (r = -0.470, p = 0.0009). Conclusions: Ultra-low frequency band power of HRV is associated with cognitive performance of middle-aged and elderly subjects with cardiovascular risk. This finding may indicate that autonomic nervous system dysregulation plays a role in developing cardiovascular risk and cognitive decline.

Sleep medicine: Practice, challenges and new frontiers.

Sleep medicine is an ambitious cross-disciplinary challenge, requiring the mutual integration between complementary specialists in order to build a solid framework. Although knowledge in the sleep field is growing impressively thanks to technical and brain imaging support and through detailed clinic-epidemiologic observations, several topics are still dominated by outdated paradigms. In this review we explore the main novelties and gaps in the field of sleep medicine, assess the commonest sleep disturbances, provide advices for routine clinical practice and offer alternative insights and perspectives on the future of sleep research.