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Journal of Sleep Research Dec 2023Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and... (Review)
Review
Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).
Topics: Adult; Humans; Sleep Initiation and Maintenance Disorders; Melatonin; Sleep; Benzodiazepines; Antidepressive Agents
PubMed: 38016484
DOI: 10.1111/jsr.14035 -
Revue Neurologique Oct 2023Narcolepsy type 1 (NT1) and type 2 (NT2), also known as narcolepsy with and without cataplexy, are sleep disorders that benefited from major scientific advances over the... (Review)
Review
Narcolepsy type 1 (NT1) and type 2 (NT2), also known as narcolepsy with and without cataplexy, are sleep disorders that benefited from major scientific advances over the last two decades. NT1 is caused by the loss of hypothalamic neurons producing orexin/hypocretin, a neurotransmitter regulating sleep and wake, which can be measured in the cerebrospinal fluid (CSF). A low CSF level of hypocretin-1/orexin-A is a highly specific and sensitive biomarker, sufficient to diagnose NT1. Orexin-deficiency is responsible for the main NT1 symptoms: sleepiness, cataplexy, disrupted nocturnal sleep, sleep-related hallucinations, and sleep paralysis. In the absence of a lumbar puncture, the diagnosis is based on neurophysiological tests (nocturnal and diurnal) and the presence of the pathognomonic symptom cataplexy. In the revised version of the International Classification of sleep Disorders, 3rd edition (ICSD-3-TR), a sleep onset rapid eye movement sleep (REM) period (SOREMP) (i.e. rapid occurrence of REM sleep) during the previous polysomnography may replace the diurnal multiple sleep latency test, when clear-cut cataplexy is present. A nocturnal SOREMP is very specific but not sensitive enough, and the diagnosis of cataplexy is usually based on clinical interview. It is thus of crucial importance to define typical versus atypical cataplectic attacks, and a list of clinical features and related degrees of certainty is proposed in this paper (expert opinion). The time frame of at least three months of evolution of sleepiness to diagnose NT1 was removed in the ICSD-3-TR, when clear-cut cataplexy or orexin-deficiency are established. However, it was kept for NT2 diagnosis, a less well-characterized disorder with unknown clinical course and absence of biolo biomarkers; sleep deprivation, shift working and substances intake being major differential diagnoses. Treatment of narcolepsy is nowadays only symptomatic, but the upcoming arrival of non-peptide orexin receptor-2 agonists should be a revolution in the management of these rare sleep diseases.
Topics: Humans; Cataplexy; Orexins; Sleepiness; Narcolepsy; Sleep
PubMed: 37634997
DOI: 10.1016/j.neurol.2023.08.001 -
Nature Reviews. Immunology Jan 2024Narcolepsy type 1 (NT1) is a chronic sleep disorder resulting from the loss of a small population of hypothalamic neurons that produce wake-promoting hypocretin (HCRT;... (Review)
Review
Narcolepsy type 1 (NT1) is a chronic sleep disorder resulting from the loss of a small population of hypothalamic neurons that produce wake-promoting hypocretin (HCRT; also known as orexin) peptides. An immune-mediated pathology for NT1 has long been suspected given its exceptionally tight association with the MHC class II allele HLA-DQB1*06:02, as well as recent genetic evidence showing associations with polymorphisms of T cell receptor genes and other immune-relevant loci and the increased incidence of NT1 that has been observed after vaccination with the influenza vaccine Pandemrix. The search for both self-antigens and foreign antigens recognized by the pathogenic T cell response in NT1 is ongoing. Increased T cell reactivity against HCRT has been consistently reported in patients with NT1, but data demonstrating a primary role for T cells in neuronal destruction are currently lacking. Animal models are providing clues regarding the roles of autoreactive CD4 and CD8 T cells in the disease. Elucidation of the pathogenesis of NT1 will allow for the development of targeted immunotherapies at disease onset and could serve as a model for other immune-mediated neurological diseases.
Topics: Animals; Humans; CD8-Positive T-Lymphocytes; Narcolepsy; Alleles
PubMed: 37400646
DOI: 10.1038/s41577-023-00902-9 -
Journal of Neurosciences in Rural... 2023The growing prevalence of dementia makes it important for us to better understand its pathophysiology and treatment modalities, to improve the quality of life of... (Review)
Review
The growing prevalence of dementia makes it important for us to better understand its pathophysiology and treatment modalities, to improve the quality of life of patients and caregivers. Alzheimer's disease (AD), a neurodegenerative disease, is the most common form of amnestic dementia in the geriatric population. Pathophysiology of AD is widely attributed to aggregation of amyloid-beta (Aβ) plaques and hyperphosphorylation of tau proteins. Initial treatment modalities aimed to increase brain perfusion in a non-specific manner. Subsequent therapy focused on rectifying neurotransmitter imbalance in the brain. Newer drugs modify the progression of the disease by acting against aggregated Aβ plaques. However, not all drugs used in therapy of AD have been granted approval by the United States Food and Drug Administration (FDA). This review categorizes and summarizes the FDA-approved drugs in the treatment of AD in a manner that would make it a convenient reference for researchers and practicing physicians alike. Drugs that mitigate symptoms of dementia may be categorized into mitigators of Behavioral and Psychological Symptoms of Dementia (BPSD), and mitigators of cognitive decline. BPSD mitigators include brexpiprazole, an atypical antipsychotic with a once-daily dosage suited to treat agitation in dementia patients, and suvorexant, an orexin receptor antagonist used to treat sleep disturbances. Cognitive decline mitigators include cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine and glutamate inhibitors such as memantine. Donepezil is the most commonly prescribed drug. It is cheap, well-tolerated, and may be prescribed orally once daily, or as a transdermal patch once weekly. It increases ACh levels, enhances oligodendrocyte differentiation and also protects against Aβ toxicity. However, regular cardiac monitoring is required due to reports of cardiac conduction side effects. Rivastigmine requires a twice-daily oral dosage or once-daily replacement of transdermal patch. It has fewer cardiac side effects than donepezil, but local application-site reactions have been noted. Galantamine, in addition to improving cognitive symptoms in a short span of time, also delays the development of BPSDs and has minimal drug-drug interactions by virtue of having multiple metabolic pathways. However, cardiac conduction disturbances must be closely monitored for. Memantine, a glutamate regulator, acts as an anti-Parkinsonian agent and an antidepressant, in addition to improving cognition and neuroprotection, and requires a once-daily dosage in the form of immediate-release or sustained-release oral tablets. Disease-modifying drugs such as aducanumab and lecanemab reduce the Aβ burden. Both act by binding with fibrillary conformations of Aβ plaques in the brain. These drugs have a risk of causing amyloid-related imaging abnormalities, especially in persons with ApoE4 gene. Aducanumab is administered once every 4 weeks and lecanemab once every 2 weeks. The decision on the choice of the drug must be made after considering the availability of drug, compliance of patient (once-daily vs. multiple doses daily), cost, specific comorbidities, and the risk-benefit ratio for the particular patient. Other non-pharmacological treatment modalities must also be adopted to have a holistic approach toward the treatment of AD.
PubMed: 38059250
DOI: 10.25259/JNRP_356_2023 -
Revue Neurologique Oct 2023Insomnia is more prevalent in neurological disorders compared to the general population, with rates ranging from 11 to 74.2% in neurodegenerative disorders, 20 to 37% in... (Review)
Review
Insomnia is more prevalent in neurological disorders compared to the general population, with rates ranging from 11 to 74.2% in neurodegenerative disorders, 20 to 37% in vascular diseases, 13.3 to 50% in inflammatory diseases, 28.9 to 74.4% in epilepsy, and nearly 70% in migraines. Insomnia in neurological disorders stems from a variety of factors, encompassing physical and neuropsychiatric factors, behavioral patterns, and disruptions in the biological clock and circadian rhythm. There are bidirectional connections between neurological disorders and insomnia. Insomnia in neurological disorders worsens symptoms, resulting in heightened depressive symptoms, elevated mortality rates, reduced quality of life, and intensified acute symptoms. Managing comorbid sleep disorders, especially in the presence of psychiatric comorbidities, is crucial. Cognitive behavioral therapy for insomnia (CBT-I) is the first-line recommendation for insomnia management in neurological disorders. Other treatments are second-line strategies. Melatonin may demonstrate effectiveness in addressing insomnia, with soporific and chronobiotic effects. Furthermore, it has the potential to alleviate "sundowning" and behavioral disturbances, while generally being well-tolerated. Other treatment options that may be of interest include morning bright light therapy, sedative antidepressants, new orexin dual antagonists and levodopa specifically indicated for Parkinson's disease. Benzodiazepines and z-drugs can be used primarily during acute phases to prevent pharmacotolerance and minimize side effects. However, they should be avoided in patients with neurological disorders and not used in patients over 75 years old due to the risk of falls and confusion. In neurological disorders, insomnia has a profound impact on daytime functioning, making its management crucial. Effective treatment can result in improved outcomes, and additional research is necessary to investigate alternative therapeutic options and enhance patient care.
Topics: Humans; Aged; Sleep Initiation and Maintenance Disorders; Prevalence; Quality of Life; Sleep; Hypnotics and Sedatives
PubMed: 37620177
DOI: 10.1016/j.neurol.2023.08.008 -
Nature Sep 2023Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive...
Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing. This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone. This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.
Topics: Humans; Body Mass Index; Cohort Studies; Cues; Electrophysiology; Evoked Potentials; Feeding and Eating Disorders; Feeding Behavior; Food; Hippocampus; Obesity; Orexins; Neural Pathways
PubMed: 37648849
DOI: 10.1038/s41586-023-06459-w -
Peptides Mar 2024
Topics: Neurons; Neuropeptides; Orexin Receptors; Orexins
PubMed: 38220091
DOI: 10.1016/j.peptides.2024.171153 -
The New England Journal of Medicine Jul 2023Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides.
METHODS
We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate.
RESULTS
Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients.
CONCLUSIONS
In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).
Topics: Humans; Cataplexy; Double-Blind Method; Narcolepsy; Orexin Receptors; Sleepiness; Treatment Outcome; Orexins; Brain Chemistry; Administration, Oral; Chemical and Drug Induced Liver Injury
PubMed: 37494485
DOI: 10.1056/NEJMoa2301940 -
Neuron Apr 2024Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may...
Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may mediate motor-dependent alleviation of anxiety. This three-neuron loop, in which the cerebellar dentate nucleus takes center stage, bridges the motor system with the emotional system. Subjecting animals to a constant rotarod engages glutamatergic cerebellar dentate neurons that drive PKCδ amygdalar neurons to elicit an anxiolytic effect. Moreover, challenging animals on an accelerated rather than a constant rotarod engages hypothalamic neurons that provide a superimposed anxiolytic effect via an orexinergic projection to the dentate neurons that activate the amygdala. Our findings reveal a cerebello-limbic pathway that may contribute to motor-triggered alleviation of anxiety and that may be optimally exploited during challenging physical exercise.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Hypothalamus; Cerebellum; Anxiety Disorders
PubMed: 38301648
DOI: 10.1016/j.neuron.2024.01.007 -
Zeitschrift Fur Gerontologie Und... Nov 2023Aging is associated with changes in sleep structure and cerebral deposition of amyloid beta and tau proteins. Sleep disturbances precede the onset of dementia by years.... (Review)
Review
Aging is associated with changes in sleep structure and cerebral deposition of amyloid beta and tau proteins. Sleep disturbances precede the onset of dementia by years. Comorbid sleep disorders, such as insomnia and sleep-disordered breathing, a family history of dementia and epigenetic factors can contribute to the development of dementia. This article explores the question of the interaction between sleep and dementia based on the existing literature. Alterations caused by slow wave sleep lead to changes in the glymphatic clearance of amyloid beta, tau proteins and other proteins. Transient and chronic sleep disorders cause disturbances in the brain areas responsible for cognition and behavior. Sleep-regulating brain areas are the first to be affected in the neurodegenerative process and accelerate the risk of dementia. Circadian age-related changes in amyloid beta and tau proteins affect the amount and depth of sleep and vice versa. Amyloid beta in cerebrospinal fluid shows an inverse correlation with sleep. Orexins modulate amyloid beta and sleep.
PubMed: 37676320
DOI: 10.1007/s00391-023-02237-5