Narcolepsy-like Phenotype Research Articles

Meet-The-Expert (ME) ME1. Sleep disorders in Parkinson’s disease

Sleep disorders are among the most frequent non-motor symptoms in parkinsonism. As many as 60% patients with Parkinson’s disease (PD) suffer from insomnia, 15–59% from REM sleep behavior disorders and 30% from excessive daytime sleepiness. Further nocturnal problems in PD patients include insomnia, painful dystonia, restless legs syndrome, dysuria, anxiety, depression or nocturnal hallucinations. REM sleep behavior disorder (RBD), a pre- symptomatic feature of neurodegeneration, with abrupt movements during REM periods, vocalizations and sometimes violent, enacted dreaming exposes the patients or their bed- partners to night-time injuries and is probably caused by lesions in the locus coeruleus and pedunculi-pontine area. Daytime sleepiness and a narcolepsy-like phenotype are also part of sleep-wake dysregulations in Parkinsonism. Sleep disordered breathing and pharmacological effects of dopaminergic therapy may furthermore disturb the initiation and maintenance of sleep, enhancing excessive daytime sleepiness. Thus, sleep disorders represent an important, multifactorial problem of the disease. A thorough diagnostic workup including interviews with the patient and his/her bedpartner as well as video-supported polysomnography can establish the specific sleep diagnosis. Sleep scales developed for PD as the Parkinson Disease Sleep Scale (PDSS-2) may further explore the various domains affected and thus facilitate therapeutic decisions. Treatment strategies include sufficient nocturnal dopaminergic stimulation such as levodopa sustained release or rotigotine patch for treating nocturnal akinesia, zopiclone ort melatonin for insomnia, clozapine against nocturnal hallucinations, and dopaminergic agents or even opioids for restless legs syndrome. RBD may be treated with clonazepam, although a current RCT did not provide evidence for efficacy. CPAP treatment can be applied in PD patients with moderate to severe obstructive sleep disorders breathing.

Sleep microstructure in attention deficit hyperactivity disorder according to the underlying sleep phenotypes.

The analysis of sleep microstructure in attention deficit hyperactivity disorder (ADHD) revealed an under-representation of the EEG slow component during NREM sleep. Previous studies either excluded or did not characterize objectively sleep disorders, which notoriously affect sleep architecture. The present study aimed to investigate the cyclic alternating pattern in a real clinical sample of children with ADHD, in whom sleep disorders could be considered. Twenty-seven consecutively enrolled drug-naïve children (mean age, 10.53 years; nine females) and 23 controls (mean age, 10.22years; 11 females) underwent a full sleep investigation, including attended video-polysomnography. Visual cyclic alternating pattern analysis was performed in a blinded way. Children with ADHD had one or more sleep disorders (a narcolepsy-like phenotype was found in two cases, sleep onset insomnia in three cases, arousal disorder in one case, movement disorder phenotype in six cases and obstructive sleep apnea in 11 cases, and six children had sleep-related epileptiform discharges). Children with ADHD and normal controls showed a similar microstructure with a cyclic alternating pattern rate of about 50%. Children with obstructive sleep apnea had a significantly higher cyclic alternating pattern rate during stage N3. Despite not reaching statistical differences, a lower cyclic alternating pattern rate and A1 index were found in children without epileptic abnormalities/obstructive sleep apnea. Our analysis might allow differentiation of the "primary form" of ADHD associated with a decrease of NREM instability from those forms associated with sleep apnea and epileptic activity.

Dual orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy.

Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unclear how orexin and MCH neurons interact to regulate sleep/wakefulness, we generated transgenic mice in which both orexin and MCH neurons could be ablated. Double-ablated mice exhibited increased wakefulness and decreased both rapid eye movement (REM) and non-REM (NREM) sleep. Double-ablated mice showed severe cataplexy compared with orexin neuron-ablated mice, suggesting that MCH neurons normally suppress cataplexy. Double-ablated mice also showed frequent sleep attacks with elevated spectral power in the delta and theta range, a unique state that we call 'delta-theta sleep'. Together, these results indicate a functional interaction between orexin and MCH neurons in vivo that suggests the synergistic involvement of these neuronal populations in the sleep/wakefulness cycle.

A patient with nocturnal visual hallucinations.

Citation:Dholakia S. A patient with nocturnal visual hallucinations. J Clin Sleep Med. 2020;16(5):821–822.

Orexin- and MCH-Neurons Double-Ablated Mice Display Severe Sleep Attacks and Cataplexy

Orexin-producing neurons (orexin neurons) and melanin-concentrating hormone-producing neurons (MCH neurons) are exclusively distributed in the lateral hypothalamus and project throughout the whole brain to regulate sleep/wakefulness. Ablation of orexin neurons in mice decreases wakefulness in the dark period and they display a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. It is unclear how interaction between orexin and MCH neurons regulates sleep/wakefulness. Here we generated transgenic mice in which both orexin and MCH neurons are ablated. These double-ablated mice show increased wakefulness and decreased rapid eye movement (REM) and non-REM sleep. Total time and duration of cataplexy were significantly increased in double-ablated mice compared with orexin neurons-ablated mice. These results suggest that MCH neurons have a suppressive role in cataplexy. Interestingly, these mice showed frequent sleep attacks with high delta and theta wave power via electroencephalograms during wakefulness, which is not classified under conventional criteria of sleep/wakefulness or cataplexy.

Sleep phenotypes in attention deficit hyperactivity disorder

ObjectiveA case-control study was performed to test the hypothesis that children with attention deficit hyperactivity disorder (ADHD) have chronic sleep deprivation and may be classified into specific sleep-related phenotypes. MethodsThirty outpatients with ADHD (nine females, mean age 10.1 ± 2.1 years) were recruited consecutively, and given a comprehensive sleep assessment, including blood exams, sleep questionnaires, laboratory video-polysomnographic recordings (v-PSG), multiple sleep latency tests, and one-week actigraphy. The PSG parameters were compared to those of 25 age-matched controls (12 females, mean age 10.34 ± 1.54 years) who underwent only the v-PSG. ResultsADHD children were classified as follows: a narcolepsy-like phenotype was found in four; delayed sleep onset insomnia in five; obstructive sleep apnea (OSA) in 15; periodic limb movements in eight, and sleep epileptiform discharges in 10 children. All subjects had a total sleep time shorter than 9 h at actigraphy, ferritin levels lower than 60 mcg/L, and a history of sleep problems (mainly OSA and insomnia). Compared to controls, the ADHD group had a higher apnea-hypopnea index at PSG. ConclusionsA full sleep assessment in children with ADHD confirmed the validity of the sleep phenotypes hypothesis, and revealed a much higher percentage of sleep problems than that found in the literature. Beyond the sleep phenotypes, all children reported a history of sleep problems and slept less than 9 h per night, indicating chronic sleep deprivation that should be evaluated as a possible unifying marker of ADHD.

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin(+) neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin(+) neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin(+) neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin(+) neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin(+) neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.

A Missense Mutation in Myelin Oligodendrocyte Glycoprotein as a Cause of Familial Narcolepsy with Cataplexy

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score ¼ 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders. [corrected].

Efficacy of modafinil on excessive daytime sleepiness in Prader–Willi syndrome

Excessive daytime sleepiness is a frequent and a highly disruptive symptom to the daily routine of children with Prader-Willi Syndrome (PWS) and their families. The objective of the study was to evaluate the efficacy of modafinil, a central stimulant, on excessive daytime sleepiness in children and adolescents with PWS. The efficacy of modafinil was evaluated in this open label pilot study comparing the Epworth sleepiness scale before and after treatment. Ten patients with molecularly confirmed PWS and a complaint of excessive daytime sleepiness underwent a night-time sleep recording and multiple sleep latency tests. One patient was excluded because of severe obstructive sleep apnea syndrome. Nine patients (4 males) with median age of 16 years (8-21) received modafinil at a starting dose of 100 mg/day. We found that all patients had excessive daytime sleepiness with an Epworth sleepiness scale at 14 (11-20) and mean sleep latency on multiple sleep latency tests at 5 (3-6) minutes. Moreover, six patients had at least two sleep-onset rapid eye movement periods showing a narcolepsy-like phenotype. Modafinil significantly improved sleepiness in all patients on the Epworth sleepiness scale from 14 (11-20) to 4 (3-12), (P = 0.007). Body mass index of the patients did not change significantly under treatment. No side effects were reported, and the drug was well-tolerated. We posit that this open label case series shows good efficacy of modafinil in nine children and adolescents with PWS.

Narcolepsy and Orexins: An Example of Progress in Sleep Research

Narcolepsy is a chronic neurodegenerative disease caused by a deficiency of orexin-producing neurons in the lateral hypothalamus. It is clinically characterized by excessive daytime sleepiness and by intrusions into wakefulness of physiological aspects of rapid eye movement sleep such as cataplexy, sleep paralysis, and hypnagogic hallucinations. The major pathophysiology of narcolepsy has been recently described on the bases of the discovery of the neuropeptides named orexins (hypocretins) in 1998; considerable evidence, summarized below, demonstrates that narcolepsy is the result of alterations in the genes involved in the pathology of the orexin ligand or its receptor. Deficient orexin transmission is sufficient to produce narcolepsy, as we describe here, animal models with dysregulated orexin signaling exhibit a narcolepsy-like phenotype. Remarkably, these narcoleptic models have different alterations of the orexinergic circuit, this diversity provide us with the means for making comparison, and have a better understanding of orexin-cell physiology. It is of particular interest that the most remarkable findings regarding this sleep disorder were fortuitous and due to keen observations. Sleep is a highly intricate and regulated state, and narcolepsy is a disorder that still remains as one of the unsolved mysteries in science. Nevertheless, advances and development of technology in neuroscience will provide us with the necessary tools to unravel the narcolepsy puzzle in the near future. Through an evaluation of the scientific literature we traced an updated picture of narcolepsy and orexins in order to provide insight into the means by which neurobiological knowledge is constructed.

Sleep dysfunction and role of dysautonomia in Parkinson's disease

Altered sleep is a common non motor symptom in Parkinson's disease. Sleep dysfunction has been reported to occur in 60-90% of all PD patients, having a detrimental impact on quality of life and increasing disability. alpha-Synuclein deposits in the lower brainstem affecting autonomic and sleep regions have been identified in the pathophysiology. The resultant non motor symptoms such as REM sleep behaviour disorder (RBD) can precede the motor symptoms by years. RBD is violent, enacted dreams that expose the patient or their sleeping partner to night-time injuries. Excessive daytime sleepiness, sometimes with a narcolepsy-like phenotype, is a common occurrence in PD, owing to lesions in the arousal systems of the brain. Restless legs syndrome and sleep disordered breathing can all affect daytime alertness of PD patients. Autonomic deregulation can also negatively affect sleep patterns, by adding to night-time wakening and disrupting sleep.

Sleep disturbances in patients with parkinsonism

Altered sleep and vigilance are among the most frequent symptoms, besides parkinsonism, in movement disorders. As many as 60% of patients with Parkinson's disease (PD) experience insomnia, 15-59% show rapid eye movement (REM) sleep behavior disorders (RBDs), and 30% show excessive daytime sleepiness. Insomnia is a distressing difficulty to maintain sleep, which is exacerbated by motor disability, painful dystonia, restless legs, dysuria, anxiety and depressed mood. Improving night-time motor control by overnight treatment with levodopa, transdermal or long-acting dopamine agonists, or bilateral subthalamus stimulation, can improve sleep continuity. RBDs are violent, enacted dreams that expose the patient or their sleeping partner to night-time injuries. A striking improvement of parkinsonism is observed during these behaviors in PD. RBDs are thought to be caused by lesions in the REM sleep atonia system, and can, in association with other early markers of neurodegenerative diseases, such as olfactory, cognitive and autonomic disturbances, precede parkinsonism by several years. Daytime sleepiness, often with a narcolepsy-like phenotype, is a common occurrence in PD, owing to lesions in the arousal systems of the brain. The use of dopamine agonists increases the risk of sleep attacks, especially when driving, suggesting a drug-disease interaction.

Hypocretin/Orexin: A Molecular Link Between Sleep, Energy Regulation, and Pleasure

Hypocretin (Hcrt) is a neurotransmitter of the dorsal and lateral hypothalamus that regulates sleep, appetite, and energy consumption. Recent evidence indicates that it is also involved in pleasure/reward-seeking. Mutation of the Hcrt-receptor gene causes narcolepsy in canines, and Hcrt knockout mice exhibit narcolepsy-like symptoms. Human narcoleptics do not commonly have mutations in the ligand or receptor but do have degeneration of Hcrt-containing neurons, possibly through an autoimmune mechanism. When Hcrt neurons degenerate in mice, hypophagia and obesity are observed, symptoms that are also present in some human narcoleptics. This article reviews the recent literature with regard to the many functions of this single molecule. The authors suggest that eating habits and impulsivity may be topics worth exploring in the evaluation of narcoleptic patients.

Elevated body temperature during sleep in orexin knockout mice

Core body temperature (Tb) is influenced by many physiological factors, including behavioral state, locomotor activity, and biological rhythms. To determine the relative roles of these factors, we examined Tb in orexin knockout (KO) mice, which have a narcolepsy-like phenotype with severe sleep-wake fragmentation. Because orexin is released during wakefulness and is thought to promote heat production, we hypothesized that orexin KO mice would have lower Tb while awake. Surprisingly, Tb was the same in orexin KO mice and wild-type (WT) littermates during sustained wakefulness. Orexin KO mice had normal diurnal variations in Tb, but the ultradian rhythms of Tb, locomotor activity, and wakefulness were markedly reduced. During the first 15 min of spontaneous sleep, the Tb of WT mice decreased by 1.0 degrees C, but Tb in orexin KO mice decreased only 0.4 degrees C. Even during intense recovery sleep after 8 h of sleep deprivation, the Tb of orexin KO mice remained 0.7 degrees C higher than in WT mice. This blunted fall in Tb during sleep may be due to inadequate activation of heat loss mechanisms or sustained activity in heat-generating systems. These observations reveal an unexpected role for orexin in thermoregulation. In addition, because heat loss is an essential aspect of sleep, the blunted fall in Tb of orexin KO mice may provide an explanation for the fragmented sleep of narcolepsy.

Temperature control: from molecular insights, regulation in king penguins and diving seals, to studies in humans

more than 100 manuscripts have been submitted in response to the special call on “Physiology and Pharmacology of Temperature Regulation,” which required spreading publication of the manuscripts over several issues of the journal. Dr. Andrej Romanovsky serves as the Special Editor for this call

Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults

The diagnosis of narcolepsy without documented cataplexy is based on the observation of two or more sleep-onset REM periods (SOREMPs) during the Multiple Sleep Latency Test (MSLT). We report on the prevalence and correlates of SOREMPs in the community-based Wisconsin Sleep Cohort Study. MSLTs were conducted following nocturnal polysomnography (NPSG) and daily sleep diaries in 289 males and 267 females (age 35-70, 97% Caucasians). Multiple SOREMPs were observed in 13.1% of males and 5.6% of females. An MSLT mean sleep latency < or =8 min and > or =2 SOREMPs (diagnostic of narcolepsy) was observed in 5.9% (males) and 1.1% (females), all without cataplexy. Because of significant sex interactions, analyses were stratified by sex. Increased prevalence of HLA-DQB1*0602, a marker of narcolepsy, was observed in males but not in females with > or =2 SOREMPs. Males with multiple SOREMPs compared with those with no SOREMPs had shorter rapid eye movement (REM) latency during NPSG, were sleepier on the MSLT and reported increased sleepiness, hypnagogic hallucinations and cataplexy-like symptoms, suggesting a narcolepsy-like phenotype. In males only, the occurrence of SOREMPs increased with shift work and some indirect markers of sleep restriction, such as shorter sleep a day before NPSG. SOREMPs were unrelated to age, body mass index, depression (Zung Scale), anxiety (State-Trait Anxiety Scale) and the number of apnea and hypopnea events per hour of sleep (AHI), but were associated with decreased mean lowest oxygen saturation in males. Finally, we found that both males and females with SOREMPs reported taking more antidepressants, but those were of the types known not to suppress REM sleep. These results suggest a high prevalence of narcolepsy without cataplexy, as defined by the International Classification of Sleep Disorders, and/or a large number of false-positives for the MSLT.

Excessive daytime sleepiness and unintended sleep in Parkinson’s disease

Patients with Parkinson's disease and parkinsonian syndromes (eg, dementia with Lewy body disease, multisystem atrophy, and Shy-Drager syndrome) suffer from daytime sleepiness. This sleepiness is common and very real, often approaching levels observed in the prototypical disorder of sudden-onset sleep, namely narcolepsy/cataplexy. Physicians need to be vigilant in assessing parkinsonian patients for sleepiness because treatment can dramatically enhance quality of life and prevent the significant morbidity and mortality that attends daytime sleepiness. Male patients with advanced disease, cognitive impairment, drug-induced psychosis, and orthostatic hypotension are most at risk for developing pathologic sleepiness. Because primary sleep disorders can coexist with parkinsonism (eg, sleep apnea, insufficient or interrupted sleep), these potential causes should be carefully assessed with polysomnography and treated appropriately. Dopaminomimetics exacerbate sleepiness in a small subset of patients in a dose-dependent fashion. Nonetheless, the primary pathologies involved in parkinsonism appear to be the greatest contributors to daytime sleepiness. Sleepiness in parkinsonism, especially a narcolepsy-like phenotype, may necessitate treatment with wake-promoting agents such as bupropion, modafinil, or traditional psychostimulants.

Excessive daytime sleepiness in parkinsonism

Excessive daytime sleepiness (EDS) can affect 20-50% of patients with Parkinson's disease (PD), whereas sleep attacks (SA), which are sleep episodes without prodroma, seem infrequent. EDS is associated with more advanced disease, higher doses of levodopa-equivalent, and sometimes the use of dopamine agonists. Patients at risk for SA have higher Epworth sleepiness scores (ESS) (although an important subset of patients under-score on this scale) and a more frequent use of ergot or non-ergot dopamine agonists. Polysomnography is a valuable tool in patients with PD, because sleep apnea may occur in 20% of patients, whereas a specific narcolepsy-like phenotype, identified on multiple-sleep latency tests, occurs in patients with most severe EDS; this suggests a lesion in sleep-wake systems. Removal or replacement of a recently introduced dopamine agonist may offer some relief for EDS. If not, the adjunction of modafinil has a good benefit-risk ratio in patients with PD. EDS (and sometimes the narcolepsy-like phenotype) may also affect patients with atypical parkinsonism, such as dementia with Lewy bodies, multiple-system atrophy, and progressive supranuclear palsy.

Sleepiness and Unintended Sleep in Parkinson's Disease.

Patients with Parkinson's disease (PD) and parkinsonian syndromes (eg, dementia with Lewy bodies, multisystem atrophy, and Shy-Drager syndrome) suffer from daytime sleepiness. Sleepiness in PD is common (10% to 50% of patients) and very real, often approaching levels observed in the prototypical disorder of sudden-onset sleep, viz, and narcolepsy with cataplexy. Physicians need to be vigilant in assessing parkinsonian patients for sleepiness, because treatment can dramatically enhance quality of life and prevent the significant morbidity and mortality that attends daytime sleepiness. Men with advanced disease, cognitive impairment, drug-induced psychosis, and orthostatic hypotension are most at risk for developing pathologic sleepiness. Because primary sleep disorders can coexist with Parkinsonism (eg, sleep apnea, insufficient or interrupted sleep), these potential causes should be carefully assessed with polysomnography and treated appropriately. Dopaminomimetics may exacerbate sleepiness in a small subset of patients. The primary pathologies involved in Parkinsonism appear to be the greatest contributors to the development of daytime sleepiness. Sleepiness in Parkinsonism, especially a narcolepsy-like phenotype, may necessitate treatment with wake-promoting agents, such as bupropion, modafinil, or traditional psychostimulants.

Parkinson's disease and sleepiness: an integral part of PD.

To investigate the potential causes of excessive daytime sleepiness in patients with PD-poor sleep quality, abnormal sleep-wakefulness control, and treatment with dopaminergic agents. The authors performed night-time polysomnography and daytime multiple sleep latency tests in 54 consecutive levodopa-treated patients with PD referred for sleepiness, 27 of whom were also receiving dopaminergic agonists. Sleep latency was 6.3 +/- 0.6 minutes (normal >8 minutes), and the Epworth Sleepiness score was 14.3 +/- 4.1 (normal <10). A narcolepsy-like phenotype (> or = 2 sleep-onset REM periods) was found in 39% of the patients, who were sleepier (4.6 +/- 0.9 minutes) than the other 61% of patients (7.4 +/- 0.7 minutes). Periodic leg movement syndromes were rare (15%, range 16 to 43/h), but obstructive sleep apnea-hypopnea syndromes were frequent (20% of patients had an apnea-hypopnea index >15/h; range 15.1 to 50.0). Severity of sleepiness was weakly correlated with Epworth Sleepiness score (r = -0.34) and daily dose of levodopa (r = 0.30) but not with dopamine-agonist treatment, age, disease duration, parkinsonian motor disability, total sleep time, periodic leg movement, apnea-hypopnea, or arousal indices. In patients with PD preselected for sleepiness, severity of sleepiness was not dependent on nocturnal sleep abnormalities, motor and cognitive impairment, or antiparkinsonian treatment. The results suggest that sleepiness-sudden onset of sleep-does not result from pharmacotherapy but is related to the pathology of PD.