The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Emmanuel Mignot - One of the best experts on this subject based on the ideXlab platform.
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challenges in diagnosing narcolepsy without Cataplexy a consensus statement
Sleep, 2014Co-Authors: Emmanuel Mignot, Sebastiaan Overeem, Gert Jan Lammers, Christian R. Baumann, Isabelle Arnulf, Y Dauvilliers, Makoto Honda, Judith A Owens, Giuseppe PlazziAbstract:BACKGROUND: Diagnosing narcolepsy without Cataplexy is often a challenge as the symptoms are nonspecific, current diagnostic tests are limited, and there are no useful biomarkers. In this report, we review the clinical and physiological aspects of narcolepsy without Cataplexy, the limitations of available diagnostic procedures, and the differential diagnoses, and we propose an approach for more accurate diagnosis of narcolepsy without Cataplexy. METHODS: A group of clinician-scientists experienced in narcolepsy reviewed the literature and convened to discuss current diagnostic tools, and to map out directions for research that should lead to a better understanding and more accurate diagnosis of narcolepsy without Cataplexy. RECOMMENDATIONS: To aid in the identification of narcolepsy without Cataplexy, we review key indicators of narcolepsy and present a diagnostic algorithm. A detailed clinical history is mainly helpful to rule out other possible causes of chronic sleepiness. The multiple sleep latency test remains the most important measure, and prior sleep deprivation, shift work, or circadian disorders should be excluded by actigraphy or sleep logs. A short REM sleep latency (Cataplexy, although sensitivity is low. Finally, measurement of hypocretin levels can helpful, as levels are low to intermediate in 10% to 30% of narcolepsy without Cataplexy patients. CITATION: Baumann CR, Mignot E, Lammers GJ, Overeem S, Arnulf I, Rye D, Dauvilliers Y, Honda M, Owens JA, Plazzi G, Scammell TE. Challenges in diagnosing narcolepsy without Cataplexy: a consensus statement. SLEEP 2014;37(6):1035-1042.
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clinical and therapeutic aspects of childhood narcolepsy Cataplexy a retrospective study of 51 children
Sleep, 2010Co-Authors: Adi Aran, Mali Einen, Seiji Nishino, G Plazzi, Emmanuel MignotAbstract:NARCOLEPSY-Cataplexy IS A COMMON DISORDER, AFFECTING 0.02% TO 0.05% OF THE POPULATION IN THE UNITED STATES. RECENT RESEARCH HAS shown that the cause of narcolepsy-Cataplexy is the loss of approximately 70,000 hypothalamic neurons producing the neuropeptide hypocretin.1–3 Hypocretin knockout mice and hypocretin receptor-2 mutated dogs have narcolepsy-Cataplexy, demonstrating that the loss of hypocretin transmission causes narcolepsy.4–6 Since 1983, it has been known that narcolepsy is associated with the HLA,7 most specifically, allele DQB1*0602.8–10 Because most diseases that are strongly HLA associated are autoimmune, these discoveries have led to the hypothesis that narcolepsy is caused by an autoimmune destruction of hypocretin cells. This finding was recently strengthened by the discovery that narcolepsy/hypocretin deficiency is strongly associated with T-cell receptor α polymorphisms,11 anti-TRIB2 antibodies12 and that streptococcus infections are a possible trigger for narcolepsy.13 Although narcolepsy is considered to be a disease of adulthood, most cases have their onset in childhood or adolescence.14 Early observation in the United States15 and Japan16 has reported that approximately half of patients with narcolepsy had onset prior to 15 years of age, with fewer than 10% with onset prior to age 5. Similarly, in our own database of 1219 cases, although fewer than 10% are children (< 18 years of age) at evaluation, 40% reported symptom onset prior to age 15, and 2.1% had onset prior to age 5 (1.1% with Cataplexy onset prior to age 5) (data not shown). With increased recognition, it is also evident that narcolepsy is diagnosed more frequently close to onset and in childhood. Early studies in the 1980s to 1990s have reported a median delay between onset and diagnosis of more than 10 years.17 With narcolepsy increasingly recognized in children and adolescents, there is a paucity of studies describing this population. Challamel et al.18 reported a high frequency of secondary cases in children, especially those younger than 5 years old. From 97 cases reported, 20 were symptomatic in origin, 12 having Niemann Pick type-C, a disorder associated with Cataplexy; 2 with diencephalic tumors; and 2 with other unspecified neurologic abnormalities. A few years later, Guilleminault and Pelayo19 reported on 51 cases but found none to be secondary in etiology. These authors found that prepubertal cases were frequently misdiagnosed as seizures, Cataplexy being the cause of referral. In older children, referral was secondary to sleepiness or abnormal behavior, for example, attention deficit or school-performance complaints.19 More recently, Vendrame et al.20 reported on the retrospective study of 125 children with a complaint of hypersomnolence, stressing the importance of sleep disordered breathing (72% of cases), delayed sleep phase syndrome (17%), and the frequency of periodic leg movements during sleep (16%) as more frequent causes. In this series, 20 patients (16%) had narcolepsy (defined using the multiple sleep latency test, MSLT), and only 3 reported Cataplexy. Other recent narcolepsy-Cataplexy case studies include a report on disease characteristics in 16 Caucasian subjects younger than 13 years old21 and the study of 29 Chinese children.22 Serra et al.,23 reporting on Cataplexy presentation in 23 young Italian subjects, stressed how Cataplexy can be polymorphic and difficult to diagnose when close to disease onset. Treatment studies are also lacking in this population. Studies have reported on the anecdotal use of modafinil and sodium oxybate in 3520,24 and 2220,25,26 children, respectively, with only 1 prepubertal subject reportedly treated “off label” with sodium oxybate.25 Huang and Guilleminault26 reported on the use of sodium oxybate versus baclofen, a gamma-amino-n-butyric acid (GABA)B-receptor agonist, in 26 teenagers, finding both drugs to be effective in treating disturbed nocturnal sleep. Because only sodium oxybate had effects on Cataplexy and daytime sleepiness, however,26 the authors suggested that sodium oxybate had a non-GABAB mediation effect on Cataplexy. A major goal of this study was to provide data on disease presentation and therapeutic response in children with narcolepsy, with an emphasis on prepubertal children. To do so, we used retrospective chart review in 51 children and prospective data collection in 40 children with narcolepsy-Cataplexy.
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behavioural and neurophysiological correlates of human Cataplexy a video polygraphic study
Clinical Neurophysiology, 2010Co-Authors: Roberto Vetrugno, Stefano Vandi, Emmanuel Mignot, Christian Franceschini, Keivan Kaveh Moghadam, Pasquale Montagna, Roberto Dangelo, Giuseppe PlazziAbstract:Abstract Objectives To investigate the behavioural and neurophysiological pattern of Cataplexy. Methods Seven narcolepsy with Cataplexy patients underwent daytime videopolygraphy using humorous movies or/and jokes to trigger cataplectic attacks. Results During segmental cataplectic attacks, EMG showed brief and irregular periods of silencing focally involving facial, neck, axial or limb muscles, sometimes coinciding with bursts of rapid eye movements. All patients enacted intentional movements in response to these segmental postural lapses. During global cataplectic attacks, EMG showed suppression of activity alternated with patterned enhancement, enhanced EMG activity in neck muscles preceding that of other cranial, axial and lower limb muscles. This waxing and waning EMG pattern ended with a complete body collapse and persistent muscle atonia. Breathing irregularities, heart rate (HR) instability and EEG desynchronization were observed during global cataplectic attacks without any appreciable blood pressure changes, but with HR deceleration and silencing of sympathetic skin response while in complete atonia. Patients subjectively perceived the involuntary postural lapses as startling and alarming. Conclusions Cataplexy in our patients showed many of the features of tonic REM sleep. Significance Cataplexy can be construed as a “freezing-like” perturbation of the orienting response with transient impairment of posture and movements resulting in a “patchwork-compromise-behaviour”.
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Sympathetic and cardiovascular activity during Cataplexy in narcolepsy
Journal of Sleep Research, 2008Co-Authors: Vincenzo Donadio, Giuseppe Plazzi, Stefano Vandi, Emmanuel Mignot, Christian Franceschini, Tomas Karlsson, Pasquale Montagna, Roberto Vetrugno, Enrico Bugiardini, Rocco LiguoriAbstract:Summary Autonomic nervous system activity changes have been described during Cataplexy as playing a role in triggering it. To confirm these previous findings, we investigated the time course of sympathetic and cardiovascular activities during Cataplexy. We made for the first time microneurographic recordings of 10 cataplectic episodes in three patients with hypocretin-deficient narcolepsy. During microneurography, muscle sympathetic nerve activity (MSNA) was recorded simultaneously with heart rate (HR), respiratory movements, arterial finger blood pressure (BP), electroencephalography, electro-oculogram and superficial electromyogram. Results showed no significant autonomic changes before the onset of the cataplectic episodes. Cataplexy was associated with a significant increase in MSNA and BP compared with baseline, whereas HR was markedly decreased. An irregular breathing pattern mainly characterized by apnea typically occurred during the attacks. In conclusion, our findings did not show significant changes in autonomic activity prior to Cataplexy onset, ruling out a triggering role of the autonomic system. However, Cataplexy was associated with co-activation of sympathetic and parasympathetic autonomic systems, a pattern reminiscent of that reported during the vigilance reaction in animals.
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anomalous hypothalamic responses to humor in Cataplexy
PLOS ONE, 2008Co-Authors: Allan L Reiss, Fumiko Hoeft, Adam S Tenforde, Wynne Chen, Dean Mobbs, Emmanuel MignotAbstract:Background: Cataplexy is observed in a subset of patients with narcolepsy and affects approximately 1 in 2,000 persons. Cataplexy is most often triggered by strong emotions such as laughter, which can result in transient, yet debilitating, muscle atonia. The objective of this study was to examine the neural systems underlying humor processing in individuals with Cataplexy. Methodology/Principal Findings: While undergoing functional Magnetic Resonance Imaging (fMRI), we showed ten narcolepsy-Cataplexy patients and ten healthy controls humorous cartoons. In addition, we examined the brain activity of one subject while in a full-blown cataplectic attack. Behavioral results showed that participants with Cataplexy rated significantly fewer humorous cartoons as funny compared to controls. Concurrent fMRI showed that patients, when compared to controls and in the absence of overt Cataplexy symptoms, showed pronounced activity in the emotional network including the ventral striatum and hypothalamus while viewing humorous versus non-humorous cartoons. Increased activity was also observed in the right inferior frontal gyri -a core component of the inhibitory circuitry. In comparison, the one subject who experienced a cataplectic attack showed dramatic reductions in hypothalamic activity. Conclusions: These findings suggest an overdrive of the emotional circuitry and possible compensatory suppression by cortical inhibitory regions in Cataplexy. Moreover, during cataplectic attacks, the hypothalamus is characterized by a marked decrease in activity similar to that observed during sleep. One possible explanation for these findings is an initial overdrive and compensatory shutdown of the hypothalamus resulting in full cataplectic symptoms.
Jerome M Siegel - One of the best experts on this subject based on the ideXlab platform.
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localized loss of hypocretin orexin cells in narcolepsy without Cataplexy
Sleep, 2009Co-Authors: Jerome M Siegel, Robert Nienhuis, Thomas C ThannickalAbstract:STANDARD NOSOLOGY CLASSIFIES PATIENTS WHO HAVE SHORT SLEEP LATENCY AND ≥ 2 SLEEP ONSET REM SLEEP PERIODS ON THE MULTIPLE SLEEP LATENCY test as narcoleptic.1 Under this definition, more than a quarter of those classified as narcoleptic do not have Cataplexy.2,3 The intensity of Cataplexy in patients classified as having narcolepsy with Cataplexy varies greatly: it is the most debilitating symptom in a few patients, causing total loss of muscle tone and consequent collapse several times a day; it occurs rarely and causes only transient weakness of the facial musculature in others.4 Narcolepsy with Cataplexy has been shown to be characterized by a loss of the hypocretin (orexin) peptide and of the cells generating this peptide.5–8 All human narcoleptic brains we have examined have some surviving hypocretin cells with approximately normal morphology.9 Unfortunately, collection of the brains of human narcoleptics has been largely limited to patients with Cataplexy. We now present data from an analysis of the complete hypothalamus of one patient with narcolepsy without Cataplexy (patient 1), data from a second narcolepsy without Cataplexy patient from which we received only anterior hypothalamic tissue (patient 2), 5 narcolepsy with Cataplexy patients, and 6 normal individuals.
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a consensus definition of Cataplexy in mouse models of narcolepsy
Sleep, 2009Co-Authors: Thomas E Scammell, Jon T Willie, Christian Guilleminault, Jerome M SiegelAbstract:People with narcolepsy often have episodes of Cataplexy, brief periods of muscle weakness triggered by strong emotions. Many researchers are now studying mouse models of narcolepsy, but definitions of Cataplexy-like behavior in mice differ across labs. To establish a common language, the International Working Group on Rodent Models of Narcolepsy reviewed the literature on Cataplexy in people with narcolepsy and in dog and mouse models of narcolepsy and then developed a consensus definition of murine Cataplexy. The group concluded that murine Cataplexy is an abrupt episode of nuchal atonia lasting at least 10 seconds. In addition, theta activity dominates the EEG during the episode, and video recordings document immobility. To distinguish a Cataplexy episode from REM sleep after a brief awakening, at least 40 seconds of wakefulness must precede the episode. Bouts of Cataplexy fitting this definition are common in mice with disrupted orexin/hypocretin signaling, but these events almost never occur in wild type mice. It remains unclear whether murine Cataplexy is triggered by strong emotions or whether mice remain conscious during the episodes as in people with narcolepsy. This working definition provides helpful insights into murine Cataplexy and should allow objective and accurate comparisons of Cataplexy in future studies using mouse models of narcolepsy. Citation: Scammell TE; Willie JT; Guilleminault C; Siegel JM. A consensus definition of Cataplexy in mouse models of narcolepsy. SLEEP 2009;32(1):111-116.
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Cataplexy active neurons in the hypothalamus implications for the role of histamine in sleep and waking behavior
Neuron, 2004Co-Authors: Jerome M Siegel, Ming-fung Wu, Joshi John, Lisa N BoehmerAbstract:Abstract Noradrenergic, serotonergic, and histaminergic neurons are continuously active during waking, reduce discharge during NREM sleep, and cease discharge during REM sleep. Cataplexy, a symptom associated with narcolepsy, is a waking state in which muscle tone is lost, as it is in REM sleep, while environmental awareness continues, as in alert waking. In prior work, we reported that, during Cataplexy, noradrenergic neurons cease discharge, and serotonergic neurons greatly reduce activity. We now report that, in contrast to these other monoaminergic "REM-off" cell groups, histamine neurons are active in Cataplexy at a level similar to or greater than that in quiet waking. We hypothesize that the activity of histamine cells is linked to the maintenance of waking, in contrast to activity in noradrenergic and serotonergic neurons, which is more tightly coupled to the maintenance of muscle tone in waking and its loss in REM sleep and Cataplexy.
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activity of dorsal raphe cells across the sleep waking cycle and during Cataplexy in narcoleptic dogs
The Journal of Physiology, 2004Co-Authors: Ming-fung Wu, Jerome M Siegel, Joshi John, Lisa N Boehmer, G B NguyenAbstract:Cataplexy, a symptom associated with narcolepsy, represents a unique dissociation of behavioural states. During cataplectic attacks, awareness of the environment is maintained, as in waking, but muscle tone is lost, as in REM sleep. We have previously reported that, in the narcoleptic dog, noradrenergic cells of the locus coeruleus cease discharge during Cataplexy. In the current study, we report on the activity of serotonergic cells of the dorsal raphe nucleus. The discharge patterns of serotonergic dorsal raphe cells across sleep–waking states did not differ from those of dorsal raphe and locus coeruleus cells recorded in normal rats, cats and monkeys, with tonic discharge in waking, reduced activity in non-REM sleep and cessation of activity in REM sleep. However, in contrast with locus coeruleus cells, dorsal raphe REM sleep-off neurones did not cease discharge during Cataplexy. Instead, discharge continued at a level significantly higher than that seen in REM sleep and comparable to that seen in non-REM sleep. We also identified several cells in the dorsal raphe whose pattern of activity was the opposite of that of the presumed serotonergic cells. These cells were maximally active in REM sleep and minimally active in waking and increased activity during Cataplexy. The difference between noradrenergic and serotonergic cell discharge profiles in Cataplexy suggests different roles for these cell groups in the normal regulation of environmental awareness and muscle tone and in the pathophysiology of narcolepsy.
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Cataplexy-RELATED NEURONS IN THE AMYGDALA OF THE NARCOLEPTIC DOG
Neuroscience, 2002Co-Authors: Seema Gulyani, Ming-fung Wu, Robert Nienhuis, Joshi John, Jerome M SiegelAbstract:Abstract The amygdala plays an important role in the interpretation of emotionally significant stimuli and has strong projections to brainstem regions regulating muscle tone and sleep. Cataplexy, a symptom of narcolepsy, is a loss of muscle tone usually triggered by sudden, strong emotions. Extracellular single-unit recordings were carried out in the amygdala of narcoleptic dogs to test the hypothesis that abnormal activity of a subpopulation of amygdala neurons is linked to Cataplexy. Of the 218 cells recorded, 31 were sleep active, 78 were active in both waking and rapid-eye-movement sleep, 88 were maximally active during waking, and 21 were state independent. Two populations of cells showed a significant change in activity with Cataplexy. A population of sleep active cells localized to central and basal nucleus increased discharges prior to and during Cataplexy. A population of wake active cells localized to the cortical nucleus decreased activity prior to and during Cataplexy. We hypothesize that these cell populations have a role in mediation or modulation of Cataplexy through interactions with meso-pontine regions controlling atonia. The anticholinesterase physostigmine, at doses which increased Cataplexy, did not alter the activity of the Cataplexy-related cells or of other amygdala cells, suggesting that its effect on Cataplexy is mediated ‘downstream’ of the amygdala. The α-1 blocker prazosin, at doses which increased Cataplexy, increased discharge in a subgroup of the Cataplexy active cells and in a number of other amygdala cells, indicating that prazosin may modulate Cataplexy by its action on amygdala cells or their afferents.
Giuseppe Plazzi - One of the best experts on this subject based on the ideXlab platform.
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automatic detection of Cataplexy
Sleep Medicine, 2018Co-Authors: Ilaria Bartolini, Fabio Pizza, Elena Antelmi, Stefano Vandi, Andrea Di Luzio, Giulia Neccia, Giuseppe PlazziAbstract:Abstract Objective Although being the most specific symptom of narcolepsy type 1 (NT1), Cataplexy is currently investigated by clinical interview only, with potential diagnostic pitfalls. Our study aimed at testing the accuracy of an automatic video detection of Cataplexy in NT1 patients vs. non-cataplectic subjects undergoing a standardized test with emotional stimulation. Methods Fifteen drug-naive NT1 patients and 15 age- and sex-balanced non-cataplectic subjects underwent a standardized video recording procedure including emotional stimulation causing laughter. Video recordings were visually inspected by human scorers to detect three typical Cataplexy facial motor patterns (ptosis, mouth opening and head drop), and then analysed by SHIATSU (Semantic-based HIearchical Automatic Tagging of videos by Segmentation using cUts). Expert-based and automatic attack detection was compared in NT1 patients and non-cataplectic subjects. Results All NT1 patients and none of the non-cataplectic subjects displayed Cataplexy during emotional stimulation. Automatic detection correlated well with experts' assessments in NT1 with an overall accuracy of 81%. In non-cataplectic subjects, automatic detection falsely identified Cataplexy in two out of 15 (13.3%) subjects who showed active eyes closure during intense laughter as a confounder with ptosis. Conclusions Automatic Cataplexy detection by applying SHIATSU to a standardized test for video documentation of Cataplexy is feasible, with an overall accuracy of 81% compared to human examiners. Further studies are warranted to enlarge the range of elementary motor patterns detected, analyse their temporal/spatial relations and quantify Cataplexy for diagnostic purposes.
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persistence of deep tendon reflexes during partial Cataplexy
Sleep Medicine, 2018Co-Authors: Lucie Barateau, Fabio Pizza, Regis Lopez, Elena Antelmi, Giuseppe Plazzi, Yves DauvilliersAbstract:Abstract Objective Deep-tendon reflexes are abolished during generalized Cataplexy, but whether this is the case in partial Cataplexy currently remains unknown. Partial Cataplexy may mimic other neurologic/psychiatric phenomena, and knowledge of the reflexes status may provide information for differential diagnosis. We assessed whether deep-tendon reflexes are persistent during partial Cataplexy. Methods Five drug-free patients with typical diagnoses of narcolepsy and clear-cut partial Cataplexy were diagnosed in Reference Narcolepsy Centers in France and Italy. Biceps and patellar reflexes were elicited by physicians in charge and video-documented during Cataplexy. Reflexes were assessed several times for each patient in different conditions and for various localizations of Cataplexy. Results The absence of tendon reflexes and complete loss of muscle tone during generalized Cataplexy was confirmed, but the persistence of those reflexes during several partial cataplectic attacks at different ages, gender, localization of Cataplexy (upper limbs, face) and reflexes (biceps, patellar) in drug-naive or withdrawal conditions was documented. Conclusion The persistence of tendon reflexes during several partial Cataplexy episodes contrasts with their absence during generalized Cataplexy. This discovery has clinical implications: the persistence of tendon reflexes does not rule out Cataplexy diagnosis for partial attacks, whereas their transient abolishment or persistence during generalized attacks indicates Cataplexy or pseudoCataplexy, respectively.
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parkinsonian tremor persisting during Cataplexy
Sleep Medicine, 2016Co-Authors: Elena Antelmi, Fabio Pizza, Stefano Vandi, Rocco Liguori, Giuseppe PlazziAbstract:Cataplexy is defined as short episodes of bilateral suddenmuscle weakness/paralysis triggered by strong emotionswith preserved consciousness [1]. Although Cataplexy is generally defined as the consequence of REM sleep atonia occurring during wakefulness, an alternative speculation suggests that Cataplexy may represent the expression of an atavistic defense response in humans [2,3]. REM sleep behavior disorder (RBD) is somehow an opposite condition, characterized by the “acting out” of dreams that occur during REM sleep allowed by the pathological loss of the REM sleep atonia [1]. While Cataplexy labels narcolepsy type 1 (NT1) [1], RBD may occur not only in NT1 [4] but also in other neurological conditions, and it has been proposed as an early marker of impending neurodegenerative conditions [5]. This study reports the observation of an NT1 patient who developed Parkinson disease (PD). Video polygraphy documents the persistence of the resting tremor during Cataplexy and during REM sleep without atonia (RWA).
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challenges in diagnosing narcolepsy without Cataplexy a consensus statement
Sleep, 2014Co-Authors: Emmanuel Mignot, Sebastiaan Overeem, Gert Jan Lammers, Christian R. Baumann, Isabelle Arnulf, Y Dauvilliers, Makoto Honda, Judith A Owens, Giuseppe PlazziAbstract:BACKGROUND: Diagnosing narcolepsy without Cataplexy is often a challenge as the symptoms are nonspecific, current diagnostic tests are limited, and there are no useful biomarkers. In this report, we review the clinical and physiological aspects of narcolepsy without Cataplexy, the limitations of available diagnostic procedures, and the differential diagnoses, and we propose an approach for more accurate diagnosis of narcolepsy without Cataplexy. METHODS: A group of clinician-scientists experienced in narcolepsy reviewed the literature and convened to discuss current diagnostic tools, and to map out directions for research that should lead to a better understanding and more accurate diagnosis of narcolepsy without Cataplexy. RECOMMENDATIONS: To aid in the identification of narcolepsy without Cataplexy, we review key indicators of narcolepsy and present a diagnostic algorithm. A detailed clinical history is mainly helpful to rule out other possible causes of chronic sleepiness. The multiple sleep latency test remains the most important measure, and prior sleep deprivation, shift work, or circadian disorders should be excluded by actigraphy or sleep logs. A short REM sleep latency (Cataplexy, although sensitivity is low. Finally, measurement of hypocretin levels can helpful, as levels are low to intermediate in 10% to 30% of narcolepsy without Cataplexy patients. CITATION: Baumann CR, Mignot E, Lammers GJ, Overeem S, Arnulf I, Rye D, Dauvilliers Y, Honda M, Owens JA, Plazzi G, Scammell TE. Challenges in diagnosing narcolepsy without Cataplexy: a consensus statement. SLEEP 2014;37(6):1035-1042.
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electroencephalogram paroxysmal theta characterizes Cataplexy in mice and children
Brain, 2013Co-Authors: Anne Vassalli, Giuseppe Plazzi, Jose M Dellepiane, Yann Emmenegger, Sonia Jimenez, Stefano Vandi, Paul Franken, Mehdi TaftiAbstract:Astute control of brain activity states is critical for adaptive behaviours and survival. In mammals and birds, electroencephalographic recordings reveal alternating states of wakefulness, slow wave sleep and paradoxical sleep (or rapid eye movement sleep). This control is profoundly impaired in narcolepsy with Cataplexy, a disease resulting from the loss of orexin/hypocretin neurotransmitter signalling in the brain. Narcolepsy with Cataplexy is characterized by irresistible bouts of sleep during the day, sleep fragmentation during the night and episodes of Cataplexy, a sudden loss of muscle tone while awake and experiencing emotions. The neural mechanisms underlying Cataplexy are unknown, but commonly thought to involve those of rapid eye movement–sleep atonia, and Cataplexy typically is considered as a rapid eye movement sleep disorder. Here we reassess Cataplexy in hypocretin ( Hcrt , also known as orexin) gene knockout mice. Using a novel video/electroencephalogram double-blind scoring method, we show that Cataplexy is not a state per se , as believed previously, but a dynamic, multi-phased process involving a reproducible progression of states. A knockout-specific state and a stereotypical paroxysmal event were introduced to account for signals and electroencephalogram spectral characteristics not seen in wild-type littermates. Cataplexy almost invariably started with a brief phase of wake-like electroencephalogram, followed by a phase featuring high-amplitude irregular theta oscillations, defining an activity profile distinct from paradoxical sleep, referred to as Cataplexy-associated state and in the course of which 1.5–2 s high-amplitude, highly regular, hypersynchronous paroxysmal theta bursts (∼7 Hz) occurred. In contrast to Cataplexy onset, exit from Cataplexy did not show a predictable sequence of activities. Altogether, these data contradict the hypothesis that Cataplexy is a state similar to paradoxical sleep, even if long cataplexies may evolve into paradoxical sleep. Although not exclusive to overt Cataplexy, Cataplexy-associated state and hypersynchronous paroxysmal theta activities are highly enriched during Cataplexy in hypocretin/orexin knockout mice. Their occurrence in an independent narcolepsy mouse model, the orexin/ataxin 3 transgenic mouse, undergoing loss of orexin neurons, was confirmed. Importantly, we document for the first time similar paroxysmal theta hypersynchronies (∼4 Hz) during Cataplexy in narcoleptic children. Lastly, we show by deep recordings in mice that the Cataplexy-associated state and hypersynchronous paroxysmal theta activities are independent of hippocampal theta and involve the frontal cortex. Cataplexy hypersynchronous paroxysmal theta bursts may represent medial prefrontal activity, associated in humans and rodents with reward-driven motor impulse, planning and conflict monitoring. * Abbreviations : CAS : Cataplexy-associated state HSPT : hypersynchronous paroxysmal theta REM : rapid eye movement
Thomas E Scammell - One of the best experts on this subject based on the ideXlab platform.
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Cataplexy and Its mimics : clinical recognition and management
Current Treatment Options in Neurology, 2017Co-Authors: Sigrid Pillen, Fabio Pizza, Thomas E Scammell, Karlien Dhondt, Sebastiaan OvereemAbstract:OPINION STATEMENT: This review describes the diagnosis and management of Cataplexy: attacks of bilateral loss of muscle tone, triggered by emotions and with preserved consciousness. Although Cataplexy is rare, its recognition is important as in most cases, it leads to a diagnosis of narcolepsy, a disorder that still takes a median of 9 years to be diagnosed. The expression of Cataplexy varies widely, from partial episodes affecting only the neck muscles to generalized attacks leading to falls. Moreover, childhood Cataplexy differs from the presentation in adults, with a prominent facial involvement, already evident without clear emotional triggers ('cataplectic facies') and 'active' motor phenomena especially of the tongue and perioral muscles. Next to narcolepsy, Cataplexy can sometimes be caused by other diseases, such as Niemann-Pick type C, Prader Willi Syndrome, or lesions in the hypothalamic or pontomedullary region. Cataplexy mimics include syncope, epilepsy, hyperekplexia, drop attacks and pseudoCataplexy. They can be differentiated from Cataplexy using thorough history taking, supplemented with (home)video recordings whenever possible. Childhood narcolepsy, with its profound facial hypotonia, can be confused with neuromuscular disorders, and the active motor phenomenona resemble those found in childhood movement disorders such as Sydenham's chorea. Currently, the diagnosis of Cataplexy is made almost solely on clinical grounds, based on history taking and (home) videos. Cataplexy shows remarkable differences in childhood compared to adults, with profound facial hypotonia and complex active motor phenomena. Over time, these severe symptoms evolve to the milder adult phenotype, and this pattern is crucial to recognize when assessing the outcome of uncontrolled case series with potential treatments such as immunomodulation. Symptomatic treatment is possible with antidepressants and sodium oxybate. Importantly, management also needs to involve sleep hygiene advice, safety measures whenever applicable and guidance with regard to the social sequelae of Cataplexy.
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gabaergic neurons of the central amygdala promote Cataplexy
The Journal of Neuroscience, 2017Co-Authors: Carrie E Mahoney, Lindsay J Agostinelli, Jessica N K Brooks, Bradford B Lowell, Thomas E ScammellAbstract:Narcolepsy is characterized by chronic sleepiness and Cataplexy—sudden muscle paralysis triggered by strong, positive emotions. This condition is caused by a lack of orexin (hypocretin) signaling, but little is known about the neural mechanisms that mediate Cataplexy. The amygdala regulates responses to rewarding stimuli and contains neurons active during Cataplexy. In addition, lesions of the amygdala reduce Cataplexy. Because GABAergic neurons of the central nucleus of the amygdala (CeA) target brainstem regions known to regulate muscle tone, we hypothesized that these cells promote emotion-triggered Cataplexy. We injected adeno-associated viral vectors coding for Cre-dependent DREADDs or a control vector into the CeA of orexin knock-out mice crossed with vGAT-Cre mice, resulting in selective expression of the excitatory hM3 receptor or the inhibitory hM4 receptor in GABAergic neurons of the CeA. We measured sleep/wake behavior and Cataplexy after injection of saline or the hM3/hM4 ligand clozapine -N- oxide (CNO) under baseline conditions and under conditions that should elicit positive emotions. In mice expressing hM3, CNO approximately doubled the amount of Cataplexy in the first 3 h after dosing under baseline conditions. Rewarding stimuli (chocolate or running wheels) also increased Cataplexy, but CNO produced no further increase. In mice expressing hM4, CNO reduced Cataplexy in the presence of chocolate or running wheels. These results demonstrate that GABAergic neurons of the CeA are sufficient and necessary for the production of Cataplexy in mice, and they likely are a key part of the mechanism through which positive emotions trigger Cataplexy. SIGNIFICANCE STATEMENT Cataplexy is one of the major symptoms of narcolepsy, but little is known about how strong, positive emotions trigger these episodes of muscle paralysis. Prior research shows that amygdala neurons are active during Cataplexy and Cataplexy is reduced by lesions of the amygdala. We found that Cataplexy is substantially increased by selective activation of GABAergic neurons in the central nucleus of the amygdala (CeA). We also demonstrate that inhibition of these neurons reduces reward-promoted Cataplexy. These results build upon prior work to establish the CeA as a crucial element in the neural mechanisms of Cataplexy. These results demonstrate the importance of the CeA in regulating responses to rewarding stimuli, shedding light on the broader neurobiology of emotions and motor control.
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role of the medial prefrontal cortex in Cataplexy
The Journal of Neuroscience, 2013Co-Authors: Yo Oishi, Rhiannan H Williams, Lindsay J Agostinelli, E Arrigoni, Patrick M Fuller, Takatoshi Mochizuki, Clifford B Saper, Thomas E ScammellAbstract:Narcolepsy is characterized by chronic sleepiness and Cataplexy, episodes of profound muscle weakness that are often triggered by strong, positive emotions. Narcolepsy with Cataplexy is caused by a loss of orexin (also known as hypocretin) signaling, but almost nothing is known about the neural mechanisms through which positive emotions trigger Cataplexy. Using orexin knock-out mice as a model of narcolepsy, we found that palatable foods, especially chocolate, markedly increased Cataplexy and activated neurons in the medial prefrontal cortex (mPFC). Reversible suppression of mPFC activity using an engineered chloride channel substantially reduced Cataplexy induced by chocolate but did not affect spontaneous Cataplexy. In addition, neurons in the mPFC innervated parts of the amygdala and lateral hypothalamus that contain neurons active during Cataplexy and that innervate brainstem regions known to regulate motor tone. These observations indicate that the mPFC is a critical site through which positive emotions trigger Cataplexy.
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amygdala lesions reduce Cataplexy in orexin knock out mice
The Journal of Neuroscience, 2013Co-Authors: Christian R Burgess, Takatoshi Mochizuki, Yo Oishi, John H Peever, Thomas E ScammellAbstract:Narcolepsy is characterized by excessive sleepiness and Cataplexy, sudden episodes of muscle weakness during waking that are thought to be an intrusion of rapid eye movement sleep muscle atonia into wakefulness. One of the most striking aspects of Cataplexy is that it is often triggered by strong, generally positive emotions, but little is known about the neural pathways through which positive emotions trigger muscle atonia. We hypothesized that the amygdala is functionally important for Cataplexy because the amygdala has a role in processing emotional stimuli and it contains neurons that are active during Cataplexy. Using anterograde and retrograde tracing in mice, we found that GABAergic neurons in the central nucleus of the amygdala heavily innervate neurons that maintain waking muscle tone such as those in the ventrolateral periaqueductal gray, lateral pontine tegmentum, locus ceruleus, and dorsal raphe. We then found that bilateral, excitotoxic lesions of the amygdala markedly reduced Cataplexy in orexin knock-out mice, a model of narcolepsy. These lesions did not alter basic sleep–wake behavior but substantially reduced the triggering of Cataplexy. Lesions also reduced the Cataplexy events triggered by conditions associated with high arousal and positive emotions (i.e., wheel running and chocolate). These observations demonstrate that the amygdala is a functionally important part of the circuitry underlying Cataplexy and suggest that increased amygdala activity in response to emotional stimuli could directly trigger Cataplexy by inhibiting brainstem regions that suppress muscle atonia.
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Feeding-elicited Cataplexy in orexin knockout mice.
Neuroscience, 2009Co-Authors: Erika L. Clark, Thomas E Scammell, Christian R. Baumann, Georgina Cano, Takatoshi MochizukiAbstract:Mice lacking orexin/hypocretin signaling have sudden episodes of atonia and paralysis during active wakefulness. These events strongly resemble Cataplexy, episodes of sudden muscle weakness triggered by strong positive emotions in people with narcolepsy, but it remains unknown whether murine Cataplexy is triggered by positive emotions. To determine whether positive emotions elicit murine Cataplexy, we placed orexin knockout (KO) mice on a scheduled feeding protocol with regular or highly palatable food. Baseline sleep/wake behavior was recorded with ad libitum regular chow. Mice were then placed on a scheduled feeding protocol in which they received 60% of their normal amount of chow 3 h after dark onset for the next 10 days. Wild-type and KO mice rapidly entrained to scheduled feeding with regular chow, with more wake and locomotor activity prior to the feeding time. On day 10 of scheduled feeding, orexin KO mice had slightly more Cataplexy during the food-anticipation period and more Cataplexy in the second half of the dark period, when they may have been foraging for residual food. To test whether more palatable food increases Cataplexy, mice were then switched to scheduled feeding with an isocaloric amount of Froot Loops, a food often used as a reward in behavioral studies. With this highly palatable food, orexin KO mice had much more Cataplexy during the food-anticipation period and throughout the dark period. The increase in Cataplexy with scheduled feeding, especially with highly palatable food, suggests that positive emotions may trigger Cataplexy in mice, just as in people with narcolepsy. Establishing this connection helps validate orexin KO mice as an excellent model of human narcolepsy and provides an opportunity to better understand the mechanisms that trigger Cataplexy.
Yves Dauvilliers - One of the best experts on this subject based on the ideXlab platform.
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persistence of deep tendon reflexes during partial Cataplexy
Sleep Medicine, 2018Co-Authors: Lucie Barateau, Fabio Pizza, Regis Lopez, Elena Antelmi, Giuseppe Plazzi, Yves DauvilliersAbstract:Abstract Objective Deep-tendon reflexes are abolished during generalized Cataplexy, but whether this is the case in partial Cataplexy currently remains unknown. Partial Cataplexy may mimic other neurologic/psychiatric phenomena, and knowledge of the reflexes status may provide information for differential diagnosis. We assessed whether deep-tendon reflexes are persistent during partial Cataplexy. Methods Five drug-free patients with typical diagnoses of narcolepsy and clear-cut partial Cataplexy were diagnosed in Reference Narcolepsy Centers in France and Italy. Biceps and patellar reflexes were elicited by physicians in charge and video-documented during Cataplexy. Reflexes were assessed several times for each patient in different conditions and for various localizations of Cataplexy. Results The absence of tendon reflexes and complete loss of muscle tone during generalized Cataplexy was confirmed, but the persistence of those reflexes during several partial cataplectic attacks at different ages, gender, localization of Cataplexy (upper limbs, face) and reflexes (biceps, patellar) in drug-naive or withdrawal conditions was documented. Conclusion The persistence of tendon reflexes during several partial Cataplexy episodes contrasts with their absence during generalized Cataplexy. This discovery has clinical implications: the persistence of tendon reflexes does not rule out Cataplexy diagnosis for partial attacks, whereas their transient abolishment or persistence during generalized attacks indicates Cataplexy or pseudoCataplexy, respectively.
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Cataplexy clinical aspects pathophysiology and management strategy
Nature Reviews Neurology, 2014Co-Authors: Yves Dauvilliers, Regis Lopez, Jerry M Siegel, Zoltan A Torontali, John H PeeverAbstract:Cataplexy is the pathognomonic symptom of narcolepsy, a condition that is caused by depletion of orexin neurons. Cataplectic attacks are characterized by sudden involuntary muscle weakness or paralysis, often triggered by strong emotions. In this article, Dauvilliers et al. review the latest understanding of potential mechanisms underlying narcolepsy and Cataplexy, the utility of experimental models, and the need for early diagnosis and therapy.
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Cataplexy—clinical aspects, pathophysiology and management strategy
Nature Reviews Neurology, 2014Co-Authors: Yves Dauvilliers, Regis Lopez, Jerry M Siegel, Zoltan A Torontali, John H PeeverAbstract:Cataplexy is the pathognomonic symptom of narcolepsy, a condition that is caused by depletion of orexin neurons. Cataplectic attacks are characterized by sudden involuntary muscle weakness or paralysis, often triggered by strong emotions. In this article, Dauvilliers et al. review the latest understanding of potential mechanisms underlying narcolepsy and Cataplexy, the utility of experimental models, and the need for early diagnosis and therapy.
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pharmacotherapy options for Cataplexy
Expert Opinion on Pharmacotherapy, 2013Co-Authors: Regis Lopez, Yves DauvilliersAbstract:Introduction: Narcolepsy with Cataplexy is a rare disabling sleep disorder characterized by two major symptoms: excessive daytime sleepiness and Cataplexy characterized by a sudden bilateral loss of voluntary muscular tone triggered by strong positive emotional factors. Pathophysiological studies have shown that the disease is caused by the early loss of hypothalamic hypocretin neurons. Areas covered: Following a literature search on PubMed using “narcolepsy,” “Cataplexy,” “treatment,” “medication,” and “drug” as keywords, we critically analyzed and reviewed current evidence about optimal management of Cataplexy in humans. The management of Cataplexy has evolved over the past few years with the widespread use of antidepressants, especially those with adrenergic uptake inhibitor properties and gamma-hydroxybutyrate (sodium oxybate). Expert opinion: Based on class 1 evidence studies, first-line pharmacological treatment of Cataplexy should be sodium oxybate. Second-line treatment should be antidepressants w...
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Facial expression recognition and emotional regulation in narcolepsy with Cataplexy
Journal of Sleep Research, 2012Co-Authors: Sophie Bayard, Muriel Croisier Langenier, Yves DauvilliersAbstract:SUMMARY Cataplexy is pathognomonic of narcolepsy with Cataplexy, and defined by a transient loss of muscle tone triggered by strong emotions. Recent researches suggest abnormal amygdala function in narcolepsy with Cataplexy. Emotion treatment and emotional regulation strategies are complex functions involving cortical and limbic structures, like the amygdala. As the amygdala has been shown to play a role in facial emotion recognition, we tested the hypothesis that patients with narcolepsy with Cataplexy would have impaired recognition of facial emotional expressions compared with patients affected with central hypersomnia without Cataplexy and healthy controls. We also aimed to determine whether Cataplexy modulates emotional regulation strategies. Emotional intensity, arousal and valence ratings on Ekman faces displaying happiness, surprise, fear, anger, disgust, sadness and neutral expressions of 21 drug-free patients with narcolepsy with Cataplexy were compared with 23 drug-free sex-, age- and intellectual level-matched adult patients with hypersomnia without Cataplexy and 21 healthy controls. All participants underwent polysomnography recording and multiple sleep latency tests, and completed depression, anxiety and emotional regulation questionnaires. Performance of patients with narcolepsy with Cataplexy did not differ from patients with hypersomnia without Cataplexy or healthy controls on both intensity rating of each emotion on its prototypical label and mean ratings for valence and arousal. Moreover, patients with narcolepsy with Cataplexy did not use different emotional regulation strategies. The level of depressive and anxious symptoms in narcolepsy with Cataplexy did not differ from the other groups. Our results demonstrate that narcolepsy with Cataplexy accurately perceives and discriminates facial emotions, and regulates emotions normally. The absence of alteration of perceived affective valence remains a major clinical interest in narcolepsy with Cataplexy, and it supports the argument for optimal behaviour and social functioning in narcolepsy with Cataplexy.