cataplexy: Topics by Science.gov

Sample records for cataplexy

Persistence of deep-tendon reflexes during partial cataplexy.

PubMed

Barateau, Lucie; Pizza, Fabio; Lopez, Régis; Antelmi, Elena; Plazzi, Giuseppe; Dauvilliers, Yves

2018-05-01

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. 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. 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. 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. Copyright © 2018. Published by Elsevier B.V.
Facial expression recognition and emotional regulation in narcolepsy with cataplexy.

PubMed

Bayard, Sophie; Croisier Langenier, Muriel; Dauvilliers, Yves

2013-04-01

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. © 2012 European Sleep Research Society.
Role of the medial prefrontal cortex in cataplexy.

PubMed

Oishi, Yo; Williams, Rhiannan H; Agostinelli, Lindsay; Arrigoni, Elda; Fuller, Patrick M; Mochizuki, Takatoshi; Saper, Clifford B; Scammell, Thomas E

2013-06-05

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.
Role of the medial prefrontal cortex in cataplexy

PubMed Central

Oishi, Yo; Williams, Rhiannan H.; Agostinelli, Lindsay; Arrigoni, Elda; Fuller, Patrick M.; Mochizuki, Takatoshi; Saper, Clifford B.; Scammell, Thomas E.

2013-01-01

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 knockout 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. PMID:23739971
A Consensus Definition of Cataplexy in Mouse Models of Narcolepsy

PubMed Central

Scammell, Thomas E.; Willie, Jon T.; Guilleminault, Christian; Siegel, Jerome M.

2009-01-01

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. PMID:19189786
A consensus definition of cataplexy in mouse models of narcolepsy.

PubMed

Scammell, Thomas E; Willie, Jon T; Guilleminault, Christian; Siegel, Jerome M

2009-01-01

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.
GABAergic Neurons of the Central Amygdala Promote Cataplexy

PubMed Central

Agostinelli, Lindsay J.; Lowell, Bradford B.

2017-01-01

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. PMID:28235898
GABAergic Neurons of the Central Amygdala Promote Cataplexy.

PubMed

Mahoney, Carrie E; Agostinelli, Lindsay J; Brooks, Jessica N K; Lowell, Bradford B; Scammell, Thomas E

2017-04-12

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. Copyright © 2017 the authors 0270-6474/17/373995-12$15.00/0.
An Interesting Case of Late Age at Onset of Narcolepsy with Cataplexy

PubMed Central

Krishnamurthy, Venkatesh B.; Nallamothu, Vijaya; Singareddy, Ravi

2014-01-01

The usual age at onset of narcolepsy with cataplexy is in the second or third decade. In cases with late onset narcolepsy with cataplexy, symptoms are usually mild with relatively less severe daytime sleepiness and less frequent cataplexy. Here we present a case of narcolepsy with cataplexy with onset of symptoms around sixty years of age. This case is unique, with severe daytime sleepiness both by subjective report as well as on objective Multiple Sleep Latency Test and having multiple cataplexy episodes in a day. Citation: Krishnamurthy VB; Nallamothu V; Singareddy R. An interesting case of late age at onset of narcolepsy with cataplexy. J Clin Sleep Med 2014;10(2):203-205. PMID:24533004
Sodium oxybate for cataplexy.

PubMed

Lemon, Michael D; Strain, Joe D; Farver, Debra K

2006-03-01

To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, precautions, dosing recommendations, and patient counseling of sodium oxybate for the treatment of cataplexy in patients with narcolepsy. OVID and PubMed databases were searched (1966-January 2006) using the key words sodium oxybate, gamma-hydroxybutyrate, narcolepsy, and cataplexy. Only English-language articles were selected. All information on sodium oxybate related to narcolepsy and cataplexy was considered. Study selection included human trials evaluating safety and efficacy of sodium oxybate for the treatment of cataplexy. Sodium oxybate is approved by the Food and Drug Administration for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. In placebo-controlled trials, sodium oxybate demonstrated efficacy in reducing the number of cataplexy attacks. The dosing regimen includes a split dose given at bedtime and 2.5-4 hours later due to its short elimination half-life. The drug is generally well tolerated, with headache, nausea, dizziness, pain, and somnolence being the most common adverse events. Sodium oxybate is safe and effective for the treatment of cataplexy. Potential disadvantages include a multiple dosing regimen, abuse potential, cost, and a closed distribution system. Potential advantages demonstrated in clinical trials include significant decreases in the number of weekly cataplexy attacks, improvement in daytime sleepiness, and improvement in the Clinical Global Impression of Change score and nighttime awakenings. Overall, sodium oxybate provides a new option for the treatment of cataplexy.
Amygdala Lesions Reduce Cataplexy in Orexin KO mice

PubMed Central

Burgess, C.R.; Oishi, Y.; Mochizuki, T.; Peever, J.H.; Scammell, T.E.

2013-01-01

Narcolepsy is characterized by excessive sleepiness and cataplexy, sudden episodes of muscle weakness during waking that are thought to be an intrusion of REM 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 grey, lateral pontine tegmentum, locus coeruleus, and dorsal raphe. We then found that bilateral, excitotoxic lesions of the amygdala markedly reduced cataplexy in orexin knockout 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. PMID:23739970
Amygdala lesions reduce cataplexy in orexin knock-out mice.

PubMed

Burgess, Christian R; Oishi, Yo; Mochizuki, Takatoshi; Peever, John H; Scammell, Thomas E

2013-06-05

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.
Complex Movement Disorders at Disease Onset in Childhood Narcolepsy with Cataplexy

ERIC Educational Resources Information Center

Plazzi, Giuseppe; Pizza, Fabio; Palaia, Vincenzo; Franceschini, Christian; Poli, Francesca; Moghadam, Keivan K.; Cortelli, Pietro; Nobili, Lino; Bruni, Oliviero; Dauvilliers, Yves; Lin, Ling; Edwards, Mark J.; Mignot, Emmanuel; Bhatia, Kailash P.

2011-01-01

Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of…
Feeding-elicited cataplexy in orexin knockout mice

PubMed Central

Clark, Erika L.; Baumann, Christian R.; Cano, Georgina; Scammell, Thomas E.; Mochizuki, Takatoshi

2009-01-01

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 lib regular chow. Mice were then placed on a scheduled feeding protocol in which they received 60% of their normal amount of chow 3 hr 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. PMID:19362119
Insufficient non-REM sleep intensity in narcolepsy-cataplexy.

PubMed

Khatami, Ramin; Landolt, Hans-Peter; Achermann, Peter; Rétey, Julia V; Werth, Esther; Mathis, Johannes; Bassetti, Claudio L

2007-08-01

To compare electroencephalogram (EEG) dynamics during nocturnal sleep in patients with narcolepsy-cataplexy and healthy controls. Fragmented nocturnal sleep is a prominent feature and contributes to excessive daytime sleepiness in narcolepsy-cataplexy. Only 3 studies have addressed changes in homeostatic sleep regulation as a possible mechanism underlying nocturnal sleep fragmentation in narcolepsy-cataplexy. Baseline sleep of 11 drug-naive patients with narcolepsy-cataplexy (19-37 years) and 11 matched controls (18-41 years) was polysomnographically recorded. The EEG was subjected to spectral analysis. None, baseline condition. All patients with narcolepsy-cataplexy but no control subjects showed a sleep-onset rapid eye movement (REM) episode. Non-REM (NREM)-REM sleep cycles were longer in patients with narcolepsy-cataplexy than in controls (P = 0.04). Mean slow-wave activity declined in both groups across the first 3 NREM sleep episodes (P<0.001). The rate of decline, however, appeared to be steeper in patients with narcolepsy-cataplexy (time constant: narcolepsy-cataplexy 51.1 +/- 23.8 minutes [mean +/- SEM], 95% confidence interval [CI]: 33.4-108.8 minutes) than in controls (169.4 +/- 81.5 minutes, 95% CI: 110.9-357.6 minutes) as concluded from nonoverlapping 95% confidence interval of the time constants. The steeper decline of SWA in narcolepsy-cataplexy compared to controls was related to an impaired build-up of slow-wave activity in the second cycle. Sleep in the second cycle was interrupted in patients with narcolepsy-cataplexy, when compared with controls, by an increased number (P = 0.01) and longer duration (P = 0.01) of short wake episodes. Insufficient NREM sleep intensity is associated with nonconsolidated nocturnal sleep in narcolepsy-cataplexy. The inability to consolidate sleep manifests itself when NREM sleep intensity has decayed below a certain level and is reflected in an altered time course of slow-wave activity across NREM sleep episodes.
Treatment with venlafaxine in six cases of children with narcolepsy and with cataplexy and hypnagogic hallucinations.

PubMed

Møller, Lene Ruge; Østergaard, John R

2009-04-01

Narcolepsy with cataplexy is a chronic neuropsychiatric disorder associated with inappropriate control of rapid eye movement (REM) sleep. The main symptoms are excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and disturbed nocturnal sleep. Cataplexy is marked by episodes of muscular weakness and may cause the patient to collapse to the ground. So far, pharmacotherapy of cataplexy and hypnagogic hallucinations has been predominantly based on tricyclic antidepressants. Recently, new drugs that block the reuptake of norepineprine and serotonin (e.g., venlafaxine) have been suggested as first-line treatment. These drugs have become our choice in treating children with cataplexy and nightmares as a symptom in narcolepsy. We describe clinical case reports of venlafaxine treatment in 6 children aged 7-12 years old when diagnosed with narcolepsy-cataplexy. In 2 cases with up to 50 daily cataplectic attacks, an initial effect of 37.5 mg of venlafaxine was initially observed. However, during the first year, the dose had to be increased to 112.5 mg daily to avoid cataplexy. A third patient with partial cataplexy was treated with 75 mg of venlafaxine daily. In 2 cases, hypnagogic hallucinations, described by the patients as nightmares, were the most troubling symptom and were successfully treated with only 37.5 mg of venlafaxine daily. Side effects included an increase of disturbed nocturnal sleep when venlafaxine was taken after 2:00 p.m. No major aggressive or suicidal thoughts and no raised blood pressure were recorded. Venlafaxine has proven to be an effective treatment of cataplexy and hypnagogic hallucinations in 6 children with narcolepsy. No severe side effects were observed.
The distinguishing motor features of cataplexy: a study from video-recorded attacks.

PubMed

Pizza, Fabio; Antelmi, Elena; Vandi, Stefano; Meletti, Stefano; Erro, Roberto; Baumann, Christian R; Bhatia, Kailash P; Dauvilliers, Yves; Edwards, Mark J; Iranzo, Alex; Overeem, Sebastiaan; Tinazzi, Michele; Liguori, Rocco; Plazzi, Giuseppe

2018-05-01

To describe the motor pattern of cataplexy and to determine its phenomenological differences from pseudocataplexy in the differential diagnosis of episodic falls. We selected 30 video-recorded cataplexy and 21 pseudocataplexy attacks in 17 and 10 patients evaluated for suspected narcolepsy and with final diagnosis of narcolepsy type 1 and conversion disorder, respectively, together with self-reported attacks features, and asked expert neurologists to blindly evaluate the motor features of the attacks. Video documented and self-reported attack features of cataplexy and pseudocataplexy were contrasted. Video-recorded cataplexy can be positively differentiated from pseudocataplexy by the occurrence of facial hypotonia (ptosis, mouth opening, tongue protrusion) intermingled by jerks and grimaces abruptly interrupting laughter behavior (i.e. smile, facial expression) and postural control (head drops, trunk fall) under clear emotional trigger. Facial involvement is present in both partial and generalized cataplexy. Conversely, generalized pseudocataplexy is associated with persistence of deep tendon reflexes during the attack. Self-reported features confirmed the important role of positive emotions (laughter, telling a joke) in triggering the attacks, as well as the more frequent occurrence of partial body involvement in cataplexy compared with pseudocataplexy. Cataplexy is characterized by abrupt facial involvement during laughter behavior. Video recording of suspected cataplexy attacks allows the identification of positive clinical signs useful for diagnosis and, possibly in the future, for severity assessment.
Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy.

PubMed

Burgess, Christian R; Tse, Gavin; Gillis, Lauren; Peever, John H

2010-10-01

To determine if the dopaminergic system modulates cataplexy, sleep attacks and sleep-wake behavior in narcoleptic mice. Hypocretin/orexin knockout (i.e., narcoleptic) and wild-type mice were administered amphetamine and specific dopamine receptor modulators to determine their effects on sleep, cataplexy and sleep attacks. Hypocretin knockout (n = 17) and wild-type mice (n = 21). Cataplexy, sleep attacks and sleep-wake behavior were identified using electroencephalogram, electromyogram and videography. These behaviors were monitored for 4 hours after an i.p. injection of saline, amphetamine and specific dopamine receptor modulators (D1- and D2-like receptor modulators). Amphetamine (2 mg/kg), which increases brain dopamine levels, decreased sleep attacks and cataplexy by 61% and 67%, suggesting that dopamine transmission modulates such behaviors. Dopamine receptor modulation also had powerful effects on sleep attacks and cataplexy. Activation (SKF 38393; 20 mg/kg) and blockade (SCH 23390; 1 mg/kg) of D1-like receptors decreased and increased sleep attacks by 77% and 88%, without affecting cataplexy. Pharmacological activation of D2-like receptors (quinpirole; 0.5 mg/kg) increased cataplectic attacks by 172% and blockade of these receptors (eticlopride; 1 mg/kg) potently suppressed them by 97%. Manipulation of D2-like receptors did not affect sleep attacks. We show that the dopaminergic system plays a role in regulating both cataplexy and sleep attacks in narcoleptic mice. We found that cataplexy is modulated by a D2-like receptor mechanism, whereas dopamine modulates sleep attacks by a D1-like receptor mechanism. These results support a role for the dopamine system in regulating sleep attacks and cataplexy in a murine model of narcolepsy.
Challenges in Diagnosing Narcolepsy without Cataplexy: A Consensus Statement

PubMed Central

Baumann, Christian R.; Mignot, Emmanuel; Lammers, Gert Jan; Overeem, Sebastiaan; Arnulf, Isabelle; Rye, David; Dauvilliers, Yves; Honda, Makoto; Owens, Judith A.; Plazzi, Giuseppe; Scammell, Thomas E.

2014-01-01

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 (≤ 15 minutes) on polysomnography can aid in the diagnosis of narcolepsy without 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. PMID:24882898
Challenges in diagnosing narcolepsy without cataplexy: a consensus statement.

PubMed

Baumann, Christian R; Mignot, Emmanuel; Lammers, Gert Jan; Overeem, Sebastiaan; Arnulf, Isabelle; Rye, David; Dauvilliers, Yves; Honda, Makoto; Owens, Judith A; Plazzi, Giuseppe; Scammell, Thomas E

2014-06-01

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. 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. 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 (≤ 15 minutes) on polysomnography can aid in the diagnosis of narcolepsy without 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.

Narcolepsy and cataplexy: a pediatric case report.

PubMed

Savaş, Tülin; Erol, Ilknur; Saygı, Semra; Habeşoğlu, Mehmet Ali

2016-12-01

Narcolepsy is characterized by excessive sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis during the rapid eye movement period of sleep. Herein, we present a boy aged eight years who was diagnosed as having narcolepsy and cataplexy about thirteen months after his first presentation. He was admitted with symptoms of daytime sleepiness. In the follow-up, cataplexy in the form of head dropping attacks developed seven months after the first admission. The patient was investigated for different prediagnoses and was eventually diagnosed as having narcolepsy and cataplexy through polysomnography and multiple sleep latency tests thirteen months after the first presentation. He is being followed up and is under drug therapy; his symptoms have improved substantially.
Complex movement disorders at disease onset in childhood narcolepsy with cataplexy

PubMed Central

Pizza, Fabio; Palaia, Vincenzo; Franceschini, Christian; Poli, Francesca; Moghadam, Keivan K.; Cortelli, Pietro; Nobili, Lino; Bruni, Oliviero; Dauvilliers, Yves; Lin, Ling; Edwards, Mark J.; Mignot, Emmanuel; Bhatia, Kailash P.

2011-01-01

Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of hypocretin-producing neurons in the hypothalamus of likely autoimmune aetiology. Noting that children with narcolepsy often display complex abnormal motor behaviours close to disease onset that do not meet the classical definition of cataplexy, we systematically analysed motor features in 39 children with narcolepsy with cataplexy in comparison with 25 age- and sex-matched healthy controls. We found that patients with narcolepsy with cataplexy displayed a complex array of ‘negative’ (hypotonia) and ‘active’ (ranging from perioral movements to dyskinetic–dystonic movements or stereotypies) motor disturbances. ‘Active’ and ‘negative’ motor scores correlated positively with the presence of hypotonic features at neurological examination and negatively with disease duration, whereas ‘negative’ motor scores also correlated negatively with age at disease onset. These observations suggest that paediatric narcolepsy with cataplexy often co-occurs with a complex movement disorder at disease onset, a phenomenon that may vanish later in the course of the disease. Further studies are warranted to assess clinical course and whether the associated movement disorder is also caused by hypocretin deficiency or by additional neurochemical abnormalities. PMID:21930661
Reward-Seeking Behavior in Human Narcolepsy

PubMed Central

Dimitrova, Alexandra; Fronczek, Rolf; Van der Ploeg, Janneke; Scammell, Thomas; Gautam, Shiva; Pascual-Leone, Alvaro; Lammers, Gert Jan

2011-01-01

Study Objectives: The hypocretin system enhances signaling in the mesolimbic pathways regulating reward processing and addiction. Because individuals with narcolepsy with cataplexy have low hypocretin levels, we hypothesized that they may be less prone to risk- and reward-seeking behaviors, including substance abuse. Design: Endpoints were performance on an array of psychometric tests (including the Eysenck Impulsiveness Scale, the Zuckerman Sensation Seeking Scale, the Gormally Binge Eating Scale, and the Beck Depression and Anxiety Inventory) and on the Balloon Analogue Risk Task (BART). Setting: Tertiary narcolepsy referral centers in Leiden (The Netherlands) and Boston (USA). Patients: Subjects with narcolepsy with cataplexy (n = 30), narcolepsy without cataplexy (n = 15), and controls (n = 32) matched for age, sex, and smoking behavior. Interventions: None. Measurements and Results: There was no difference in risk-taking behavior between narcolepsy with or without cataplexy and the control group, as measured using the BART and the array of questionnaires. However, subjects in the narcolepsy with cataplexy group had significantly higher scores on the Eysenck Impulsiveness Scale (p < 0.05), with 10.0% categorized as impulsive, compared to 6.7% of the narcolepsy without cataplexy group and none of the controls. Narcoleptics with cataplexy also scored significantly higher than controls on the Binge Eating Scale (p < 0.05), with moderate or severe binge eating in 23%. On the depression and anxiety scales, all narcolepsy patients, especially those with cataplexy, scored significantly higher than controls. Conclusions: We found that narcoleptics with or without cataplexy generally have normal risk-taking behavior, but narcoleptics with cataplexy were more impulsive and more prone to binge eating than patients without cataplexy and controls. Our findings shed new light on the relation between sleepiness and impulsiveness. Furthermore, rates of depression and anxiety were higher in all narcoleptic subjects. However, using the current methods, no evidence could be found to support the hypothesis that hypocretin deficiency would affect reward-processing in humans. Citation: Dimitrova A; Fronczek R; Van der Ploeg J; Scammell T; Gautam S; Pascual-Leone A; Lammers GJ. Reward-seeking behavior in human narcolepsy. J Clin Sleep Med 2011;7(3):293-300. PMID:21677900
Time to Response with Sodium Oxybate for the Treatment of Excessive Daytime Sleepiness and Cataplexy in Patients with Narcolepsy

PubMed Central

Bogan, Richard K.; Roth, Thomas; Schwartz, Jonathan; Miloslavsky, Maja

2015-01-01

Study Objectives: This post hoc analysis evaluated the time to response that can be expected with sodium oxybate (SXB) for treatment of excessive daytime sleepiness (EDS) and cataplexy in patients with narcolepsy. Methods: Data were from a 4-week, double-blind, randomized, placebo-controlled trial (GHB-2; N = 136) of oral SXB 3 g, 6 g, and 9 g nightly, and its 12-month open-label extension (GHB-3). Two response definitions were utilized: ≥ 20% improvement in Epworth Sleepiness Scale (ESS) score (EDS responders), and ≥ 50% reduction in weekly cataplexy attacks (cataplexy responders). These thresholds were previously determined to be clinically relevant based on analysis of the relationship of Clinical Global Impression of Change with ESS and number of cataplexy attacks. Kaplan-Meier curves and median times to first response, based on above criteria, and to maximum response were estimated. Results: Among 86 patients randomized to SXB in GHB-2 and continued into GHB-3, 77.6% and 90.7% were EDS and cataplexy responders, respectively. The median (95% CI) times to first response were 37 (31–50) days for EDS and 25 (17–29) days for cataplexy, and median times to maximum response were 106 (85–164) days for EDS and 213 (94–279) days for cataplexy. GHB-3 results among 31 patients initially randomized to placebo were consistent with those treated with SXB throughout, but with longer times to maximum response. Conclusions: Response onset, assessed as clinically meaningful improvements in EDS and cataplexy, was observed in most patients within 2 months; a longer period is needed to achieve maximum response. Clinicians should recognize that time to initial and maximum response may take weeks to months. Citation: Bogan RK, Roth T, Schwartz J, Miloslavsky M. Time to response with sodium oxybate for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. J Clin Sleep Med 2015;11(4):427–432. PMID:25580605
Tolerance and Efficacy of Sodium Oxybate in Childhood Narcolepsy with Cataplexy: A Retrospective Study

PubMed Central

Lecendreux, Michel; Poli, Francesca; Oudiette, Delphine; Benazzouz, Fatima; Donjacour, Claire E.H.M; Franceschini, Christian; Finotti, Elena; Pizza, Fabio; Bruni, Oliviero; Plazzi, Giuseppe

2012-01-01

Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness, irresistible sleep episodes, and sudden loss of muscle tone (cataplexy) mostly triggered by emotions. Narcolepsy with cataplexy is a disabling lifelong disorder frequently arising during childhood. Pediatric narcolepsy often results in severe learning and social impairment. Improving awareness about this condition increases early diagnosis and may allow patients to rapidly access adequate treatments, including pharmacotherapy and/or non-medication-based approaches. Even though children currently undergo pharmacotherapy, data about safety and efficacy in the pediatric population are scarce. Lacking international guidelines as well as drugs registered for childhood narcolepsy with cataplexy, physicians have no other alternative but to prescribe in an off-label manner medications identical to those recommended for adults. We retrospectively evaluated 27 children ranging from 6 to 16 years old, suffering from narcolepsy with cataplexy, who had been treated with off-label sodium oxybate and had been followed in a clinical setting. Throughout a semi-structured interview, we documented the good efficacy and tolerability of sodium oxybate in the majority of the patients. This study constitutes a preliminary step towards a further randomized controlled trial in childhood narcolepsy with cataplexy. Citation: Lecendreux M; Poli F; Oudiette D; Benazzouz F; Donjacour CEHM; Franceschini C; Finotti E; Pizza F; Bruni O; Plazzi G. Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy: a retrospective study. SLEEP 2012;35(5):709-711. PMID:22547897
Clinical and polysomnographic course of childhood narcolepsy with cataplexy.

PubMed

Pizza, Fabio; Franceschini, Christian; Peltola, Hanna; Vandi, Stefano; Finotti, Elena; Ingravallo, Francesca; Nobili, Lino; Bruni, Oliviero; Lin, Ling; Edwards, Mark J; Partinen, Markku; Dauvilliers, Yves; Mignot, Emmanuel; Bhatia, Kailash P; Plazzi, Giuseppe

2013-12-01

Our aim was to investigate the natural evolution of cataplexy and polysomnographic features in untreated children with narcolepsy with cataplexy. To this end, clinical, polysomnographic, and cataplexy-video assessments were performed at diagnosis (mean age of 10 ± 3 and disease duration of 1 ± 1 years) and after a median follow-up of 3 years from symptom onset (mean age of 12 ± 4 years) in 21 children with narcolepsy with cataplexy and hypocretin 1 deficiency (tested in 19 subjects). Video assessment was also performed in two control groups matched for age and sex at first evaluation and follow-up and was blindly scored for presence of hypotonic (negative) and active movements. Patients' data at diagnosis and at follow-up were contrasted, compared with controls, and related with age and disease duration. At diagnosis children with narcolepsy with cataplexy showed an increase of sleep time during the 24 h; at follow-up sleep time and nocturnal sleep latency shortened, in the absence of other polysomnographic or clinical (including body mass index) changes. Hypotonic phenomena and selected facial movements decreased over time and, tested against disease duration and age, appeared as age-dependent. At onset, childhood narcolepsy with cataplexy is characterized by an abrupt increase of total sleep over the 24 h, generalized hypotonia and motor overactivity. With time, the picture of cataplexy evolves into classic presentation (i.e., brief muscle weakness episodes triggered by emotions), whereas total sleep time across the 24 h decreases, returning to more age-appropriate levels.
Clinical and polysomnographic course of childhood narcolepsy with cataplexy

PubMed Central

Pizza, Fabio; Franceschini, Christian; Peltola, Hanna; Vandi, Stefano; Finotti, Elena; Ingravallo, Francesca; Nobili, Lino; Bruni, Oliviero; Lin, Ling; Edwards, Mark J.; Partinen, Markku; Dauvilliers, Yves; Mignot, Emmanuel; Bhatia, Kailash P.

2013-01-01

Our aim was to investigate the natural evolution of cataplexy and polysomnographic features in untreated children with narcolepsy with cataplexy. To this end, clinical, polysomnographic, and cataplexy-video assessments were performed at diagnosis (mean age of 10 ± 3 and disease duration of 1 ± 1 years) and after a median follow-up of 3 years from symptom onset (mean age of 12 ± 4 years) in 21 children with narcolepsy with cataplexy and hypocretin 1 deficiency (tested in 19 subjects). Video assessment was also performed in two control groups matched for age and sex at first evaluation and follow-up and was blindly scored for presence of hypotonic (negative) and active movements. Patients’ data at diagnosis and at follow-up were contrasted, compared with controls, and related with age and disease duration. At diagnosis children with narcolepsy with cataplexy showed an increase of sleep time during the 24 h; at follow-up sleep time and nocturnal sleep latency shortened, in the absence of other polysomnographic or clinical (including body mass index) changes. Hypotonic phenomena and selected facial movements decreased over time and, tested against disease duration and age, appeared as age-dependent. At onset, childhood narcolepsy with cataplexy is characterized by an abrupt increase of total sleep over the 24 h, generalized hypotonia and motor overactivity. With time, the picture of cataplexy evolves into classic presentation (i.e. brief muscle weakness episodes triggered by emotions), whereas total sleep time across the 24 h decreases, returning to more age-appropriate levels. PMID:24142146
Cataplexy leading to the diagnosis of Niemann-Pick disease type C.

PubMed

Smit, Liesbeth S; Lammers, Gert Jan; Catsman-Berrevoets, Coriene E

2006-07-01

Cataplexy in childhood is a rare and often misdiagnosed symptom. It is described as a brief episode of bilateral loss of muscle tone with intact consciousness, triggered by a variety of strong emotions and in particular with unexpected laughter. This report presents a 9-year old male with progressive cerebellar and pyramidal symptoms and a cognitive decline since the age of 4. His recently developed "drop attacks" on laughter were recognized as cataplexy and led to the diagnosis of Niemann-Pick type C disease. With biochemical studies this diagnosis, a lysosomal storage disease, was confirmed. With cataplexy narcolepsy, Niemann-Pick type C disease, Norrie disease, Prader-Willi syndrome, and Coffin-Lowry syndrome are associated disorders. Recognition of cataplexy in children with concomitant neurologic symptoms may lead to an early and straight diagnosis of one of these disorders.
Isolated Cataplexy and REM Sleep Behavior Disorder After Pontine Stroke

PubMed Central

Reynolds, Thomas Q.; Roy, Asim

2011-01-01

Cataplexy is a complex neurologic phenomenon during wakefulness probably resulting from impairment of pontine and hypothalamic control over muscle tone. REM sleep behavior disorder (RSBD) is characterized by the presence of REM sleep without atonia manifesting clinically as disruptive or injurious behaviors. We present here a patient with both cataplexy and RSBD following pontine encephalomalacia. The clinical presentation provides insight into the possible pathobiology of both waking and sleeping disorders of REM sleep regulation. Citation: Reynolds TQ; Roy A. Isolated cataplexy and REM sleep behavior disorder after pontine stroke. J Clin Sleep Med 2011;7(2):211-213. PMID:21509338
Prevalence of the HLA-DQB1*0602 allele in narcolepsy and idiopathic hypersomnia patients seen at a sleep disorders outpatient unit in São Paulo.

PubMed

Coelho, Fernando Morgadinho Santos; Pradella-Hallinan, Márcia; Predazzoli Neto, Mario; Bittencourt, Lia Rita Azeredo; Tufik, Sérgio

2009-03-01

Narcolepsy (with and without cataplexy) and idiopathic hypersomnia, are disorders with common features but with different HLA-DQB1*0602 allele prevalence. The present study describes the prevalence of HLA-DQB1*0602 allele in narcoleptics with and without cataplexy and in patients with idiopathic hypersomnia. Subjects comprised 68 patients who were diagnosed for narcolepsy or idiopathic hypersomnia and 23 healthy controls according to the International Classification of Sleep Disorders-2. Subjects comprised 43 patients with narcolepsy and cataplexy, 11 patients with narcolepsy but without cataplexy, 14 patients with idiopathic hypersomnia and 23 healthy controls. Genotyping of HLA-DQB1*0602 allele was performed for all subjects. The prevalence of the HLA-DQB1*0602 allele was increased in idiopathic hypersomnia and in narcoleptic patients with and without cataplexy when compared to healthy subjects (p = 0.04; p = 0.03 and p < 0.0001, respectively). This finding is in accordance with those of previous studies. The gold standard exam of narcolepsy with cataplexy is Hypocretin-1 dosage, but in patients without cataplexy and idiopathic hypersomnia, there are no specific diagnostic lab findings. The presence of the HLA-DQB1* 0602 allele may be important for the differential diagnosis of situations that resemble those sleep disorders such as secondary changes in sleep structure due to drugs' consumption.
Assessing narcolepsy with cataplexy in children and adolescents: development of a cataplexy diary and the ESS-CHAD

PubMed Central

Wang, Y Grace; Benmedjahed, Khadra; Lambert, Jérémy; Evans, Christopher J; Hwang, Steve; Black, Jed; Johns, Murray W

2017-01-01

Objective The aim of this study was to qualitatively evaluate concepts for incorporation into a daily diary to capture cataplexy frequency and to assess the content validity of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) in pediatric patients with narcolepsy. Patients and methods Face-to-face concept elicitation and cognitive interviews were conducted with children (7–9 years; n=13) and adolescents (10–17 years; n=16) who have narcolepsy with cataplexy, and their parents/caregivers. Results Similarities and differences were noted between narcolepsy concepts described by children and their parents/caregivers, suggesting some different but complementary perspectives; parents may not recognize cataplexy symptoms/triggers as well as children, but parents have greater recognition of the circumstances of falling asleep. Cataplexy diary modifications included changes in definitions and examples of cataplexy, using child-friendly terminology, adding a quantitative question to determine daily frequency, and standardizing the questionnaire for evening administration with self-completion by the child. Modifications were made to ESS-CHAD for child-friendly wording and to ensure that items reflect activities (eating, watching TV/video) and environments (school, bus/car transport) in which children are likely to participate. Two ESS-CHAD versions were proposed: one with a 1-month recall period, for general use, and the other with a recall period of “since your last study visit,” for research, which could be shorter or longer than 1 month (as short as 1 week). Conclusion The cataplexy diary and ESS-CHAD were modified for the assessment of children and adolescents. Further psychometric validation is recommended. These measures are being used in a Phase III, placebo-controlled clinical trial of sodium oxybate in children and adolescents with narcolepsy. PMID:28860883
Running Promotes Wakefulness and Increases Cataplexy in Orexin Knockout Mice

PubMed Central

España, Rodrigo A.; McCormack, Sarah L.; Mochizuki, Takatoshi; Scammell, Thomas E.

2007-01-01

Study Objective: People with narcolepsy and mice lacking orexin/hypocretin have disrupted sleep/wake behavior and reduced physical activity. Our objective was to identify physiologic mechanisms through which orexin deficiency reduces locomotor activity. Design: We examined spontaneous wheel running activity and its relationship to sleep/wake behavior in wild type (WT) and orexin knockout (KO) mice. Additionally, given that physical activity promotes alertness, we also studied whether orexin deficiency reduces the wake-promoting effects of exercise. Measurements and Results: Orexin KO mice ran 42% less than WT mice. Their ability to run appeared normal as they initiated running as often as WT mice and ran at normal speeds. However, their running bouts were considerably shorter, and they often had cataplexy or quick transitions into sleep after running. Wheel running increased the total amount of wakefulness in WT and orexin KO mice similarly, however, KO mice continued to have moderately fragmented sleep/wake behavior. Wheel running also doubled the amount of cataplexy by increasing the probability of transitioning into cataplexy. Conclusions: Orexin KO mice run significantly less than normal, likely due to sleepiness, imminent cataplexy, or a reduced motivation to run. Orexin is not required for the wake-promoting effects of wheel running given that both WT and KO mice had similar increases in wakefulness with running wheels. In addition, the clear increase in cataplexy with wheel running suggests the possibility that positive emotions or reward can trigger murine cataplexy, similar to that seen in people and dogs with narcolepsy. Citation: España RA; McCormack SL; Mochizuki T; Scammell TE. Running promotes wakefulness and increases cataplexy in orexin knockout mice. SLEEP 2007;30(11):1417-1425. PMID:18041476
Narcolepsy-cataplexy and loss of sphincter control.

PubMed Central

Vgontzas, A. N.; Sollenberger, S. E.; Kales, A.; Bixler, E. O.; Vela-Bueno, A.

1996-01-01

We describe the case of a 34-year-old man who presented intermittent faecal incontinence as a manifestation of cataplexy. The patient's sleep history was positive for the full narcoleptic tetrad (sleep attacks, cataplexy, sleep paralysis and hypnagogic hallucinations) while extensive neuropsychiatric work up was negative for any neurologic or psychiatric illness. Repeat polysomnograms (including a polysomnogram with a full seizure montage) were positive for pathologic sleepiness, but there was no evidence of a seizure disorder. The course of the patient's symptomatology and the favourable response of his symptoms to stimulants and imipramine support the theory that his intermittent loss of sphincter control is part of his narcolepsy-cataplexy. PMID:8796217
Running promotes wakefulness and increases cataplexy in orexin knockout mice.

PubMed

España, Rodrigo A; McCormack, Sarah L; Mochizuki, Takatoshi; Scammell, Thomas E

2007-11-01

People with narcolepsy and mice lacking orexin/hypocretin have disrupted sleep/wake behavior and reduced physical activity. Our objective was to identify physiologic mechanisms through which orexin deficiency reduces locomotor activity. We examined spontaneous wheel running activity and its relationship to sleep/wake behavior in wild type (WT) and orexin knockout (KO) mice. Additionally, given that physical activity promotes alertness, we also studied whether orexin deficiency reduces the wake-promoting effects of exercise. Orexin KO mice ran 42% less than WT mice. Their ability to run appeared normal as they initiated running as often as WT mice and ran at normal speeds. However, their running bouts were considerably shorter, and they often had cataplexy or quick transitions into sleep after running. Wheel running increased the total amount of wakefulness in WT and orexin KO mice similarly, however, KO mice continued to have moderately fragmented sleep/wake behavior. Wheel running also doubled the amount of cataplexy by increasing the probability of transitioning into cataplexy. Orexin KO mice run significantly less than normal, likely due to sleepiness, imminent cataplexy, or a reduced motivation to run. Orexin is not required for the wake-promoting effects of wheel running given that both WT and KO mice had similar increases in wakefulness with running wheels. In addition, the clear increase in cataplexy with wheel running suggests the possibility that positive emotions or reward can trigger murine cataplexy, similar to that seen in people and dogs with narcolepsy.
Cataplexy in anxious patients: is subclinical narcolepsy underrecognized in anxiety disorders?

PubMed

Flosnik, Dawn L; Cortese, Bernadette M; Uhde, Thomas W

2009-06-01

Excessive daytime sleepiness, hypnagogic-hypnopompic hallucinations, sleep paralysis, and cataplexy are symptoms associated with narcolepsy. Recent findings indicate that anxiety disorders also are associated with excessive daytime sleepiness, hypnagogic-hypnopompic hallucinations, and sleep paralysis. These observations suggest a possible relationship between anxiety disorders and narcolepsy. Cataplexy is considered the most specific symptom of narcolepsy, but its association with anxiety disorders is unknown. This preliminary investigation examined the prevalence and types of cataplexy in patients with primary anxiety disorders. Sex- and age-matched patients with anxiety disorders (N = 33) and healthy volunteers (N = 33) were assessed on standardized and validated measures of subjective sleep quality (Pittsburgh Sleep Quality Index) and subclinical narcoleptic events in the form of cataplexy (Stanford Center for Narcolepsy Revised Sleep Inventory). Patients were recruited from October 2006 to January 2007 from 2 programs of the Penn State Behavioral Health Clinic. Anxiety disorder patients as a group reported poorer sleep quality and endorsed a larger number of different types of situations (e.g., surprise, embarrassment) associated with cataplectic events. Among anxious patients, 33.3% (11 of 33) endorsed events specific for classic cataplexy, as opposed to 9.1% (3 of 33) of healthy volunteers (chi(2) = 5.80, p = .016). Our preliminary findings suggest that anxiety disorders are associated with increased rates of cataplexy. Future research is indicated to elucidate the relationship between anxiety and narcolepsy, with a particular focus on panic and generalized anxiety disorders. Copyright 2009 Physicians Postgraduate Press, Inc.
Narcolepsy with Cataplexy Mimicry: The Strange Case of Two Sisters

PubMed Central

Pizza, Fabio; Vandi, Stefano; Poli, Francesca; Moghadam, Keivan Kaveh; Franceschini, Christian; Bellucci, Claudia; Cipolli, Carlo; Ingravallo, Francesca; Natalini, Giuliana; Mignot, Emmanuel; Plazzi, Giuseppe

2013-01-01

We report on two sisters, 17 and 12 years of age, with clinical features suggesting narcolepsy with cataplexy (NC): daytime sleepiness, spontaneous and emotionally triggered sudden falls to the ground, and overweight/obesity. MSLT showed borderline sleep latency, with 1 and 0 sleep onset REM periods. HLA typing disclosed the DQB1*0602 allele. Video-polygraphy of the spells ruled out NC diagnosis by demonstrating their easy elicitation by suggestion, with wake EEG, electromyo-graphic persistence of muscle tone, and stable presence of tendon reflexes (i.e., pseudo-cataplexy), together with normal cerebrospinal hypocretin-1 levels. Our cases emphasize the need of a clear depiction of cataplexy pattern at the different ages, the usefulness of examining ictal neurophysiology, and collecting all available disease markers in ambiguous cases. Citation: Pizza F; Vandi S; Poli F; Moghadam KK; Fran-ceschini C; Bellucci C; Cipolli C; Ingravallo F; Natalini G; Mignot E; Plazzi G. Narcolepsy with cataplexy mimicry: the strange case of two sisters. J Clin Sleep Med 2013;9(6):611-612. PMID:23772196
Cataplexy and monoamine oxidase deficiency in Norrie disease.

PubMed

Vossler, D G; Wyler, A R; Wilkus, R J; Gardner-Walker, G; Vlcek, B W

1996-05-01

Norrie disease (ND) is an X-linked recessive disorder causing ocular atrophy, mental retardation, deafness, and dysmorphic features. Virtually absent monoamine oxidase (MAO) type-A and -B activity has been found in some boys with chromosome deletions. We report the coexistence of cataplexy and abnormal REM sleep organization with ND. Three related boys, referred for treatment of medically refractory atonic spells and apneas, underwent extended EEG-video-polysomnographic monitoring. They demonstrated attacks of cataplexy and inappropriate periods of REM sleep during which they were unarousable. One boy also had generalized tonic-clonic seizures. Previous testing revealed that all three have complete ND gene deletions. In all subjects, platelet MAO-B activity was absent, serum serotonin levels were markedly increased, and plasma catecholamine levels were normal. Data from the canine narcolepsy syndrome model implicate abnormal catecholaminergic and cholinergic activities in the pathogenesis of cataplexy. Our findings suggest that abnormal MAO activity or an imbalance between serotonin and other neurotransmitter levels may be involved in the pathogenesis of human cataplexy.
English Translations Of The First Clinical Reports On Narcolepsy And Cataplexy By Westphal And Gélineau In The Late 19th Century, With Commentary

PubMed Central

Schenck, Carlos H.; Bassetti, Claudio L.; Arnulf, Isabelle; Mignot, Emmanuel

2007-01-01

Study Objectives: To publish the first English translations, with commentary, of the original reports describing narcolepsy and cataplexy by Westphal in German (1877) and by Gélineau in French (1880). Methods: A professional translation service translated the 2 reports from either German or French to English, with each translation then being slightly edited by one of the authors. All authors then provided commentary. Results: Both Westphal and Gélineau correctly identified and described the new clinical entities of cataplexy and narcolepsy, with recurrent, self-limited sleep attacks and/or cataplectic attacks affecting 2 otherwise healthy people. Narcolepsy was named by Gélineau (and cataplexy was named by Henneberg in 1916). The evidence in both cases is sufficiently convincing to conclude that they were likely each HLA-DQB1*0602 positive and hypocretin deficient. Conclusions: The original descriptions of narcolepsy and cataplexy are now available in English, allowing for extensive clinical and historical commentary. Citations: Schenck CH; Bassetti CL; Arnulf I et al. English translations of the first clinical reports on narcolepsy and cataplexy by Westphal and Gélineau in the late 19th century, with commentary. J Clin Sleep Med 2007;3(3):301–311 PMID:17561602
Pituitary Macrotumor Causing Narcolepsy-Cataplexy in a Dachshund.

PubMed

Schmid, S; Hodshon, A; Olin, S; Pfeiffer, I; Hecht, S

2017-03-01

Familial narcolepsy secondary to breed-specific mutations in the hypocretin receptor 2 gene and sporadic narcolepsy associated with hypocretin ligand deficiencies occur in dogs. In this report, a pituitary mass is described as a unique cause of narcolepsy-cataplexy in a dog. A 6-year-old male neutered Dachshund had presented for acute onset of feeding-induced cataplexy and was found to have a pituitary macrotumor on magnetic resonance imaging (MRI). Cerebral spinal fluid hypocretin-1 levels were normal, indicating that tumor effect on the ventral lateral nucleus of the hypothalamus was not the cause of the dog's narcolepsy-cataplexy. The dog was also negative for the hypocretin receptor 2 gene mutation associated with narcolepsy in Dachshunds, ruling out familial narcolepsy. The Dachshund underwent stereotactic radiotherapy (SRT), which resulted in reduction in the mass and coincident resolution of the cataplectic attacks. Nine months after SRT, the dog developed clinical hyperadrenocorticism, which was successfully managed with trilostane. These findings suggest that disruptions in downstream signaling of hypocretin secondary to an intracranial mass effect might result in narcolepsy-cataplexy in dogs and that brain MRI should be strongly considered in sporadic cases of narcolepsy-cataplexy. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.
CSF Hypocretin-1 Levels and Clinical Profiles in Narcolepsy and Idiopathic CNS Hypersomnia in Norway

PubMed Central

Heier, Mona Skard; Evsiukova, Tatiana; Vilming, Steinar; Gjerstad, Michaela D.; Schrader, Harald; Gautvik, Kaare

2007-01-01

Objective: To evaluate the relationship between CSF hypocretin-1 levels and clinical profiles in narcolepsy and CNS hypersomnia in Norwegian patients. Method: CSF hypocretin-1 was measured by a sensitive radioimmunoassay in 47 patients with narcolepsy with cataplexy, 7 with narcolepsy without cataplexy, 10 with idiopathic CNS hypersomnia, and a control group. Results: Low hypocretin-1 values were found in 72% of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy. Patients with low CSF hypocretin-1 levels reported more extensive muscular involvement during cataplectic attacks than patients with normal levels. Hypnagogic hallucinations and sleep paralysis occurred more frequently in patients with cataplexy than in the other patient groups, but with no correlation to hypocretin-1 levels. Conclusion: About three quarters of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy had low CSF hypocretin-1 values, and appear to form a distinct clinical entity. Narcolepsy without cataplexy could not be distinguished from idiopathic CNS hypersomnia by clinical symptoms or biochemical findings. Citation: Heier MS; Evsiukova T; Vilming S; Gjerstad MD; Schrader H; Gautvik K. CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in norway. SLEEP 2007;30(8):969-973. PMID:17702265

Body Mass Index-Independent Metabolic Alterations in Narcolepsy with Cataplexy

PubMed Central

Poli, Francesca; Plazzi, Giuseppe; Di Dalmazi, Guido; Ribichini, Danilo; Vicennati, Valentina; Pizza, Fabio; Mignot, Emmanuel; Montagna, Pasquale; Pasquali, Renato; Pagotto, Uberto

2009-01-01

Study Objectives: To contribute to the anthropometric and metabolic phenotyping of orexin-A–deficient narcoleptic patients, and to explore a possible risk of their developing a metabolic syndrome. Design: We performed a cross-sectional study comparing metabolic alterations in patients with narcolepsy with cataplexy (NC) and patients with idiopathic hypersomnia without long sleep time. Setting: University hospital. Patients: Fourteen patients with narcolepsy with cataplexy and 14 sex and age-matched patients with idiopathic hypersomnia without long sleep time. Interventions: N/A. Measurements and results: Metabolic parameters were evaluated by measuring body mass index (BMI), waist circumference (also with abdominal computed tomography), blood pressure, and daily calorie intake (3-day diary). Chronotypes were assessed through the morningness-eveningness questionnaire. Lumbar puncture for cerebrospinal fluid orexin-A determination and HLA typing were performed. Patients with narcolepsy with cataplexy (all HLA DQB1*0602 positive and with cerebrospinal fluid orexin-A levels < 110 pg/mL) had a higher BMI and BMI-independent metabolic alterations, namely waist circumference, high-density lipoprotein cholesterol, and glucose/insulin ratio (an insulin resistance index), with respect to patients with idiopathic hypersomnia without long sleep time (cerebrospinal fluid orexin-A levels > 300 pg/mL). Despite lower daily food intake, patients with narcolepsy with cataplexy displayed significant alterations in metabolic parameters resulting in a diagnosis of metabolic syndrome in more than half the cases. Conclusions: BMI-independent metabolic alterations and the relative hypophagia of patients with narcolepsy with cataplexy, as compared with patients with idiopathic hypersomnia without long sleep time, suggest that orexin-A influences the etiology of this phenotype. Moreover, considering that these dysmetabolic alterations are present from a young age, a careful metabolic follow-up of patients diagnosed with narcolepsy with cataplexy is mandatory. Citation: Poli F; Plazzi G; Dalmazi GD; Ribichini D; Vicennati V; Pizza F; Mignot E; Montagna P; Pasquali R; Pagotto U. Body mass index-independent metabolic alterations in narcolepsy with cataplexy. SLEEP 2009;32(11):1491-1497. PMID:19928388
Safety and efficacy of long-term use of sodium oxybate for narcolepsy with cataplexy in routine clinical practice.

PubMed

Drakatos, Panagis; Lykouras, Dimosthenis; D'Ancona, Grainne; Higgins, Sean; Gildeh, Nadia; Macavei, Raluca; Rosenzweig, Ivana; Steier, Joerg; Williams, Adrian J; Muza, Rexford; Kent, Brian D; Leschziner, Guy

2017-07-01

Sodium oxybate is licensed in Europe for the treatment of narcolepsy with cataplexy in adults. The aim of this study was to assess the efficacy and safety of sodium oxybate in clinical practice in patients with narcolepsy and cataplexy refractory to other treatments. This was a retrospective single centre study including patients with severe narcolepsy with cataplexy refractory to other treatments, who were initiated on sodium oxybate between 2009 and 2015. Patients were allowed to be on other stimulants or/and anti-cataplectic agents. Epworth sleepiness scale (ESS) and weekly cataplexy events were recorded. Side effects (SEs) were recorded at every follow-up visit. 90 patients were prescribed sodium oxybate, with a total of 3116 patient-months of drug exposure. ESS and weekly cataplexy events were significantly reduced by sodium oxybate for all patients (ΔESS = 4.3 ± 4.4 and Δcataplexy = 21.8 ± 18.5 events/week; p < 0.0001, respectively). The required maintenance dose could not be predicted based upon gender, body mass index, or clinical factors. 60% of patients were able to reduce or come off other medications. Half of the patients experienced at least one SE, and 26.6% had to stop treatment due to limiting SEs. Nausea, mood swings and enuresis were the most commonly reported SEs. SEs that led to drug discontinuation, particularly psychosis, were associated with increasing age and were observed early after the initiation of the drug. Sodium oxybate provides a good clinical efficacy and acceptable safety profile in routine clinical practice for the treatment of patients suffering from narcolepsy with cataplexy. A quarter of patients experience SEs requiring withdrawal of the drug with older patients being more vulnerable to the more serious SEs. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
The ICSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical relevance and practicality.

PubMed

Ruoff, Chad; Rye, David

2016-07-20

Narcolepsy is a chronic neurological disease manifesting as difficulty with maintaining continuous wake and sleep. Clinical presentation varies but requires excessive daytime sleepiness (EDS) occurring alone or together with features of rapid-eye movement (REM) sleep dissociation (e.g., cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis), and disrupted nighttime sleep. Narcolepsy with cataplexy is associated with reductions of cerebrospinal fluid (CSF) hypocretin due to destruction of hypocretin peptide-producing neurons in the hypothalamus in individuals with a specific genetic predisposition. Updated diagnostic criteria include the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) and International Classification of Sleep Disorders Third Edition (ICSD-3). DSM-5 criteria require EDS in association with any one of the following: (1) cataplexy; (2) CSF hypocretin deficiency; (3) REM sleep latency ≤15 minutes on nocturnal polysomnography (PSG); or (4) mean sleep latency ≤8 minutes on multiple sleep latency testing (MSLT) with ≥2 sleep-onset REM-sleep periods (SOREMPs). ICSD-3 relies more upon objective data in addition to EDS, somewhat complicating the diagnostic criteria: 1) cataplexy and either positive MSLT/PSG findings or CSF hypocretin deficiency; (2) MSLT criteria similar to DSM-5 except that a SOREMP on PSG may count as one of the SOREMPs required on MSLT; and (3) distinct division of narcolepsy into type 1, which requires the presence of cataplexy or documented CSF hypocretin deficiency, and type 2, where cataplexy is absent, and CSF hypocretin levels are either normal or undocumented. We discuss limitations of these criteria such as variability in clinical presentation of cataplexy, particularly when cataplexy may be ambiguous, as well as by age; multiple and/or invasive CSF diagnostic test requirements; and lack of normative diagnostic test data (e.g., MSLT) in certain populations. While ICSD-3 criteria reflect narcolepsy pathophysiology, DSM-5 criteria have greater clinical practicality, suggesting that valid and reliable biomarkers to help standardize narcolepsy diagnosis would be welcomed.
Diagnosis of narcolepsy and idiopathic hypersomnia. An update based on the International classification of sleep disorders, 2nd edition.

PubMed

Billiard, Michel

2007-10-01

Defining the precise nosological limits of narcolepsy and idiopathic hypersomnia is an ongoing process dating back to the first description of the two conditions. The most recent step forward has been done within the preparation of the second edition of the "International classification of sleep disorders" published in June 2005. Appointed by Dr Emmanuel Mignot, the Task Force on "Hypersomnias of central origin, not due to a circadian rhythm sleep disorder, sleep related breathing disorder, or other causes of disturbed nocturnal sleep" thoroughly revisited the nosology of narcolepsy and of idiopathic hypersomnia. Narcolepsy is now distinguished into three different entities, narcolepsy with cataplexy, narcolepsy without cataplexy and narcolepsy due to medical condition, and idiopathic hypersomnia into two entities, idiopathic hypersomnia with long sleep time and idiopathic hypersomnia without long sleep time. Nevertheless there are still a number of pending issues. What are the limits of narcolepsy without cataplexy? Is there a continuum in the pathophysiology of narcolepsy with and without cataplexy? Should sporadic and familial forms of narcolepsy with cataplexy appear as subgroups in the classification? Are idiopathic hypersomnia with long sleep time and idiopathic hypersomnia without long sleep time, two forms of the same condition or two different conditions? Is there a pathophysiological relationship between narcolepsy without cataplexy and idiopathic hypersomnia without long sleep time?
Sodium Oxybate

MedlinePlus

Sodium oxybate is used to prevent attacks of cataplexy (episodes of muscle weakness that begin suddenly and ... urge to sleep during daily activities, and cataplexy). Sodium oxybate is in a class of medications called ...
Narcolepsy with cataplexy mimicry: the strange case of two sisters.

PubMed

Pizza, Fabio; Vandi, Stefano; Poli, Francesca; Moghadam, Keivan Kaveh; Franceschini, Christian; Bellucci, Claudia; Cipolli, Carlo; Ingravallo, Francesca; Natalini, Giuliana; Mignot, Emmanuel; Plazzi, Giuseppe

2013-06-15

We report on two sisters, 17 and 12 years of age, with clinical features suggesting narcolepsy with cataplexy (NC): daytime sleepiness, spontaneous and emotionally triggered sudden falls to the ground, and overweight/obesity. MSLT showed borderline sleep latency, with 1 and 0 sleep onset REM periods. HLA typing disclosed the DQB1*0602 allele. Video-polygraphy of the spells ruled out NC diagnosis by demonstrating their easy elicitation by suggestion, with wake EEG, electromyographic persistence of muscle tone, and stable presence of tendon reflexes (i.e., pseudo-cataplexy), together with normal cerebrospinal hypocretin-1 levels. Our cases emphasize the need of a clear depiction of cataplexy pattern at the different ages, the usefulness of examining ictal neurophysiology, and collecting all available disease markers in ambiguous cases.
Activity of dorsal raphe cells across the sleep–waking cycle and during cataplexy in narcoleptic dogs

PubMed Central

Wu, M-F; John, J; Boehmer, L N; Yau, D; Nguyen, G B; Siegel, J M

2004-01-01

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. PMID:14678502
Virtual-reality-based system for controlled study of cataplexy

NASA Astrophysics Data System (ADS)

Augustine, Kurt E.; Cameron, Bruce M.; Camp, Jon J.; Krahn, Lois E.; Robb, Richard A.

2002-05-01

Cataplexy is a sudden loss of voluntary muscle control experienced by narcolepsy patients. It is usually triggered by strong, spontaneous emotions and is more common in times of stress. The Sleep Disorders Unit and the Biomedical Imaging Resource at Mayo Clinic are developing interactive display technology for reliably inducing cataplexy during clinical monitoring. The project is referred to as the Cataplexy/Narcolepsy Activation Program, or CatNAP. We have developed an automobile driving simulation that introduces humorous, surprising, and stress-inducing events and objects as the patient attempts to navigate a vehicle through a virtual town. The patient wears a head-mounted display and controls the vehicle via a driving simulator steering wheel and pedal cluster. As the patient attempts to drive through the town, various objects, sounds or conditions occur that distract, startle, frustrate or amuse. These responses may trigger a cataplectic episode, which can then be clinically evaluated. We believe CatNAP is a novel and innovative example of the effective application of virtual reality technology to study an important clinical problem that has resisted previous approaches. An evaluation phase with volunteer patients previously diagnosed with cataplexy has been completed. The prototype system is being prepared for a full clinical study.
Comparison of Polysomnography and Multiple Sleep Latency Test Findings in Subjects with Narcolepsy and İdiopathic Hypersomnia.

PubMed

Erdem, Murat; Bolu, Abdullah; Ünlü, A Gazi; Alper, Mustafa; Yetkin, Sinan

2013-09-01

Both narcolepsy and idiopathic hypersomnia are the main causes of excessive daytime sleepiness. In this study, we aimed to compare polysomnography (PSG) and multiple sleep latency test (MSLT) findings in narcolepsy and idiopathic hypersomnia patients. The files of patients with narcolepsy and hypersomnia who were admitted between 1995 and 2009 were reviewed. We evaluated data from 94 patients with narcolepsy with cataplexy, 49 with narcolepsy without cataplexy and 140 patients with idiopathic hypersomnia. Sleep latency and REM latency were longer in idiopathic hypersomnia group than in narcolepsy with and without cataplexy group. Mean sleep latency in MSLT was the shortest in narcolepsy with cataplexy group. There was no difference in sleep efficiency, percentage of sleep stage and number of awakenings in PSG between three groups. The findings of the study indicated that narcolepsy patients differ from idiopathic hypersomnia patients in terms of sleep latency and REM latency in PSG.
Status cataplecticus as initial presentation of late onset narcolepsy.

PubMed

Panda, Samhita

2014-02-15

Narcolepsy, one of the important causes of hypersomnia, is an under diagnosed sleep disorder. It has a bimodal age of onset around 15 and 35 years. It is characterized by the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic/ hypnopompic hallucinations, and sleep paralysis. Cataplexy is by far the most predictive feature of narcolepsy. Status cataplecticus is the occurrence of cataplexy repeatedly for hours or days, a rare presentation of narcolepsy. This report describes an elderly gentleman with late onset narcolepsy in the sixth decade of life presenting with initial and chief symptom of status cataplecticus.
Pharmacological management of narcolepsy with and without cataplexy.

PubMed

Kallweit, Ulf; Bassetti, Claudio L

2017-06-01

Narcolepsy is an orphan neurological disease and presents with sleep-wake, motoric, neuropsychiatric and metabolic symptoms. Narcolepsy with cataplexy is most commonly caused by an immune-mediated process including genetic and environmental factors, resulting in the selective loss of hypocretin-producing neurons. Narcolepsy has a major impact on workableness and quality of life. Areas covered: This review provides an overview of the temporal available treatment options for narcolepsy (type 1 and 2) in adults, including authorization status by regulatory agencies. First- and second-line options are discussed as well as combination therapies. In addition, treatment options for frequent coexisting co-morbidities and different phenotypes of narcolepsy are presented. Finally, this review considers potential future management strategies. Non-pharmacological approaches are important in the management of narcolepsy but will not be covered in this review. Expert opinion: Concise evaluation of symptoms and type of narcolepsy, coexisting co-morbidities and patients´ distinct needs is mandatory in order to identify a suitable, individual pharmacological treatment. First-line options include Modafinil/Armodafinil (for excessive daytime sleepiness, EDS), Sodium Oxybate (for EDS and/with cataplexy), Pitolisant (for EDS and cataplexy) and Venlafaxine (for cataplexy (off-label) and co-morbid depression). New symptomatic and causal treatment most probably will be completed by hypocretin-replacement and immune-modifying strategies.
Anti-Tribbles Homolog 2 Autoantibodies in Japanese Patients with Narcolepsy

PubMed Central

Toyoda, Hiromi; Tanaka, Susumu; Miyagawa, Taku; Honda, Yutaka; Tokunaga, Katsushi; Honda, Makoto

2010-01-01

Study Objectives: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and cataplexy. The association with human leukocyte antigen (HLA)-DQB1*0602 and T-cell receptor alpha locus suggests that autoimmunity plays a role in narcolepsy. A recent study reported an increased prevalence of autoantibodies against Tribbles homolog 2 (TRIB2) in patients with narcolepsy. To replicate this finding, we examined anti-TRIB2 autoantibodies in Japanese patients with narcolepsy. Design: We examined anti-TRIB2 autoantibodies against a full-length [35S]-labeled TRIB2 antigen in Japanese patients with narcolepsy-cataplexy (n = 88), narcolepsy without cataplexy (n = 18), and idiopathic hypersomnia with long sleep time (n = 11). The results were compared to Japanese healthy controls (n = 87). Thirty-seven healthy control subjects were positive for HLA-DRB1*1501-DQB1*0602. We also examined autoantibodies against another Tribbles homolog, TRIB3, as an experimental control. Measurements and Results: Autoantibodies against TRIB2 were found in 26.1% of patients with narcolepsy-cataplexy, a significantly higher prevalence than the 2.3% in healthy controls. We found that anti-TRIB3 autoantibodies were rare in patients with narcolepsy and showed no association with anti-TRIB2 indices. No significant correlation was found between anti-TRIB2 positivity and clinical information. Conclusions: We confirmed the higher prevalence and specificity of anti-TRIB2 autoantibodies in Japanese patients with narcolepsy-cataplexy. This suggests a subgroup within narcolepsy-cataplexy might be affected by an anti-TRIB2 autoantibody-mediated autoimmune mechanism. Citation: Toyoda H; Tanaka S; Miyagawa T; Honda Y; Tokunaga K; Honda M. Anti-Tribbles homolog 2 autoantibodies in Japanese patients with narcolepsy. SLEEP 2010;33(7):875-878. PMID:20614847
Mazindol in narcolepsy and idiopathic and symptomatic hypersomnia refractory to stimulants: a long-term chart review.

PubMed

Nittur, Nandini; Konofal, Eric; Dauvilliers, Yves; Franco, Patricia; Leu-Semenescu, Smaranda; Cock, Valérie Cochen De; Inocente, Clara O; Bayard, Sophie; Scholtz, Sabine; Lecendreux, Michel; Arnulf, Isabelle

2013-01-01

Mazindol is a tricyclic, anorectic, non-amphetamine stimulant used in narcolepsy and obesity since 1970. This study aimed to evaluate the long-term benefit/risk ratio in drug-resistant hypersomniacs and cataplexy sufferers. By retrospective analysis of the patients' files in the hospitals of Paris-Salpêtrière (n=91), Montpellier (n=40) and Lyon (n=8), the benefit (Epworth Sleepiness Score (ESS), cataplexy frequency, authorization renewal) and tolerance (side-effects, vital signs, electrocardiogram and cardiac echography) of mazindol were assessed. The 139 patients (45% men) aged 36±15years (range: 9-74) suffered narcolepsy (n=94, 66% with cataplexy), idiopathic (n=37) and symptomatic hypersomnia (n=8) refractory to modafinil, methylphenidate and sodium oxybate. Under mazindol (3.4±1.3mg/day, 1-6mg) for an average of 30months, the ESS decreased from 17.7±3.5 to 12.8±5.1, with an average fall of -4.6±4.7 (p<0.0001) and the frequency of cataplexy fell from 4.6±3.1 to 2±2.8 episodes per week. The cataplexy was eliminated in 14.5% of patients, improved in 27.5%, and unchanged in 29% (missing data in 29%). The treatment was maintained long term in 83 (60%) patients, and stopped because of a lack of efficacy (22%) and/or secondary effects (9%). There was no pulmonary hypertension in the 45 patients who underwent a cardiac echography. The most common adverse effects were dry mouth (13%), palpitations (10%, including one with ventricular hyperexcitability), anorexia (6%), nervousness (6%) and headaches (6%). Mazindol has a long-term, favorable benefit/risk ratio in 60% of drug-resistant hypersomniacs, including a clear benefit on cataplexy. Copyright © 2012 Elsevier B.V. All rights reserved.
Treatment of cataplexy in Niemann-Pick disease type C with the use of miglustat.

PubMed

Zarowski, Marcin; Steinborn, Barbara; Gurda, Barbara; Dvorakova, Lenka; Vlaskova, Hana; Kothare, Sanjeev V

2011-01-01

Cataplexy is the sudden muscle weakness brought on by strong emotions, particularly joking, laughter, or anger. Cataplexy may involve only certain group of muscles or the entire voluntary musculature. In rare cases, symptoms of cataplexy can be seen during the course of some inherited diseases (Niemann-Pick type C (NPC), Prader-Willi syndrome, myotonic dystrophy, Norrie disease). We report the successful use of miglustat, a reversible inhibitor of the enzyme glucosylceramide synthase, approved for use in Gaucher's disease, and which catalyses the first step in the biosynthesis of most glycosphingolipid, in a boy with NPC with cataplexy. A 9-year-old boy was admitted for assessments of frequent "drop attacks" while laughing. The filipin fluorescence tests of cultured skin fibroblasts revealed massive accumulation of unesterified cholesterol, confirming the diagnosis of NPC disease. Molecular studies confirmed the diagnosis of NPC too. After approval from the bioethics committee, miglustat was initiated on the child at 100mg three times a day. Cataplectic attacks disappeared completely after 6 months on treatment, and patient continues to be in remission from the cataplectic attacks at 16 months follow-up. There was no further progression of neurological signs or symptoms or splenomegaly, with some improvement in cognitive function as well as social, affective and attention problems, up-gaze, and gait. Miglustat was well tolerated with no side effects observed. In summary, this is the first report of miglustat treatment of cataplexy in NPC. Long-term follow-up for continuing efficacy and tolerability in a larger cohort with NPC is needed to substantiate our observation. © 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Association Study of HLA-DQB1*0602 Allele in Iranian Patients with Narcolepsy.

PubMed

Geremew, Demeke; Rahimi-Golkhandan, Ania; Sadeghniiat-Haghighi, Khosro; Shakiba, Yadollah; Khajeh-Mehrizi, Ahmad; Ansaripour, Bita; Izad, Maryam

2017-10-01

Narcolepsy is a rare, disabling disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. Several studies demonstrated its association with HLA-DQB1*0602 in various ethnic groups. Our study aimed to determine the prevalence of HLA-DQB1*0602 allele in Iranian patients with narcolepsy and assess its predictive parameters for diagnosing narcolepsy. In addition, car accidents and job problems were assessed among narcoleptic patients. We studied 44 narcoleptic patients, 30 patients with other types of excessive daytime sleepiness (EDS) and 50 healthy age and sex matched individuals in this case-control study. Patients and controls filled out a questionnaire including items about car accidents due to sleepiness and job problems. International classification of sleep disorders-2 criteria was used as the gold standard for diagnosis of narcolepsy. The DNAs isolated from whole blood samples were collected from the patients and controls to assess the presence of HLA-DQB1*0602. The results showed that HLA DQB1*0602 was present in 4 (8%) individual of controls and 20 (45.5%) patients with higher prevalence in patients with cataplexy (78.9%) than patients without cataplexy (p<0.001). The sensitivities of the DQB1*0602 for diagnosing narcolepsy with cataplexy and narcolepsy without cataplexy were 78.9 and 20; specificities were 88 and 72.4, respectively. 18.2% of patients had car accidents due to sleepiness and 68.2% suffered from job problems. Our study shows that evaluation of DQB1*0602 in patients suspected to narcolepsy could be helpful especially in complex cases with atypical cataplexy and indistinguishable multiple sleep latency test MSLT results. Moreover, high rates of car accidents and job problems are found among narcoleptic patients.
Usefulness of a Nocturnal SOREMP for Diagnosing Narcolepsy with Cataplexy in a Pediatric Population

PubMed Central

Reiter, Joel; Katz, Eliot; Scammell, Thomas E.; Maski, Kiran

2015-01-01

Study Objectives: We investigated the diagnostic accuracy of a nocturnal sleep onset rapid eye movement sleep period (nSOREMP) for the identification of narcolepsy with cataplexy (N+C) among children and adolescents referred to the sleep laboratory for an overnight polysomnography (PSG) and multiple sleep latency test (MSLT). Design: Retrospective chart review of sleep clinic notes and PSG and MSLT reports. Setting: Boston Children's Hospital sleep laboratory and outpatient clinics. Patients: All patients 6–18 y old, referred for consecutive PSG and MSLT for the evaluation of central hypersomnias, between January 2005 and January 2014. Measurements and Results: We analyzed the records of 148 patients and established diagnostic categories using the International Classification of Sleep Disorders, 2nd Edition. Patient diagnoses included narcolepsy with cataplexy (28.4%), narcolepsy without cataplexy (8.1%), other hypersomnia conditions (9.5%), delayed sleep phase syndrome (12.2%), behaviorally induced insufficient sleep syndrome (4.1%), other sleep disorders (obstructive sleep apnea, periodic limb movements of sleep; 6.8%), isolated cataplexy (2%), and various diagnoses (29.1%). There were 54.8% of the N+C patients who had an nSOREMP, but only 2.4% of all other patients had an nSOREMP. The specificity of an nSOREMP for detection of N+C was high at 97.3% (95% confidence interval [CI]: 92.2–99.4%), but the sensitivity was moderate at 54.8% (95% CI: 38.7–70.2%). Overall, the positive predictive value of an nSOREMP for the diagnosis of N+C was 88.5% (95% CI: 69.8–97.4%). Conclusions: In children, the presence of an nocturnal sleep onset rapid eye movement sleep period is highly suggestive of narcolepsy with cataplexy and provides further evidence of rapid eye movement sleep dysregulation in this condition. Citation: Reiter J, Katz E, Scammell TE, Maski K. Usefulness of a nocturnal SOREMP for diagnosing narcolepsy with cataplexy in a pediatric population. SLEEP 2015;38(6):859–865. PMID:25325489
Predictors of Hypocretin (Orexin) Deficiency in Narcolepsy Without Cataplexy

PubMed Central

Andlauer, Olivier; Moore, Hyatt; Hong, Seung-Chul; Dauvilliers, Yves; Kanbayashi, Takashi; Nishino, Seiji; Han, Fang; Silber, Michael H.; Rico, Tom; Einen, Mali; Kornum, Birgitte R.; Jennum, Poul; Knudsen, Stine; Nevsimalova, Sona; Poli, Francesca; Plazzi, Giuseppe; Mignot, Emmanuel

2012-01-01

Study Objectives: To compare clinical, electrophysiologic, and biologic data in narcolepsy without cataplexy with low (≤ 110 pg/ml), intermediate (110–200 pg/ml), and normal (> 200 pg/ml) concentrations of cerebrospinal fluid (CSF) hypocretin-1. Setting: University-based sleep clinics and laboratories. Patients: Narcolepsy without cataplexy (n = 171) and control patients (n = 170), all with available CSF hypocretin-1. Design and interventions: Retrospective comparison and receiver operating characteristics curve analysis. Patients were also recontacted to evaluate if they developed cataplexy by survival curve analysis. Measurements and Results: The optimal cutoff of CSF hypocretin-1 for narcolepsy without cataplexy diagnosis was 200 pg/ml rather than 110 pg/ml (sensitivity 33%, specificity 99%). Forty-one patients (24%), all HLA DQB1*06:02 positive, had low concentrations (≤ 110 pg/ml) of CSF hypocretin-1. Patients with low concentrations of hypocretin-1 only differed subjectively from other groups by a higher Epworth Sleepiness Scale score and more frequent sleep paralysis. Compared with patients with normal hypocretin-1 concentration (n = 117, 68%), those with low hypocretin-1 concentration had higher HLA DQB1*06:02 frequencies, were more frequently non-Caucasians (notably African Americans), with lower age of onset, and longer duration of illness. They also had more frequently short rapid-eye movement (REM) sleep latency (≤ 15 min) during polysomnography (64% versus 23%), and shorter sleep latencies (2.7 ± 0.3 versus 4.4 ± 0.2 min) and more sleep-onset REM periods (3.6 ± 0.1 versus 2.9 ± 0.1 min) during the Multiple Sleep Latency Test (MSLT). Patients with intermediate concentrations of CSF hypocretin-1 (n = 13, 8%) had intermediate HLA DQB1*06:02 and polysomnography results, suggesting heterogeneity. Of the 127 patients we were able to recontact, survival analysis showed that almost half (48%) with low concentration of CSF hypocretin-1 had developed typical cataplexy at 26 yr after onset, whereas only 2% had done so when CSF hypocretin-1 concentration was normal. Almost all patients (87%) still complained of daytime sleepiness independent of hypocretin status. Conclusion: Objective (HLA typing, MSLT, and sleep studies) more than subjective (sleepiness and sleep paralysis) features predicted low concentration of CSF hypocretin-1 in patients with narcolepsy without cataplexy. Citation: Andlauer O; Moore H; Hong SC; Dauvilliers Y; Kanbayashi T; Nishino S; Han F; Silber MH; Rico T; Einen M; Kornum BR; Jennum P; Knudsen S; Nevsimalova S; Poli F; Plazzi G; Mignot E. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. SLEEP 2012;35(9):1247–1255. PMID:22942503
[NARCOLEPSY WITH CATAPLEXY: TYPE 1 NARCOLEPSY].

PubMed

Dauvilliers, Yves; Lopez, Régis

2016-06-01

Narcolepsy with cataplexy or narcolepsy type 1 in a rare, disabling sleep disorder, with a prevalence of 20 to 30 per 100,000. Its onset peaks in the second decade. The main features are excessive daytime sleepiness and cataplexy or sudden less of muscle tone triggered by emotional situations. Other less consistent symptoms include hypnagogic hallucinations, sleep paralysis, disturbed nighttime sleep, and weight gain. Narcolepsy with cataplexy remains a clinical diagnosis but nighttime and daytime polysomnography (multiple sleep latency tests) are useful to document mean sleep latency below 8 min and at least two sleep-onset REM periods. HLA typing shows an association with HLA DQB1*0602 in more than 92% of cases but was not included in the new diagnostic criteria. In contrast, a low hypocretin-1/orexin-A levels (values below 110 pg/mL) in the cerebrospinal fluid was highly specific for narcolepsy with cataplexy and was included in the recent diagnostic criteria for narcolepsy. The deficiency of the hypocretin system is well-established in human narcoleptics with a reduction of cerebrospinal fluid hypocretin levels in relation with an early loss of hypocretin neurons. The cause of human narcolepsy remains unknown, however an autoimmune process in most probable acting on a highly genetic background with environmental factors such as streptococcal infections, and H1N1 AS03-adjuvanted vaccine named Pandemrix.
Status Cataplecticus as Initial Presentation of Late Onset Narcolepsy

PubMed Central

Panda, Samhita

2014-01-01

Narcolepsy, one of the important causes of hypersomnia, is an under diagnosed sleep disorder. It has a bimodal age of onset around 15 and 35 years. It is characterized by the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic/ hypnopompic hallucinations, and sleep paralysis. Cataplexy is by far the most predictive feature of narcolepsy. Status cataplecticus is the occurrence of cataplexy repeatedly for hours or days, a rare presentation of narcolepsy. This report describes an elderly gentleman with late onset narcolepsy in the sixth decade of life presenting with initial and chief symptom of status cataplecticus. Citation: Panda S. Status cataplecticus as initial presentation of late onset narcolepsy. J Clin Sleep Med 2014;10(2):207-209. PMID:24533005
Clinical and Neurobiological Aspects of Narcolepsy

PubMed Central

Nishino, Seiji

2007-01-01

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy and/or other dissociated manifestations of rapid eye movement (REM) sleep (hypnagogic hallucinations and sleep paralysis). Narcolepsy is currently treated with amphetamine-like central nervous system (CNS) stimulants (for EDS) and antidepressants (for cataplexy). Some other classes of compounds such as modafinil (a non-amphetamine wake-promoting compound for EDS) and gamma-hydroxybutyrate (GHB, a short-acting sedative for EDS/fragmented nighttime sleep and cataplexy) given at night are also employed. The major pathophysiology of human narcolepsy has been recently elucidated based on the discovery of narcolepsy genes in animals. Using forward (i.e., positional cloning in canine narcolepsy) and reverse (i.e., mouse gene knockout) genetics, the genes involved in the pathogenesis of narcolepsy (hypocretin/orexin ligand and its receptor) in animals have been identified. Hypocretins/orexins are novel hypothalamic neuropeptides also involved in various hypothalamic functions such as energy homeostasis and neuroendocrine functions. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in many narcolepsy-cataplexy cases. In this review, the clinical, pathophysiological and pharmacological aspects of narcolepsy are discussed. PMID:17470414

Narcolepsy: a review

PubMed Central

Akintomide, Gbolagade Sunmaila; Rickards, Hugh

2011-01-01

Narcolepsy is a lifelong sleep disorder characterized by a classic tetrad of excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucination, and sleep paralysis. There are two distinct groups of patients, ie, those having narcolepsy with cataplexy and those having narcolepsy without cataplexy. Narcolepsy affects 0.05% of the population. It has a negative effect on the quality of life of its sufferers and can restrict them from certain careers and activities. There have been advances in the understanding of the pathogenesis of narcolepsy. It is thought that narcolepsy with cataplexy is secondary to loss of hypothalamic hypocretin neurons in those genetically predisposed to the disorder by possession of human leukocyte antigen DQB1*0602. The diagnostic criteria for narcolepsy are based on symptoms, laboratory sleep tests, and serum levels of hypocretin. There is no cure for narcolepsy, and the present mainstay of treatment is pharmacological treatment along with lifestyle changes. Some novel treatments are also being developed and tried. This article critically appraises the evidence for diagnosis and treatment of narcolepsy. PMID:21931493
Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy.

PubMed

Kaushik, Mahesh K; Aritake, Kosuke; Imanishi, Aya; Kanbayashi, Takashi; Ichikawa, Tadashi; Shimizu, Tetsuo; Urade, Yoshihiro; Yanagisawa, Masashi

2018-06-05

Narcolepsy-cataplexy is a chronic neurological disorder caused by loss of orexin (hypocretin)-producing neurons, associated with excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, hypnagogic hallucinations, and fragmentation of nighttime sleep. Currently, human narcolepsy is treated by providing symptomatic therapies, which can be associated with an array of side effects. Although peripherally administered orexin does not efficiently penetrate the blood-brain barrier, centrally delivered orexin can effectively alleviate narcoleptic symptoms in animal models. Chronic intrathecal drug infusion through an implantable pump is a clinically available strategy to treat a number of neurological diseases. Here we demonstrate that the narcoleptic symptoms of orexin knockout mice can be reversed by lumbar-level intrathecal orexin delivery. Orexin was delivered via a chronically implanted intrathecal catheter at the upper lumbar level. The computed tomographic scan confirmed that intrathecally administered contrast agent rapidly moved from the spinal cord to the brain. Intrathecally delivered orexin was detected in the brain by radioimmunoassay at levels comparable to endogenous orexin levels. Cataplexy and sleep-onset REM sleep were significantly decreased in orexin knockout mice during and long after slow infusion of orexin (1 nmol/1 µL/h). Sleep/wake states remained unchanged both quantitatively as well as qualitatively. Intrathecal orexin failed to induce any changes in double orexin receptor-1 and -2 knockout mice. This study supports the concept of intrathecal orexin delivery as a potential therapy for narcolepsy-cataplexy to improve the well-being of patients.
Health-Related Quality of Life Among Drug-Naïve Patients with Narcolepsy with Cataplexy, Narcolepsy Without Cataplexy, and Idiopathic Hypersomnia Without Long Sleep Time

PubMed Central

Ozaki, Akiko; Inoue, Yuichi; Nakajima, Toru; Hayashida, Kenichi; Honda, Makoto; Komada, Yoko; Takahashi, Kiyohisa

2008-01-01

Objective: To evaluate the health-related quality life (HRQOL) of drugnaïve patients with narcolepsy with cataplexy (NA with CA), narcolepsy without cataplexy (NA without CA) and idiopathic hypersomnia without long sleep time (IHS without LST), and to explore the factors influencing the HRQOL. Factors associated with the occurrence of automobile accidents are also discussed. Methods: A total of 137 consecutive drug naïve patients who met the criteria of the 2nd edition of the International Classification of Sleep Disorders (NA with CA, n = 28; NA without CA, n = 27; IHS without LST, n = 82) were enrolled. The patients were asked to fill out questionnaires, including the SF-36, Epworth Sleepiness Scale (ESS), sociodemographic variables, and items regarding driving habits and the experiences related to automobile accidents. Results: All 3 diagnostic groups had significantly lower scores in most SF-36 domains compared with Japanese normative data. Significant differences among the 3 diagnostic groups were not observed. Specific factors in SF-36 domains were not found with multiple linear regression analyses, while disease duration was positively correlated with mental health among all subjects. Among the patients reporting driving habits, ESS score (≥16) was positively associated with the experience of automobile accidents. Conclusions: Our results indicated that HRQOL decreases in drugnaïve patients with hypersomnia, but neither disease category nor severity of the disorder appears as an associated factor. Increased severity of hypersomnia, however, was thought to play an important role in the occurrence of automobile accidents. Citation: Ozaki A; Inoue Y; Nakajima T; Hayashida K; Honda M; Komada Y; Takahashi K. Health-related quality of life among drug-naïve patients with narcolepsy with cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia without long sleep time. J Clin Sleep Med 2008;4(6):572-578. PMID:19110887
Cardiovascular fitness in narcolepsy is inversely related to sleepiness and the number of cataplexy episodes.

PubMed

Matoulek, Martin; Tuka, Vladimír; Fialová, Magdalena; Nevšímalová, Soňa; Šonka, Karel

2017-06-01

Cardiopulmonary fitness depends on daily energy expenditure or the amount of daily exercise. Patients with narcolepsy spent more time being sleepy or asleep than controls; thus we may speculate that they have a lower quantity and quality of physical activity. The aim of the present study was thus to test the hypothesis that exercise tolerance in narcolepsy negatively depends on sleepiness. The cross-sectional study included 32 patients with narcolepsy with cataplexy, 10 patients with narcolepsy without cataplexy, and 36 age- and gender-matched control subjects, in whom a symptom-limited exercise stress test with expired gas analysis was performed. A linear regression analysis with multivariate models was used with stepwise variable selection. In narcolepsy patients, maximal oxygen uptake (VO 2peak ) was 30.1 ± 7.5 mL/kg/min, which was lower than 36.0 ± 7.8 mL/kg/min, p = 0.001, in controls and corresponded to 86.4% ± 20.0% of the population norm (VO 2peak %) and to a standard deviation (VO 2peak SD) of -1.08 ± 1.63 mL/kg/min of the population norm. VO 2peak depended primarily on gender (p = 0.007) and on sleepiness (p = 0.046). VO 2peak % depended on sleepiness (p = 0.028) and on age (p = 0.039). VO 2peak SD depended on the number of cataplexy episodes per month (p = 0.015) and on age (p = 0.030). Cardiopulmonary fitness in narcolepsy and in narcolepsy without cataplexy is inversely related to the degree of sleepiness and cataplexy episode frequency. Copyright © 2017 Elsevier B.V. All rights reserved.
Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy.

PubMed

Black, Sarah Wurts; Morairty, Stephen R; Fisher, Simon P; Chen, Tsui-Ming; Warrier, Deepti R; Kilduff, Thomas S

2013-03-01

Humans with narcolepsy and orexin/ataxin-3 transgenic (TG) mice exhibit extensive, but incomplete, degeneration of hypo-cretin (Hcrt) neurons. Partial Hcrt cell loss also occurs in Parkinson disease and other neurologic conditions. Whether Hcrt antagonists such as almorexant (ALM) can exert an effect on the Hcrt that remains after Hcrt neurodegeneration has not yet been determined. The current study was designed to evaluate the hypnotic and cataplexy-inducing efficacy of a Hcrt antagonist in an animal model with low Hcrt tone and compare the ALM efficacy profile in the disease model to that produced in wild-type (WT) control animals. Counterbalanced crossover study. Home cage. Nine TG mice and 10 WT mice. ALM (30, 100, 300 mg/kg), vehicle and positive control injections, dark/active phase onset. During the 12-h dark period after dosing, ALM exacerbated cataplexy in TG mice and increased nonrapid eye movement sleep with heightened sleep/wake fragmentation in both genotypes. ALM showed greater hypnotic potency in WT mice than in TG mice. The 100 mg/kg dose conferred maximal promotion of cataplexy in TG mice and maximal promotion of REM sleep in WT mice. In TG mice, ALM (30 mg/ kg) paradoxically induced a transient increase in active wakefulness. Core body temperature (Tb) decreased after acute Hcrt receptor blockade, but the reduction in Tb that normally accompanies the wake-to-sleep transition was blunted in TG mice. These complex dose- and genotype-dependent interactions underscore the importance of effector mechanisms downstream from Hcrt receptors that regulate arousal state. Cataplexy promotion by ALM warrants cautious use of Hcrt antagonists in patient populations with Hcrt neurodegeneration, but may also facilitate the discovery of anticataplectic medications. Black SW; Morairty SR; Fisher SP; Chen TM; Warrier DR; Kilduff TS. Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. SLEEP 2013;36(3):325-336.
Narcolepsy in children: a diagnostic and management approach.

PubMed

Babiker, Mohamed O E; Prasad, Manish

2015-06-01

To provide a diagnostic and management approach for narcolepsy in children. Narcolepsy is a chronic disabling disorder characterized by excessive daytime sleepiness, cataplexy, hypnogogic and/or hypnopompic hallucinations, and sleep paralysis. All four features are present in only half of the cases. Excessive daytime sleepiness is the essential feature of narcolepsy at any age and is usually the first symptom to manifest. A combination of excessive daytime sleepiness and definite cataplexy is considered pathognomonic of narcolepsy syndrome. New treatment options have become available over the past few years. Early diagnosis and management can significantly improve the quality of life of patients with narcolepsy with cataplexy. This review summarizes the pathophysiology, clinical features, and management options for children with narcolepsy. Copyright © 2015 Elsevier Inc. All rights reserved.
Facing emotions in narcolepsy with cataplexy: haemodynamic and behavioural responses during emotional stimulation.

PubMed

de Zambotti, Massimiliano; Pizza, Fabio; Covassin, Naima; Vandi, Stefano; Cellini, Nicola; Stegagno, Luciano; Plazzi, Giuseppe

2014-08-01

Narcolepsy with cataplexy is a complex sleep disorder that affects the modulation of emotions: cataplexy, the key symptom of narcolepsy, is indeed strongly linked with emotions that usually trigger the episodes. Our study aimed to investigate haemodynamic and behavioural responses during emotional stimulation in narco-cataplexy. Twelve adult drug-naive narcoleptic patients (five males; age: 33.3 ± 9.4 years) and 12 healthy controls (five males; age: 30.9 ± 9.5 years) were exposed to emotional stimuli (pleasant, unpleasant and neutral pictures). Heart rate, arterial blood pressure and mean cerebral blood flow velocity of the middle cerebral arteries were continuously recorded using photoplethysmography and Doppler ultrasound. Ratings of valence and arousal and coping strategies were scored by the Self-Assessment Manikin and by questionnaires, respectively. Narcoleptic patients' haemodynamic responses to pictures overlapped with the data obtained from controls: decrease of heart rate and increase of mean cerebral blood flow velocity regardless of pictures' content, increase of systolic blood pressure during the pleasant condition, and relative reduction of heart rate during pleasant and unpleasant conditions. However, when compared with controls, narcoleptic patients reported lower arousal scores during the pleasant and neutral stimulation, and lower valence scores during the pleasant condition, respectively, and also a lower score at the 'focus on and venting of emotions' dimensions of coping. Our results suggested that adult narcoleptic patients, compared with healthy controls, inhibited their emotion-expressive behaviour to emotional stimulation, and that may be related to the development of adaptive cognitive strategies to face emotions avoiding cataplexy. © 2014 European Sleep Research Society.
Narcolepsy in a three-year-old girl: A case report.

PubMed

Park, Eu Gene; Lee, Jiwon; Joo, Eun Yeon; Lee, Munhyang; Lee, Jeehun

2016-01-01

Narcolepsy is characterized by excessive daytime somnolence associated with sleep paralysis, hallucinations when falling asleep or awakening, and cataplexy. Early recognition of pediatric narcolepsy is essential for growth and development. We experienced a case of narcolepsy in a three-year-old girl. The patient underwent brain MRI and 24h video-electroencephalogram (EEG) monitoring. Polysomnography (PSG) with multiple sleep latency test (MSLT) and human leukocyte antigen (HLA) DQ typing was performed. The brain MRI was normal. 24h video-EEG monitoring revealed no abnormal slow or epileptiform discharge on interictal EEG, and no EEG change during tongue thrusting, dropping head with laughter, or flopping down, which was consistent with cataplexy associated with narcolepsy. A mean sleep latency of 2.5 min and four episodes of sleep-onset REM periods in five naps were observed in PSG with MSLT. She was positive in HLA-DQB1*0602. Based on these findings, she was diagnosed as narcoleptic with cataplexy. The history, combined with PSG and MSLT, was helpful in the diagnosis of narcolepsy. We report a case of early-onset narcolepsy presenting with excessive sleepiness and cataplexy. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system.

PubMed

Nishino, Seiji; Kanbayashi, Takashi

2005-08-01

Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy-cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602). The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be often associated with non-hypothalamic structures. CSF hypocretin-1 measurement were also carried out in a limited number of symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n=5), head trauma (n=3), vascular disorders (n=5), encephalopathies (n=3), degeneration (n=30), demyelinating disorder (n=7), genetic/congenital disorders (n=11) and others (n=2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) appeared, but they are not linked with hypocretin ligand deficiency. In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in symptomatic cases. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.
HLA DQB1*06:02 Negative Narcolepsy with Hypocretin/Orexin Deficiency

PubMed Central

Han, Fang; Lin, Ling; Schormair, Barbara; Pizza, Fabio; Plazzi, Giuseppe; Ollila, Hanna M.; Nevsimalova, Sona; Jennum, Poul; Knudsen, Stine; Winkelmann, Juliane; Coquillard, Cristin; Babrzadeh, Farbod; Strom, Tim M.; Wang, Chunlin; Mindrinos, Michael; Vina, Marcelo Fernandez; Mignot, Emmanuel

2014-01-01

Study Objectives: To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02. Settings: China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University). Design: CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes. Measurements and Results: Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing. Conclusions: Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges. Citation: Han F, Lin L, Schormair B, Pizza F, Plazzi G, Ollila HM, Nevsimalova S, Jennum P, Knudsen S, Winkelmann J, Coquillard C, Babrzadeh F, Strom TM, Wang C, Mindrinos M, Vina MF, Mignot E. HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. SLEEP 2014;37(10):1601-1608. PMID:25197808
Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France.

PubMed

Dauvilliers, Yves; Arnulf, Isabelle; Lecendreux, Michel; Monaca Charley, Christelle; Franco, Patricia; Drouot, Xavier; d'Ortho, Marie-Pia; Launois, Sandrine; Lignot, Séverine; Bourgin, Patrice; Nogues, Béatrice; Rey, Marc; Bayard, Sophie; Scholz, Sabine; Lavault, Sophie; Tubert-Bitter, Pascale; Saussier, Cristel; Pariente, Antoine

2013-08-01

An increased incidence of narcolepsy in children was detected in Scandinavian countries where pandemic H1N1 influenza ASO3-adjuvanted vaccine was used. A campaign of vaccination against pandemic H1N1 influenza was implemented in France using both ASO3-adjuvanted and non-adjuvanted vaccines. As part of a study considering all-type narcolepsy, we investigated the association between H1N1 vaccination and narcolepsy with cataplexy in children and adults compared with matched controls; and compared the phenotype of narcolepsy with cataplexy according to exposure to the H1N1 vaccination. Patients with narcolepsy-cataplexy were included from 14 expert centres in France. Date of diagnosis constituted the index date. Validation of cases was performed by independent experts using the Brighton collaboration criteria. Up to four controls were individually matched to cases according to age, gender and geographic location. A structured telephone interview was performed to collect information on medical history, past infections and vaccinations. Eighty-five cases with narcolepsy-cataplexy were included; 23 being further excluded regarding eligibility criteria. Of the 62 eligible cases, 59 (64% males, 57.6% children) could be matched with 135 control subjects. H1N1 vaccination was associated with narcolepsy-cataplexy with an odds ratio of 6.5 (2.1-19.9) in subjects aged<18 years, and 4.7 (1.6-13.9) in those aged 18 and over. Sensitivity analyses considering date of referral for diagnosis or the date of onset of symptoms as the index date gave similar results, as did analyses focusing only on exposure to ASO3-adjuvanted vaccine. Slight differences were found when comparing cases with narcolepsy-cataplexy exposed to H1N1 vaccination (n=32; mostly AS03-adjuvanted vaccine, n=28) to non-exposed cases (n=30), including shorter delay of diagnosis and a higher number of sleep onset rapid eye movement periods for exposed cases. No difference was found regarding history of infections. In this sub-analysis, H1N1 vaccination was strongly associated with an increased risk of narcolepsy-cataplexy in both children and adults in France. Even if, as in every observational study, the possibility that some biases participated in the association cannot be completely ruled out, the associations appeared robust to sensitivity analyses, and a specific analysis focusing on ASO3-adjuvanted vaccine found similar increase.
CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome.

PubMed

Kanbayashi, Takashi; Kodama, Tohru; Kondo, Hideaki; Satoh, Shinsuke; Inoue, Yuichi; Chiba, Shigeru; Shimizu, Tetsuo; Nishino, Seiji

2009-02-01

To (1) replicate our prior result of low cerebrospinal fluid (CSF) histamine levels in human narcolepsy in a different sample population and to (2) evaluate if histamine contents are altered in other types of hypersomnia with and without hypocretin deficiency. Cross sectional studies. Sixty-seven narcolepsy subjects, 26 idiopathic hypersomnia (IHS) subjects, 16 obstructive sleep apnea syndrome (OSAS) subjects, and 73 neurological controls were included. All patients were Japanese. Diagnoses were made according to ICSD-2. We found significant reductions in CSF histamine levels in hypocretin deficient narcolepsy with cataplexy (mean +/- SEM; 176.0 +/- 25.8 pg/mL), hypocretin non-deficient narcolepsy with cataplexy (97.8 +/- 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (113.6 +/- 16.4 pg/mL), and idiopathic hypersomnia (161.0 +/- 29.3 pg/ mL); the levels in OSAS (259.3 +/- 46.6 pg/mL) did not statistically differ from those in the controls (333.8 +/- 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients; significant reductions in histamine levels were evident in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (112.1 +/- 16.3 pg/ mL) and idiopathic hypersomnia (143.3 +/- 28.8 pg/mL), while the levels in the medicated patients were in the normal range. The study confirmed reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin.
Presentations of primary hypersomnia in Chinese children.

PubMed

Han, Fang; Lin, Ling; Li, Jing; Aran, Adi; Dong, Song X; An, Pei; Zhao, Long; Li, Ming; Li, Qian Y; Yan, Han; Wang, Jie S; Gao, Hui Y; Li, Mei; Gao, Zhan C; Strohl, Kingman P; Mignot, Emmanuel

2011-05-01

To retrospectively describe childhood presentations of primary hypersomnia with an emphasis on narcolepsy-cataplexy in a Chinese population. A total of 417 children (< 18 years old) successively presenting with complaints of hypersomnia without anatomic cause or sleep apnea risk were evaluated using the Stanford Sleep Inventory, human leukocyte antigen (HLA) DQB1*0602 typing, and MSLT recordings. CSF hypocretin-1 was measured in 47 cases to document hypocretin deficiency. A subgroup ("narcolepsy/hypocretin deficiency") with likely hypocretin deficiency (low hypocretin-1 or HLA positive with clear-cut cataplexy) was further examined for presentations prior to, around, or after puberty. Narcolepsy with (n = 361) or without (n = 17) cataplexy presented at an earlier age and with increased male predominance when compared to idiopathic hypersomnia (n = 39, P < 0.01). Nearly 70% of those with narcolepsy/hypocretin deficiency (n = 271) had disease onset before age 10 y, and 15% had onset before age 6, an unusually young age distribution. Onset was prior to puberty in 78% of cases. Clinical features were similar in presentations across puberty groups except for sleep paralysis, which increased in frequency with age/puberty. Mean sleep latency (MSL) decreased and the number of sleep onset REM periods (SOREMPs) increased with age/puberty, but MSLT diagnosis criteria (MSL ≤ 8 min, ≥ 2 SOREMPs) were similarly positive across groups. Familial clustering was present in only 1.7% of probands. In children presenting with a complaint of primary hypersomnia to a sleep clinic in China, 86% (361/417) meet criteria for narcolepsy with cataplexy. Puberty did not affect positivity on the MSLT as a diagnostic feature. Sleep paralysis was the only symptom that increased with increasing age. In addition, narcolepsy with cataplexy in our clinic population appeared to begin at a younger age than usually reported in other studies.
Update on therapy for narcolepsy.

PubMed

Thorpy, Michael J

2015-05-01

Narcolepsy is a severe, incurable, neurological disorder that is treated by pharmacological management of its symptoms. The main symptoms are excessive daytime sleepiness (EDS) and cataplexy, although addition symptoms that may require treatment include sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. Sodium oxybate and modafinil/armodafinil are the first-line treatments for EDS, and sodium oxybate for cataplexy. Sodium oxybate treats all the symptoms of narcolepsy, whereas modafinil is effective for EDS only. Alternative medications for EDS include methylphenidate or amphetamines such as dextroamphetamine, lisdexamfetamine, methamphetamine, or combination amphetamine salts. Non-FDA approved medications for cataplexy include norepinephrine reuptake inhibitors such as venlafaxine or atomoxetine. Combination therapy can be more effective for sleepiness such as sodium oxybate and modafinil/armodafinil. Medication for narcolepsy is generally well tolerated and usually required life-long although does not eliminate all symptoms of narcolepsy.
REM sleep enhancement and behavioral cataplexy following orexin (hypocretin)-II receptor antisense perfusion in the pontine reticular formation.

PubMed

Thakkar, M M; Ramesh, V; Cape, E G; Winston, S; Strecker, R E; McCarley, R W

1999-01-01

Orexin (hypocretin)-containing neurons of the hypothalamus project to brainstem sites that are involved in the neural control of REM sleep, including the locus coeruleus, the dorsal raphe nucleus, the cholinergic zone of the mesopontine tegmentum, and the pontine reticular formation (PRF). Orexin knockout mice exhibit narcolepsy/cataplexy, and a mutant and defective gene for the orexin type II receptor is present in dogs with an inherited form of narcolepsy/cataplexy. However, the physiological systems mediating these effects have not been described. We reasoned that, since the effector neurons for the majority of REM sleep signs, including muscle atonia, were located in the PRF, this region was likely implicated in the production of these orexin-related abnormalities. To test this possibility, we used microdialysis perfusion of orexin type II receptor antisense in the PRF of rats. Ten to 24 hours after antisense perfusion, REM sleep increased two- to three-fold during both the light period (quiescent phase) and the dark period (active phase), and infrared video showed episodes of behavioral cataplexy. Moreover, preliminary data indicated no REM-related effects following perfusion with nonsense DNA, or when perfusion sites were outside the PRF. More work is needed to provide precise localization of the most effective site of orexin-induced inhibition of REM sleep phenomena.
Concomitant loss of dynorphin, NARP, and orexin in narcolepsy

PubMed Central

Crocker, Amanda; España, Rodrigo A.; Papadopoulou, Maria; Saper, Clifford B.; Faraco, Juliette; Sakurai, Takeshi; Honda, Makoto; Mignot, Emmanuel; Scammell, Thomas E.

2008-01-01

Background Narcolepsy with cataplexy is associated with a loss of orexin/hypocretin. It is speculated that an autoimmune process kills the orexin-producing neurons, but these cells may survive yet fail to produce orexin. Objective To examine whether other markers of the orexin neurons are lost in narcolepsy with cataplexy. Methods We used immunohistochemistry and in situ hybridization to examine the expression of orexin, neuronal activity-regulated pentraxin (NARP), and prodynorphin in hypothalami from five control and two narcoleptic individuals. Results In the control hypothalami, at least 80% of the orexin-producing neurons also contained prodynorphin mRNA and NARP. In the patients with narcolepsy, the number of cells producing these markers was reduced to about 5–10% of normal. Conclusions Narcolepsy with cataplexy is likely caused by a loss of the orexin-producing neurons. In addition, loss of dynorphin and NARP may contribute to the symptoms of narcolepsy. PMID:16247044
Levothyroxine Improves Subjective Sleepiness in a Euthyroid Patient with Narcolepsy without Cataplexy

PubMed Central

Sobol, Danielle L.; Spector, Andrew R.

2014-01-01

Objective: We discuss the use of levothyroxine for excessive daytime sleepiness (EDS) and prolonged nocturnal sleep time in a euthyroid patient with narcolepsy. Methods: After failure of first-line narcolepsy treatments, a 48-year-old female began levothyroxine (25 mcg/day). After 12 weeks of treatment, the patient was evaluated for improvement in total sleep time and subjective daytime sleepiness assessed by Epworth Sleepiness Scale (ESS). Results: At baseline, ESS score was 16 and total sleep time averaged 16 h/day. After 12 weeks, ESS was 13 and reported total sleep time was 13 h/day. Conclusions: Levothyroxine improved EDS and total sleep time in a euthyroid patient with narcolepsy without cataplexy after 12 weeks without side effects. Citation: Sobol DL, Spector AR. Levothyroxine improves subjective sleepiness in a euthyroid patient with narcolepsy without cataplexy. J Clin Sleep Med 2014;10(11):1231-1232. PMID:25325591
Benefit and risk of modafinil in idiopathic hypersomnia vs. narcolepsy with cataplexy.

PubMed

Lavault, Sophie; Dauvilliers, Yves; Drouot, Xavier; Leu-Semenescu, Smaranda; Golmard, Jean-Louis; Lecendreux, Michel; Franco, Patricia; Arnulf, Isabelle

2011-06-01

The benefit/risk ratio of modafinil was recently re-evaluated by the European Medicines Agency and was shown to be negative for idiopathic hypersomnia (IH) because of insufficient data. To evaluate the benefit/risk ratio of modafinil in idiopathic hypersomnia (with and without long sleep time) vs. narcolepsy/cataplexy. The benefit (Epworth sleepiness score, ESS; visual analog scale, patient and clinician opinions) and risks (habituation, adverse effects) of modafinil were studied in a consecutive clinical cohort of 104 IH patients (59 with long sleep time) and 126 patients with narcolepsy/cataplexy. Modafinil was the first line treatment in 96-99% of patients. It produced a similar ESS change in IH patients and in narcolepsy patients (-2.6±5.1 vs. -3±5.1) and a similar benefit as estimated by the patients (6.9±2.7 vs. 6.5±2.5 on a visual analog scale) and clinicians. The ESS change was lower in IH patients with long sleep time than in those without. Sudden loss of efficacy and habituation were rare in both groups. Patients with IH reported similar but more frequent adverse effects with modafinil than narcolepsy patients: nervousness (14%), palpitations (13%), and headache (11%). Modafinil has an excellent benefit/risk ratio in idiopathic hypersomnia, with or without long sleep time, similar to its effect on narcolepsy/cataplexy. Copyright © 2011 Elsevier B.V. All rights reserved.
Update on the treatment of narcolepsy: clinical efficacy of pitolisant

PubMed Central

Calik, Michael W

2017-01-01

Narcolepsy is a neurological disease that affects 1 in 2,000 individuals and is characterized by excessive daytime sleepiness (EDS). In 60–70% of individuals with narcolepsy, it is also characterized by cataplexy or a sudden loss of muscle tone that is triggered by positive or negative emotions. Narcolepsy decreases the quality of life of the afflicted individuals. Currently used drugs treat EDS alone (modafinil/armodafinil, methylphenidate, and amphetamine), cataplexy alone (“off-label” use of antidepressants), or both EDS and cataplexy (sodium oxybate). These drugs have abuse, tolerability, and adherence issues. A greater diversity of drug options is needed to treat narcolepsy. The small molecule drug, pitolisant, acts as an inverse agonist/antagonist at the H3 receptor, thus increasing histaminergic tone in the wake promoting system of the brain. Pitolisant has been studied in animal models of narcolepsy and used in clinical trials as a treatment for narcolepsy. A comprehensive search of online databases (eg, Medline, PubMed, EMBASE, the Cochrane Library Database, Ovid MEDLINE, Europe PubMed Central, EBSCOhost CINAHL, ProQuest Research Library, Google Scholar, and ClinicalTrials.gov) was performed. Nonrandomized and randomized studies were included. This review focuses on the outcomes of four clinical trials of pitolisant to treat narcolepsy. These four trials show that pitolisant is an effective drug to treat EDS and cataplexy in narcolepsy. PMID:28490912
Efficiency of a Combination of Pharmacological Treatment and Nondrug Interventions in Childhood Narcolepsy.

PubMed

Kacar Bayram, Ayşe; Per, Hüseyin; Ismailoğullari, Sevda; Canpolat, Mehmet; Gumus, Hakan; Aksu, Murat

2016-12-01

Objective Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic and/or hypnopompic hallucinations, and sleep paralysis. It is one of the most important causes of excessive daytime sleepiness in the pediatric population. The aim of this study is to present the clinical and laboratory findings, and treatment results of pediatric patients with narcolepsy. Materials and Methods We studied five unrelated consecutive children with narcolepsy, focusing on clinical and laboratory features, the therapy and outcome over the 33-month follow-up period. Results The study subjects included two boys and three girls. The mean age at diagnosis was 11.8 ± 3.3 years (range: 8-16 years). Three patients had cataplexy. There were no hypnagogic hallucinations and/or sleep paralysis in any patients. All patients were educated about sleep hygiene, appropriate nutrition, and regular exercise. Three patients were treated with modafinil, while two patients received methylphenidate. Sodium oxybate was added to existing treatment in patients with cataplexy. Cataplexy attacks did not respond well to the treatment in one patient; therefore intravenous immunoglobulin therapy was given. Conclusions Early diagnosis is important to help narcoleptic patients in improving their quality of life. A combination of pharmacological treatment and nondrug interventions can greatly improve children's clinical symptoms. Georg Thieme Verlag KG Stuttgart · New York.

Differences in Brain Morphological Findings between Narcolepsy with and without Cataplexy

PubMed Central

Nakamura, Masaki; Nishida, Shingo; Hayashida, Kenichi; Ueki, Yoichiro; Dauvilliers, Yves; Inoue, Yuichi

2013-01-01

Objective Maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) obtained by diffusion tensor imaging (DTI) can detect microscopic axonal changes by estimating the diffusivity of water molecules using magnetic resonance imaging (MRI). We applied an MRI voxel-based statistical approach to FA and ADC maps to evaluate microstructural abnormalities in the brain in narcolepsy and to investigate differences between patients having narcolepsy with and without cataplexy. Methods Twelve patients with drug-naive narcolepsy with cataplexy (NA/CA), 12 with drug-naive narcolepsy without cataplexy (NA w/o CA) and 12 age-matched healthy normal controls (NC) were enrolled. FA and ADC maps for these 3 groups were statistically compared by using voxel-based one-way ANOVA. In addition, we investigated the correlation between FA and ADC values and clinical variables in the patient groups. Results Compared to the NC group, the NA/CA group showed higher ADC values in the left inferior frontal gyrus and left amygdala, and a lower ADC value in the left postcentral gyrus. The ADC value in the right inferior frontal gyrus and FA value in the right precuneus were higher for NA/CA group than for the NA w/o CA group. However, no significant differences were observed in FA and ADC values between the NA w/o CA and NC groups in any of the areas investigated. In addition, no correlation was found between the clinical variables and ADC and FA values of any brain areas in these patient groups. Conclusions Several microstructural changes were noted in the inferior frontal gyrus and amygdala in the NA/CA but not in the NA w/o CA group. These findings suggest that these 2 narcolepsy conditions have different pathological mechanisms: narcolepsy without cataplexy form appears to be a potentially broader condition without any significant brain imaging differences from normal controls. PMID:24312261
Depression: relationships to sleep paralysis and other sleep disturbances in a community sample

PubMed Central

Szklo-Coxe, Mariana; Young, Terry; Finn, Laurel; Mignot, Emmanuel

2009-01-01

SUMMARY Sleep disturbances are important correlates of depression, with epidemiologic research heretofore focused on insomnia and sleepiness. This epidemiologic study’s aim was to investigate, in a community sample, depression’s relationships to other sleep disturbances: sleep paralysis (SP), hypnagogic/hypnopompic hallucinations (HH), cataplexy – considered rapid eye movement-related disturbances – and automatic behavior (AB). Although typical of narcolepsy, these disturbances are prevalent, albeit under-studied, in the population. Cross-sectional analyses (1998–2002), based on Wisconsin Sleep Cohort Study population-based data from 866 participants (mean age 54, 53% male), examined: depression (Zung Self-Rating Depression Scale), trait anxiety (Spielberger State-Trait Anxiety Inventory, STAI-T ≥ 75th percentile), and self-reported sleep disturbances. Descriptive sleep data were obtained by overnight polysomnography. Adjusted logistic regression models estimated depression’s associations with each (>few times ever) outcome – SP, HH, AB, and cataplexy. Depression’s associations with self-reported SP and cataplexy were not explained by anxiety. After anxiety adjustment, severe depression (Zung ≥55), vis-à-vis Zung <50, increased SP odds ~500% (P = 0.0008). Depression (Zung ≥50), after stratification by anxiety given an interaction (P = 0.02), increased self-reported cataplexy odds in non-anxious (OR 8.9, P = 0.0008) but not anxious (OR 1.1, P = 0.82) participants. Insomnia and sleepiness seemed only partial mediators or confounders for depression’s associations with self-reported cataplexy and SP. Anxiety (OR 1.9, P = 0.04) partially explained depression’s (Zung ≥55) association with HH (OR 2.2, P = 0.08). Anxiety (OR 1.6, P = 0.02) was also more related than depression to AB. Recognizing depression’s relationships to oft-neglected sleep disturbances, most notably SP, might assist in better characterizing depression and the full range of its associated sleep problems in the population. Longitudinal studies are warranted to elucidate mediators and causality. PMID:17716279
Childhood narcolepsy with cataplexy: comparison between post-H1N1 vaccination and sporadic cases.

PubMed

Pizza, Fabio; Peltola, Hanna; Sarkanen, Tomi; Moghadam, Keivan K; Plazzi, Giuseppe; Partinen, Markku

2014-02-01

We aimed to compare post-Pandemrix vaccination (postvaccine) childhood narcolepsy with cataplexy (NC) vs. sporadic pre-H1N1 pandemic (pre-H1N1) cases. Clinical, anthropometric, polysomnographic, and cerebrospinal hypocretin 1 (hcrt-1) measurements were collected together with the video recordings of cataplexy in 27 Finnish patients with NC onset after H1N1 Pandemrix vaccination (mean age, 12±4 years; 52% boys) and 42 Italian NC patients with NC onset before the H1N1 pandemic (mean age, 11±3 years; 48% boys). All subjects carried the HLA-DQB1*0602 allele. Postvaccine subjects were older at NC onset (12±3 vs. 9±3 years; P=.008) and displayed a shorter mean sleep latency in multiple sleep latency tests (MSLT) (2.3±2.2 vs. 3.7±2.9 min; P=.026) compared to pre-H1N1 cases. Anthropometric, clinical (core NC symptoms), hcrt-1 deficiency, and polysomnographic data did not differ among groups, but higher disrupted nocturnal sleep was observed in postvaccine subjects. Comparison of cataplexy features at video assessment showed an overlapping picture with the exception for hyperkinetic movements which appeared to be more evident in pre-H1N1 subjects. The clinical picture of childhood NC was similar in postvaccine and pre-H1N1 children. Copyright © 2013 Elsevier B.V. All rights reserved.
Medical exposures in youth and the frequency of narcolepsy with cataplexy: a population-based case-control study in genetically predisposed people

PubMed Central

Koepsell, Thomas D.; Longstreth, William T.; Ton, Thanh G. N.

2012-01-01

SUMMARY Epidemiological observations suggest that exposures in youth may trigger narcolepsy in genetically predisposed individuals. In this population-based case–control study, we sought to identify all prevalent cases of narcolepsy with cataplexy aged 18–50 years as of 1 July 2001, in King County, Washington. The 45 eligible cases who were DQB1*0602-positive were compared with 95 controls with this allele, identified through random-digit dialing and buccal smears. Cases and controls were interviewed in person about physician-diagnosed infectious and non-infectious illnesses, immunizations, head trauma and parasomnias or psychiatric problems during youth. Narcolepsy with cataplexy was more frequent in African-Americans and in poorer households. Adjusting for these factors, the condition was 5.4-fold more common [95% confidence interval (CI) = 1.5–19.1] among people reporting a physician-diagnosed strep throat before the age of 21 years. No other significant associations with childhood diseases, immunizations or head trauma were found. However, prevalence was increased 16.3-fold (95% CI = 6.1–44.1) in subjects who reported having had ‘night terrors’. Strep throat may be related to narcolepsy with cataplexy in genetically susceptible individuals. The association with night terrors could simply reflect early symptoms of narcolepsy, or they could be a prodromal sign of disturbed sleep physiology. keywords epidemiology, head injuries, immunization, narcolepsy, night terrors, streptococcal infections PMID:19732319
Abnormal activity in reward brain circuits in human narcolepsy with cataplexy.

PubMed

Ponz, Aurélie; Khatami, Ramin; Poryazova, Rositsa; Werth, Esther; Boesiger, Peter; Bassetti, Claudio L; Schwartz, Sophie

2010-02-01

Hypothalamic hypocretins (or orexins) regulate energy metabolism and arousal maintenance. Recent animal research suggests that hypocretins may also influence reward-related behaviors. In humans, the loss of hypocretin-containing neurons results in a major sleep-wake disorder called narcolepsy-cataplexy, which is associated with emotional disturbances. Here, we aim to test whether narcoleptic patients show an abnormal pattern of brain activity during reward processing. We used functional magnetic resonance imaging in 12 unmedicated patients with narcolepsy-cataplexy to measure the neural responses to expectancy and experience of monetary gains and losses. We statistically compared the patients' data with those obtained in a group of 12 healthy matched controls. Our results reveal that activity in the dopaminergic ventral midbrain (ventral tegmental area) was not modulated in narcolepsy-cataplexy patients during high reward expectancy (unlike controls), and that ventral striatum activity was reduced during winning. By contrast, the patients showed abnormal activity increases in the amygdala and in dorsal striatum for positive outcomes. In addition, we found that activity in the nucleus accumbens and the ventral-medial prefrontal cortex correlated with disease duration, suggesting that an alternate neural circuit could be privileged over the years to control affective responses to emotional challenges and compensate for the lack of influence from ventral midbrain regions. Our study offers a detailed picture of the distributed brain network involved during distinct stages of reward processing and shows for the first time, to our knowledge, how this network is affected in hypocretin-deficient narcoleptic patients.
Rare missense mutations in P2RY11 in narcolepsy with cataplexy.

PubMed

Degn, Matilda; Dauvilliers, Yves; Dreisig, Karin; Lopez, Régis; Pfister, Corinne; Pradervand, Sylvain; Rahbek Kornum, Birgitte; Tafti, Mehdi

2017-06-01

The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients. No mutations were found in healthy controls. Six of the eight narcolepsy-associated P2Y11 mutations resulted in significant functional deficits in P2Y11 signalling through both Ca2+ and cAMP signalling pathways. In conclusion, our data show that decreased P2Y11 signalling plays an important role in the development of narcolepsy with cataplexy. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
CSF Histamine Contents in Narcolepsy, Idiopathic Hypersomnia and Obstructive Sleep Apnea Syndrome

PubMed Central

Kanbayashi, Takashi; Kodama, Tohru; Kondo, Hideaki; Satoh, Shinsuke; Inoue, Yuichi; Chiba, Shigeru; Shimizu, Tetsuo; Nishino, Seiji

2009-01-01

Study Objective: To (1) replicate our prior result of low cerebrospinal fluid (CSF) histamine levels in human narcolepsy in a different sample population and to (2) evaluate if histamine contents are altered in other types of hypersomnia with and without hypocretin deficiency. Design: Cross sectional studies. Setting and Patients: Sixty-seven narcolepsy subjects, 26 idiopathic hypersomnia (IHS) subjects, 16 obstructive sleep apnea syndrome (OSAS) subjects, and 73 neurological controls were included. All patients were Japanese. Diagnoses were made according to ICSD-2. Results: We found significant reductions in CSF histamine levels in hypocretin deficient narcolepsy with cataplexy (mean ± SEM; 176.0 ± 25.8 pg/mL), hypocretin non-deficient narcolepsy with cataplexy (97.8 ± 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (113.6 ± 16.4 pg/mL), and idiopathic hypersomnia (161.0 ± 29.3 pg/mL); the levels in OSAS (259.3 ± 46.6 pg/mL) did not statistically differ from those in the controls (333.8 ± 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients; significant reductions in histamine levels were evident in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (112.1 ± 16.3 pg/mL) and idiopathic hypersomnia (143.3 ± 28.8 pg/mL), while the levels in the medicated patients were in the normal range. Conclusion: The study confirmed reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin. Citation: Kanbayashi T; Kodama T; Kondo H; Satoh S; Inoue Y; Chiba S; Shimizu T; Nishino S. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. SLEEP 2009;32(2):181–187. PMID:19238805
Presentations of Primary Hypersomnia in Chinese Children

PubMed Central

Han, Fang; Lin, Ling; Li, Jing; Aran, Adi; Dong, Song X.; An, Pei; Zhao, Long; Li, Ming; Li, Qian Y.; Yan, Han; Wang, Jie S.; Gao, Hui Y.; Li, Mei; Gao, Zhan C.; Strohl, Kingman P.; Mignot, Emmanuel

2011-01-01

Objective: To retrospectively describe childhood presentations of primary hypersomnia with an emphasis on narcolepsy-cataplexy in a Chinese population. Methods: A total of 417 children (< 18 years old) successively presenting with complaints of hypersomnia without anatomic cause or sleep apnea risk were evaluated using the Stanford Sleep Inventory, human leukocyte antigen (HLA) DQB1*0602 typing, and MSLT recordings. CSF hypocretin-1 was measured in 47 cases to document hypocretin deficiency. A subgroup (“narcolepsy/hypocretin deficiency”) with likely hypocretin deficiency (low hypocretin-1 or HLA positive with clear-cut cataplexy) was further examined for presentations prior to, around, or after puberty. Results: Narcolepsy with (n = 361) or without (n = 17) cataplexy presented at an earlier age and with increased male predominance when compared to idiopathic hypersomnia (n = 39, P < 0.01). Nearly 70% of those with narcolepsy/hypocretin deficiency (n = 271) had disease onset before age 10 y, and 15% had onset before age 6, an unusually young age distribution. Onset was prior to puberty in 78% of cases. Clinical features were similar in presentations across puberty groups except for sleep paralysis, which increased in frequency with age/puberty. Mean sleep latency (MSL) decreased and the number of sleep onset REM periods (SOREMPs) increased with age/puberty, but MSLT diagnosis criteria (MSL ≤ 8 min, ≥ 2 SOREMPs) were similarly positive across groups. Familial clustering was present in only 1.7% of probands. Conclusion: In children presenting with a complaint of primary hypersomnia to a sleep clinic in China, 86% (361/417) meet criteria for narcolepsy with cataplexy. Puberty did not affect positivity on the MSLT as a diagnostic feature. Sleep paralysis was the only symptom that increased with increasing age. In addition, narcolepsy with cataplexy in our clinic population appeared to begin at a younger age than usually reported in other studies. Citation: Han F; Lin L; Li J; Aran A; Dong SX; An P; Zhao L; Li M; Li QY; Yan H; Wang JS; Gao HY; Li M; Gao ZC; Strohl KP; Mignot E. Presentations of primary hypersomnia in Chinese children. SLEEP 2011;34(5):627-632. PMID:21532956
Health-related quality of life among drug-naïve patients with narcolepsy with cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia without long sleep time.

PubMed

Ozaki, Akiko; Inoue, Yuichi; Nakajima, Toru; Hayashida, Kenichi; Honda, Makoto; Komada, Yoko; Takahashi, Kiyohisa

2008-12-15

To evaluate the health-related quality life (HRQOL) of drug-naïve patients with narcolepsy with cataplexy (NAwith CA), narcolepsy without cataplexy (NA without CA) and idiopathic hypersomnia without long sleep time (IHS without LST), and to explore the factors influencing the HRQOL. Factors associated with the occurrence of automobile accidents are also discussed. A total of 137 consecutive drug naïve patients who met the criteria of the 2nd edition of the International Classification of Sleep Disorders (NA with CA, n = 28; NA without CA, n = 27; IHS without LST, n = 82) were enrolled. The patients were asked to fill out questionnaires, including the SF-36, Epworth Sleepiness Scale (ESS), sociodemographic variables, and items regarding driving habits and the experiences related to automobile accidents. All 3 diagnostic groups had significantly lower scores in most SF-36 domains compared with Japanese normative data. Significant differences among the 3 diagnostic groups were not observed. Specific factors in SF-36 domains were not found with multiple linear regression analyses, while disease duration was positively correlated with mental health among all subjects. Among the patients reporting driving habits, ESS score (> or =16) was positively associated with the experience of automobile accidents. Our results indicated that HRQOL decreases in drug-naïve patients with hypersomnia, but neither disease category nor severity of the disorder appears as an associated factor. Increased severity of hypersomnia, however, was thought to play an important role in the occurrence of automobile accidents.
HYPOCRETIN/OREXIN AND NARCOLEPSY NEW BASIC AND CLINICAL INSIGHTS

PubMed Central

NISHINO, Seiji; OKURO, Masashi; KOTORII, Nozomu; ANEGAWA, Emiko; ISHIMARU, Yuji; MATSUMURA, Mari; KANBAYASHI, Takashi

2009-01-01

Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Both sporadic (95%) and familial (5%) forms of narcolepsy exist in humans. The major pathophysiology of human narcolepsy has been recently discovered based on the discovery of narcolepsy genes in animals; the genes involved in the pathology of the hypocretin/orexin ligand and its receptor. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in a large majority of narcolepsy with cataplexy. Hypocretin ligand deficiency in human narcolepsy is likely due to the postnatal cell death of hypocretin neurons. Although tight association between human leukocyte antigen (HLA) association and human narcolepsy with cataplexy suggests an involvement of autoimmune mechanisms, this has not yet been proven. Hypocretin deficiency is also found in symptomatic cases of narcolepsy and EDS with various neurological conditions, including immune-mediated neurological disorders, such as Guillain-Barre syndrome, MA2-positive paraneoplastic syndrome and neuromyelitis optica (NMO) related disorder. These findings likely have significant clinical relevance and for understanding the mechanisms of hypocretin cell death and choice of treatment option. These series of discoveries in humans lead to the establishment of the new diagnostic test of narcolepsy (i.e. low cerebrospinal fluid [CSF] hypocretin-1 levels for narcolepsy with cataplexy and narcolepsy due to medical condition). Since a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress. PMID:19555382
Polymorphism Located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 Haplotype Confer Susceptibility to CNS Hypersomnias (Essential Hypersomnia)

PubMed Central

Miyagawa, Taku; Honda, Makoto; Kawashima, Minae; Shimada, Mihoko; Tanaka, Susumu; Honda, Yutaka; Tokunaga, Katsushi

2009-01-01

Background SNP rs5770917 located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype were previously identified as susceptibility loci for narcolepsy with cataplexy. This study was conducted in order to investigate whether these genetic markers are associated with Japanese CNS hypersomnias (essential hypersomnia: EHS) other than narcolepsy with cataplexy. Principal Findings EHS was significantly associated with SNP rs5770917 (Pallele = 3.6×10−3; OR = 1.56; 95% c.i.: 1.12–2.15) and HLA-DRB1*1501-DQB1*0602 haplotype (P positivity = 9.2×10−11; OR = 3.97; 95% c.i.: 2.55–6.19). No interaction between the two markers (SNP rs5770917 and HLA-DRB1*1501-DQB1*0602 haplotype) was observed in EHS. Conclusion CPT1B, CHKB and HLA are candidates for susceptibility to CNS hypersomnias (EHS), as well as narcolepsy with cataplexy. PMID:19404393
PubMed

Monaca, C; Franco, P; Philip, P; Dauvilliers, Y

In the new international classification of sleep disorders (ICSD-3), narcolepsy is differentiated into two distinct pathologies: type 1 narcolepsy (NT1) and type 2 narcolepsy (NT2). NT1 is characterised by periods of an irrepressible need to sleep, cataplexy (a sudden loss of muscle tone triggered by emotion) and in some cases the presence of symptoms such as hypnagogic hallucinations, sleep paralysis and disturbed night-time sleep. Its physiopathology is based on the loss of hypocretin neurons in the hypothalamus, seemingly connected to an auto-immune process. By definition, cataplexy is absent and the hypocretin levels in the CSF are normal in NT2. Confirming the diagnosis requires polysomnography and multiple sleep latency tests. The choice of further investigations is based on the presence or absence of typical cataplexy. Further investigations include HLA typing, lumbar puncture to measure the hypocretin level in the CSF, or even brain imagery in the case of narcolepsy suspected to be secondary to an underlying pathology. In this consensus we propose recommendations for the work-up to be carried out during diagnosis and follow-up for patients suffering from narcolepsy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
[Narcolepsy with cataplexy: an autoimmune disease?].

PubMed

Jacob, Louis; Dauvilliers, Yves

2014-12-01

Narcolepsy type 1 (also named narcolepsy-cataplexy or hypocretin deficiency syndrome) is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy, plus frequently hypnagogic hallucinations, sleep paralysis and nocturnal sleep disturbances. Narcolepsy type 1 is an immune system-associated disease linked with the destruction of 70.000-90.000 hypocretin neurons notably involved in wakefulness. Among narcoleptic patients, 98% are positive for HLA-DQB1*06:02, a HLA class II allele, against 20-25% in general population. Individuals carrying HLA-DQB1*06:02 have an extraordinary risk to develop narcolepsy (odd ratio: 251). Other genes involved in CD4+ T cells and immune system activation as T-cell receptor α are also associated with narcolepsy. The development of the disease is linked with environmental factors such as influenza and streptococcal infections. Narcolepsy type 1 incidence also increased in Europe following the use of Pandemrix, a 2009 H1N1 AS03-adjuvanted vaccine manufactured by GlaxoSmithKline. Interestingly, such increase was not observed with Arepanrix, another vaccine developed by GSK very similar to Pandemrix. © 2014 médecine/sciences – Inserm.
Paraneoplastic limbic encephalitis and possible narcolepsy in a patient with testicular cancer: case study.

PubMed Central

Landolfi, Joseph C.; Nadkarni, Mangala

2003-01-01

We describe a patient who presented with a clinical syndrome of limbic encephalitis, narcolepsy, and cataplexy. The anti-Ma2 antibody was positive. Although there was no mass on imaging, orchiectomy was performed in this patient, and testicular carcinoma was found. This is the first known case of limbic encephalitis and anti-Ma2 antibody to be associated with cataplexy and possible narcolepsy. Neurological symptoms precede the diagnosis of cancer in 50% of patients with paraneoplastic syndromes, and clinicians are therefore strongly advised to evaluate patients with neurological symptoms for this condition. PMID:12816728
Environmental factors in the development of narcolepsy with cataplexy. A case-control study.

PubMed

Peraita-Adrados, R; del Rio-Villegas, R; Vela-Bueno, A

2015-06-16

Epidemiological studies suggest the importance of environmental factors in the etiology of narcolepsy-cataplexy in genetically predisposed subjects. To assess the role of environmental factors in the development of narcolepsy-cataplexy, using a case-control design with control subjects being matched for ethnicity and age. All patients were recruited through two outpatient clinics at the community of Madrid, ant the diagnosis of narcolepsy fulfilled the criteria of the International Classification on Sleep Disorders-2005. A questionnaire, including 54 environmental psychological stressor life events and 42 infectious diseases items, was administered to 54 patients. We specifically assessed the stressful factors and infectious diseases that occurred in the year preceding the onset of the first symptom of narcolepsy (excessive daytime sleepiness and/or cataplexy). The same questionnaire was administered to 84 control subjects recruited from non-related family members of the same community. Fifty four patients (55.6% males) answered the questionnaire, The mean age at onset of the first symptom was 21.6 ± 9.3 years, and the mean age at diagnosis was 36.5 ± 12.4 years. The main finding in narcoleptic patients as compared to control subjects was major changes in the 'number of arguments with partner, family, or friends' (odds ratio: 5.2; 95% confidence interval: 1.8-14.5). This can be interpreted as having a protective function and it suggests that psychological mechanisms are present since the beginning of the disease. As for the infectious factors, chickenpox was the most frequently reported. No significant differences were found in terms of total numbers of stress-related and infectious factors between cases and controls. Prospective studies regarding the interaction between environmental and genetic factors are warranted.
Test-Retest Reliability of the Multiple Sleep Latency Test in Narcolepsy without Cataplexy and Idiopathic Hypersomnia

PubMed Central

Trotti, Lynn Marie; Staab, Beth A.; Rye, David B.

2013-01-01

Study Objectives: Differentiation of narcolepsy without cataplexy from idiopathic hypersomnia relies entirely upon the multiple sleep latency test (MSLT). However, the test-retest reliability for these central nervous system hypersomnias has never been determined. Methods: Patients with narcolepsy without cataplexy, idiopathic hypersomnia, and physiologic hypersomnia who underwent two diagnostic multiple sleep latency tests were identified retrospectively. Correlations between the mean sleep latencies on the two studies were evaluated, and we probed for demographic and clinical features associated with reproducibility versus change in diagnosis. Results: Thirty-six patients (58% women, mean age 34 years) were included. Inter -test interval was 4.2 ± 3.8 years (range 2.5 months to 16.9 years). Mean sleep latencies on the first and second tests were 5.5 (± 3.7 SD) and 7.3 (± 3.9) minutes, respectively, with no significant correlation (r = 0.17, p = 0.31). A change in diagnosis occurred in 53% of patients, and was accounted for by a difference in the mean sleep latency (N = 15, 42%) or the number of sleep onset REM periods (N = 11, 31%). The only feature predictive of a diagnosis change was a history of hypnagogic or hypnopompic hallucinations. Conclusions: The multiple sleep latency test demonstrates poor test-retest reliability in a clinical population of patients with central nervous system hypersomnia evaluated in a tertiary referral center. Alternative diagnostic tools are needed. Citation: Trotti LM; Staab BA; Rye DB. Test- retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J Clin Sleep Med 2013;9(8):789-795. PMID:23946709
Allergies and Disease Severity in Childhood Narcolepsy: Preliminary Findings.

PubMed

Aydinoz, Secil; Huang, Yu-Shu; Gozal, David; Inocente, Clara O; Franco, Patricia; Kheirandish-Gozal, Leila

2015-12-01

Narcolepsy frequently begins in childhood, and is characterized by excessive daytime sleepiness, with the presence of cataplexy reflecting a more severe phenotype. Narcolepsy may result from genetic predisposition involving deregulation of immune pathways, particularly involving T helper 2 cells (Th2). Increased activation of Th2 cells is usually manifested as allergic conditions such as rhinitis, atopic dermatitis, and asthma. We hypothesized that the presence of allergic conditions indicative of increased Th2 balance may dampen the severity of the phenotype in children with narcolepsy. A retrospective chart review of childhood narcolepsy patients was conducted at three major pediatric sleep centers. Patients were divided into those with narcolepsy without cataplexy (NC-) and narcolepsy with cataplexy (NC+). Demographics, polysomnographic and multiple sleep latency test data, and extraction of information on the presence of allergic diseases such allergic rhinitis, atopic dermatitis, and asthma was performed. There were 468 children identified, with 193 children in NC- group and 275 patients in the NC+ group. Overall, NC+ children were significantly younger, had higher body mass index, and had shorter mean sleep latencies and increased sleep onset rapid eye movement events. The frequency of allergic conditions, particularly asthma and allergic rhinitis, was markedly lower in NC+ (58/275) compared to NC- patients (94/193; P < 0.0001). Involvement of the immune system plays an important role in the pathophysiology of narcolepsy. Current findings further suggest that an increased shift toward T helper 2 cells, as indicated by the presence of allergic conditions, may modulate the severity of the phenotype in childhood narcolepsy, and reduce the prevalence of cataplexy in these patients. © 2015 Associated Professional Sleep Societies, LLC.
Narcolepsy in African Americans.

PubMed

Kawai, Makoto; O'Hara, Ruth; Einen, Mali; Lin, Ling; Mignot, Emmanuel

2015-11-01

Although narcolepsy affects 0.02-0.05% of individuals in various ethnic groups, clinical presentation in different ethnicities has never been fully characterized. Our goal was to study phenotypic expression across ethnicities in the United States. Cases of narcolepsy from 1992 to 2013 were identified from searches of the Stanford Center for Narcolepsy Research database. International Classification of Sleep Disorders, Third Edition diagnosis criteria for type 1 and type 2 narcolepsy were used for inclusion, but subjects were separated as with and without cataplexy for the purpose of data presentation. Information extracted included demographics, ethnicity and clinical data, HLA-DQB1*06:02, polysomnography (PSG), multiple sleep latency test (MSLT) data, and cerebrospinal fluid (CSF) hypocretin-1 level. 182 African-Americans, 839 Caucasians, 35 Asians, and 41 Latinos with narcolepsy. Sex ratio, PSG, and MSLT findings did not differ across ethnicities. Epworth Sleepiness Scale (ESS) score was higher and age of onset of sleepiness earlier in African Americans compared with other ethnicities. HLA-DQB1*06:02 positivity was higher in African Americans (91.0%) versus others (76.6% in Caucasians, 80.0% in Asians, and 65.0% in Latinos). CSF hypocretin-1 level, obtained in 222 patients, was more frequently low (≤ 110 pg/ml) in African Americans (93.9%) versus Caucasians (61.5%), Asians (85.7%) and Latinos (75.0%). In subjects with low CSF hypocretin-1, African Americans (28.3%) were 4.5 fold more likely to be without cataplexy when compared with Caucasians (8.1%). Narcolepsy in African Americans is characterized by earlier symptom onset, higher Epworth Sleepiness Scale score, higher HLA-DQB1*06:02 positivity, and low cerebrospinal fluid hypocretin-1 level in the absence of cataplexy. In African Americans, more subjects without cataplexy have type 1 narcolepsy. © 2015 Associated Professional Sleep Societies, LLC.
Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity.

PubMed

Hasegawa, Emi; Maejima, Takashi; Yoshida, Takayuki; Masseck, Olivia A; Herlitze, Stefan; Yoshioka, Mitsuhiro; Sakurai, Takeshi; Mieda, Michihiro

2017-04-25

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing.
Orexin neurons suppress narcolepsy via 2 distinct efferent pathways

PubMed Central

Hasegawa, Emi; Yanagisawa, Masashi; Sakurai, Takeshi; Mieda, Michihiro

2014-01-01

The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron–dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy. PMID:24382351

Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity

PubMed Central

Hasegawa, Emi; Maejima, Takashi; Yoshida, Takayuki; Herlitze, Stefan; Yoshioka, Mitsuhiro; Sakurai, Takeshi; Mieda, Michihiro

2017-01-01

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing. PMID:28396432
Narcolepsy and Predictors of Positive MSLTs in the Wisconsin Sleep Cohort

PubMed Central

Goldbart, Aviv; Peppard, Paul; Finn, Laurel; Ruoff, Chad M.; Barnet, Jodi; Young, Terry; Mignot, Emmanuel

2014-01-01

Study Objectives: To study whether positive multiple sleep latency tests (MSLTs, mean sleep latency [MSL] ≤ 8 minutes, ≥ 2 sleep onset REM sleep periods [SOREMPs]) and/or nocturnal SOREMP (REM sleep latency ≤ 15 minutes during nocturnal polysomonography [NPSG]) are stable traits and can reflect incipient narcolepsy. Design and Setting: Cross-sectional and longitudinal investigation of the Wisconsin Sleep Cohort Study. Participants: Adults (44% females, 30-81 years) underwent NPSG (n = 4,866 in 1,518 subjects), and clinical MSLT (n = 1,135), with 823 having a repeat NPSG-MSLT at 4-year intervals, totaling 1725 NPSG with MSLT studies. Data were analyzed using linear mixed-effects models, and the stability of positive MSLTs was explored using κ statistics. Measurements and Results: Prevalence of a nocturnal SOREMP on a NPSG, of ≥ 2 SOREMPs on the MSLT, of MSL ≤ 8 minutes on the MSLT, and of a positive MSLT (MSL ≤ 8 minutes plus ≥ 2 SOREMPs) were 0.35%, 7.0%, 22%, and 3.4%, respectively. Correlates of a positive MSLT were shift work (OR = 7.8, P = 0.0001) and short sleep (OR = 1.51/h, P = 0.04). Test-retest for these parameters was poor, with κ < 0.2 (n.s.) after excluding shift workers and short sleepers. Excluding shift-work, short sleep, and subjects with negative MSLTs, we found one undiagnosed subject with possible cataplexy (≥ 1/month) and a NPSG SOREMPs; one subject previously diagnosed with narcolepsy without cataplexy with 2 NPSG SOREMPs and a positive MSLT, and two subjects with 2 independently positive MSLTs (66% human leukocyte antigen [HLA] positive). The proportions for narcolepsy with and without cataplexy were 0.07% (95% CI: 0.02-0.37%) and 0.20% (95% CI: 0.07-0.58%), respectively. Conclusions: The diagnostic value of multiple sleep latency tests is strongly altered by shift work and to a lesser extent by chronic sleep deprivation. The prevalence of narcolepsy without cataplexy may be 3-fold higher than that of narcolepsy-cataplexy. Citation: Goldbart A, Peppard P, Finn L, Ruoff CM, Barnet J, Young T, Mignot E. Narcolepsy and predictors of positive MSLTs in the Wisconsin Sleep Cohort. SLEEP 2014;37(6):1043-1051. PMID:24882899
Challenges in the development of therapeutics for narcolepsy.

PubMed

Black, Sarah Wurts; Yamanaka, Akihiro; Kilduff, Thomas S

2017-05-01

Narcolepsy is a neurological disorder that afflicts 1 in 2000 individuals and is characterized by excessive daytime sleepiness and cataplexy-a sudden loss of muscle tone triggered by positive emotions. Features of narcolepsy include dysregulation of arousal state boundaries as well as autonomic and metabolic disturbances. Disruption of neurotransmission through the hypocretin/orexin (Hcrt) system, usually by degeneration of the HCRT-producing neurons in the posterior hypothalamus, results in narcolepsy. The cause of Hcrt neurodegeneration is unknown but thought to be related to autoimmune processes. Current treatments for narcolepsy are symptomatic, including wake-promoting therapeutics that increase presynaptic dopamine release and anticataplectic agents that activate monoaminergic neurotransmission. Sodium oxybate is the only medication approved by the US Food and Drug Administration that alleviates both sleep/wake disturbances and cataplexy. Development of therapeutics for narcolepsy has been challenged by historical misunderstanding of the disease, its many disparate symptoms and, until recently, its unknown etiology. Animal models have been essential to elucidating the neuropathology underlying narcolepsy. These models have also aided understanding the neurobiology of the Hcrt system, mechanisms of cataplexy, and the pharmacology of narcolepsy medications. Transgenic rodent models will be critical in the development of novel therapeutics for the treatment of narcolepsy, particularly efforts directed to overcome challenges in the development of hypocretin replacement therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.
Cataplectic facies: clinical marker in the diagnosis of childhood narcolepsy-report of two cases.

PubMed

Prasad, Manish; Setty, Gururaj; Ponnusamy, Athi; Hussain, Nahin; Desurkar, Archana

2014-05-01

Narcolepsy is a chronic disease and is commonly diagnosed in adulthood. However, more than half of the patients have onset of symptoms in childhood and/or adolescence. The full spectrum of clinical manifestations, namely excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis, is usually not present at disease onset, delaying diagnosis during childhood. Mean delay in diagnosis since symptom onset is known to be several years. Initial manifestations can sometimes be as subtle as only partial drooping of eyelids leading to confusion with a myasthenic condition. We present two children who presented with "cataplectic facies," an unusual facial feature only recently described in children with narcolepsy with cataplexy. The diagnosis of narcolepsy was confirmed by multiple sleep latency test along with human leukocyte antigen typing and cerebrospinal fluid hypocretin assay. The diagnosis of narcolepsy with cataplexy at onset can be challenging in young children. With more awareness of subtle signs such as cataplectic facies, earlier diagnosis is possible. To date, only 11 children between 6 and 18 years of age presenting with typical cataplectic facies have been reported in the literature. We present two patients, one of whom is the youngest individual (4 years old) yet described with the typical cataplectic facies. Copyright © 2014 Elsevier Inc. All rights reserved.
Narcolepsy in African Americans

PubMed Central

Kawai, Makoto; O'Hara, Ruth; Einen, Mali; Lin, Ling; Mignot, Emmanuel

2015-01-01

Study Objectives: Although narcolepsy affects 0.02–0.05% of individuals in various ethnic groups, clinical presentation in different ethnicities has never been fully characterized. Our goal was to study phenotypic expression across ethnicities in the United States. Design/Setting: Cases of narcolepsy from 1992 to 2013 were identified from searches of the Stanford Center for Narcolepsy Research database. International Classification of Sleep Disorders, Third Edition diagnosis criteria for type 1 and type 2 narcolepsy were used for inclusion, but subjects were separated as with and without cataplexy for the purpose of data presentation. Information extracted included demographics, ethnicity and clinical data, HLA-DQB1*06:02, polysomnography (PSG), multiple sleep latency test (MSLT) data, and cerebrospinal fluid (CSF) hypocretin-1 level. Patients: 182 African-Americans, 839 Caucasians, 35 Asians, and 41 Latinos with narcolepsy. Results: Sex ratio, PSG, and MSLT findings did not differ across ethnicities. Epworth Sleepiness Scale (ESS) score was higher and age of onset of sleepiness earlier in African Americans compared with other ethnicities. HLA-DQB1*06:02 positivity was higher in African Americans (91.0%) versus others (76.6% in Caucasians, 80.0% in Asians, and 65.0% in Latinos). CSF hypocretin-1 level, obtained in 222 patients, was more frequently low (≤ 110 pg/ml) in African Americans (93.9%) versus Caucasians (61.5%), Asians (85.7%) and Latinos (75.0%). In subjects with low CSF hypocretin-1, African Americans (28.3%) were 4.5 fold more likely to be without cataplexy when compared with Caucasians (8.1%). Conclusions: Narcolepsy in African Americans is characterized by earlier symptom onset, higher Epworth Sleepiness Scale score, higher HLA-DQB1*06:02 positivity, and low cerebrospinal fluid hypocretin-1 level in the absence of cataplexy. In African Americans, more subjects without cataplexy have type 1 narcolepsy. Citation: Kawai M, O'Hara R, Einen M, Lin L, Mignot E. Narcolepsy in African Americans. SLEEP 2015;38(11):1673–1681. PMID:26158891
Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions.

PubMed

Dauvilliers, Yves; Delallée, Nathalie; Jaussent, Isabelle; Scholz, Sabine; Bayard, Sophie; Croyal, Mickael; Schwartz, Jean-Charles; Robert, Philippe

2012-10-01

To determine the activity of cerebral histaminergic system evaluated by CSF levels of histamine (HA) and tele-methylhistamine (t-MHA), its major metabolite, and their relationships with hypocretin-1 levels in a large population of patients with hypersomnia and neurological conditions. sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay was developed for the simultaneous quantification of CSF HA and t-MHA. ata were collected and CSF hypocretin-1 levels were measured using radioimmunoassay at the Sleep Disorders Center, Montpellier, France. CSF HA and t-MHA were measured in Bioprojet-Biotech, France One hundred fourteen unrelated patients with a suspicion of central hypersomnia underwent one night of polysomnography followed by the multiple sleep latency test. Sleep disorders were diagnosed clinically and using sleep studies: narcolepsy-cataplexy NC (n = 56), narcolepsy without cataplexy NwC (n = 27), idiopathic hypersomnia IH (n = 11), secondary narcolepsy (n = 3), and unspecified hypersomnia Uns EDS (n = 17). Fifty neurological patients without daytime sleepiness were included as controls. No between-hypersomnia group differences were found for CSF HA levels (median 708.62 pM extreme range [55.92-3335.50] in NC; 781.34 [174.08-4391.50] in NwC; 489.42 [177.45-906.70] in IH, and 1155.40 [134.80-2736.59] in Uns EDS) or for t-MHA levels. No association was found between CSF HA, t-MHA, or HA + t-MHA, sleepiness, treatment intake, and frequency of cataplexy. A slight negative correlation was found between age and HA levels. Further adjustment for the age revealed no significant HA levels difference between hypersomnia patients and controls. CSF histamine and tele-methylhistamine did not significantly differ between patients with narcolepsy-cataplexy and other etiologies of non-hypocretin-1 deficient central hypersomnias; these measurements, therefore, are not useful in assessing the etiology or severity of centrally mediated hypersomnia.
Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia.

PubMed

Trotti, Lynn Marie; Staab, Beth A; Rye, David B

2013-08-15

Differentiation of narcolepsy without cataplexy from idiopathic hypersomnia relies entirely upon the multiple sleep latency test (MSLT). However, the test-retest reliability for these central nervous system hypersomnias has never been determined. Patients with narcolepsy without cataplexy, idiopathic hypersomnia, and physiologic hypersomnia who underwent two diagnostic multiple sleep latency tests were identified retrospectively. Correlations between the mean sleep latencies on the two studies were evaluated, and we probed for demographic and clinical features associated with reproducibility versus change in diagnosis. Thirty-six patients (58% women, mean age 34 years) were included. Inter -test interval was 4.2 ± 3.8 years (range 2.5 months to 16.9 years). Mean sleep latencies on the first and second tests were 5.5 (± 3.7 SD) and 7.3 (± 3.9) minutes, respectively, with no significant correlation (r = 0.17, p = 0.31). A change in diagnosis occurred in 53% of patients, and was accounted for by a difference in the mean sleep latency (N = 15, 42%) or the number of sleep onset REM periods (N = 11, 31%). The only feature predictive of a diagnosis change was a history of hypnagogic or hypnopompic hallucinations. The multiple sleep latency test demonstrates poor test-retest reliability in a clinical population of patients with central nervous system hypersomnia evaluated in a tertiary referral center. Alternative diagnostic tools are needed.
Narcolepsy and disorders of excessive somnolence.

PubMed

Dyken, Mark E; Yamada, Thoru

2005-06-01

Recent studies provide valid criteria that help differentiate idiopathic narcolepsy from other disorders of excessive daytime somnolence [3]. Research to date suggests that idiopathic narcolepsy might properly be considered a disorder of excessive sleepiness with dysfunctional REM-sleep mechanisms, clinically evidenced as cataplexy and electrophysiologically recognized as SOREMPs. Given these criteria, a diagnosis can generally be made using a combination of history, PSG, and MSLT. Traditionally, the medical treatment of idiopathic narcolepsy has centered on a two-drug regimen (stimulants for sleepiness and TCAs for cataplexy and auxiliary symptoms). Some newer medications are proving efficacious for sleepiness with minimal adverse effects, whereas others may provide a single-drug regimen that simultaneously addresses sleepiness and cataplexy [18]. New research has allowed some experts to hypothesize that idiopathic narcolepsy may be the result of a genetic predisposition to autoimmune disease [176]. It is possible that aberrant genetic coding of elements in the hypocretin/orexin systems allows a sensitivity to inducible and possibly virally mediated changes, which leave cells in the lateral hypothalamus susceptible to autoimmune attack [96]. As such, genetic screening of high-risk individuals might eventually rationalize the prophylactic use of immunosuppressants in some instances. In the future, for atypical cases(poorly responsive to therapy), genetic, CSF, and brain imaging studies, and possibly even neuronal transplantation may prove beneficial in the assessment and treatment of idiopathic narcolepsy.
Orexin Gene Transfer into Zona Incerta Neurons Suppresses Muscle Paralysis in Narcoleptic Mice

PubMed Central

Liu, Meng; Konadhode, RodaRani; Begum, Suraiya; Pelluru, Dheeraj; Gerashchenko, Dmitry; Sakurai, Takeshi; Yanagisawa, Masashi; van den Pol, Anthony N.

2011-01-01

Cataplexy, a sudden unexpected muscle paralysis, is a debilitating symptom of the neurodegenerative sleep disorder, narcolepsy. During these attacks, the person is paralyzed, but fully conscious and aware of their surroundings. To identify potential neurons that might serve as surrogate orexin neurons to suppress such attacks, the gene for orexin (hypocretin), a peptide lost in most human narcoleptics, was delivered into the brains of the orexin-ataxin-3 transgenic mouse model of human narcolepsy. Three weeks after the recombinant adenoassociated virus (rAAV)-mediated orexin gene transfer, sleep–wake behavior was assessed. rAAV-orexin gene delivery into neurons of the zona incerta (ZI), or the lateral hypothalamus (LH) blocked cataplexy. Orexin gene transfer into the striatum or in the melanin-concentrating hormone neurons in the ZI or LH had no such effect, indicating site specificity. In transgenic mice lacking orexin neurons but given rAAV-orexin, detectable levels of orexin-A were evident in the CSF, indicating release of the peptide from the surrogate neurons. Retrograde tracer studies showed that the amygdala innervates the ZI consistent with evidence that strong emotions trigger cataplexy. In turn, the ZI projects to the locus ceruleus, indicating that the ZI is part of a circuit that stabilizes motor tone. Our results indicate that these neurons might also be recruited to block the muscle paralysis in narcolepsy. PMID:21508228
Treatment Options for Narcolepsy.

PubMed

Barateau, Lucie; Lopez, Régis; Dauvilliers, Yves

2016-05-01

Narcolepsy type 1 and narcolepsy type 2 are central disorders of hypersomnolence. Narcolepsy type 1 is characterized by excessive daytime sleepiness and cataplexy and is associated with hypocretin-1 deficiency. On the other hand, in narcolepsy type 2, cerebrospinal fluid hypocretin-1 levels are normal and cataplexy absent. Despite major advances in our understanding of narcolepsy mechanisms, its current management is only symptomatic. Treatment options may vary from a single drug that targets several symptoms, or multiple medications that each treats a specific symptom. In recent years, narcolepsy treatment has changed with the widespread use of modafinil/armodafinil for daytime sleepiness, antidepressants (selective serotonin and dual serotonin and noradrenalin reuptake inhibitors) for cataplexy, and sodium oxybate for both symptoms. Other psychostimulants can also be used, such as methylphenidate, pitolisant and rarely amphetamines, as third-line therapy. Importantly, clinically relevant subjective and objective measures of daytime sleepiness are required to monitor the treatment efficacy and to provide guidance on whether the treatment goals are met. Associated symptoms and comorbid conditions, such as hypnagogic/hypnopompic hallucinations, sleep paralysis, disturbed nighttime sleep, unpleasant dreams, REM- and non REM-related parasomnias, depressive symptoms, overweight/obesity, and obstructive sleep apnea, should also be taken into account and managed, if required. In the near future, the efficacy of new wake-promoting drugs, anticataplectic agents, hypocretin replacement therapy and immunotherapy at the early stages of the disease should also be evaluated.
DQB1 Locus Alone Explains Most of the Risk and Protection in Narcolepsy with Cataplexy in Europe

PubMed Central

Tafti, Mehdi; Hor, Hyun; Dauvilliers, Yves; Lammers, Gert J.; Overeem, Sebastiaan; Mayer, Geert; Javidi, Sirous; Iranzo, Alex; Santamaria, Joan; Peraita-Adrados, Rosa; Vicario, José L.; Arnulf, Isabelle; Plazzi, Giuseppe; Bayard, Sophie; Poli, Francesca; Pizza, Fabio; Geisler, Peter; Wierzbicka, Aleksandra; Bassetti, Claudio L.; Mathis, Johannes; Lecendreux, Michel; Donjacour, Claire E.H.M.; van der Heide, Astrid; Heinzer, Raphaël; Haba-Rubio, José; Feketeova, Eva; Högl, Birgit; Frauscher, Birgit; Benetó, Antonio; Khatami, Ramin; Cañellas, Francesca; Pfister, Corinne; Scholz, Sabine; Billiard, Michel; Baumann, Christian R.; Ercilla, Guadalupe; Verduijn, Willem; Claas, Frans H.J.; Dubois, Valérie; Nowak, Jacek; Eberhard, Hans-Peter; Pradervand, Sylvain; Hor, Charlotte N.; Testi, Manuela; Tiercy, Jean-Marie; Kutalik, Zoltán

2014-01-01

Study Objective: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects. Design: Retrospective case-control study. Setting: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10-4 mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication. Patients and Participants: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included. Measurements and Results: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10-9) and rs1154155 within the TRA locus (P < 2x10-8) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified. Conclusion: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy. Citation: Tafti M; Hor H; Dauvilliers Y; Lammers GJ; Overeem S; Mayer G; Javidi S; Iranzo A; Santamaria J; Peraita-Adrados R; Vicario JL; Arnulf I; Plazzi G; Bayard S; Poli F; Pizza F; Geisler P; Wierzbicka A; Bassetti CL; Mathis J; Lecendreux M; Donjacour CE; van der Heide A; Heinzer R; Haba-Rubio J; Feketeova E; Högl B; Frauscher B; Benetó A; Khatami R; Cañellas F; Pfister C; Scholz S; Billiard M; Baumann CR; Ercilla G; Verduijn W; Claas FH; Dubois V; Nowak J; Eberhard HP; Pradervand S; Hor CN; Testi M; Tiercy JM; Kutalik Z; on Behalf of the European Narcolepsy Network (EU-NN). DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. SLEEP 2014;37(1):19-25. PMID:24381371
Narcolepsy: Fact Sheet

MedlinePlus

... go limp or unable to move (cataplexy), vivid dream-like images or hallucinations, and total paralysis just ... REM) sleep after about 60 to 90 minutes. Dreams occur during REM sleep, and the brain keeps ...
Normal Cerebrospinal Fluid Histamine and tele-Methylhistamine Levels in Hypersomnia Conditions

PubMed Central

Dauvilliers, Yves; Delallée, Nathalie; Jaussent, Isabelle; Scholz, Sabine; Bayard, Sophie; Croyal, Mickael; Schwartz, Jean-Charles; Robert, Philippe

2012-01-01

Study Objectives: To determine the activity of cerebral histaminergic system evaluated by CSF levels of histamine (HA) and tele-methylhistamine (t-MHA), its major metabolite, and their relationships with hypocretin-1 levels in a large population of patients with hypersomnia and neurological conditions. Design: sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay was developed for the simultaneous quantification of CSF HA and t-MHA. Setting: ata were collected and CSF hypocretin-1 levels were measured using radioimmunoassay at the Sleep Disorders Center, Montpellier, France. CSF HA and t-MHA were measured in Bioprojet-Biotech, France Participants: One hundred fourteen unrelated patients with a suspicion of central hypersomnia underwent one night of polysomnography followed by the multiple sleep latency test. Sleep disorders were diagnosed clinically and using sleep studies: narcolepsy-cataplexy NC (n = 56), narcolepsy without cataplexy NwC (n = 27), idiopathic hypersomnia IH (n = 11), secondary narcolepsy (n = 3), and unspecified hypersomnia Uns EDS (n = 17). Fifty neurological patients without daytime sleepiness were included as controls. Measurements and Results: No between-hypersomnia group differences were found for CSF HA levels (median 708.62 pM extreme range [55.92-3335.50] in NC; 781.34 [174.08-4391.50] in NwC; 489.42 [177.45-906.70] in IH, and 1155.40 [134.80-2736.59] in Uns EDS) or for t-MHA levels. No association was found between CSF HA, t-MHA, or HA + t-MHA, sleepiness, treatment intake, and frequency of cataplexy. A slight negative correlation was found between age and HA levels. Further adjustment for the age revealed no significant HA levels difference between hypersomnia patients and controls. Conclusion: CSF histamine and tele-methylhistamine did not significantly differ between patients with narcolepsy-cataplexy and other etiologies of non-hypocretin-1 deficient central hypersomnias; these measurements, therefore, are not useful in assessing the etiology or severity of centrally mediated hypersomnia. Citation: Dauvilliers Y; Delalléee N; Jaussent I; Scholz S; Bayard S; Croyal M; Schwartz JC; Robert P. Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions. SLEEP 2012;35(10):1359-1366. PMID:23024434
[Narcolepsy in childhood and adolescence: symptoms, diagnosis, and therapy. A case report].

PubMed

Gehrmann, Jochen; Siegler, Dominik; Ignacy, Evelin; Reimer, Inga

2017-03-01

Narcolepsy is a rare, multifactorial disease of the hypothalamus characterized by its leading symptoms of excessive daytime sleepiness and cataplexy. Sleep-EEG and a HLA-DR-genotype serve to secure the diagnosis. We report here on a 14-year-old girl suffering from anxieties, depression, school refusal, social withdrawal as well as very frequent attacks of sleep during the day and cataplexy. Currently, there is no approved drug for children and adolescents suffering from narcolepsy. Our patient benefited significantly and quickly from an off-label treatment with methylphenidate in combination with psychoeducation, cognitive behavioral therapy, and family therapy. Narcolepsy is a very rare but probably underestimated differential diagnosis applied to unclear daytime sleepiness, anxieties, or depression in childhood and adolescence. Both the key symptoms and the comorbid symptoms improve significantly under treatment with stimulants, albeit at a higher dosage.
Comparison of clinical characteristics among narcolepsy with and without cataplexy and idiopathic hypersomnia without long sleep time, focusing on HLA-DRB1( *)1501/DQB1( *)0602 finding.

PubMed

Sasai, Taeko; Inoue, Yuichi; Komada, Yoko; Sugiura, Tatsuki; Matsushima, Eisuke

2009-10-01

Clinical characteristics of narcolepsy without cataplexy (NA w/o CA) and its relation to positivity of HLA-DRB1( *)1501/DQB1( *)0602 remain unclarified. We investigated clinical features of NA w/o CA, particularly addressing HLA-DRB1( *)1501/DQB1( *)0602. Comparisons of the Epworth Sleepiness Scale (ESS), multiple sleep latency test (MSLT) variables, rapid eye movement (REM)-related symptoms, and treatment response to psychostimulant medication were made for four patient groups (narcolepsy with cataplexy; NA-CA, NA w/o CA HLA-positive, NA w/o CA HLA-negative, and idiopathic hypersomnia without long sleep time; IHS w/o LST). Mean sleep latency was significantly shorter and the rate of reduction of ESS after medication was lower in both NA-CA and NA w/o CA HLA-positive groups than those in the IHS w/o LST group. Among the three narcoleptic groups, the NA w/o CA HLA-negative group showed the lowest REM latency and the highest reduction rate of ESS after treatment. Neither these subjective and objective sleepiness measures nor the treatment response measure was significantly different between this group and the IHS w/o LST group. In NA w/o CA, HLA-positivity might affect hypersomnia severity and REM propensity. The NA w/o CA HLA-negative group and the IHS w/o LST group exhibit equivalent hypersomnia severity.
French consensus. Management of patients with hypersomnia: Which strategy?

PubMed

Lopez, R; Arnulf, I; Drouot, X; Lecendreux, M; Dauvilliers, Y

Central hypersomnias principally involves type 1 narcolepsy (NT1), type 2 narcolepsy (NT2) and idiopathic hypersomnia (IH). Despite great progress made in understanding the physiopathology of NT1 with low cerebrospinal fluid hypocretin-1 levels, current treatment remains symptomatic. The same applies to NT2 and IH, for which the physiopathology is still largely unknown. Controlling excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed night-time sleep are key therapeutic targets in NT1. For IH and NT2, reducing EDS is the main objective. Based on European and American directives for the treatment of narcolepsy, we propose French recommendations for managing central hypersomnias as well as strategies in the case of drug-resistance. Stimulating treatments target EDS, and Modafinil is the first-line treatment. Other stimulants such as methylphenidate, pitolisant, and exceptionally dextro-amphetamine can be prescribed. Selective serotonin and noradrenaline reuptake inhibitor antidepressants are effective for the management of cataplexy in NT1. Sodium oxybate is an effective treatment for several symptoms, including EDS, cataplexy and disturbed night-time sleep. Treatment of central hypersomnia must also take into consideration frequent cardiovascular, metabolic and psychiatric comorbidities, particularly in NT1. New therapies are currently under study with the development of new stimulants and anti-cataplectics. The next few years will see innovative emerging therapies, based on a physiopathological approach, aiming to restore hypocretinergic transmission or to interrupt the autoimmune processes causing the loss of hypocretin neurons. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
A comparison of idiopathic hypersomnia and narcolepsy-cataplexy using self report measures and sleep diary data.

PubMed Central

Bruck, D; Parkes, J D

1996-01-01

Eighteen patients with idiopathic hypersomnia (IH) were compared with 50 patients with the narcoleptic syndrome of cataplexy and daytime sleepiness (NLS) using self report questionnaires and a diary of sleep/wake patterns. The IH group reported more consolidated nocturnal sleep, a lower propensity to nap, greater refreshment after naps, and a greater improvement in excessive daytime sleepiness since onset than the NLS group. In IH, the onset of excessive daytime sleepiness was predominantly associated with familial inheritance or a viral illness. Two variable--number of reported awakenings during nocturnal sleep and the reported change in sleepiness since onset--provided maximum discrimination between the IH and NLS groups. Confusional arousals, extended naps or nocturnal sleep, autonomic nervous system dysfunction, low ratings of medication effectiveness, or side effects of medication were not associated differentially with either IH or NLS. PMID:8778267
Narcolepsy with cataplexy in a child with Charcot-Marie-Tooth disease. Case Report.

PubMed

Zheng, Feixia; Wang, Shuang

2016-09-01

We report an 8-year-old boy diagnosed with both CMT1 and narcolepsy, which were not reported simultaneously presenting in one person. The boy presented with a history of increased suddenly falling frequency and excessive daytime sleepiness for 3 months. CMT1 was diagnosed by electrophysiology and genetic testing. Narcolepsy had not been diagnosed until the frequently falling caused by sudden and transient episodes of legs weakness triggered by emotion was found. Multiple sleep latency test showed multiple sleep onset REM periods with reduced sleep latency. When CMT1 and narcolepsy were coexist in an individual, the latter might be overlooked. Cataplexy caused by narcolepsy might be disregard as distal muscle weakness of CMT1. The daytime sleepiness might also be ignored. Therefore, we recommend that patients with sleep disorders should be queried about the symptoms of narcolepsy.
Effective treatment of narcolepsy-like symptoms with high-frequency repetitive transcranial magnetic stimulation: A case report.

PubMed

Lai, Jian-Bo; Han, Mao-Mao; Xu, Yi; Hu, Shao-Hua

2017-11-01

Narcolepsy is a rare sleep disorder with disrupted sleep-architecture. Clinical management of narcolepsy lies dominantly on symptom-driven pharmacotherapy. The treatment role of repetitive transcranial magnetic stimulation (rTMS) for narcolepsy remains unexplored. In this paper, we present a case of a 14-year-old young girl with excessive daytime sleepiness (EDS), cataplexy and hypnagogic hallucinations. After excluding other possible medical conditions, this patient was primarily diagnosed with narcolepsy. The patient received 25 sessions of high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC). The symptoms of EDS and cataplexy significantly improved after rTMS treatment. Meanwhile, her score in the Epworth sleep scale (ESS) also remarkably decreased. This case indicates that rTMS may be selected as a safe and effective alternative strategy for treating narcolepsy-like symptoms. Well-designed researches are warranted in future investigations on this topic.
Effective treatment of narcolepsy-like symptoms with high-frequency repetitive transcranial magnetic stimulation

PubMed Central

Lai, Jian-bo; Han, Mao-mao; Xu, Yi; Hu, Shao-hua

2017-01-01

Abstract Rationale: Narcolepsy is a rare sleep disorder with disrupted sleep-architecture. Clinical management of narcolepsy lies dominantly on symptom-driven pharmacotherapy. The treatment role of repetitive transcranial magnetic stimulation (rTMS) for narcolepsy remains unexplored. Patient concerns: In this paper, we present a case of a 14-year-old young girl with excessive daytime sleepiness (EDS), cataplexy and hypnagogic hallucinations. Diagnoses: After excluding other possible medical conditions, this patient was primarily diagnosed with narcolepsy. Interventions: The patient received 25 sessions of high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC). Outcomes: The symptoms of EDS and cataplexy significantly improved after rTMS treatment. Meanwhile, her score in the Epworth sleep scale (ESS) also remarkably decreased. Lessons: This case indicates that rTMS may be selected as a safe and effective alternative strategy for treating narcolepsy-like symptoms. Well-designed researches are warranted in future investigations on this topic. PMID:29145290

Nocturnal Dynamics of Sleep-Wake Transitions in Patients With Narcolepsy.

PubMed

Zhang, Xiaozhe; Kantelhardt, Jan W; Dong, Xiao Song; Krefting, Dagmar; Li, Jing; Yan, Han; Pillmann, Frank; Fietze, Ingo; Penzel, Thomas; Zhao, Long; Han, Fang

2017-02-01

We investigate how characteristics of sleep-wake dynamics in humans are modified by narcolepsy, a clinical condition that is supposed to destabilize sleep-wake regulation. Subjects with and without cataplexy are considered separately. Differences in sleep scoring habits as a possible confounder have been examined. Four groups of subjects are considered: narcolepsy patients from China with (n = 88) and without (n = 15) cataplexy, healthy controls from China (n = 110) and from Europe (n = 187, 2 nights each). After sleep-stage scoring and calculation of sleep characteristic parameters, the distributions of wake-episode durations and sleep-episode durations are determined for each group and fitted by power laws (exponent α) and by exponentials (decay time τ). We find that wake duration distributions are consistent with power laws for healthy subjects (China: α = 0.88, Europe: α = 1.02). Wake durations in all groups of narcolepsy patients, however, follow the exponential law (τ = 6.2-8.1 min). All sleep duration distributions are best fitted by exponentials on long time scales (τ = 34-82 min). We conclude that narcolepsy mainly alters the control of wake-episode durations but not sleep-episode durations, irrespective of cataplexy. Observed distributions of shortest wake and sleep durations suggest that differences in scoring habits regarding the scoring of short-term sleep stages may notably influence the fitting parameters but do not affect the main conclusion. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.
Sleep-disordered breathing and periodic limb movements in narcolepsy with cataplexy: a systematic analysis of 35 consecutive patients.

PubMed

Pizza, Fabio; Tartarotti, Sonja; Poryazova, Rositsa; Baumann, Christian R; Bassetti, Claudio L

2013-01-01

Disturbed sleep is a core feature of narcolepsy with cataplexy (NC). Few studies have independently assessed sleep-disordered breathing (SDB) and periodic limb movements (PLMs) in non-homogeneous series of patients with and without cataplexy. We systematically assessed both SDB and PLMs in well-defined NC patients. We analyzed the clinical and polysomnographic features of 35 consecutive NC patients (mean age 40 ± 16 years, 51% males, 23/23 hypocretin-deficient) to assess the prevalence of SDB (apnea-hypopnea index >5) and PLMs (periodic leg movements in sleep (PLMI) >15) together with their impact on nocturnal sleep and daytime sleepiness using the multiple sleep latency test. 11 (31%) and 14 (40%) patients had SDB and PLMs, respectively. SDB was associated with older age (49 ± 16 vs. 35 ± 13 years, p = 0.02), higher BMI (30 ± 5 vs. 27 ± 6, p = 0.05), and a trend towards higher PLMI (25 ± 20 vs. 12 ± 23, p = 0.052), whereas PLMs with older age (50 ± 16 vs. 33 ± 11 years, p = 0.002) and reduced and fragmented sleep (e.g. sleep efficiency of 82 ± 12% vs. 91 ± 6%, p = 0.015; sleep time of 353 ± 66 vs. 395 ± 28, p = 0.010). SDB and PLMs were also mutually associated (p = 0.007), but not correlated to daytime sleepiness. SDB and PLMs are highly prevalent and associated in NC. Nevertheless, SDB and PLMs are rarely severe, suggesting an overall limited effect on clinical manifestations. Copyright © 2013 S. Karger AG, Basel.
Narcolepsy: Let the Patient’s Voice Awaken Us!

PubMed Central

Flygare, Julie; Parthasarathy, Sairam

2014-01-01

This is a “patient-centered” review about narcolepsy that aims to awaken the reader to the narcolepsy condition and to the trials and tribulations of patients with sleep problems in general. Narcolepsy is a neurological disorder with a classic tetrad of symptoms consisting of excessive daytime sleepiness, cataplexy, sleep onset hallucinations, and sleep paralysis. The diagnosis of narcolepsy and other sleep disorders are often overlooked and could be attributed to other medical or even psychiatric conditions with years of missed diagnosis. Implementation of “two sleep-related questions” to the review of systems in the primary care physicians’ office visit may help address the issue of missed diagnosis and allow patients to seek prompt medical attention. Definitive diagnosis can be made by overnight sleep study followed by a nap test, “multiple sleep latency test” (MSLT). There is currently no cure for narcolepsy with the treatments addressing symptoms of excessive daytime sleepiness, cataplexy, and nighttime sleep disruption with stimulants (modafinil, methylphenidate, and amphetamines), anti-cataplexy medications (Serotonin-specific reuptake inhibitors and tricyclic antidepressants) and sedative-hypnotics including sodium oxybate. Narcolepsy, like other sleep disorders, can lead to marked reductions of health-related quality of life and affect patients’ social and work lives deleteriously. While traditional healthcare approaches are focused more on hard biomedical outcomes, a patient-centered approach with novel methods for better sleep assessment of patients, that can bypass the “impossibly crammed” physician office visit, would allow healthcare providers to better detect, diagnose and treat narcolepsy and other such sleep problems. PMID:24931392
Two cases of childhood narcolepsy mimicking epileptic seizures in video-EEG/EMG.

PubMed

Yanagishita, Tomoe; Ito, Susumu; Ohtani, Yui; Eto, Kaoru; Kanbayashi, Takashi; Oguni, Hirokazu; Nagata, Satoru

2018-06-06

Narcolepsy is characterized by excessive sleepiness, hypnagogic hallucinations, and sleep paralysis, and can occur with or without cataplexy. Here, we report two children with narcolepsy presenting with cataplexy mimicking epileptic seizures as determined by long-term video-electroencephalography (EEG) and electromyography (EMG) monitoring. Case 1 was a 15-year-old girl presenting with recurrent episodes of "convulsions" and loss of consciousness, who was referred to our hospital with a diagnosis of epilepsy showing "convulsions" and "complex partial seizures". The long-term video-polygraph showed a clonic attack lasting for 15 s, which corresponded to 1-2 Hz with interruption of mentalis EMG discharges lasting for 70-300 ms without any EEG changes. Narcolepsy was suspected due to the attack induced by hearty laughs and the presence of sleep attacks, and confirmed by low orexin levels in cerebrospinal fluid (CSF). Case 2 was an 11-year-old girl presenting with recurrent episodes of myoclonic attacks simultaneously with dropping objects immediately after hearty laughs, in addition to sleep attacks, hypnagogic hallucinations, and sleep paralysis. The long-term video-polygraph showed a subtle attack, characterized by dropping chopsticks from her hand, which corresponded to an interruption of ongoing deltoid EMG discharges lasting 140 ms without any EEG changes. A diagnosis of narcolepsy was confirmed by the low orexin levels in CSF. These cases demonstrate that children with narcolepsy may have attacks of cataplexy that resemble clonic or myoclonic seizures. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Narcolepsy (with and without cataplexy) and commercial motor vehicle driver safety.

DOT National Transportation Integrated Search

2009-10-01

The purpose of this evidence report is to address several questions posed by FMCSA regarding the topic of narcolepsy and commercial motor vehicle (CMV) driver safety. In the early scope development work conducted by the Agency and the Medical Review ...
Daytime continuous polysomnography predicts MSLT results in hypersomnias of central origin.

PubMed

Pizza, Fabio; Moghadam, Keivan K; Vandi, Stefano; Detto, Stefania; Poli, Francesca; Mignot, Emmanuel; Ferri, Raffaele; Plazzi, Giuseppe

2013-02-01

In the diagnostic work-up of hypersomnias of central origin, the complaint of excessive daytime sleepiness should be objectively confirmed by MSLT findings. Indeed, the features and diagnostic utility of spontaneous daytime sleep at 24 h continuous polysomnography (PSG) have never been investigated. We compared daytime PSG features to MSLT data in 98 consecutive patients presenting with excessive daytime sleepiness and with a final diagnosis of narcolepsy with cataplexy/hypocretin deficiency (n = 39), narcolepsy without cataplexy (n = 7), idiopathic hypersomnia without long sleep time (n = 19), and 'hypersomnia' with normal sleep latency at MSLT (n = 33). Daytime sleep time was significantly higher in narcolepsy-cataplexy but similar in the other groups. Receiver operating characteristics (ROC) curves showed that the number of naps during daytime PSG predicted a mean sleep latency ≤8 min at MSLT with an area under the curve of 0.67 ± 0.05 (P = 0.005). The number of daytime sleep-onset REM periods (SOREMPs) in spontaneous naps strikingly predicted the scheduled occurrence of two or more SOREMPs at MSLT, with an area under the ROC curve of 0.93 ± 0.03 (P < 10(-12) ). One spontaneous SOREMP during daytime had a sensitivity of 96% with specificity of 74%, whereas two SOREMPs had a sensitivity of 75%, with a specificity of 95% for a pathological REM sleep propensity at MSLT. The features of spontaneous daytime sleep well correlated with MSLT findings. Notably, the occurrence of multiple spontaneous SOREMPs during daytime clearly identified patients with narcolepsy, as well as during the MSLT. © 2012 European Sleep Research Society.
Narcolepsy with and without cataplexy, idiopathic hypersomnia with and without long sleep time: a cluster analysis.

PubMed

Šonka, Karel; Šusta, Marek; Billiard, Michel

2015-02-01

The successive editions of the International Classification of Sleep Disorders (ICSD) reflect the evolution of the concepts of various sleep disorders. This is particularly the case for central disorders of hypersomnolence, with continuous changes in terminology and divisions of narcolepsy, idiopathic hypersomnia, and recurrent hypersomnia. According to the ICSD 2nd Edition (ICSD-2), narcolepsy with cataplexy (NwithC), narcolepsy without cataplexy (Nw/oC), idiopathic hypersomnia with long sleep time (IHwithLST), and idiopathic hypersomnia without long sleep time (IHw/oLST) are four, well-defined hypersomnias of central origin. However, in the absence of biological markers, doubts have been raised as to the relevance of a division of idiopathic hypersomnia into two forms, and it is not yet clear whether Nw/oC and IHw/oLST are two distinct entities. With this in mind, it was decided to empirically review the ICSD-2 classification by using a hierarchical cluster analysis to see whether this division has some relevance, even though the terms "with long sleep time" and "without long sleep time" are inappropriate. The cluster analysis differentiated three main clusters: Cluster 1, "combined monosymptomatic hypersomnia/narcolepsy type 2" (people initially diagnosed with IHw/oLST and Nw/oC); Cluster 2 "polysymptomatic hypersomnia" (people initially diagnosed with IHwithLST); and Cluster 3, narcolepsy type 1 (people initially diagnosed with NwithC). Cluster analysis confirmed that narcolepsy type 1 and polysymptomatic hypersomnia are independent sleep disorders. People who were initially diagnosed with Nw/oC and IHw/oLST formed a single cluster, referred to as "combined monosymptomatic hypersomnia/narcolepsy type 2." Copyright © 2014 Elsevier B.V. All rights reserved.
White matter alterations in narcolepsy patients with cataplexy: tract-based spatial statistics.

PubMed

Park, Yun K; Kwon, Oh-Hun; Joo, Eun Yeon; Kim, Jae-Hun; Lee, Jong M; Kim, Sung T; Hong, Seung B

2016-04-01

Functional imaging studies and voxel-based morphometry analysis of brain magnetic resonance imaging showed abnormalities in the hypothalamus-thalamus-orbitofrontal pathway, demonstrating altered hypocretin pathway in narcolepsy. Those distinct morphometric changes account for problems in wake-sleep control, attention and memory. It also raised the necessity to evaluate white matter changes. To investigate brain white matter alterations in drug-naïve narcolepsy patients with cataplexy and to explore relationships between white matter changes and patient clinical characteristics, drug-naïve narcolepsy patients with cataplexy (n = 22) and healthy age- and gender-matched controls (n = 26) were studied. Fractional anisotropy and mean diffusivity images were obtained from whole-brain diffusion tensor imaging, and tract-based spatial statistics were used to localize white matter abnormalities. Compared with controls, patients showed significant decreases in fractional anisotropy of white matter of the bilateral anterior cingulate, fronto-orbital area, frontal lobe, anterior limb of the internal capsule and corpus callosum, as well as the left anterior and medial thalamus. Patients and controls showed no differences in mean diffusivity. Among patients, mean diffusivity values of white matter in the bilateral superior frontal gyri, bilateral fronto-orbital gyri and right superior parietal gyrus were positively correlated with depressive mood. This tract-based spatial statistics study demonstrated that drug-naïve patients with narcolepsy had reduced fractional anisotropy of white matter in multiple brain areas and significant relationship between increased mean diffusivity of white matter in frontal/cingulate and depression. It suggests the widespread disruption of white matter integrity and prevalent brain degeneration of frontal lobes according to a depressive symptom in narcolepsy. © 2015 European Sleep Research Society.
Multiple sleep latency test in narcolepsy type 1 and narcolepsy type 2: A 5-year follow-up study.

PubMed

Huang, Yu-Shu; Guilleminault, Christian; Lin, Cheng-Hui; Chen, Chia-Hsiang; Chin, Wei-Chih; Chen, Tzu-Shuang

2018-05-29

Excessively sleepy teenagers and young adults without sleep-disordered breathing are diagnosed with either narcolepsy type 1 or narcolepsy type 2, or hypersomnia, based on the presence/absence of cataplexy and the results of a multiple sleep latency test. However, there is controversy surrounding this nomenclature. We will try to find the differences between different diagnoses of hypersomnia from the results of the long-term follow-up evaluation of a sleep study. We diagnosed teenagers who had developed excessive daytime sleepiness based on the criteria of the International Classification of Sleep Disorders, 3rd edition. Each individual received the same clinical neurophysiologic testing every year for 5 years after the initial diagnosis of narcolepsy type 1 (n = 111) or type 2 (n = 46). The follow-up evaluation demonstrated that narcolepsy type 1 (narcolepsy-cataplexy) is a well-defined clinical entity, with very reproducible clinical neurophysiologic findings over time, whereas patients with narcolepsy type 2 presented clear clinical and test variability. By the fifth year of the follow-up evaluation, 17.6% of subjects did not meet the diagnostic criteria of narcolepsy type 2, and 23.9% didn't show any two sleep-onset rapid eye movement periods in multiple sleep latency during the 5-year follow-up. Therefore narcolepsy type 1 (narcolepsy-cataplexy) is a well-defined syndrome, with the presentation clearly related to the known consequences of destruction of hypocretin/orexin neurons. Narcolepsy type 2 covers patients with clinical and test variability over time, thus bringing into question the usage of the term "narcolepsy" to label these patients. © 2018 European Sleep Research Society.
Neocortical 40 Hz oscillations during carbachol-induced rapid eye movement sleep and cataplexy.

PubMed

Torterolo, Pablo; Castro-Zaballa, Santiago; Cavelli, Matías; Chase, Michael H; Falconi, Atilio

2016-02-01

Higher cognitive functions require the integration and coordination of large populations of neurons in cortical and subcortical regions. Oscillations in the gamma band (30-45 Hz) of the electroencephalogram (EEG) have been involved in these cognitive functions. In previous studies, we analysed the extent of functional connectivity between cortical areas employing the 'mean squared coherence' analysis of the EEG gamma band. We demonstrated that gamma coherence is maximal during alert wakefulness and is almost absent during rapid eye movement (REM) sleep. The nucleus pontis oralis (NPO) is critical for REM sleep generation. The NPO is considered to exert executive control over the initiation and maintenance of REM sleep. In the cat, depending on the previous state of the animal, a single microinjection of carbachol (a cholinergic agonist) into the NPO can produce either REM sleep [REM sleep induced by carbachol (REMc)] or a waking state with muscle atonia, i.e. cataplexy [cataplexy induced by carbachol (CA)]. In the present study, in cats that were implanted with electrodes in different cortical areas to record polysomnographic activity, we compared the degree of gamma (30-45 Hz) coherence during REMc, CA and naturally-occurring behavioural states. Gamma coherence was maximal during CA and alert wakefulness. In contrast, gamma coherence was almost absent during REMc as in naturally-occurring REM sleep. We conclude that, in spite of the presence of somatic muscle paralysis, there are remarkable differences in cortical activity between REMc and CA, which confirm that EEG gamma (≈40 Hz) coherence is a trait that differentiates wakefulness from REM sleep. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
Narcolepsy with Long Sleep Time: A Specific Entity?

PubMed Central

Vernet, Cyrille; Arnulf, Isabelle

2009-01-01

Background: The classical narcolepsy patient reports intense feelings of sleepiness (with/out cataplexy), normal or disrupted nighttime sleep, and takes short and restorative naps. However, with long-term monitoring, we identified some narcoleptics resembling patients with idiopathic hypersomnia. Objective: To isolate and describe a new subtype of narcolepsy with long sleep time). Setting: University Hospital Design: Controlled, prospective cohort Participants: Out of 160 narcoleptics newly diagnosed within the past 3 years, 29 (18%) had a long sleep time (more than 11 h/24 h). We compared narcoleptics with (n = 23) and without (n = 29) long sleep time to 25 hypersomniacs with long sleep time and 20 healthy subjects. Intervention: Patients and controls underwent face-to face interviews, questionnaires, human leukocyte antigen (HLA) genotype, an overnight polysomnography, multiple sleep latency tests, and 24-h ad libitum sleep monitoring. Results: Narcoleptics with long sleep time had a similar disease course and similar frequencies of cataplexy, sleep paralysis, hallucinations, multiple sleep onset in REM periods, short mean sleep latencies, and HLA DQB1*0602 positivity as narcoleptics with normal sleep time did. However, they had longer sleep time during 24 h, and higher sleep efficiency, lower Epworth Sleepiness Scale scores, and reported their naps were more often unrefreshing. Only 3/23 had core narcolepsy (HLA and cataplexy positive). Conclusions: The subgroup of narcoleptics with a long sleep time comprises 18% of narcoleptics. Their symptoms combine the disabilities of both narcolepsy (severe sleepiness) and idiopathic hypersomnia (long sleep time and unrefreshing naps). Thus, they may constitute a group with multiple arousal system dysfunctions. Citation: Vernet C; Arnulf I. Narcolepsy with long sleep time: a specific entity? SLEEP 2009;32(9):1229-1235. PMID:19750928
A standardized test to document cataplexy.

PubMed

Vandi, Stefano; Pizza, Fabio; Antelmi, Elena; Neccia, Giulia; Iloti, Martina; Mazzoni, Alice; Avoni, Patrizia; Plazzi, Giuseppe

2017-10-09

Cataplexy is the pathognomonic symptom of narcolepsy type 1 (NT1). Since it is considered difficult to be directly observed or documented by clinicians, its diagnosis relies mainly on history taking. Our study aimed at testing the feasibility of a standardized video recording procedure under emotional stimulation to document cataplexy in the diagnostic work-up of suspected hypersomnia of central origin. Two-hundred-eight consecutive patients underwent the diagnostic work-up and reached the final diagnosis of NT1 (n = 133), idiopathic hypersomnia or narcolepsy type 2 (IH/NT2 group, n = 33), or subjective excessive daytime sleepiness (sEDS group, n = 42). All subjects underwent a standardized video recording procedure while watching funny movies selected according to individual preferences, and a technician blind to clinical features reviewed the recordings to identify hypotonic phenomena that were finally confirmed by patients. The video recording under emotional stimulation captured hypotonic phenomena in 72.2%, 9.1% and 4.8% of NT1, IH/NT2, and sEDS subjects (p < 0.0001), respectively. When tested against CSF hypocretin deficiency, the documentation of a hypotonic episode at the test showed an area under the ROC curve of 0.823 ± 0.033 (p < 0.0001). NT1 patients under anticataplectic medications showed less frequently hypotonic episodes than untreated ones (48.0% vs 77.8%, p = 0.003). A standardized video recording procedure under emotional stimulation can help in the characterization of suspected hypersomnia of central origin. Further multi-center studies are warranted to extend the present findings and integrate a shared procedure for the laboratory work-up of narcolepsy. Copyright © 2017 Elsevier B.V. All rights reserved.
The inappropriate occurrence of rapid eye movement sleep in narcolepsy is not due to a defect in homeostatic regulation of rapid eye movement sleep.

PubMed

Roman, Alexis; Meftah, Soraya; Arthaud, Sébastien; Luppi, Pierre-Hervé; Peyron, Christelle

2018-06-01

Narcolepsy type 1 is a disabling disorder with four primary symptoms: excessive-daytime-sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. The later three symptoms together with a short rapid eye movement (REM) sleep latency have suggested impairment in REM sleep homeostatic regulation with an enhanced propensity for (i.e. tendency to enter) REM sleep. To test this hypothesis, we challenged REM sleep homeostatic regulation in a recognized model of narcolepsy, the orexin knock-out (Orex-KO) mice and their wild-type (WT) littermates. We first performed 48 hr of REM sleep deprivation using the classic small-platforms-over-water method. We found that narcoleptic mice are similarly REM sleep deprived to WT mice. Although they had shorter sleep latency, Orex-KO mice recovered similarly to WT during the following 10 hr of recovery. Interestingly, Orex-KO mice also had cataplexy episodes immediately after REM sleep deprivation, anticipating REM sleep rebound, at a time of day when cataplexy does not occur in baseline condition. We then evaluated REM sleep propensity using our new automated method of deprivation that performs a specific and efficient REM sleep deprivation. We showed that REM sleep propensity is similar during light phase in Orex-KO and WT mice. However, during the dark phase, REM sleep propensity was not suppressed in Orex-KO mice when hypocretin/orexin neuropeptides are normally released. Altogether our data suggest that in addition to the well-known wake-promoting role of hypocretin/orexin, these neuropeptides would also suppress REM sleep. Therefore, hypocretin/orexin deficiency would facilitate the occurrence of REM sleep at any time of day in an opportunistic manner as seen in human narcolepsy.
Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin An American Academy of Sleep Medicine Report

PubMed Central

Morgenthaler, Timothy I.; Kapur, Vishesh K.; Brown, Terry; Swick, Todd J.; Alessi, Cathy; Aurora, R. Nisha; Boehlecke, Brian; Chesson, Andrew L.; Friedman, Leah; Maganti, Rama; Owens, Judith; Pancer, Jeffrey; Zak, Rochelle

2007-01-01

These practice parameters pertain to the treatment of hypersomnias of central origin. They serve as both an update of previous practice parameters for the therapy of narcolepsy and as the first practice parameters to address treatment of other hypersomnias of central origin. They are based on evidence analyzed in the accompanying review paper. The specific disorders addressed by these parameters are narcolepsy (with cataplexy, without cataplexy, due to medical condition and unspecified), idiopathic hypersomnia (with long sleep time and without long sleep time), recurrent hypersomnia and hypersomnia due to medical condition. Successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce the fullest possible return of normal function, and regular follow-up to monitor response to treatment. Modafinil, sodium oxybate, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and selegiline are effective treatments for excessive sleepiness associated with narcolepsy, while tricyclic antidepressants and fluoxetine are effective treatments for cataplexy, sleep paralysis, and hypnagogic hallucinations; but the quality of published clinical evidence supporting them varies. Scheduled naps can be beneficial to combat sleepiness in narcolepsy patients. Based on available evidence, modafinil is an effective therapy for sleepiness due to idiopathic hypersomnia, Parkinson's disease, myotonic dystrophy, and multiple sclerosis. Based on evidence and/or long history of use in the therapy of narcolepsy committee consensus was that modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate are reasonable options for the therapy of hypersomnias of central origin. Citation: Morgenthaler TI; Kapur VK; Brown T; Swick TJ; Alessi C; Aurora RN; Boehlecke B; Chesson AL; Friedman L; Maganti R; Owens J; Pancer J; Zak R; Standards of Practice Committee of the AASM. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. SLEEP 2007;30(12):1705-1711. PMID:18246980
Hypocretin-1 deficiency in a girl with ROHHAD syndrome.

PubMed

Dhondt, Karlien; Verloo, Patrick; Verhelst, Hélène; Van Coster, Rudy; Overeem, Sebastiaan

2013-09-01

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare and complex pediatric syndrome, essentially caused by dysfunction of 3 vital systems regulating endocrine, respiratory, and autonomic nervous system functioning. The clinical spectrum of ROHHAD is broad, but sleep/wake disorders have received relatively little attention so far, although the central hypothalamic dysfunction would make the occurrence of sleep symptoms likely. In this case report, we expand the phenotype of ROHHAD with a number of striking sleep symptoms that together can be classified as a secondary form of narcolepsy. We present a 7-year-old girl with ROHHAD who displayed the classic features of narcolepsy with cataplexy: excessive daytime sleepiness with daytime naps, visual hallucinations, and partial cataplexy reflected in intermittent loss of facial muscle tone. Nocturnal polysomnography revealed sleep fragmentation and a sleep-onset REM period characteristic for narcolepsy. The diagnosis was confirmed by showing an absence of hypocretin-1 in the cerebrospinal fluid. We discuss potential pathophysiological implications as well as symptomatic treatment options.
The diagnosis and treatment of pediatric narcolepsy.

PubMed

Nevsimalova, Sona

2014-08-01

Narcolepsy in children is a serious disorder marked by a chronic course and lifelong handicap in school performance and choice of employment, by free time activity limitation, and by behavior and personality changes, all of which constitute a major influence on the quality of life. Increased daytime sleepiness may be the only sign at the disease onset, with attacks of sleep becoming longer and lasting up to hours. Also present may be confusional arousals with features of sleep drunkenness. Paradoxically, preschool and young children may show inattentiveness, emotional lability, and hyperactive behavior. Cataplexy may develop after onset of sleepiness and affect mainly muscles of the face. Hypnagogic hallucinations and sleep paralysis are seldom present. Multiple Sleep Latency Test criteria are not available for children younger than 6 years. The haplotype (HLA-DQB1:0602) can be associated with the disorder; however, the best predictor of narcolepsy-cataplexy is hypocretin deficiency. The treatment generally used in adults is regarded as off-label in childhood, which is why the management of pediatric narcolepsy is difficult.
Homeostatic and Circadian Abnormalities in Sleep and Arousal in Gulf War Syndrome

DTIC Science & Technology

2016-10-01

prefrontal cortex have been reported in patients with clinical sleep disorders, including insomnia and cataplexy.7-9 A recent hdEEG analysis of...and parietal gray matter in chronic insomnia : a voxel-based morphometric study. Biol Psychiatry 2010;67:182-5. 8. Joo EY, Tae WS, Kim ST, Hong SB
The Psychosocial Problems of Children with Narcolepsy and Those with Excessive Daytime Sleepiness of Uncertain Origin

ERIC Educational Resources Information Center

Stores, Gregory; Montgomery, Paul; Wiggs, Luci

2007-01-01

Background: Narcolepsy is a predominantly rapid eye movement sleep disorder with onset usually in the second decade but often in earlier childhood. Classically it is characterized by combinations of excessive sleepiness especially sleep attacks, cataplexy, hypnagogic hallucinations, and sleep paralysis. The psychosocial effects of this lifelong…
Executive functions, information sampling, and decision making in narcolepsy with cataplexy.

PubMed

Delazer, Margarete; Högl, Birgit; Zamarian, Laura; Wenter, Johanna; Gschliesser, Viola; Ehrmann, Laura; Brandauer, Elisabeth; Cevikkol, Zehra; Frauscher, Birgit

2011-07-01

Narcolepsy with cataplexy (NC) affects neurotransmitter systems regulating emotions and cognitive functions. This study aimed to assess executive functions, information sampling, reward processing, and decision making in NC. Twenty-one NC patients and 58 healthy participants performed an extensive neuropsychological test battery. NC patients scored as controls in executive function tasks assessing set shifting, reversal learning, working memory, and planning. Group differences appeared in a task measuring information sampling and reward sensitivity. NC patients gathered less information, tolerated a higher level of uncertainty, and were less influenced by reward contingencies than controls. NC patients also showed reduced learning in decision making and had significantly lower scores than controls in the fifth block of the IOWA gambling task. No correlations were found with measures of sleepiness. NC patients may achieve high performance in several neuropsychological domains, including executive functions. Specific differences between NC patients and controls highlight the importance of the hypocretin system in reward processing and decision making and are in line with previous neuroimaging and neurophysiological studies. PsycINFO Database Record (c) 2011 APA, all rights reserved.
Central Disorders of Hypersomnolence

PubMed Central

Khan, Zeeshan

2015-01-01

The central disorders of hypersomnolence are characterized by severe daytime sleepiness, which is present despite normal quality and timing of nocturnal sleep. Recent reclassification distinguishes three main subtypes: narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia (IH), which are the focus of this review. Narcolepsy type 1 results from loss of hypothalamic hypocretin neurons, while the pathophysiology underlying narcolepsy type 2 and IH remains to be fully elucidated. Treatment of all three disorders focuses on the management of sleepiness, with additional treatment of cataplexy in those patients with narcolepsy type 1. Sleepiness can be treated with modafinil/armodafinil or sympathomimetic CNS stimulants, which have been shown to be beneficial in randomized controlled trials of narcolepsy and, quite recently, IH. In those patients with narcolepsy type 1, sodium oxybate is effective for the treatment of both sleepiness and cataplexy. Despite these treatments, there remains a subset of hypersomnolent patients with persistent sleepiness, in whom alternate therapies are needed. Emerging treatments for sleepiness include histamine H3 antagonists (eg, pitolisant) and possibly negative allosteric modulators of the gamma-aminobutyric acid-A receptor (eg, clarithromycin and flumazenil). PMID:26149554

Central Disorders of Hypersomnolence: Focus on the Narcolepsies and Idiopathic Hypersomnia.

PubMed

Khan, Zeeshan; Trotti, Lynn Marie

2015-07-01

The central disorders of hypersomnolence are characterized by severe daytime sleepiness, which is present despite normal quality and timing of nocturnal sleep. Recent reclassification distinguishes three main subtypes: narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia (IH), which are the focus of this review. Narcolepsy type 1 results from loss of hypothalamic hypocretin neurons, while the pathophysiology underlying narcolepsy type 2 and IH remains to be fully elucidated. Treatment of all three disorders focuses on the management of sleepiness, with additional treatment of cataplexy in those patients with narcolepsy type 1. Sleepiness can be treated with modafinil/armodafinil or sympathomimetic CNS stimulants, which have been shown to be beneficial in randomized controlled trials of narcolepsy and, quite recently, IH. In those patients with narcolepsy type 1, sodium oxybate is effective for the treatment of both sleepiness and cataplexy. Despite these treatments, there remains a subset of hypersomnolent patients with persistent sleepiness, in whom alternate therapies are needed. Emerging treatments for sleepiness include histamine H3 antagonists (eg, pitolisant) and possibly negative allosteric modulators of the gamma-aminobutyric acid-A receptor (eg, clarithromycin and flumazenil).
Interactions of the histamine and hypocretin systems in CNS disorders.

PubMed

Shan, Ling; Dauvilliers, Yves; Siegel, Jerome M

2015-07-01

Histamine and hypocretin neurons are localized to the hypothalamus, a brain area critical to autonomic function and sleep. Narcolepsy type 1, also known as narcolepsy with cataplexy, is a neurological disorder characterized by excessive daytime sleepiness, impaired night-time sleep, cataplexy, sleep paralysis and short latency to rapid eye movement (REM) sleep after sleep onset. In narcolepsy, 90% of hypocretin neurons are lost; in addition, two groups reported in 2014 that the number of histamine neurons is increased by 64% or more in human patients with narcolepsy, suggesting involvement of histamine in the aetiology of this disorder. Here, we review the role of the histamine and hypocretin systems in sleep-wake modulation. Furthermore, we summarize the neuropathological changes to these two systems in narcolepsy and discuss the possibility that narcolepsy-associated histamine abnormalities could mediate or result from the same processes that cause the hypocretin cell loss. We also review the changes in the hypocretin and histamine systems, and the associated sleep disruptions, in Parkinson disease, Alzheimer disease, Huntington disease and Tourette syndrome. Finally, we discuss novel therapeutic approaches for manipulation of the histamine system.
Cataplexy as a side effect of modafinil in a patient without narcolepsy☆

PubMed Central

Lopes, Eduardo; Pereira, Danielle; da Silva Behrens, Nilce Sanny Costa; de Almeida Fonseca, Hassana; Calvancanti, Paola Oliveira; de Araújo Lima, Taís Figueiredo; Pradella-Hallinan, Marcia; Castro, Juliana; Tufik, Sergio; Coelho, Fernando Morgadinho Santos

2014-01-01

Narcolepsy is a disease in which there is diurnal excessive sleepiness with sleep attacks and a prevalence in the general population of 1/4000 individuals. Classically, it is characterized by cataplexy, sleep paralysis, hypnagogic hallucinations and fragmented sleep. The use of modafinil in the treatment of narcolepsy is the first option of treatment for diurnal excessive sleepiness. Although considered a safe drug for use in patients with narcolepsy, being utilized for more than 20 years, modafinil possesses a series of side effects, some of them still not fully researched or described. Side effects such as headache, nausea, anxiety, insomnia, lumbago, diarrhea, dyspepsia, rhinitis and vertigo are the most frequent. However, the clinical follow-up of patients under treatment with modafinil must be intensive and the side effects ought to be noted and evaluated. The under-response to treatment or the unexpected side effects must always be directed to differential diagnostics. The objective of this article is to describe an unexpected side effect of the use of modafinil in a patient with incorrect diagnosis of narcolepsy. PMID:26483900
Hypocretin Receptor Expression in Canine and Murine Narcolepsy Models and in Hypocretin-Ligand Deficient Human Narcolepsy

PubMed Central

Mishima, Kazuo; Fujiki, Nobuhiro; Yoshida, Yasushi; Sakurai, Takeshi; Honda, Makoto; Mignot, Emmanuel; Nishino, Seiji

2008-01-01

Study Objective: To determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy. Design: Animal and human study. We measured hcrtR1 and hcrtR2 expression in the frontal cortex and pons using the RT-PCR method in murine models (8-week-old and 27-week-old orexin/ataxin-3 transgenic (TG) hypocretin cell ablated mice and wild-type mice from the same litter, 10 mice for each group), in canine models (8 genetically narcoleptic Dobermans with null mutations in the hcrtR2, 9 control Dobermans, 3 sporadic ligand-deficient narcoleptics, and 4 small breed controls), and in humans (5 narcolepsy-cataplexy patients with hypocretin deficiency (average age 77.0 years) and 5 control subjects (72.6 years). Measurement and Results: 27-week-old (but not 8-week-old) TG mice showed significant decreases in hcrtR1 expression, suggesting the influence of the long-term ligand loss on the receptor expression. Both sporadic narcoleptic dogs and human narcolepsy-cataplexy subjects showed a significant decrease in hcrtR1 expression, while declines in hcrtR2 expression were not significant in these cases. HcrtR2-mutated narcoleptic Dobermans (with normal ligand production) showed no alteration in hcrtR1 expression. Conclusions: Moderate declines in hcrtR expressions, possibly due to long-term postnatal loss of ligand production, were observed in hypocretin-ligand deficient narcoleptic subjects. These declines are not likely to be progressive and complete. The relative preservation of hcrtR2 expression also suggests that hypocretin based therapies are likely to be a viable therapeutic options in human narcolepsy-cataplexy. Citation: Mishima K; Fujiki N; Yoshida Y; Sakurai T; Honda M; Mignot E; Nishino S. Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. SLEEP 2008;31(8):1119-1126. PMID:18714784
Identification of the variations in the CPT1B and CHKB genes along with the HLA-DQB1*06:02 allele in Turkish narcolepsy patients and healthy persons.

PubMed

Cingoz, Sultan; Agilkaya, Sinem; Oztura, Ibrahim; Eroglu, Secil; Karadeniz, Derya; Evlice, Ahmet; Altungoz, Oguz; Yilmaz, Hikmet; Baklan, Baris

2014-04-01

The HLA-DQB1*06:02 allele across all ethnic groups and the rs5770917 variation between CPT1B and CHKB genes in Japanese and Koreans are common genetic susceptibility factors for narcolepsy. This comprehensive genetic study sought to assess variations in CHKB and CPT1B susceptibility genes and HLA-DQB1*06:02 allele status in Turkish patients with narcolepsy and healthy persons. CHKB/CPT1B genes were sequenced in patients with narcolepsy (n=37) and healthy persons (n=100) to detect variations. The HLA-DQB1*06:02 allele status was determined by sequence specific polymerase chain reaction. The HLA-DQB1*06:02 allele was significantly more frequent in narcoleptic patients than in healthy persons (p=2×10(-7)) and in patients with narcolepsy and cataplexy than in those without (p=0.018). The mean of the multiple sleep latency test, sleep-onset rapid eye movement periods, and frequency of sleep paralysis significantly differed in the HLA-DQB1*06:02-positive patients. rs5770917, rs5770911, rs2269381, and rs2269382 were detected together as a haplotype in three patients and 11 healthy persons. In addition to this haplotype, the indel variation (rs144647670) was detected in the 5' upstream region of the human CHKB gene in the patients and healthy persons carrying four variants together. This study identified a novel haplotype consisting of the indel variation, which had not been detected in previous studies in Japanese and Korean populations, and observed four single-nucleotide polymorphisms in CHKB/CPT1B. The study confirmed the association of the HLA-DQB1*06:02 allele with narcolepsy and cataplexy susceptibility. The findings suggest that the presence of HLA-DQB1*06:02 may be a predictor of cataplexy in narcoleptic patients and could therefore be used as an additional diagnostic marker alongside hypocretin.
Autonomic Response to Periodic Leg Movements during Sleep in Narcolepsy-Cataplexy

PubMed Central

Dauvilliers, Yves; Pennestri, Marie-Hélène; Whittom, Shirley; Lanfranchi, Paola A.; Montplaisir, Jacques Y.

2011-01-01

Study Objectives: To test the hypothesis of autonomic nervous system dysfunction in patients with narcolepsy-cataplexy (NC) by assessing the physiologic activations associated with periodic limb movements during sleep (PLMS). Design: Sleep and heart rate (HR) were recorded during 1 night of polysomnography. Setting: Data were collected at the Sleep Disorders Center, Sacre-Coeur Hospital, Montreal, Canada. Participants: Data from 14 patients with NC (6 men, 8 women, mean age: 52.5 ± 11.9 years) were compared with data from 14 healthy control subjects matched for age and sex. Interventions: NA. Measurements and Results: Analyses included sleep stages, PLMS, microarousals, RR intervals converted into beats per minute on segments lasting 25 heartbeats (10 RR intervals before PLMS and 15 after), and cardiac-activation amplitudes. A Group-by-Heartbeat interaction was noted for PLMS without microarousals; the patients had a tachycardia of lower amplitude and a delayed and lower-amplitude bradycardia, compared with normal control subjects. Similar significant HR modifications were observed for PLMS with microarousals between patients with NC and control subjects. Patients with NC had a reduced magnitude of cardiac activation associated with PLMS with and without microarousals, as compared with control subjects. A negative correlation was noted between cardiac-activation amplitude and age in patients with NC, but no correlation with PLMS index was found in either patients with NC or control subjects. Conclusion: A significant reduction in the amplitude of PLMS-related HR responses in both tachycardia and bradycardia was found in patients with NC. These findings favor the physiologic relevance of the action of hypocretin on autonomic function that may be of clinical significance, i.e., increasing the risk of cardiovascular diseases. Citation: Dauvilliers Y; Pennestri MH; Whittom S; Lanfranchi PA; Montplaisir JY. Autonomic response to periodic leg movements during sleep in narcolepsy-cataplexy. SLEEP 2011;34(2):219-223. PMID:21286243
Delayed Diagnosis, Range of Severity, and Multiple Sleep Comorbidities: A Clinical and Polysomnographic Analysis of 100 Patients of the Innsbruck Narcolepsy Cohort

PubMed Central

Frauscher, Birgit; Ehrmann, Laura; Mitterling, Thomas; Gabelia, David; Gschliesser, Viola; Brandauer, Elisabeth; Poewe, Werner; Högl, Birgit

2013-01-01

Study Objectives: Narcolepsy is reported to affect 26-56/100,000 in the general population. We aimed to describe clinical and polysomnographic features of a large narcolepsy cohort in order to comprehensively characterize the narcoleptic spectrum. Methods: We performed a chart- and polysomnographybased review of all narcolepsy patients of the Innsbruck narcolepsy cohort. Results: A total of 100 consecutive narcolepsy patients (87 with cataplexy [NC], 13 without cataplexy [N]) were included in the analysis. All subjects had either excessive daytime sleepiness or cataplexy as their initial presenting clinical feature. Age at symptom onset was 20 (6-69) years. Diagnostic delay was 6.5 (0-39) years. The complete narcolepsy tetrad was present in 36/100 patients; 28/100 patients had three cardinal symptoms; 29/100 had two; and 7/100 had only excessive daytime sleepiness. Severity varied broadly with respect to excessive daytime sleepiness (median Epworth Sleepiness Scale score: 18, range 10-24), cataplexy (8-point Likert scale: median 4.5, range 1-8), hypnagogic hallucinations (median 4.5, range 1-7), and sleep paralysis (median 3, range 1-7). Sleep comorbidity was highly prevalent and ranged from sleeprelated movement disorders (n = 55/100), parasomnias (n = 34/100), and sleeprelated breathing disorders (n = 24/100), to insomnia (n = 28/100). REM sleep without atonia or a periodic limb movement in sleep index > 5/h were present in most patients (90/100 and 75/100). A high percentage of narcoleptic patients in the present study had high frequency leg movements (35%) and excessive fragmentary myoclonus (22%). Of the narcolepsy patients with clinical features of REM sleep behavior disorder (RBD), 76.5% had EMG evidence for RBD on the multiple sleep latency test (MSLT), based on a standard cutoff of a minimum of 18% of 3-sec miniepochs. Conclusion: This study is one of the largest monocentric polysomnographic studies to date of patients with narcolepsy and confirms the frequent comorbidity of narcolepsy with many other sleep disorders. Our study is the first to evaluate the percentage of patients with high frequency leg movements and excessive fragmentary myoclonus in narcolepsy and is the first to demonstrate EMG evidence of RBD in the MSLT. These findings add to the growing body of literature suggesting that motor instability is a key feature of narcolepsy. Citation: Frauscher B; Ehrmann L; Mitterling T; Gabelia D; Gschliesser V; Brandauer E; Poewe W; Högl B. Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the Innsbruck narcolepsy cohort. J Clin Sleep Med 2013;9(8):805-812. PMID:23946711
Orexin research: patent news from 2016.

PubMed

Boss, Christoph; Roch, Catherine

2017-10-01

The orexin system consists of two G-protein-coupled receptors, orexin 1 and orexin 2 and two endogenous ligands, orexin A and orexin B . It is evolutionarily highly conserved. It is involved in the promotion of wakefulness as well as in anxiety and addictive disorders. In addition, its activation via the Ox1 receptor triggers apoptosis in several cancer cell lines. Dual orexin receptor antagonists are successfully used to treat primary insomnia. The major open questions are now related to the clinical validation of Ox1 selective antagonists. A strong rationale exists for orexin agonism in the treatment of narcolepsy with cataplexy. Areas covered: The patent applications from Thomson Reuters Integrity Database added in 2016 are summarized and discussed together with the most important findings published in the scientific literature. Expert opinion: The large number of patents shows the continuing interest in the orexin receptors as targets. The structural scope covered is narrow. Questions about novelty and inventiveness are evident. The additional information published on X-ray structures on both orexin receptors opens new ways of optimizing antagonists. It might also influence the efforts in the identification of orexin receptor agonists. Being potential treatments for narcolepsy with cataplexy.
REM Sleep at its Core – Circuits, Neurotransmitters, and Pathophysiology

PubMed Central

Fraigne, Jimmy J.; Torontali, Zoltan A.; Snow, Matthew B.; Peever, John H.

2015-01-01

Rapid eye movement (REM) sleep is generated and maintained by the interaction of a variety of neurotransmitter systems in the brainstem, forebrain, and hypothalamus. Within these circuits lies a core region that is active during REM sleep, known as the subcoeruleus nucleus (SubC) or sublaterodorsal nucleus. It is hypothesized that glutamatergic SubC neurons regulate REM sleep and its defining features such as muscle paralysis and cortical activation. REM sleep paralysis is initiated when glutamatergic SubC cells activate neurons in the ventral medial medulla, which causes release of GABA and glycine onto skeletal motoneurons. REM sleep timing is controlled by activity of GABAergic neurons in the ventrolateral periaqueductal gray and dorsal paragigantocellular reticular nucleus as well as melanin-concentrating hormone neurons in the hypothalamus and cholinergic cells in the laterodorsal and pedunculo-pontine tegmentum in the brainstem. Determining how these circuits interact with the SubC is important because breakdown in their communication is hypothesized to underlie narcolepsy/cataplexy and REM sleep behavior disorder (RBD). This review synthesizes our current understanding of mechanisms generating healthy REM sleep and how dysfunction of these circuits contributes to common REM sleep disorders such as cataplexy/narcolepsy and RBD. PMID:26074874
Narcolepsy: Autoimmunity, Effector T Cell Activation Due to Infection, or T Cell Independent, Major Histocompatibility Complex Class II Induced Neuronal Loss?

ERIC Educational Resources Information Center

Fontana, Adriano; Gast, Heidemarie; Reith, Walter; Recher, Mike; Birchler, Thomas; Bassetti, Claudio L.

2010-01-01

Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of…
Sleep and Wakefulness Handbook for Flight Medical Officers

DTIC Science & Technology

1987-07-01

cataplexy, sleep paralysis and hypnagogic hallucinations. There may also be disturbed nocturnal sleep with awakenings, body movements and Uttle...sleep. It may occur many times a day, or once a week or even less, and may disappear completely. Sleep paralysis and hypnagogic hallucinations occur...muscles except those controUing the eyes, and this state is often accompanied by intense fear and by hypnagogic hallucinations. Respiration is not
Narcolepsy with Cataplexy Associated with Nocturnal Compulsive Behaviors: A Case-Control Study

PubMed Central

Palaia, Vincenzo; Poli, Francesca; Pizza, Fabio; Antelmi, Elena; Franceschini, Christian; Moghadam, Keivan Kaveh; Provini, Frederica; Pagotto, Uberto; Montagna, Pasquale; Schenck, Carlos H.; Mignot, Emmanuel; Plazzi, Giuseppe

2011-01-01

Study Objectives: To assess the prevalence of sleep related-eating disorder (SRED) and nocturnal smoking (NS) in patients with narcolepsy with cataplexy (NC). Design: Case-control study. Setting: University hospital. Patients or Participants: 65 consecutive adult NC patients (33 men; mean age 43.9 ± 19.2 years) and 65 age-, sex-, and geographical origin-matched controls. Interventions: Validated questionnaires were used to investigate SRED, NS, restless legs syndrome (RLS), and psychopathological traits (using Eating Disorder Inventory-2 [EDI-2]; Maudsley Obsessive-Compulsive Inventory [MOCI]; and Beck Depression Inventory [BDI]). Measurements and Results: NC patients showed a higher prevalence of SRED (32% vs 3%, P = 0.00001), NS (21% vs 0%, P = 0.00006), and RLS (18% vs 5%, P = 0.013) than controls. Moreover, NC patients presented more frequently with an eating-related pathological profile on the EDI-2 (80% vs 46%, P = 0.00006) and had a higher prevalence of depressed mood on the BDI (41% vs 18%, P = 0.004). In comparison to patients without SRED, NC patients with SRED were more frequently women (71% vs 39%, P = 0.013), had higher “bulimic” (29% vs 2%, P = 0.004) and “social insecurity” (48% vs 18%, P = 0.013) traits on the EDI-2, had higher obsessive-compulsiveness on the MOCI (29% vs 4%, P = 0.009), and were more depressed on the BDI (67% vs 29%, P = 0.005). NC patients with NS showed more frequent pathological profiles on the EDI-2 (100% vs 75%, P = 0.035), including the “bulimic” (29% vs 6%, P = 0.015), “perfectionism” (43% vs 14%, P = 0.016), and “social insecurity” (50% vs 22, P = 0.035) profiles. Conclusion: Our study shows a strong association of the compulsive nocturnal behaviors SRED and NS with adult NC. Citation: Palaia V; Poli F; Pizza F; Antelmi E; Franceschini C; Moghadam KK; Provini F; Pagotto U; Montagna P; Schenck CH; Mignot E; Plazzi G. Narcolepsy with cataplexy associated with nocturnal compulsive behaviors: a case-control study. SLEEP 2011;34(10):1365-1371. PMID:21966068
High Prevalence of Precocious Puberty and Obesity in Childhood Narcolepsy with Cataplexy

PubMed Central

Poli, Francesca; Pizza, Fabio; Mignot, Emmanuel; Ferri, Raffaele; Pagotto, Uberto; Taheri, Shahrad; Finotti, Elena; Bernardi, Filippo; Pirazzoli, Piero; Cicognani, Alessandro; Balsamo, Antonio; Nobili, Lino; Bruni, Oliviero; Plazzi, Giuseppe

2013-01-01

Study Objectives: We analyzed the potential predictive factors for precocious puberty, observed in some cases of childhood narcolepsy with cataplexy (NC) and for obesity, a much more common feature of NC, through a systematic assessment of pubertal staging, body mass index (BMI), and metabolic/endocrine biochemical analyses. Design: Cross-sectional on consecutive recruitment. Setting: Hospital sleep center and pediatric unit. Patients: Forty-three children and adolescents with NC versus 52 age-matched obese children as controls. Interventions: N/A. Measurements and Results: Patients underwent clinical interview, polysomnographic recordings, cerebrospinal fluid hypocretin-1 measurement, and human leukocyte antigen typing. Height, weight, arterial blood pressure, and Tanner pubertal stage were evaluated. Plasma lipid and glucose profiles were analyzed. When an altered pubertal development was clinically suspected, plasma concentrations of hypothalamic-pituitary-gonadal axis hormones were determined. Children with NC showed a high prevalence of overweight/obesity (74%) and a higher occurrence of precocious puberty (17%) than obese controls (1.9%). Isolated signs of accelerated pubertal development (thelarche, pubic hair, advanced bone age) were also present (41%). Precocious puberty was significantly predicted by a younger age at first NC symptom onset but not by overweight/obesity or other factors. In addition, overweight/obesity was predicted by younger age at diagnosis; additional predictors were found for overweight/obesity (short disease duration, younger age at weight gain and lower high-density lipoprotein cholesterol), which did not include precocious puberty. NC symptoms, pubertal signs appearance, and body weight gain developed in close temporal sequence. Conclusions: NC occurring during prepubertal age is frequently accompanied by precocious puberty and overweight/obesity, suggesting an extended hypothalamic dysfunction. The severity of these comorbidities and the potential related risks require a multidiagnostic approach and a tailored therapeutic management. Citation: Poli F; Pizza F; Mignot E; Ferri R; Pagotto U; Taheri S; Finotti E; Bernardi F; Pirazzoli P; Cicognani A; Balsamo A; Nobili L; Bruni O; Plazzi G. High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy. SLEEP 2013;36(2):175–181. PMID:23372264
Niemann-Pick disease type C

PubMed Central

2010-01-01

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations. PMID:20525256
New developments in the management of narcolepsy.

PubMed

Abad, Vivien C; Guilleminault, Christian

2017-01-01

Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%-0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy's strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss. Current treatment modalities alleviate the main symptoms of excessive daytime somnolence (EDS) and cataplexy and, to a lesser extent, reduce nocturnal sleep disruption, hypnagogic hallucinations, and sleep paralysis. Sodium oxybate (SXB), a sodium salt of γ hydroxybutyric acid, is a first-line agent for cataplexy and EDS and may help sleep disruption, hypnagogic hallucinations, and sleep paralysis. Various antidepressant medications including norepinephrine serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants are second-line agents for treating cataplexy. In addition to SXB, modafinil and armodafinil are first-line agents to treat EDS. Second-line agents for EDS are stimulants such as methylphenidate and extended-release amphetamines. Emerging therapies include non-hypocretin-based therapy, hypocretin-based treatments, and immunotherapy to prevent hypocretin neuronal death. Non-hypocretin-based novel treatments for narcolepsy include pitolisant (BF2.649, tiprolisant); JZP-110 (ADX-N05) for EDS in adults; JZP 13-005 for children; JZP-386, a deuterated sodium oxybate oral suspension; FT 218 an extended-release formulation of SXB; and JNJ-17216498, a new formulation of modafinil. Clinical trials are investigating efficacy and safety of SXB, modafinil, and armodafinil in children. γ-amino butyric acid (GABA) modulation with GABA A receptor agonists clarithromycin and flumazenil may help daytime somnolence. Other drugs investigated include GABA B agonists (baclofen), melanin-concentrating hormone antagonist, and thyrotropin-releasing hormone agonists. Hypocretin-based therapies include hypocretin peptide replacement administered either through an intracerebroventricular route or intranasal route. Hypocretin neuronal transplant and transforming stem cells into hypothalamic neurons are also discussed in this article. Immunotherapy to prevent hypocretin neuronal death is reviewed.
New developments in the management of narcolepsy

PubMed Central

Abad, Vivien C; Guilleminault, Christian

2017-01-01

Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%–0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy’s strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss. Current treatment modalities alleviate the main symptoms of excessive daytime somnolence (EDS) and cataplexy and, to a lesser extent, reduce nocturnal sleep disruption, hypnagogic hallucinations, and sleep paralysis. Sodium oxybate (SXB), a sodium salt of γ hydroxybutyric acid, is a first-line agent for cataplexy and EDS and may help sleep disruption, hypnagogic hallucinations, and sleep paralysis. Various antidepressant medications including norepinephrine serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants are second-line agents for treating cataplexy. In addition to SXB, modafinil and armodafinil are first-line agents to treat EDS. Second-line agents for EDS are stimulants such as methylphenidate and extended-release amphetamines. Emerging therapies include non-hypocretin-based therapy, hypocretin-based treatments, and immunotherapy to prevent hypocretin neuronal death. Non-hypocretin-based novel treatments for narcolepsy include pitolisant (BF2.649, tiprolisant); JZP-110 (ADX-N05) for EDS in adults; JZP 13-005 for children; JZP-386, a deuterated sodium oxybate oral suspension; FT 218 an extended-release formulation of SXB; and JNJ-17216498, a new formulation of modafinil. Clinical trials are investigating efficacy and safety of SXB, modafinil, and armodafinil in children. γ-amino butyric acid (GABA) modulation with GABAA receptor agonists clarithromycin and flumazenil may help daytime somnolence. Other drugs investigated include GABAB agonists (baclofen), melanin-concentrating hormone antagonist, and thyrotropin-releasing hormone agonists. Hypocretin-based therapies include hypocretin peptide replacement administered either through an intracerebroventricular route or intranasal route. Hypocretin neuronal transplant and transforming stem cells into hypothalamic neurons are also discussed in this article. Immunotherapy to prevent hypocretin neuronal death is reviewed. PMID:28424564
Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

DTIC Science & Technology

2015-11-01

somnolence without cataplexy and, in rat, decreases active wake and increases the time spent in non-rapid eye movement (NREM) and (REM) sleep (Brisbare-Roch...system results in a narcoleptic phenotype characterized by excessive sleepiness, fragmented sleep, abnormally timed Rapid- Eye -Movement (REM) sleep, and...spent in non-rapid eye movement (NREM) and (REM) sleep with differential effects on various neurotransmitter systems. To date, no studies have reported
Challenges in the development of therapeutics for narcolepsy

PubMed Central

Black, Sarah Wurts; Yamanaka, Akihiro; Kilduff, Thomas S.

2016-01-01

Narcolepsy is a neurological disorder that afflicts 1 in 2000 individuals and is characterized by excessive daytime sleepiness and cataplexy—a sudden loss of muscle tone triggered by positive emotions. Features of narcolepsy include dysregulation of arousal state boundaries as well as autonomic and metabolic disturbances. Disruption of neurotransmission through the hypocretin/orexin (Hcrt) system, usually by degeneration of the HCRT-producing neurons in the posterior hypothalamus, results in narcolepsy. The cause of Hcrt neurodegeneration is unknown but thought to be related to autoimmune processes. Current treatments for narcolepsy are symptomatic, including wake-promoting therapeutics that increase presynaptic dopamine release and anticataplectic agents that activate monoaminergic neurotransmission. Sodium oxybate is the only medication approved by the US Food and Drug Administration that alleviates both sleep/wake disturbances and cataplexy. Development of therapeutics for narcolepsy has been challenged by historical misunderstanding of the disease, its many disparate symptoms and, until recently, its unknown etiology. Animal models have been essential to elucidating the neuropathology underlying narcolepsy. These models have also aided understanding the neurobiology of the Hcrt system, mechanisms of cataplexy, and the pharmacology of narcolepsy medications. Transgenic rodent models will be critical in the development of novel therapeutics for the treatment of narcolepsy, particularly efforts directed to overcome challenges in the development of hypocretin replacement therapy. PMID:26721620
An autoantibody in narcolepsy disrupts colonic migrating motor complexes.

PubMed

Jackson, Michael W; Reed, Joanne H; Smith, Anthony J F; Gordon, Tom P

2008-12-03

Despite strong circumstantial evidence for the autoimmune hypothesis of narcolepsy, conventional immunological methods have failed to detect an autoantibody. This study investigated the real-time effects of narcoleptic immunoglobulins on a spontaneous colonic migrating motor complex (CMMC) preparation. IgG from patients with narcolepsy with cataplexy or healthy controls was added directly to isolated mouse colons undergoing CMMC activity to test for autoantibodies that disrupt colonic motility. The effect of immunoglobulins prepared for clinical intravenous treatment (IVIg) on autoantibody-mediated colonic disruption was also assessed. Narcoleptic IgGs markedly reduced the frequency of CMMCs or irreversibly abolished them. Abrogation of CMMCs was followed by an increase in the resting tension of the colon preparation and appearance of atropine-sensitive phasic smooth muscle contractions. IVIg partially neutralized the inhibitory effect of narcoleptic IgG on the CMMCs. The dramatic effect of narcoleptic IgG on CMMC generation is consistent with an autoantibody-mediated disruption of enteric neural pathways. The ex vivo whole-organ approach allows real-time examination of the physiological effects of the narcoleptic autoantibody and offers a new avenue for exploring the autoimmune basis of narcolepsy. The neutralizing effect of IVIg on the autoantibody provides a rationale for the reported clinical improvement in cataplexy when IVIg are given at disease onset.
Comparing Treatment Effect Measurements in Narcolepsy: The Sustained Attention to Response Task, Epworth Sleepiness Scale and Maintenance of Wakefulness Test.

PubMed

van der Heide, Astrid; van Schie, Mojca K M; Lammers, Gert Jan; Dauvilliers, Yves; Arnulf, Isabelle; Mayer, Geert; Bassetti, Claudio L; Ding, Claire-Li; Lehert, Philippe; van Dijk, J Gert

2015-07-01

To validate the Sustained Attention to Response Task (SART) as a treatment effect measure in narcolepsy, and to compare the SART with the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS). Validation of treatment effect measurements within a randomized controlled trial (RCT). Ninety-five patients with narcolepsy with or without cataplexy. The RCT comprised a double-blind, parallel-group, multicenter trial comparing the effects of 8-w treatments with pitolisant (BF2.649), modafinil, or placebo (NCT01067222). MWT, ESS, and SART were administered at baseline and after an 8-w treatment period. The severity of excessive daytime sleepiness and cataplexy was also assessed using the Clinical Global Impression scale (CGI-C). The SART, MWT, and ESS all had good reliability, obtained for the SART and MWT using two to three sessions in 1 day. The ability to distinguish responders from nonresponders, classified using the CGI-C score, was high for all measures, with a high performance for the SART (r = 0.61) and the ESS (r = 0.54). The Sustained Attention to Response Task is a valid and easy-to-administer measure to assess treatment effects in narcolepsy, enhanced by combining it with the Epworth Sleepiness Scale. © 2015 Associated Professional Sleep Societies, LLC.

Narcolepsy with cataplexy and hyperthyroidism sudden appeared after H1N1 vaccination

PubMed Central

Leiva, Silvia; Madrazo, Jimena; Podesta, Claudio

2018-01-01

Narcolepsy type 1 (NT1) is a chronic sleep disorder, characterized by excessive daytime sleepiness, cataplexy and fragmented nocturnal sleep. It is caused by a hypocretin deficiency due to a significant reduction of the neurons producing it. In the last years, it has been postulated that an autoimmune mechanism would be responsible for the destruction of these neurons in those genetically predisposed patients. The increased incidence of narcolepsy after the pandemic H1N1 influenza vaccination campaign in 2009-2010 is known. We present below the case of an adult patient who, 10 days after receiving H1N1 vaccination, suffers a traffic accident after falling asleep. Subsequent studies revealed hyperthyroidism due to Graves disease. In spite of the treatment, the patient persisted with daily and disabling daytime sleepiness, sleep attacks and episodes of generalized muscle atony with preservation of consciousness. A nocturnal polysomnography and multiple sleep latency test (MSLT) were performed with a diagnosis of NT1. The particularity of this case is the presentation of 2 autoimmune diseases triggered by an H1N1 vaccine without adjuvant, so far there is only evidence of NT1 associated with vaccines with adjuvant and viral infection. The association of both entities has made us reflect on the autoimmune mechanism, reinforcing the theory of its role in the onset of the disease. PMID:29796199
[Symptomatic hypersomnia due to orexin deficiency in hypothalamic lesions].

PubMed

Kanbayashi, Takashi; Arii, Junko; Kubota, Hiroaki; Yano, Tamami; Kashiwagi, Mitsuru; Yoshikawa, Sousuke; Tohyama, Jun; Sawaishi, Yukio

2006-09-01

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy and other abnormal manifestations of REM sleep. Recently, it was discovered that the pathophysiology of idiopathic narcolepsy-cataplexy is linked to orexin ligand deficiency in the brain and cerebrospinal fluid. Orexin neurons localize in the posterior hypothalamic area, which was previously described as "waking center" by von Economo in 1920s. Hypersomnia due to orexin ligand deficiency can also occur during the course of other neurological conditions, such as hypothalamic tumor, encephalopathy and demyelinating disorder (i.e. symptomatic hypersomnia). We experienced 8 pediatric cases with symptomatic hypersomnia. These cases were diagnosed as brain tumor (n = 2), head trauma (n = 1), encephalopathy (n = 1), demyelinating disorder (n = 3) and infarction (n = 1). Six pediatric cases with orexin measurements from the literatures were additionally included and total 14 cases were studied. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, a review of the case histories reveals numerous unquestionable cases of symptomatic hypersomnia. In these cases, the occurrences of the hypersomnia run parallel with the rise and fall of the causative diseases. Most of symptomatic hypersomnia cases show both extended nocturnal sleep time and EDS consisting of prolonged sleep episodes of NREM sleep. The features of nocturnal sleep and EDS in symptomatic hypersomnia are more similar to idiopathic hypersomnia than to narcolepsy.
Melanin concentrating hormone in central hypersomnia.

PubMed

Peyron, Christelle; Valentin, Françoise; Bayard, Sophie; Hanriot, Lucie; Bedetti, Christophe; Rousset, Bernard; Luppi, Pierre-Hervé; Dauvilliers, Yves

2011-09-01

Narcolepsy with cataplexy (NC) is a disabling disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations, due to a deficient hypocretin/orexin neurotransmission. Melanin concentrating hormone (MCH) neurons involved in the homeostatic regulation of REM sleep are intact. We hypothesized that an increased release of MCH in NC would be partly responsible for the abnormal REM sleep manifestations. Twenty-two untreated patients affected with central hypersomnia were included: 14 NC, six idiopathic hypersomnia with long sleep time, and two post-traumatic hypersomnia. Fourteen neurological patients without any sleep disorders were included as controls. Using radioimmunoassays, we measured hypocretin-1 and MCH levels in cerebrospinal fluid (CSF). The MCH level was slightly but significantly lower in patients with hypersomnia (98 ± 32 pg/ml) compared to controls (118 ± 20 pg/ml). After exclusion of patients affected with post-traumatic hypersomnia the difference became non-significant. We also failed to find any association between MCH level and hypocretin level, the severity of daytime sleepiness, the number of SOREMPs, the frequency of cataplexy, and the presence of hypnagogic hallucinations or sleep paralysis. This study reports the first measurement of MCH in CSF using radioimmunoassay technology. It appears to be a non-informative tool to differentiate etiologies of central hypersomnia with or without REM sleep dysregulation. Copyright © 2011 Elsevier B.V. All rights reserved.
Narcolepsy: current treatment options and future approaches

PubMed Central

Billiard, Michel

2008-01-01

The management of narcolepsy is presently at a turning point. Three main avenues are considered in this review: 1) Two tendencies characterize the conventional treatment of narcolepsy. Modafinil has replaced methylphenidate and amphetamine as the first-line treatment of excessive daytime sleepiness (EDS) and sleep attacks, based on randomized, double blind, placebo-controlled clinical trials of modafinil, but on no direct comparison of modafinil versus traditional stimulants. For cataplexy, sleep paralysis, and hypnagogic hallucinations, new antidepressants tend to replace tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) in spite of a lack of randomized, double blind, placebo-controlled clinical trials of these compounds; 2) The conventional treatment of narcolepsy is now challenged by sodium oxybate, the sodium salt of gammahydroxybutyrate, based on a series of randomized, double-blind, placebo-controlled clinical trials and a long-term open label study. This treatment has a fairly good efficacy and is active on all symptoms of narcolepsy. Careful titration up to an adequate level is essential both to obtain positive results and avoid adverse effects; 3) A series of new treatments are currently being tested, either in animal models or in humans, They include novel stimulant and anticataplectic drugs, endocrine therapy, and, more attractively, totally new approaches based on the present state of knowledge of the pathophysiology of narcolepsy with cataplexy, hypocretine-based therapies, and immunotherapy. PMID:18830438
Comorbidity of Narcolepsy Type 1 With Autoimmune Diseases and Other Immunopathological Disorders: A Case-Control Study

PubMed Central

Martinez-Orozco, Francisco Javier; Vicario, Jose Luis; De Andres, Clara; Fernandez-Arquero, Miguel; Peraita-Adrados, Rosa

2016-01-01

Background Several evidences suggest that autoimmune diseases (ADs) tend to co-occur in an individual and within the same family. Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a selective loss of hypocretin-producing neurons due to a mechanism of neural destruction that indicates an autoimmune pathogenesis, although no evidence is available. We report on the comorbidity of ADs and other immunopathological diseases (including allergy diseases) in narcolepsy. Methods We studied 158 Caucasian NT1 patients (60.7% male; mean age 49.4 ± 19.7 years), in whom the diagnosis was confirmed by polysomnography followed by a multiple sleep latency test, or by hypocretin-1 levels measurements. Results Thirty out of 158 patients (18.99%; 53.3% female; 29 sporadic and one familial cases) had one or more immunopathological diseases associated. A control group of 151 subjects were matched by gender and age with the narcolepsy patients. Results demonstrated that there was a higher frequency of ADs in our series of narcolepsy patients compared to the sample of general population (odds ratio: 3.17; 95% confidence interval: 1.01 - 10.07; P = 0.040). A temporal relationship with the age at onset of the diseases was found. Conclusions Cataplexy was significantly more severe in NT1 patients with immunopathological diseases, and immunopathological diseases are a risk factor for severe forms of cataplexy in our series (odds ratio: 23.6; 95% confidence interval: 5.5 - 100.1). PMID:27298657
Epigenome-wide association study of DNA methylation in narcolepsy: an integrated genetic and epigenetic approach.

PubMed

Shimada, Mihoko; Miyagawa, Taku; Toyoda, Hiromi; Tokunaga, Katsushi; Honda, Makoto

2018-04-01

Narcolepsy with cataplexy, which is a hypersomnia characterized by excessive daytime sleepiness and cataplexy, is a multifactorial disease caused by both genetic and environmental factors. Several genetic factors including HLA-DQB1*06:02 have been identified; however, the disease etiology is still unclear. Epigenetic modifications, such as DNA methylation, have been suggested to play an important role in the pathogenesis of complex diseases. Here, we examined DNA methylation profiles of blood samples from narcolepsy and healthy control individuals and performed an epigenome-wide association study (EWAS) to investigate methylation loci associated with narcolepsy. Moreover, data from the EWAS and a previously performed narcolepsy genome-wide association study were integrated to search for methylation loci with causal links to the disease. We found that (1) genes annotated to the top-ranked differentially methylated positions (DMPs) in narcolepsy were associated with pathways of hormone secretion and monocarboxylic acid metabolism. (2) Top-ranked narcolepsy-associated DMPs were significantly more abundant in non-CpG island regions and more than 95 per cent of such sites were hypomethylated in narcolepsy patients. (3) The integrative analysis identified the CCR3 region where both a single methylation site and multiple single-nucleotide polymorphisms were found to be associated with the disease as a candidate region responsible for narcolepsy. The findings of this study suggest the importance of future replication studies, using methylation technologies with wider genome coverage and/or larger number of samples, to confirm and expand on these results.
Potentiation of a functional autoantibody in narcolepsy by a cholinesterase inhibitor.

PubMed

Jackson, Michael W; Spencer, Nicolas J; Reed, Joanne H; Smith, Anthony J F; Gordon, Tom P

2009-12-01

We have recently reported the presence of an immunoglobulin G (IgG) autoantibody (Ab) in patients with narcolepsy with cataplexy that abolishes spontaneous colonic migrating motor complexes (CMMCs) and increases smooth muscle tension and atropine-sensitive phasic contractions in a physiological assay of an isolated colon. In this study, we used the cholinesterase inhibitor, neostigmine, to explore the mechanism of the narcoleptic IgG-mediated disruption of enteric motor function in four patients with narcolepsy with cataplexy and to identify a pharmacological mimic of the Ab. Neostigmine potentiated the narcoleptic IgG-mediated increase in smooth muscle resting tension and phasic smooth muscle contractions by an atropine-sensitive mechanism but exerted no effect on resting tension in the presence of control IgG. Decreased frequency of CMMCs mediated by IgG with anti-M3R activity was reversed by neostigmine. Therefore, a challenge with a cholinesterase inhibitor improves the specificity of the CMMC assay for narcoleptic IgG. Tetrodotoxin (TTX), a neuronal sodium channel blocker, also abolished CMMCs and increased resting tone, and a similar potentiation was observed with neostigmine; thus, TTX is a mimic of the functional effects of the narcoleptic IgG in this bioassay. These findings provide a link to pharmacological studies of canine narcolepsy and are consistent with a functional blockade of both excitatory and inhibitory motor neurons by the narcoleptic Ab, similar to the TTX mimic, presumably by binding to an autoantigenic target expressed in both populations of neurons.
Clinical and practical considerations in the pharmacologic management of narcolepsy.

PubMed

Thorpy, Michael J; Dauvilliers, Yves

2015-01-01

Despite published treatment recommendations and the availability of approved and off-label pharmacologic therapies for narcolepsy, the clinical management of this incurable, chronic neurologic disorder remains challenging. While treatment is generally symptomatically driven, decisions regarding which drug(s) to use need to take into account a variety of factors that may affect adherence, efficacy, and tolerability. Type 1 narcolepsy (predominantly excessive daytime sleepiness with cataplexy) or type 2 narcolepsy (excessive daytime sleepiness without cataplexy) may drive treatment decisions, with consideration given either to a single drug that targets multiple symptoms or to multiple drugs that each treat a specific symptom. Other drug-related characteristics that affect drug choice are dosing regimens, tolerability, and potential drug-drug interactions. Additionally, the patient should be an active participant in treatment decisions, and the main symptomatic complaints, treatment goals, psychosocial setting, and use of lifestyle substances (ie, alcohol, nicotine, caffeine, and cannabis) need to be discussed with respect to treatment decisions. Although there is a lack of narcolepsy-specific instruments for monitoring therapeutic effects, clinically relevant subjective and objective measures of daytime sleepiness (eg, Epworth Sleepiness Scale and Maintenance of Wakefulness Test) can be used to provide guidance on whether treatment goals are being met. These considerations are discussed with the objective of providing clinically relevant recommendations for making treatment decisions that can enhance the effective management of patients with narcolepsy. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
Degenerative pontine lesions in patients with familial narcolepsy.

PubMed

Stepień, Adam; Staszewski, Jacek; Domzał, Teofan M; Tomczykiewicz, Kazimierz; Skrobowska, Ewa; Durka-Kesy, Marta

2010-01-01

Narcolepsy is characterized by chronic excessive daytime sleepiness with episodic sleep attacks. There are several associated symptoms of narcolepsy: cataplexy (bilateral muscle weakness without loss of consciousness provoked by an emotional trigger, e.g. laughter), sleep paralysis and hypnagogic-hypnopompic hallucinations. Most cases are sporadic; familial narcolepsy contributes to only 1-5% of all cases. While most cases of narcolepsy are idiopathic and are not associated with clinical or radiographic evidence of brain pathology, symptomatic or secondary narcolepsy may occur occasionally in association with lesions caused by tumours, demyelination or strokes of the diencephalon, midbrain, and pons. There are some examples of non-specific brainstem lesions found in magnetic resonance imaging (MRI) in patients with idiopathic narcolepsy. The authors present eleven patients from a five-generation family with many members who suffer from episodic excessive daytime sleepiness. Narcolepsy was diagnosed in 9 patients. Sleepiness was frequently associated with cataplexy, hypnagogic-hypnopompic hallucinations and sleep paralysis. Improvement in their clinical state was observed during the treatment with modafinil. All probands had MRI of the brain, routine blood tests, EEG, polysomnography, examination of the level of hypocretin in cerebrospinal fluid and evaluation by means of Epworth and Stanford Sleepiness Scales. In 9 patients with narcolepsy, decreased thickness of the substantia nigra was found and in six of them degenerative lesions in the pontine substantia nigra were also noticed. The significance of these changes remains unclear. No data have been published until now concerning the presence of any brain lesions in patients with familial narcolepsy.
High bicarbonate levels in narcoleptic children.

PubMed

Franco, Patricia; Junqua, Aurelie; Guignard-Perret, Anne; Raoux, Aude; Perier, Magali; Raverot, Veronique; Claustrat, Bruno; Gustin, Marie-Paule; Inocente, Clara Odilia; Lin, Jian-Sheng

2016-04-01

The objective of this study was to evaluate the levels of plasma bicarbonate levels in narcoleptic children. Clinical, electrophysiological data and bicarbonate levels were evaluated retrospectively in children seen in our paediatric national reference centre for hypersomnia. The cohort included 23 control subjects (11.5 ± 4 years, 43% boys) and 51 patients presenting de-novo narcolepsy (N) (12.7 ± 3.7 years, 47% boys). In narcoleptic children, cataplexy was present in 78% and DQB1*0602 was positive in 96%. The control children were less obese (2 versus 47%, P = 0.001). Compared with control subjects, narcoleptic children had higher bicarbonate levels (P = 0.02) as well as higher PCO2 (P < 0.01) and lower venous pH gas (P < 0.01). Bicarbonate levels higher than 27 mmol L(-1) were found in 41.2% of the narcoleptic children and 4.2% of the controls (P = 0.001). Bicarbonate levels were correlated with the Adapted Epworth Sleepiness Scale (P = 0.01). Narcoleptic patients without obesity often had bicarbonate levels higher than 27 mmol L (-1) (55 versus 25%, P = 0.025). No differences were found between children with and without cataplexy. In conclusion, narcoleptic patients had higher bicarbonate plasma levels compared to control children. This result could be a marker of hypoventilation in this pathology, provoking an increase in PCO2 and therefore a respiratory acidosis, compensated by an increase in plasma bicarbonates. This simple screening tool could be useful for prioritizing children for sleep laboratory evaluation in practice. © 2015 European Sleep Research Society.
Mechanism of action of narcolepsy medications.

PubMed

Gowda, Chandan R; Lundt, Leslie P

2014-12-01

The medications used to treat narcolepsy are targeted toward alleviating symptoms such as excessive sleepiness and cataplexy. The cause of this neurological sleep disorder is still not completely clear, though a destruction of hypocretin/orexin neurons has been implicated. The destruction of these neurons is linked to inactivity of neurotransmitters including histamine, norepinephrine, acetylcholine, and serotonin, causing a disturbance in the sleep/wake cycles of narcoleptic patients. Stimulants and MAOIs have traditionally been used to counteract excessive daytime sleepiness and sleep attacks by inhibiting the breakdown of catecholamines. Newer drugs, called wake-promoting agents, have recently become first-line agents due to their better side-effect profile, efficacy, and lesser potential for abuse. These agents similarly inhibit reuptake of dopamine, but have a novel mechanism of action, as they have been found to increase neuronal activity in the tuberomamillary nucleus and in orexin neurons. Sodium oxybate, a sodium salt of gamma-hydroxybutyrate (GHB), is another class that is used to treat many symptoms of narcolepsy, and is the only U.S. Food and Drug Administration (FDA)-approved medication for cataplexy. It has a different mechanism of action than either stimulants or wake-promoting agents, as it binds to its own unique receptor. Antidepressants, like selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), have also been used, as similar to stimulants, they inhibit reuptake of specific catecholamines. In this article, we seek to review the mechanisms behind these classes of drugs in relation to the proposed pathophysiology of narcolepsy. Appropriate clinical strategies will be discussed, including specific combinations of medications that have been shown to be effective.
Heart rate variability during carbachol-induced REM sleep and cataplexy.

PubMed

Torterolo, Pablo; Castro-Zaballa, Santiago; Cavelli, Matías; Velasquez, Noelia; Brando, Victoria; Falconi, Atilio; Chase, Michael H; Migliaro, Eduardo R

2015-09-15

The nucleus pontis oralis (NPO) exerts an executive control over REM sleep. Cholinergic input to the NPO is critical for REM sleep generation. In the cat, a single microinjection of carbachol (a cholinergic agonist) into the NPO produces either REM sleep (REMc) or wakefulness with muscle atonia (cataplexy, CA). In order to study the central control of the heart rate variability (HRV) during sleep, we conducted polysomnographic and electrocardiogram recordings from chronically prepared cats during REMc, CA as well as during sleep and wakefulness. Subsequently, we performed statistical and spectral analyses of the HRV. The heart rate was greater during CA compared to REMc, NREM or REM sleep. Spectral analysis revealed that the low frequency band (LF) power was significantly higher during REM sleep in comparison to REMc and CA. Furthermore, we found that during CA there was a decrease in coupling between the RR intervals plot (tachogram) and respiratory activity. In contrast, compared to natural behavioral states, during REMc and CA there were no significant differences in the HRV based upon the standard deviation of normal RR intervals (SDNN) and the mean squared difference of successive intervals (rMSSD). In conclusion, there were differences in the HRV during naturally-occurring REM sleep compared to REMc. In addition, in spite of the same muscle atonia, the HRV was different during REMc and CA. Therefore, the neuronal network that controls the HRV during REM sleep can be dissociated from the one that generates the muscle atonia during this state. Copyright © 2015 Elsevier B.V. All rights reserved.
Different fates of excessive daytime sleepiness: survival analysis for remission.

PubMed

Kim, T; Lee, J H; Lee, C S; Yoon, I Y

2016-07-01

Excessive daytime sleepiness (EDS) is a symptom frequently presented in sleep clinics. Only a paucity of data has addressed clinical courses of sleep disorders with EDS. Therefore, we sought to compare clinical outcomes of patients presenting EDS. A retrospective observational study was performed in the setting of sleep laboratory and outpatient department in a university hospital. One hundred and eight patients who presented EDS underwent polysomnography and multiple sleep latency test. Each patient was diagnosed as one of the following four categories: (1) narcolepsy with cataplexy (N + C; n = 29); (2) narcolepsy without cataplexy (N - C; n = 22); (3) idiopathic hypersomnia (IH; n = 24); and (4) subjective hypersomnolence (SH; n = 33) with mean sleep latency >8 min. Remission of EDS and treatment response were determined based on clinical evaluation. Kaplan-Meier survival analysis was performed. Remission rates were significantly different (P < 0.001, overall log-rank test) among four groups except those between N - C and IH (P = 0.489). While N + C showed no remission, predicted remission rates of N - C and IH group were 44.6% at 5 years and 32.5% at 5.5 years after diagnosis. The predicted remission rate of SH group was 71.7% at 3 years after diagnosis. The similarity of clinical courses between N - C and IH suggests that N - C may be more related to IH compared to N + C. Considering different clinical courses among EDS patients, thorough evaluation of EDS should be warranted before starting treatment. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Narcolepsy Type 1 and Idiopathic Generalized Epilepsy: Diagnostic and Therapeutic Challenges in Dual Cases.

PubMed

Baiardi, Simone; Vandi, Stefano; Pizza, Fabio; Alvisi, Lara; Toscani, Lucia; Zambrelli, Elena; Tinuper, Paolo; Mayer, Geert; Plazzi, Giuseppe

2015-11-15

The aim of this study is to describe the possible co-occurrence of narcolepsy type 1 and generalized epilepsy, focusing on diagnostic challenge and safety of dual treatments. Four patients with comorbidity for narcolepsy type 1 and idiopathic generalized epilepsy are reported: in three cases the onset of epilepsy preceded narcolepsy type 1 appearance, whereas in one case epileptic spells onset was subsequent. Patients presented with absences, myoclonic and tonic-clonic seizure type: in the patient with tonic-clonic seizures the dual pathology was easily recognized, in the other cases the first diagnosis caused the comorbid disease to be overlooked, independent of the time-course sequence. All four patients underwent neurological examination, video-electroencephalogram during which ictal and interictal epileptic discharges were recorded, and sleep polysomnographic studies. Repeated sleep onset rapid eye movement periods (SOREMPs) were documented with the multiple sleep latency test (MLST) in all the four cases. All patients had unremarkable brain magnetic resonance imaging studies and cerebrospinal hypocretin-1 was assessed in two patients, revealing undetectable levels. The association of antiepileptic drugs and substances currently used to treat narcolepsy type 1, including sodium oxybate, was effective in improving seizures, sleep disturbance, and cataplexy. Narcolepsy type 1 may occur in association with idiopathic generalized epilepsy, leading to remarkable diagnostic and therapeutic challenges. Electrophysiological studies as well as a comprehensive somnologic interview can help confirm the diagnosis in patients with ambiguous neurological history. Sodium oxybate in combination with antiepileptic drugs is safe and effective in treating cataplexy and excessive daytime sleepiness. © 2015 American Academy of Sleep Medicine.
Parkinson's disease and narcolepsy-like symptoms.

PubMed

Ylikoski, Ari; Martikainen, Kirsti; Sarkanen, Tomi; Partinen, Markku

2015-04-01

Various sleep-related problems, for example, insomnia and symptoms of rapid eye movement behavior disorder (RBD), are common in patients with Parkinson's disease (PD). We studied the prevalence of symptoms of narcolepsy (NARC), hallucinations, and RBD and their association with other symptoms. Altogether, 1447 randomly selected patients with PD, aged 43-89 years, participated in a questionnaire study. A structured questionnaire with 207 items was based on the Basic Nordic Sleep Questionnaire. Questions on demographics, PD, RBD, and other issues were included. The response rate was 59.0%; of these patients, 73% had answered to all questions that were used in the analyses (N = 623). The occurrence of suspected narcolepsy (Ullanlinna Narcolepsy Scale ≥ 14 and Epworth Sleepiness Scale ≥ 11) was observed in 9.3% of the subjects (PD with NARC), RBD (REM Sleep Behavior Disorder Screening Questionnaire ≥ 6) in 39.2% of all patients with PD, and in 62.1% of those with PD and NARC. In patients with PD, hallucinations before going to bed in the evening occurred in 5.8%, hypnagogic hallucinations in 4.0%, hallucinations during night 8.3%, and hypnopompic hallucinations in 3.2%. Cataplexy symptoms occurred in 43.1% of subjects with PD and NARC. In a logistic regression analysis, PD with NARC was associated with RBD, all types of hallucinations, daytime sleepiness, fatigue, insomnia, and intense dreaming also when adjusted for age, sex, disease duration, and levodopa. Narcolepsy-like symptoms may be present in patients with PD. Symptoms of RBD were associated with symptoms of narcolepsy including symptoms of cataplexy. Copyright © 2014 Elsevier B.V. All rights reserved.
The neurobiology, diagnosis, and treatment of narcolepsy.

PubMed

Scammell, Thomas E

2003-02-01

Narcolepsy is a common cause of chronic sleepiness distinguished by intrusions into wakefulness of physiological aspects of rapid eye movement sleep such as cataplexy and hallucinations. Recent advances provide compelling evidence that narcolepsy may be a neurodegenerative or autoimmune disorder resulting in a loss of hypothalamic neurons containing the neuropeptide orexin (also known as hypocretin). Because orexin promotes wakefulness and inhibits rapid eye movement sleep, its absence may permit inappropriate transitions between wakefulness and sleep. These discoveries have considerably improved our understanding of the neurobiology of sleep and should foster the development of rational treatments for a variety of sleep disorders.
A new DRB1*1202 allele (DRB1*12022) found in association with DQA1*0102 and DQB1*0602 in two Black narcoleptic subjects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Behar, E.; Grumet, F.C.; Lin, X.

1995-01-01

DQB1*0602 is a better genetic marker than DR2 for narcolepsy susceptibility across all ethnic groups; for instance, only 75% of African American narcoleptics are DR2+ compared with 96% DQB1*0602+. We studied DRB1 genes of DR2- but DQB1*0602+ African American patients with cataplexy and observed two with an unusual DR12, DQA1*0102, DQB1*0602 haplotype; a new allelic variant of DRB1*1202 has been designated DRB*12022. 8 refs.
CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice.

PubMed

Bernard-Valnet, Raphaël; Yshii, Lidia; Quériault, Clémence; Nguyen, Xuan-Hung; Arthaud, Sébastien; Rodrigues, Magda; Canivet, Astrid; Morel, Anne-Laure; Matthys, Arthur; Bauer, Jan; Pignolet, Béatrice; Dauvilliers, Yves; Peyron, Christelle; Liblau, Roland S

2016-09-27

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.
Identification of Differentially Expressed Genes in Blood Cells of Narcolepsy Patients

PubMed Central

Tanaka, Susumu; Honda, Yutaka; Honda, Makoto

2007-01-01

Study Objective: A close association between the human leukocyte antigen (HLA)-DRB1*1501/DQB1*0602 and abnormalities in some inflammatory cytokines have been demonstrated in narcolepsy. Specific alterations in the immune system have been suggested to occur in this disorder. We attempted to identify alterations in gene expression underlying the abnormalities in the blood cells of narcoleptic patients. Designs: Total RNA from 12 narcolepsy-cataplexy patients and from 12 age- and sex-matched healthy controls were pooled. The pooled samples were initially screened for candidate genes for narcolepsy by differential display analysis using annealing control primers (ACP). The second screening of the samples was carried out by semiquantitative PCR using gene-specific primers. Finally, the expression levels of the candidate genes were further confirmed by quantitative real-time PCR using a new set of samples (20 narcolepsy-cataplexy patients and 20 healthy controls). Results: The second screening revealed differential expression of 4 candidate genes. Among them, MX2 was confirmed as a significantly down-regulated gene in the white blood cells of narcoleptic patients by quantitative real-time PCR. Conclusion: We found the MX2 gene to be significantly less expressed in comparison with normal subjects in the white blood cells of narcoleptic patients. This gene is relevant to the immune system. Although differential display analysis using ACP technology has a limitation in that it does not help in determining the functional mechanism underlying sleep/wakefulness dysregulation, it is useful for identifying novel genetic factors related to narcolepsy, such as HLA molecules. Further studies are required to explore the functional relationship between the MX2 gene and narcolepsy pathophysiology. Citation: Tanaka S; Honda Y; Honda M. Identification of differentially expressed genes in blood cells of narcolepsy patients. SLEEP 2007;30(8):974-979. PMID:17702266
Specificity of Direct Transition from Wake to REM Sleep in Orexin/ataxin-3 Transgenic Narcoleptic Mice

PubMed Central

Fujiki, Nobuhiro; Cheng, Timothy; Yoshino, Fuyumi; Nishino, Seiji

2009-01-01

To create operational criteria for polygraphic assessments of direct transitions from wake to REM sleep (DREM), as a murine analog of human cataplexy, we have analyzed DREM episodes in congenic lines of orexin/ataxin-3 transgenic [TG] mice and wild-type littermates. The sleep stage of each 10-second epoch was visually scored using our standard criteria. Specificity of DREM for narcoleptic TG mice and sensitivity to detect DREM was evaluated using different DREM criteria. We found that DREM transitions by 10-second epoch scoring are not specific for narcoleptic TG mice and also occur in WT mice during light period. These wake-to-REM transitions in WT mice (also seen in TG mice during light period) were characteristically different from DREM transitions in TG mice during dark period; they tended to occur as brief bouts of wakefulness interrupting extended episodes of REM sleep, suggesting that these transitions do not represent abnormal manifestations of REM sleep. We therefore defined the DREM transitions by requiring a minimum number of preceding wake epochs. Requiring no fewer than four consecutive epochs of wakefulness produced the best combination of specificity (95.9%) and sensitivity (66.0%). By definition, DREM in dark-period is 100% specific to narcolepsy and was 95.9% specific overall. In addition, we found that desipramine, a trycyclic anticataplectic, potently reduces DREM, while two wake-promoting compounds have moderate (d-amphetamine) and no (modafinil) effect on DREM; the effects mirror the anticataplectic effects of these compounds reported in canine and human narcolepsy. Our definition of DREM in murine narcolepsy may provide good electrophysiological measure for cataplexy-equivalent episodes. PMID:19416673

Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs

PubMed Central

Tannenbaum, Pamela L.; Stevens, Joanne; Binns, Jacquelyn; Savitz, Alan T.; Garson, Susan L.; Fox, Steven V.; Coleman, Paul; Kuduk, Scott D.; Gotter, Anthony L.; Marino, Michael; Tye, Spencer J.; Uslaner, Jason M.; Winrow, Christopher J.; Renger, John J.

2014-01-01

The ability to awaken from sleep in response to important stimuli is a critical feature of normal sleep, as is maintaining sleep continuity in the presence of irrelevant background noise. Dual orexin receptor antagonists (DORAs) effectively promote sleep across species by targeting the evolutionarily conserved wake-promoting orexin signaling pathway. This study in dogs investigated whether DORA-induced sleep preserved the ability to awaken appropriately to salient acoustic stimuli but remain asleep when exposed to irrelevant stimuli. Sleep and wake in response to DORAs, vehicle, GABA-A receptor modulators (diazepam, eszopiclone and zolpidem) and antihistamine (diphenhydramine) administration were evaluated in telemetry-implanted adult dogs with continuous electrocorticogram, electromyogram (EMG), electrooculogram (EOG), and activity recordings. DORAs induced sleep, but GABA-A modulators and antihistamine induced paradoxical hyperarousal. Thus, salience gating studies were conducted during DORA-22 (0.3, 1, and 5 mg/kg; day and night) and vehicle nighttime sleep. The acoustic stimuli were either classically conditioned using food reward and positive attention (salient stimulus) or presented randomly (neutral stimulus). Once conditioned, the tones were presented at sleep times corresponding to maximal DORA-22 exposure. In response to the salient stimuli, dogs woke completely from vehicle and orexin-antagonized sleep across all sleep stages but rarely awoke to neutral stimuli. Notably, acute pharmacological antagonism of orexin receptors paired with emotionally salient anticipation produced wake, not cataplexy, in a species where genetic (chronic) loss of orexin receptor signaling leads to narcolepsy/cataplexy. DORA-induced sleep in the dog thereby retains the desired capacity to awaken to emotionally salient acoustic stimuli while preserving uninterrupted sleep in response to irrelevant stimuli. PMID:24904334
Genome-wide analysis of CNV (copy number variation) and their associations with narcolepsy in a Japanese population.

PubMed

Yamasaki, Maria; Miyagawa, Taku; Toyoda, Hiromi; Khor, Seik-Soon; Koike, Asako; Nitta, Aino; Akiyama, Kumi; Sasaki, Tsukasa; Honda, Yutaka; Honda, Makoto; Tokunaga, Katsushi

2014-05-01

In humans, narcolepsy with cataplexy (narcolepsy) is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Narcolepsy is caused by a reduction in the number of neurons that produce hypocretin (orexin) neuropeptide. Both genetic and environmental factors contribute to the development of narcolepsy.Rare and large copy number variations (CNVs) reportedly play a role in the etiology of a number of neuropsychiatric disorders. Narcolepsy is considered a neurological disorder; therefore, we sought to investigate any possible association between rare and large CNVs and human narcolepsy. We used DNA microarray data and a CNV detection software application, PennCNV-Affy, to detect CNVs in 426 Japanese narcoleptic patients and 562 healthy individuals. Overall, we found a significant enrichment of rare and large CNVs (frequency ≤1%, size ≥100 kb) in the patients (case-control ratio of CNV count=1.54, P=5.00 × 10(-4)). Next, we extended a region-based association analysis by including CNVs with its size ≥30 kb. Rare and large CNVs in PARK2 region showed a significant association with narcolepsy. Four patients were assessed to carry duplications of the gene region, whereas no controls carried the duplication, which was further confirmed by quantitative PCR assay. This duplication was also found in 2 essential hypersomnia (EHS) patients out of 171 patients. Furthermore, a pathway analysis revealed enrichments of gene disruptions by rare and large CNVs in immune response, acetyltransferase activity, cell cycle regulation and regulation of cell development. This study constitutes the first report on the risk association between multiple rare and large CNVs and the pathogenesis of narcolepsy. In the future, replication studies are needed to confirm the associations.
Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats

PubMed Central

Lu, Jackie W; Fenik, Victor B; Branconi, Jennifer L; Mann, Graziella L; Rukhadze, Irma; Kubin, Leszek

2007-01-01

Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABAA receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABAA receptor antagonist, bicuculline (20 nl, 1 mm), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABAA receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABAA receptor-expressing PF neurones may cause narcolepsy/cataplexy. PMID:17495048
What Does One Sleep-Onset REM Period—During Either Nocturnal Polysomnography or Multiple Sleep Latency Test—Mean in Differential Diagnosis of Central Hypersomnias?

PubMed

Bozluolcay, Melda; Nalbantoglu, Mecbure; Benbir Senel, Gulcin; Karadeniz, Derya

2015-08-01

The differentiation of narcolepsy without cataplexy from idiopathic hypersomnia is based on the number of sleep-onset rapid eye movement periods (SOREMPs) observed by multiple sleep latency test (MSLT) and nocturnal polysomnography. The main aim of this study was to investigate the utility of SOREMP in differential diagnosis of central hypersomnias. The authors retrospectively evaluated consecutive 101 patients with a normal polysomnography other than the presence of SOREMP and/or REM without atonia and a latency of ≤8 minutes in MSLT. The authors classified patients as follows: 52 patients had at least 2 SOREMPs (narcolepsy group), 23 had no SOREMPs (idiopathic hypersomnia group), and 26 patients had only 1 SOREMP (intermediate group). In polysomnographic recordings, both mean sleep latency and REM latency were significantly shorter in the narcolepsy (P = 0.012, P < 0.001, respectively) and intermediate groups (P = 0.005 and P = 0.035, respectively) compared with the idiopathic hypersomnia group. In MSLT recordings, sleep latency was 2.7 ± 2.2 minutes in the narcolepsy group, 3.6 ± 1.4 minutes in the intermediate group, and 5.2 ± 2.7 minutes in the idiopathic hypersomnia group (P < 0.001). The mean REM latency and sleep stages SOREMPs arised from were similar between the narcolepsy and intermediate groups. To date, SOREMPs in MSLT and polysomnography remain the sole electrodiagnostic feature that discriminates narcolepsy without cataplexy from idiopathic hypersomnia. Different parameters or combined criteria are being increasingly investigated to increase the sensitivity and specificity of MSLT. The findings showed an altered instability of REM sleep not only in patients with 2 or more SOREMPs in MSLT but also in patients with one SOREMP.
First rapid eye movement sleep periods and sleep-onset rapid eye movement periods in sleep-stage sequencing of hypersomnias.

PubMed

Drakatos, Panagis; Kosky, Christopher A; Higgins, Sean E; Muza, Rexford T; Williams, Adrian J; Leschziner, Guy D

2013-09-01

Discrimination between narcolepsy, idiopathic hypersomnia, and behavior-induced inadequate sleep syndrome (BIISS) is based on clinical features and on specific nocturnal polysomnography (NPSG) and multiple sleep latency test (MSLT) results. However, previous studies have cast doubt on the specificity and sensitivity of these diagnostic tools. Eleven variables of the NPSG were analyzed in 101 patients who were retrospectively diagnosed with narcolepsy with cataplexy (N+C) (n=24), narcolepsy without cataplexy (N-C) (n=38), idiopathic hypersomnia with long sleep period (IHL) (n=21), and BIISS (n=18). Fifteen out of 24 N+C and 8 out of 38 N-C entered the first rapid eye movement (REM) sleep period (FREMP) from sleep stage 1 (N1) or wake (W), though this sleep-stage sequence did not arise in the other patient groups. FREMP stage sequence was a function of REM sleep latency (REML) for both N+C and N-C groups. FREMP stage sequence was not associated with mean sleep latency (MSL) in N+C but was associated in N-C, which implies heterogeneity within the N-C group. REML also was a useful discriminator. Depending on the cutoff period, REML had a sensitivity and specificity of up to 85.5% and 97.4%, respectively. The FREMP stage sequence may be a useful tool in the diagnosis of narcolepsy, particularly in conjunction with sleep-stage sequence analysis of sleep-onset REM periods (SOREMPs) in the MSLT; it also may provide a helpful intermediate phenotype in the clarification of heterogeneity in the N-C diagnostic group. However, larger prospective studies are necessary to confirm these findings. Copyright © 2013 Elsevier B.V. All rights reserved.
Diagnostic delay in narcolepsy type 1: combining the patients' and the doctors' perspectives.

PubMed

Taddei, Raquel N; Werth, Esther; Poryazova, Rositsa; Baumann, Christian R; Valko, Philipp O

2016-12-01

Narcolepsy type 1 is a neurological disorder characterized by a unique syndrome, including the pathognomonic symptom of cataplexy. The diagnosis can be confirmed by objective measures, such as typical findings in the multiple sleep latency test, reduced or undetectable levels of orexin (hypocretin) in the cerebrospinal fluid, and linkage to a specific HLA haplotype. Nevertheless, the mean time that elapses from symptom onset to the correct diagnosis ranges between 10 and 20 years, and the causes and correlates of this delay are poorly understood. Diagnostic delay was assessed on 52 well-defined patients with narcolepsy type 1, evaluating clinical, electrophysiological and neurochemical parameters and the results of a 41-item questionnaire developed to obtain the patients' perspective on various aspects of the diagnostic process. The mean time gap between disease onset and first medical consultation was 3.2 ± 5.1 years; the mean diagnostic delay was 8.9 ± 11.0 years. Prior to correct diagnosis, patients received a wide variety of misdiagnoses. The self-ratings of the patients revealed that the undiagnosed symptoms caused high levels of anxiety and unjustified criticism by family, friends and employers. Multiple regression analysis identified higher cerebrospinal fluid orexin levels (β = 0.311, P = 0.01), and a longer interval between the onset of excessive daytime sleepiness and cataplexy (β = 0.368, P = 0.002) as independent associates of longer diagnostic delay. The diagnostic delay decreased over the last decades (β = -0.672, P < 0.001). In conclusion, delayed diagnosis of narcolepsy type 1 is very common, associated with many adverse consequences, and requires educational efforts to improve awareness on narcolepsy among healthcare providers and the general population. © 2016 European Sleep Research Society.
CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

PubMed Central

Bernard-Valnet, Raphaël; Yshii, Lidia; Quériault, Clémence; Nguyen, Xuan-Hung; Arthaud, Sébastien; Rodrigues, Magda; Canivet, Astrid; Morel, Anne-Laure; Matthys, Arthur; Bauer, Jan; Pignolet, Béatrice; Dauvilliers, Yves; Peyron, Christelle; Liblau, Roland S.

2016-01-01

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. PMID:27621438
Sodium Oxybate treatment in pediatric type 1 narcolepsy.

PubMed

Moresco, Monica; Pizza, Fabio; Antelmi, Elena; Plazzi, Giuseppe

2018-03-05

Narcolepsy type 1 (NT1) is a rare chronic neurologic disorder characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations and disrupted nocturnal sleep, usually with onset during childhood/adolescence. Pediatric NT1 is associated with limitations on children's activities and achievements, especially poor performance at school, difficulty with peers due to disease symptoms and comorbidities including depression, obesity, and precocious puberty. NT1 disease is caused by the selective loss of hypocretin-producing neurons in the lateral hypothalamus, most probably related to an autoimmune pathophysiology. Indeed a strong genetic predisposition including the HLA system and other associations in genes involved in immune responses has been found together with the triggering role of environmental agents such as H1N1 influenza infections and vaccinations. Sodium Oxybate (SO) is a sodium salt of γ-hydroxybutyric (GHB) acid that is synthetized by neurons in the brain and functions as neurotransmitter. GHB is a central nervous system depressant and produces dose-dependent sedation. SO is a first line medication for cataplexy and excessive daytime sleepiness in adults with NT1, but can be helpful also for sleep disruption, hypnagogic hallucination and sleep paralysis in these patients. Although in the majority of patients narcolepsy develops before 15 years of age, there are no approved treatments for pediatric NT1. However, SO has been widely used off-label to treat narcolepsy symptoms in children and adolescents with NT1 in non-controlled studies, showing a similar safety profile and therapeutic response to adult patients. Current therapy is based only on empirical data shared among expert sleep disorders clinicians. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Disorders of Excessive Daytime Sleepiness Including Narcolepsy and Idiopathic Hypersomnia.

PubMed

Berkowski, Joseph Andrew; Shelgikar, Anita Valanju

2016-09-01

Central disorders of hypersomnolence are rare conditions with a poorly understood pathophysiology, making the identification and management challenging for sleep clinicians. Clinical history is essential for ruling out secondary causes of hypersomnolence and distinguishing among diagnoses. Current diagnostic criteria rely heavily on the polysomnogram and multiple sleep latency test. The current focus of treatment of hypersomnolence is on drugs that promote alertness. Additionally, in the case of narcolepsy type 1, medication management addresses control of cataplexy, the hallmark symptom of this disorder. Elucidation of pathophysiology of these disorders in the future will be essential to better categorization and management. Published by Elsevier Inc.
[Hypersomnia: a diagnostic problem].

PubMed

Kranenburg, Guido; Teunissen, Laurien L

2014-01-01

Hypersomnia is a frequently occurring problem. When taking a medical history it is important to distinguish between fatigue and sleepiness. We present a 14-year-old girl with narcolepsy and a 59-year-old man with idiopathic hypersomnia. Features that are typical of narcolepsy are cataplexy and weight gain. Features that are typical of both narcolepsy and idiopathic hypersomnia are daytime naps, insomnia, sleep paralysis and hypnagogic hallucinations. Additional testing in patients with hypersomnia should include a polysomnography in order to exclude other sleeping disorders, and a mean sleep latency test. Practice shows that both patients with narcolepsy and those with idiopathic hypersomnia benefit from treatment with stimulating drugs such as modafinil.
Neuroimaging of Narcolepsy and Kleine-Levin Syndrome.

PubMed

Hong, Seung Bong

2017-09-01

Narcolepsy is a chronic neurologic disorder with the abnormal regulation of the sleep-wake cycle, resulting in excessive daytime sleepiness, disturbed nocturnal sleep, and manifestations related to rapid eye movement sleep, such as cataplexy, sleep paralysis, and hypnagogic hallucination. Over the past decade, numerous neuroimaging studies have been performed to characterize the pathophysiology and various clinical features of narcolepsy. This article reviews structural and functional brain imaging findings in narcolepsy and Kleine-Levin syndrome. Based on the current state of research, brain imaging is a useful tool to investigate and understand the neuroanatomic correlates and brain abnormalities of narcolepsy and other hypersomnia. Copyright © 2017 Elsevier Inc. All rights reserved.
Narcolepsy in Adolescence—A Missed Diagnosis: A Case Report

PubMed Central

Gupta, Anoop K.; Sahoo, Swapnajeet

2017-01-01

ABSTRACT: Narcolepsy is an uncommon sleep cycle disorder with a usual onset in adolescence, but it is often misdiagnosed and underdiagnosed. Rarely is the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis seen in patients. The clinical characteristics of narcolepsy are often confused with many psychiatric and neurologic disorders. Lack of clinical awareness about narcolepsy leads to frequent prescriptions of antiepileptics and psychotropics, which can adversely affect the quality of life of children and adolescents. We report a case of an adolescent male who presented with all four cardinal symptoms of narcolepsy and had been misdiagnosed with epilepsy, psychosis, and depression. We discuss various issues regarding narcolepsy in children and adolescents. PMID:29616151
Narcolepsy

PubMed Central

Murray, T. J.; Foley, Anita

1974-01-01

Narcolepsy is a disorder of sleep control characterized by a tetrad of symptoms: sleep attacks, cataplexy, sleep paralysis and hypnagogic hallucinations. A diagnosis is made from a careful history. The incidence is estimated as high as 0.3% of the population. Unfortunately patients go for many years before the diagnosis is made and often have experienced disruption of their employment, social and family life, and may have experienced a number of car accidents because of falling asleep at the wheel. An unknown number of narcoleptics kill themselves on the highways before the diagnosis is ever made. Sleep attacks can usually be controlled by methylphenidate, and if the other symptoms persist they can often be effectively managed by imipramine. PMID:4809449
Narcolepsy in Adolescence-A Missed Diagnosis: A Case Report.

PubMed

Gupta, Anoop K; Sahoo, Swapnajeet; Grover, Sandeep

2017-01-01

Narcolepsy is an uncommon sleep cycle disorder with a usual onset in adolescence, but it is often misdiagnosed and underdiagnosed. Rarely is the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis seen in patients. The clinical characteristics of narcolepsy are often confused with many psychiatric and neurologic disorders. Lack of clinical awareness about narcolepsy leads to frequent prescriptions of antiepileptics and psychotropics, which can adversely affect the quality of life of children and adolescents. We report a case of an adolescent male who presented with all four cardinal symptoms of narcolepsy and had been misdiagnosed with epilepsy, psychosis, and depression. We discuss various issues regarding narcolepsy in children and adolescents.
Different sleep onset criteria at the multiple sleep latency test (MSLT): an additional marker to differentiate central nervous system (CNS) hypersomnias.

PubMed

Pizza, Fabio; Vandi, Stefano; Detto, Stefania; Poli, Francesca; Franceschini, Christian; Montagna, Pasquale; Plazzi, Giuseppe

2011-03-01

Excessive daytime sleepiness (EDS) has different correlates in non-rapid eye movement (NREM) [idiopathic hypersomnia (IH) without long sleep time] and REM sleep [narcolepsy without cataplexy (NwoC) and narcolepsy with cataplexy (NC)]-related hypersomnias of central origin. We analysed sleep onset characteristics at the multiple sleep latency test (MSLT) applying simultaneously two sleep onset criteria in 44 NC, seven NwoC and 16 IH consecutive patients referred for subjective EDS complaint. Sleep latency (SL) at MSLT was assessed both as the time elapsed to the occurrence of a single epoch of sleep Stage 1 NREM (SL) and of unequivocal sleep [three sleep Stage 1 NREM epochs or any other sleep stage epoch, sustained SL (SusSL)]. Idiopathic hypersomnia patients showed significantly (P<0.0001) longer SusSL than SL (7.7±2.5 versus 5.6±1.3 min, respectively) compared to NwoC (5.8±2.5 versus 5.3±2.2 min) and NC patients (4.1±3 versus 3.9±3 min). A mean difference threshold between SusSL and SL ≥27 s reached a diagnostic value to discriminate IH versus NC and NwoC sufferers (sensitivity 88%; specificity 82%). Moreover, NC patients showed better subjective sleepiness perception than NwoC and IH cases in the comparison between naps with or without sleep occurrence. Simultaneous application of the two widely used sleep onset criteria differentiates IH further from NC and NwoC patients: IH fluctuate through a wake-Stage 1 NREM sleep state before the onset of sustained sleep, while NC and NwoC shift abruptly into a sustained sleep. The combination of SusSL and SL determination at MSLT should be tested as an additional objective differential criterion for EDS disorders. © 2010 European Sleep Research Society.
Narcolepsy Type 1 and Idiopathic Generalized Epilepsy: Diagnostic and Therapeutic Challenges in Dual Cases

PubMed Central

Baiardi, Simone; Vandi, Stefano; Pizza, Fabio; Alvisi, Lara; Toscani, Lucia; Zambrelli, Elena; Tinuper, Paolo; Mayer, Geert; Plazzi, Giuseppe

2015-01-01

Study Objectives: The aim of this study is to describe the possible co-occurrence of narcolepsy type 1 and generalized epilepsy, focusing on diagnostic challenge and safety of dual treatments. Methods and Results: Four patients with comorbidity for narcolepsy type 1 and idiopathic generalized epilepsy are reported: in three cases the onset of epilepsy preceded narcolepsy type 1 appearance, whereas in one case epileptic spells onset was subsequent. Patients presented with absences, myoclonic and tonic-clonic seizure type: in the patient with tonic-clonic seizures the dual pathology was easily recognized, in the other cases the first diagnosis caused the comorbid disease to be overlooked, independent of the time-course sequence. All four patients underwent neurological examination, video-electroencephalogram during which ictal and interictal epileptic discharges were recorded, and sleep polysomnographic studies. Repeated sleep onset rapid eye movement periods (SOREMPs) were documented with the multiple sleep latency test (MLST) in all the four cases. All patients had unremarkable brain magnetic resonance imaging studies and cerebrospinal hypocretin-1 was assessed in two patients, revealing undetectable levels. The association of antiepileptic drugs and substances currently used to treat narcolepsy type 1, including sodium oxybate, was effective in improving seizures, sleep disturbance, and cataplexy. Conclusions: Narcolepsy type 1 may occur in association with idiopathic generalized epilepsy, leading to remarkable diagnostic and therapeutic challenges. Electrophysiological studies as well as a comprehensive somnologic interview can help confirm the diagnosis in patients with ambiguous neurological history. Sodium oxybate in combination with antiepileptic drugs is safe and effective in treating cataplexy and excessive daytime sleepiness. Citation: Baiardi S, Vandi S, Pizza F, Alvisi L, Toscani L, Zambrelli E, Tinuper P, Mayer G, Plazzi G. Narcolepsy type 1 and idiopathic generalized epilepsy: diagnostic and therapeutic challenges in dual cases. J Clin Sleep Med 2015;11(11):1257–1262. PMID:26156948
Attention-Deficit/Hyperactivity Disorder (ADHD) Symptoms in Pediatric Narcolepsy: A Cross-Sectional Study.

PubMed

Lecendreux, Michel; Lavault, Sophie; Lopez, Régis; Inocente, Clara Odilia; Konofal, Eric; Cortese, Samuele; Franco, Patricia; Arnulf, Isabelle; Dauvilliers, Yves

2015-08-01

To evaluate the frequency, severity, and associations of symptoms of attention-deficit/hyperactivity disorder (ADHD) in children with narcolepsy with and without cataplexy. Cross-sectional survey. Four French national reference centers for narcolepsy. One hundred eight consecutively referred children aged younger than 18 y with narcolepsy, with (NwC, n = 86) or without cataplexy (NwoC, n = 22), and 67 healthy controls. The participants, their families, and sleep specialists completed a structured interview and questionnaires about sleep, daytime sleepiness, fatigue, and ADHD symptoms (ADHD-rating scale based upon Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] symptoms), and use of psychostimulants for the treatment of narcolepsy (administered in 68.2%). Polysomnographic measures were collected. Clinically significant levels of ADHD symptoms were found in 4.8% of controls compared with 35.3% in patients with NwoC (P < 0.001) and 19.7% in patients with NwC (P < 0.01). Total ADHD scores were 6.4 (95% confidence interval [CI]: 4.5, 9.0) in controls compared with 14.2 (95% CI: 10.6, 18.9; P < 0.001), in patients with NwoC and 12.2 (95% CI: 9.8, 15.3; P < 0.01) in patients with NwC; subscores of inattention and hyperactivity/impulsivity were also significantly higher in both narcolepsy groups compared with controls. No difference was found between the NwC and NwoC groups for any ADHD measure. ADHD symptom severity was associated with increased levels of sleepiness, fatigue, and insomnia. Compared with the 34 untreated patients, the 73 patients treated with psychostimulants (modafinil in 91%) showed a trend toward lower narcolepsy symptoms but not lower ADHD symptoms. Pediatric patients with narcolepsy have high levels of treatment-resistant attention-deficit/hyperactivity disorder (ADHD) symptoms. The optimal treatment for ADHD symptoms in these patients warrants further evaluation in longitudinal intervention studies. © 2015 Associated Professional Sleep Societies, LLC.
Executive Control of Attention in Narcolepsy

PubMed Central

Bayard, Sophie; Croisier Langenier, Muriel; Cochen De Cock, Valérie; Scholz, Sabine; Dauvilliers, Yves

2012-01-01

Background Narcolepsy with cataplexy (NC) is a disabling sleep disorder characterized by early loss of hypocretin neurons that project to areas involved in the attention network. We characterized the executive control of attention in drug-free patients with NC to determine whether the executive deficits observed in patients with NC are specific to the disease itself or whether they reflect performance changes due to the severity of excessive daytime sleepiness. Methodology Twenty-two patients with NC compared to 22 patients with narcolepsy without cataplexy (NwC) matched for age, gender, intellectual level, objective daytime sleepiness and number of sleep onset REM periods (SOREMPs) were studied. Thirty-two matched healthy controls were included. All participants underwent a standardized interview, completed questionnaires, and neuropsychological tests. All patients underwent a polysomnography followed by multiple sleep latency tests (MSLT), with neuropsychological evaluation performed the same day between MSLT sessions. Principal Findings Irrespective of diagnosis, patients reported higher self-reported attentional complaints associated with the intensity of depressive symptoms. Patients with NC performed slower and more variably on simple reaction time tasks than patients with NwC, who did not differ from controls. Patients with NC and NwC generally performed slower, reacted more variably, and made more errors than controls on executive functioning tests. Individual profile analyses showed a clear heterogeneity of the severity of executive deficit. This severity was related to objective sleepiness, higher number of SOREMPs on the MSLT, and lower intelligence quotient. The nature and severity of the executive deficits were unrelated to NC and NwC diagnosis. Conclusions We demonstrated that drug-free patients with NC and NwC complained of attention deficit, with altered executive control of attention being explained by the severity of objective sleepiness and global intellectual level. Further studies are needed to explore whether medications that promote wakefulness can improve the executive functions in narcolepsy. PMID:22558075
Use of PCR with Sequence-specific Primers for High-Resolution Human Leukocyte Antigen Typing of Patients with Narcolepsy

PubMed Central

Woo, Hye In; Joo, Eun Yeon; Lee, Kyung Wha

2012-01-01

Background Narcolepsy is a neurologic disorder characterized by excessive daytime sleepiness, symptoms of abnormal rapid eye movement (REM) sleep, and a strong association with HLA-DRB1*1501, -DQA1*0102, and -DQB1*0602. Here, we investigated the clinico-physical characteristics of Korean patients with narcolepsy, their HLA types, and the clinical utility of high-resolution PCR with sequence-specific primers (PCR-SSP) as a simple typing method for identifying DRB1*15/16, DQA1, and DQB1 alleles. Methods The study population consisted of 67 consecutively enrolled patients having unexplained daytime sleepiness and diagnosed narcolepsy based on clinical and neurological findings. Clinical data and the results of the multiple sleep latency test and polysomnography were reviewed, and HLA typing was performed using both high-resolution PCR-SSP and sequence-based typing (SBT). Results The 44 narcolepsy patients with cataplexy displayed significantly higher frequencies of DRB1*1501 (Pc= 0.003), DQA1*0102 (Pc=0.001), and DQB1*0602 (Pc=0.014) than the patients without cataplexy. Among patients carrying DRB1*1501-DQB1*0602 or DQA1*0102, the frequencies of a mean REM sleep latency of less than 20 min in nocturnal polysomnography and clinical findings, including sleep paralysis and hypnagogic hallucination were significantly higher. SBT and PCR-SSP showed 100% concordance for high-resolution typing of DRB1*15/16 alleles and DQA1 and DQB1 loci. Conclusions The clinical characteristics and somnographic findings of narcolepsy patients were associated with specific HLA alleles, including DRB1*1501, DQA1*0102, and DQB1*0602. Application of high-resolution PCR-SSP, a reliable and simple method, for both allele- and locus-specific HLA typing of DRB1*15/16, DQA1, and DQB1 would be useful for characterizing clinical status among subjects with narcolepsy. PMID:22259780
Diagnosis and management of central hypersomnias

PubMed Central

Susta, Marek

2012-01-01

Central hypersomnias are diseases manifested in excessive daytime sleepiness (EDS) not caused by disturbed nocturnal sleep or misaligned circadian rhythms. Central hypersomnias includes narcolepsy with and without cataplexy, recurrent hypersomnia, idiopathic hypersomnia, with and without long sleep time, behaviorally induced insufficient sleep syndrome, hypersomnia and narcolepsy due to medical conditions, and finally hypersomnia induced by substance intake. The Epworth Sleepiness Scale is a subjective tool mostly used for EDS assessment, while the Multiple Sleep Latency Test serves as an objective diagnostic method for narcolepsy and idiopathic hypersomnias. As for symptomatic therapy of EDS, the central nervous system stimulants modafinil and methylphenidate seem to work well in most cases and in narcolepsy and Parkinson’s disease; sodium oxybate also has notable therapeutic value. PMID:22973425

Increased anxiety but normal fear and safety learning in orexin-deficient mice.

PubMed

Khalil, Radwa; Fendt, Markus

2017-03-01

The loss of orexin neurons in humans leads to the disease narcolepsy, characterized by daytime sleepiness and cataplexy. Recent data suggest that orexin is also involved in emotional processing. The goal of the present study was to evaluate fear and safety learning as well as unconditioned fear (anxiety) in orexin-deficient animals. Orexin-deficient mice are an established animal model used to investigate the neuropathology and potential treatments for narcolepsy. Here, we present novel data showing that orexin-deficient mice express increased anxiety in the open field, light-dark box test and carnivore odor-induced avoidance, but are normal in fear and safety learning. These findings suggest an important role of orexin in brain areas involved in anxiety. Copyright © 2016 Elsevier B.V. All rights reserved.
Orexin in sleep, addiction and more: is the perfect insomnia drug at hand?

PubMed

Hoyer, Daniel; Jacobson, Laura H

2013-12-01

Orexins A and B (hypocretins 1 and 2) and their two receptors (OX1R and OX2R) were discovered in 1998 by two different groups. Orexin A and B are derived from the differential processing of a common precursor, the prepro-orexin peptide. The neuropeptides are expressed in a few thousand cells located in the lateral hypothalamus (LH), but their projections and receptor distribution are widespread throughout the brain. Remarkably, prepro peptide and double (OX1R/OX2R) receptor knock out (KO) mice reproduce a sleep phenotype known in humans and dogs as narcolepsy/cataplexy. In humans, this disease is characterized by the absence of orexin producing cells in the LH, and severely depleted levels of orexin the cerebrospinal fluid. Null mutation of the individual OX1R or OX2R in mice substantially ameliorates the narcolepsy/cataplexy phenotype compared to the OX1R/OX2R KO, and highlights specific roles of the individual receptors in sleep architecture, the OX1R KO demonstrating an a attenuated sleep phenotype relative to the OX2R KO. It has therefore been suggested that orexin is a master regulator of the sleep-wake cycle, with high activity of the LH orexin cells during wake and almost none during sleep. Less than 10years later, the first orexin antagonist, almorexant, a dual orexin receptor antagonist (DORA), was reported to be effective in inducing sleep in volunteers and insomnia patients. Although development was stopped for almorexant and for Glaxo's DORA SB-649868, no less than 4 orexin receptor antagonists have reached phase II for insomnia, including Filorexant (MK-6096) and Suvorexant (MK-4305) from Merck. Suvorexant has since progressed to Phase III and dossier submission to the FDA. These four compounds are reported as DORAs, however, they equilibrate very slowly at one and/or the other orexin receptor, and thus at equilibrium may show more or less selectivity for OX1R or OX2R. The appropriate balance of antagonism of the two receptors for sleep is a point of debate, although in rodent models OX2R antagonism alone appears sufficient to induce sleep, whereas OX1R antagonism is largely devoid of this effect. Orexin is involved in a number of other functions including reward and feeding, where OX1R (possibly OX2R) antagonists display anti-addictive properties in rodent models of alcohol, smoking, and drug self-administration. However, despite early findings in feeding and appetite control, orexin receptor antagonists have not produced the anticipated effects in models of increased food intake or obesity in rodents, nor have they shown marked effects on weight in the existing clinical trials. The role of orexin in a number of other domains such as pain, mood, anxiety, migraine and neurodegenerative diseases is an active area of research. The progress of the orexin field is thus extraordinary, and the community awaits the clinical testing of more receptor selective antagonists in sleep and other disorders, as well as that of orexin agonists, with the latter expected to produce positive outcomes in narcolepsy/cataplexy and other conditions. Copyright © 2013. Published by Elsevier Ltd.
Does Narcolepsy Symptom Severity Vary According to HLA-DQB1*0602 Allele Status?

PubMed Central

Watson, Nathaniel F.; Ton, Thanh G.N.; Koepsell, Thomas D.; Gersuk, Vivian H.; Longstreth, W.T.

2010-01-01

Study Objectives: To investigate associations between HLA-DQB1*0602 allele status and measures of narcolepsy symptom severity. Design: Cross-sectional study of population-based narcolepsy patients. Setting: King County, Washington. Participants: All prevalent cases (n = 279) of physician-diagnosed narcolepsy ascertained from 2001-2005. Interventions: N/A Measurements: Narcolepsy diagnosis was based on cataplexy status, diagnostic sleep study results, and chart review. The number of HLA-DQB1 alleles was determined from buccal genomic DNA. Symptom severity instruments included the Epworth Sleepiness Scale (ESS), the Ullanlinna Narcolepsy Scale (UNS), age of symptom onset, subjective sleep latency and duration, and various clinical sleep parameters. We used linear regression adjusted for African American race and an extended chi-square test of trend to assess relationships across ordered groups defined by allele number (0, 1, or 2). Results: Narcolepsy patients were 63% female and 82% Caucasian, with a mean age of 47.6 years (SD = 17.1). One hundred forty-one (51%) patients had no DQB1*0602 alleles; 117 (42%) had one; and 21 (7%) had two. In the complete narcolepsy sample after adjustment for African American race, we observed a linear relationship between HLA-DQB1*0602 frequency and sleepiness as defined by the ESS (P < 0.01), narcolepsy severity as defined by UNS (P < 0.001), age of symptom onset (P < 0.05), and sleep latency (P < 0.001). In univariate analyses, HLA-DQB1*0602 frequency was also associated with napping (P < 0.05) and increased car and work accidents or near accidents (both P < 0.01). Habitual sleep duration was not associated with HLA status. These race-adjusted associations remained for the ESS (P < 0.05), UNS (P < 0.01), and sleep latency (P < 0.001) when restricting to narcolepsy with cataplexy. Conclusions: Narcolepsy symptom severity varies in a linear manner according to HLA-DQB1*0602 allele status. These findings support the notion that HLA-DQ is a disease-modifying gene. Citation: Watson NF; Ton TGN; Koepsell TD; Gersuk VH; Longstreth WT. Does narcolepsy symptom severity vary according to HLA-DQB1*0602 allele status? SLEEP 2010;33(1):29-35. PMID:20120618
Narcolepsy and the hypocretins.

PubMed

Wurtman, Richard J

2006-10-01

Narcolepsy is a chronic neurologic disease characterized by excessive daytime sleepiness and one or more of three additional symptoms (cataplexy, or sudden loss of muscle tone; vivid hallucinations; and brief periods of total paralysis) related to the occurrence of rapid eye movement (REM) sleep at inappropriate times. The daytime sleepiness typically presents as a sudden overwhelming urge to sleep, followed by periods of sleep that last for seconds or minutes, or even longer. During daytime sleep episodes, patients may exhibit "automatic behavior," performing conventionalized functions (eg, taking notes), but not remembering having done so once they are awake. About 10% of narcoleptics are members of familial clusters; however, genetic factors alone are apparently insufficient to cause the disease, inasmuch as the most common genetic disorder, a mutation in chromosome 6 controlling the HLA antigen immune complex, although seen in 90% to 100% of patients, also occurs in as many as 50% of people without narcolepsy. A dog model of narcolepsy exhibits a mutation on chromosome 12 that disrupts the processing of the peptide neurotransmitter hypocretin. No such mutation characterizes human narcolepsy; however, cerebrospinal fluid (CSF) hypocretin levels are profoundly depressed in narcoleptic patients, and a specific reduction in hypocretin-containing neurons has been described. One hypothesis concerning the pathophysiology of narcolepsy proposes that the HLA subtype resulting from the mutation on chromosome 6 increases the susceptibility of hypocretin-containing brain neurons to immune attack. Because hypocretin may normally participate in the maintenance of wakefulness, the loss of neurons that release this peptide might allow REM sleep to occur at inappropriate times, ie, while the patient is awake, in contrast to its normal cyclic appearance after a period of slow-wave sleep. The cataplexy, hallucinations, and/or paralysis associated with REM episodes normally are unnoticed-or, at least, not remembered-when the transition to REM follows slow wave sleep, as is normally the case; however, they are remembered when, in people with narcolepsy, the REM episode starts during a period of wakefulness. The association of narcolepsy with a deficiency in a specific neurotransmitter, in this case, hypocretin, is reminiscent of the associations between Parkinson disease and dopamine, or early Alzheimer disease and acetylcholine.
The Familial Risk and HLA Susceptibility among Narcolepsy Patients in Hong Kong Chinese

PubMed Central

Chen, Lei; Fong, S.Y.Y.; Lam, Ching W.; Tang, Nelson L.S.; Ng, Margaret H. L.; Li, Albert M.; Ho, C.K.W.; Cheng, Suk-Hang; Lau, Kin-Mang; Wing, Yun Kwok

2007-01-01

Study Objectives: To explore the familial aggregation and HLA susceptibility of narcolepsy in Hong Kong Chinese by objective sleep measurements and HLA typing. Design: Case control design Participants: Twelve narcoleptic probands, 34 first-degree relatives, and 30 healthy controls. Interventions: N/A Measurements and Results: Each subject underwent a standardized nocturnal polysomnogram (PSG), followed by a daytime multiple sleep latency test (MSLT). HLA typing was performed for all subjects. One relative (2.9%) was diagnosed as suffering from narcolepsy with cataplexy. Nearly 30% of the relatives fulfilled the criteria of narcolepsy spectrum disorder (shortened mean sleep latency [MSL] and/or the presence of sleep onset REM periods [SOREMPs]). When using the population data for comparison, the relative risk of narcolepsy in first-degree relatives was 85.3. The odds ratio of narcolepsy spectrum disorder in first-degree relatives was 5.8 (95% CI: 1.2 – 29.3) when compared to healthy controls. There existed 6 multiplex families, in which all 10 relatives with narcolepsy spectrum disorders, including all 3 relatives with multiple SOREMPs, were positive for HLA DQB1*0602. Conclusions: Our study demonstrated a definitive familial aggregation of narcolepsy, narcolepsy spectrum disorders, and possibly cataplexy in Hong Kong Chinese. This familial aggregation supported an inherited basis for narcolepsy spectrum. The tight co-segregation of HLA DQB1*0602 and narcolepsy spectrum disorders might suggest that HLA typing, especially DQB1*0602, at least partly confer the familial risk of narcolepsy. In addition, our study suggested that the subjective questionnaire measurements including Ullanlinna Narcolepsy Scale and Epworth Sleepiness Scale were unable to detect the presence of narcolepsy spectrum disorders among the relatives. A stringent objective measurement-based design for family studies is suggested for future study. Further studies are indicated for the determination of the mode and molecular level of narcolepsy transmission. Citation: Chen L; Fong SYY; Lam CW et al. The familial risk and HLA susceptibility among narcolepsy patients in Hong Kong Chinese. SLEEP 2007;30(7):851-858. PMID:17682655
Clarifying the association of genes within the major histocompatibility complex with narcolepsy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Acton, R.T.; Watson, B.; Rivers, C.

1994-09-01

HLA-DR2 and DQwl has been reported to be strongly associated with narcolepsy. The particular phenotype and strength of these associations varies between races. For example DQB*0601 has been reported associated with some African American (AA) narcoleptics while some Caucasian American (CA) narcoleptics do not possess DR2 or DQw1. We have sought to clarify the relationship of MHC genes with narcolepsy in the local CA and AA population. There was no significant difference in the frequency of DR phenotypes in CA or AA narcoleptics compared to race, age, sex and geographic region-matched controls. DR2 was increased in CA cataplexy positive (Cat+)more » narcoleptics compared to controls (p=0.028, odds ratio (OR)=2.4) and to Cat- narcoleptics (p=<0.001, OR=8.8). DR11 was increased in AA Cat+ narcoleptics compared to controls (p=0.004, OR=11.2) and to Cat- narcoleptics (p=0.002). DQB1*0601 was not significantly associated with narcolepsy in our AA population. We have assessed the frequency of the TNFa (13 alleles, 1.1Mb telomeric to DQ{alpha}), D6S105 (13 alleles, 1kb telomeric of HLA-A), and GLP-1R (19 alleles, 18.5 Mb centromeric of DQ{alpha}), dinucleotide repeats in narcoleptics compared to controls. The TNFa allele 117 was increased in CA Cat+ vs. controls (p=0.003). The GLP-1R allele 144 was increased in CA Cat- vs. controls (p=0.02). In AA narcoleptics, the TNFa allele 109 was significantly increased (p=0.04) along with the D6S105 allele 130 (p=0.02) compared to controls. The D6S105 allele 130 was increased in AA Cat- vs. controls (p=0.03). The GLP-1R allele 154 was significantly decreased in AA Cat+ vs. Cat- (p=0.04). These data suggest that DR and/or DQ genes are not responsible for narcolepsy and that cataplexy is associated with different regions around the MHC in various racial groups.« less
Increased Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland

PubMed Central

Partinen, Markku; Saarenpää-Heikkilä, Outi; Ilveskoski, Ismo; Hublin, Christer; Linna, Miika; Olsén, Päivi; Nokelainen, Pekka; Alén, Reija; Wallden, Tiina; Espo, Merimaaria; Rusanen, Harri; Olme, Jan; Sätilä, Heli; Arikka, Harri; Kaipainen, Pekka; Julkunen, Ilkka; Kirjavainen, Turkka

2012-01-01

Background Narcolepsy is a rare neurological sleep disorder especially in children who are younger than 10 years. In the beginning of 2010, an exceptionally large number of Finnish children suffered from an abrupt onset of excessive daytime sleepiness (EDS) and cataplexy. Therefore, we carried out a systematic analysis of the incidence of narcolepsy in Finland between the years 2002–2010. Methods All Finnish hospitals and sleep clinics were contacted to find out the incidence of narcolepsy in 2010. The national hospital discharge register from 2002 to 2009 was used as a reference. Findings Altogether 335 cases (all ages) of narcolepsy were diagnosed in Finland during 2002–2009 giving an annual incidence of 0.79 per 100 000 inhabitants (95% confidence interval 0.62–0.96). The average annual incidence among subjects under 17 years of age was 0.31 (0.12–0.51) per 100 000 inhabitants. In 2010, 54 children under age 17 were diagnosed with narcolepsy (5.3/100 000; 17-fold increase). Among adults ≥20 years of age the incidence rate in 2010 was 0.87/100 000, which equals that in 2002–2009. Thirty-four of the 54 children were HLA-typed, and they were all positive for narcolepsy risk allele DQB1*0602/DRB1*15. 50/54 children had received Pandemrix vaccination 0 to 242 days (median 42) before onset. All 50 had EDS with abnormal multiple sleep latency test (sleep latency <8 min and ≥2 sleep onset REM periods). The symptoms started abruptly. Forty-seven (94%) had cataplexy, which started at the same time or soon after the onset of EDS. Psychiatric symptoms were common. Otherwise the clinical picture was similar to that described in childhood narcolepsy. Interpretation A sudden increase in the incidence of abrupt childhood narcolepsy was observed in Finland in 2010. We consider it likely that Pandemrix vaccination contributed, perhaps together with other environmental factors, to this increase in genetically susceptible children. PMID:22470463
Pseudotumor cerebri syndrome in a patient with narcolepsy type 1.

PubMed

Rossor, Thomas; Lim, Ming; VanDenEshof, Kirandeep; Gringras, Paul

2018-01-01

Type 1 narcolepsy (NT1) is a chronic primary disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disrupted nocturnal sleep. NT1 is linked to hypothalamic hypocretin deficiency, strongly associated with Human Leukocyte Antigen (HLA) marker DQB1*06:02 and of probable autoimmune origin. NT1 is usually associated with increased rates of overweight and obesity, and sometimes with increases in overnight blood pressure and increased rates of hypoventilation with raised CO 2 levels overnight. Many of these are predisposing factors for pseudotumor cerebri syndrome (PTCS). We present a case of a young girl with both NT1 and PTCS that responded well to treatment with acetazolamide after early identification, with improvement of headache and resolution of hypoventilation. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Cerebrospinal fluid hypocretin (orexin) levels are elevated by play but are not raised by exercise and its associated heart rate, blood pressure, respiration or body temperature changes.

PubMed

Wu, M-F; Nienhuis, R; Maidment, N; Lam, H A; Siegel, J M

2011-11-07

Hypocretin (Hcrt) has been implicated in the control of motor activity and in respiration and cardiovascular changes. Loss of Hcrt in narcolepsy is linked to sleepiness and to cataplexy, a sudden loss of muscle tone which is triggered by sudden strong emotions. In the current study we have compared the effects of treadmill running, to yard play on cerebrospinal fluid (CSF) Hcrt level in normal dogs. We find that treadmill locomotion, at a wide range of speeds, does not increase Hcrt level beyond baseline, whereas yard play produces a substantial increase in Hcrt, even though both activities produce comparable increases in heart rate, respiration and body temperature. We conclude that motor and cardiovascular changes are not sufficient to elevate CSF levels of Hcrt and we hypothesize that the emotional aspects of yard play account for the observed increase in Hcrt.
The hypocretin system and psychiatric disorders.

PubMed

Pizza, Fabio; Magnani, Michele; Indrio, Camilla; Plazzi, Giuseppe

2014-02-01

The hypocretin system is constituted by a small group of hypothalamic neurons with widespread connections within the entire central nervous system producing two neuropeptides involved in several key physiological functions such as the regulation of sleep and wakefulness, motor control, autonomic functions, metabolism, feeding behavior, and reward. Narcolepsy with cataplexy is a neurological disorder regarded as a disease model for the selective hypocretin system damage, and also shares several psychopatological traits and comorbidities with psychiatric disorders. We reviewed the available literature on the involvement of the hypocretin system in psychiatric nosography. Different evidences such as cerebrospinal hypocretin-1 levels, genetic polymorphisms of the neuropeptides or their receptors, response to treatments, clinical, experimental and functional data directly or indirectly linked the hypocretin system to schizophrenia, mood, anxiety and eating disorders, as well as to addiction. Future genetic and pharmacological studies will disentangle the hypocretin system role in the field of psychiatry.
Cases of pediatric narcolepsy after misdiagnoses.

PubMed

Kauta, Shilpa R; Marcus, Carole L

2012-11-01

Narcolepsy is characterized by recurrent brief attacks of irresistible sleepiness. Signs can begin during childhood. However, diagnoses are frequently delayed by 10-15 years because of unfamiliarity with pediatric narcolepsy and variable presentations of its associated features (cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis). Therefore, patients may remain untreated during their formative years. Three children with narcolepsy who were initially misdiagnosed are described. Each child's signs were initially related to depression, hypothyroidism, jaw dysfunction, or conversion disorder. However, after a multiple sleep latency test, the diagnosis of narcolepsy was established. All three patients were treated appropriately with stimulant medications, selective serotonin reuptake inhibitors, or sodium oxybate, and demonstrated positive responses. Although no definitive cure exists for narcolepsy, early recognition and appropriate symptomatic treatment with medications can allow affected children to improve quality of life and achieve normality, both academically and socially. Copyright © 2012 Elsevier Inc. All rights reserved.
The hypocretins (orexins) mediate the “phasic” components of REM sleep: A new hypothesis

PubMed Central

Torterolo, Pablo; Chase, Michael H.

2014-01-01

In 1998, a group of phenotypically distinct neurons were discovered in the postero-lateral hypothalamus which contained the neuropeptides hypocretin 1 and hypocretin 2 (also called orexin A and orexin B), which are excitatory neuromodulators. Hypocretinergic neurons project throughout the central nervous system and have been involved in the generation and maintenance of wakefulness. The sleep disorder narcolepsy, characterized by hypersomnia and cataplexy, is produced by degeneration of these neurons. The hypocretinergic neurons are active during wakefulness in conjunction with the presence of motor activity that occurs during survival-related behaviors. These neurons decrease their firing rate during non-REM sleep; however there is still controversy upon the activity and role of these neurons during REM sleep. Hence, in the present report we conducted a critical review of the literature of the hypocretinergic system during REM sleep, and hypothesize a possible role of this system in the generation of REM sleep. PMID:26483897
Differential diagnosis in hypersomnia.

PubMed

Dauvilliers, Yves

2006-03-01

Hypersomnia includes a group of disorders in which the primary complaint is excessive daytime sleepiness. Chronic hypersomnia is characterized by at least 3 months of excessive sleepiness prior to diagnosis and may affect 4% to 6% of the population. The severity of daytime sleepiness needs to be quantified by subjective scales (at least the Epworth sleepiness scale) and objective tests such as the multiple sleep latency test. Chronic hypersomnia does not correspond to an individual clinical entity but includes numerous different etiologies of hypersomnia as recently reported in the revised International Classification of Sleep Disorders. This review details most of those disorders, including narcolepsy with and without cataplexy, idiopathic hypersomnia with and without long sleep time, recurrent hypersomnia, behaviorally induced insufficient sleep syndrome, hypersomnia due to medical condition, hypersomnia due to drug or substance, hypersomnia not due to a substance or known physiologic condition, and also sleep-related disordered breathing and periodic leg movement disorders.
Idiopathic hypersomnia: a report of three adolescent-onset cases in a two-generation family.

PubMed

Janácková, Sona; Motte, Jacques; Bakchine, Serge; Sforza, Emilia

2011-04-01

Idiopathic hypersomnia is an uncommon sleep disorder characterized by prolonged sleep time and excessive daytime sleepiness without cataplexy. This study concerned a case of familial occurrence. The proband expressed an idiopathic hypersomnia with long sleep time at the age of 12 years. Clinical interview and ad libitum polysomnographic study did not reveal any symptoms of narcolepsy or other sleep disorders. Family history revealed that a 20-year-old sister had experienced symptoms of hypersomnia from the age of 16 and their mother had been diagnosed with idiopathic hypersomnia previously. The diagnosis of idiopathic hypersomnia with long sleep time was confirmed in the sister by clinical interview and ad libitum polysomnography. Human leukocyte antigen (HLA) did not reveal the DQB1-0602 phenotype in the proband and relatives. This report confirms the hypothesis of a genetic predisposition in idiopathic hypersomnia.
Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction.

PubMed

Blouin, Ashley M; Fried, Itzhak; Wilson, Charles L; Staba, Richard J; Behnke, Eric J; Lam, Hoa A; Maidment, Nigel T; Karlsson, Karl Æ; Lapierre, Jennifer L; Siegel, Jerome M

2013-01-01

The neurochemical changes underlying human emotions and social behaviour are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 and melanin-concentrating hormone, measured in the human amygdala. We show that hypocretin-1 levels are maximal during positive emotion, social interaction and anger, behaviours that induce cataplexy in human narcoleptics. In contrast, melanin-concentrating hormone levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. Melanin-concentrating hormone levels increase at sleep onset, consistent with a role in sleep induction, whereas hypocretin-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized.
Autoimmunity in narcolepsy.

PubMed

Bonvalet, Melodie; Ollila, Hanna M; Ambati, Aditya; Mignot, Emmanuel

2017-11-01

Summarize the recent findings in narcolepsy focusing on the environmental and genetic risk factors in disease development. Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Recent studies suggest both humoral and cellular immune responses in the disease development. Narcolepsy is a severe sleep disorder, in which neurons producing orexin/hypocretin in the hypothalamus are destroyed. The core symptoms of narcolepsy are debilitating, extreme sleepiness, cataplexy, and abnormalities in the structure of sleep. Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Importantly, the highest environmental risk is seen with influenza-A infection and immunization. However, how the cells are destroyed is currently unknown. In this review we summarize the disease symptoms, and focus on the immunological findings in narcolepsy. We also discuss the environmental and genetic risk factors as well as propose a model for disease development.
Narcolepsy in pediatric age – Experience of a tertiary pediatric hospital

PubMed Central

Dias Costa, Filipa; Barreto, Maria Inês; Clemente, Vanda; Vasconcelos, Mónica; Estêvão, Maria Helena; Madureira, Núria

2014-01-01

Narcolepsy, a chronic disorder of the sleep–wake cycle of multifactorial etiology, is characterized by excessive daytime sleepiness, often associated with cataplexy, hypnagogic/hypnopompic hallucinations and sleep paralysis. Both early clinical suspicion and therapeutic approach are essential for promotion of cognitive development and social integration of these children. The authors present a descriptive retrospective study of a series of eight children in whom symptoms first started between 6.8 and 10.5 years of age. Diagnostic delay ranged from 4 months to 2 years. One child had H1N1 flu vaccination eight months before the clinical onset. The first multiple sleep latency test was positive in 6 of 8 cases. All cases were treated with methylphenidate, and venlafaxine was associated in 4 of them. In one case the initial therapy was exclusively behavioral. In all cases, symptomatic improvement, better school performance and social integration were achieved after therapeutic adjustment. PMID:26483902
Narcolepsy

PubMed Central

Mitler, Merrill M.; Hajdukovic, Roza; Erman, Milton; Koziol, James A.

2008-01-01

Summary Narcolepsy is a neurological condition with a prevalence of up to 1 per 1,000 that is characterized by irresistible bouts of sleep. Associated features include the pathological manifestations of rapid-eye-movement (REM) sleep: cataplexy, sleep paralysis, hypnagogic hallucinations, and abnormal sleep-onset REM periods and disturbed nocturnal sleep. The condition is strongly associated with the HLA-DR2 and DQw1 phenotype. The phenomenology of narcolepsy is discussed, and diagnostic procedures are reviewed. Treatment modalities involving central nervous system stimulants for somnolence and tricyclic drugs for REM-sleep abnormalities are discussed. Sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine, protriptyline, and viloxazine are presented. Data suggest that: (1) methylphenidate and dextro-amphetamine objectively improve somnolence; (2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence but may improve certain aspects of performance; and (3) protriptyline and viloxazine are effective anticataplectic agents that produce little improvement in somnolence. PMID:1968069
Evidence for Metabolic Hypothalamo-Amygdala Dysfunction in Narcolepsy

PubMed Central

Poryazova, Rositsa; Schnepf, Betina; Werth, Esther; Khatami, Ramin; Dydak, Ulrike; Meier, Dieter; Boesiger, Peter; Bassetti, Claudio L.

2009-01-01

Study Objectives: Proton resonance spectroscopy (1H-MRS) allows noninvasive chemical tissue analysis in the living brain. As neuronal loss and gliosis have been described in narcolepsy, metabolites of primary interest are N-acetylaspartate (NAA), a marker of neuronal integrity and myo-Inositol (mI), a glial marker and second messenger involved in the regulation of intracellular calcium. One 1H-MRS study in narcolepsy found no metabolic changes in the pontomedullary junction. Another study showed a reduction in NAA/creatine-phosphocreatine (Cr) in the hypothalamus of narcolepsy patients with cataplexy. We aimed to test for metabolic changes in specific brain areas, “regions of interest,” thought to be involved in emotional processing, sleep regulation and pathophysiology of narcolepsy: hypothalamus, pontomesencephalic junction and both amygdalae. Design: We performed 1H-MRS using a 3T Philips Achieva whole body MR scanner. Single-voxel proton MR spectra were acquired and quantified with LCModel to determine metabolite concentration ratios. Setting: The participants in the study were recruited at the outpatient clinic for sleep medicine, Department of Neurology and magnetic resonance spectroscopy was performed at the MRI facility, University Hospital Zurich. Participants: 1H-MRS was performed in fourteen narcolepsy patients with cataplexy, CSF hypocretin deficiency (10/10) and HLA-DQB1*0602 positivity (14/14) and 14 age, gender and body mass index matched controls. Patients were treatment naïve or off therapy for at least 14 days before scanning. Measurements and Results: No differences were observed in the regions of interest for (total NAA)/Cr ratios. Myo-Inositol (mI)/Cr was significantly lower in the right amygdala of the patients, compared to controls (P < 0.042). Significant negative correlations only in the patients group were found between (total NAA)/Cr in hypothalamus and mI/Cr in the right amygdala (r = −0.89, P < 0.001), between mI/Cr in hypothalamus and (total NAA)/Cr in the right amygdala (r = −63, P < 0.05) and between mI/Cr in the left amygdala and total NAA)/Cr in the pontomesencephalic junction (r = −0.69, P < 0.05). Conclusion: Our findings suggest amygdala involvement and possible hypothalamo-amygdala dysfunction in narcolepsy. Citation: Poryazova R; Werth E; Khatami R; Dydak U; Meier D; Boesiger P; Bassetti CL. Evidence for metabolic hypothalamo-amygdala dysfunction in narcolepsy. SLEEP 2009;32(5):607-613. PMID:19480227
The Xyrem risk management program.

PubMed

Fuller, David E; Hornfeldt, Carl S; Kelloway, Judy S; Stahl, Pamela J; Anderson, Todd F

2004-01-01

Sodium oxybate, also known as gamma-hydroxybutyric acid (GHB), was discovered in 1960 and has been described both as a therapeutic agent with high medical value and, more recently, a substance of abuse. The naturally occurring form of this drug is found in various body tissues but has been studied most extensively in the CNS where its possible function as a neurotransmitter continues to be studied. Sodium oxybate has been approved in different countries for such varied uses as general anaesthesia, the treatment of alcohol withdrawal and addiction, and, most recently, cataplexy associated with narcolepsy. During the 1980s, easy access to GHB-containing products led to various unapproved uses, including weight loss, bodybuilding and the treatment of sleeplessness, sometimes with serious long-term effects. The availability of these unapproved and unregulated forms of the drug led to GHB and its analogues being popularised as substances of abuse and subsequent notoriety as agents used in drug-facilitated sexual assault, or 'date rape', eventually leading to the prohibition of GHB sales in the US. Legal efforts to control the sale and distribution of GHB and its analogues nearly prevented the clinical development of sodium oxybate for narcolepsy in the US. However, following extensive discussions with a variety of interested parties, a satisfactory solution was devised, including legislative action and the development of the Xyrem Risk Management Program. Amendments to the US Controlled Substances Act made GHB a schedule I drug, but also contained provisions that allow US FDA-approved products to be placed under schedule III. This unique, bifurcated schedule for sodium oxybate/GHB allowed the clinical development of sodium oxybate to proceed and, in July 2002, it was approved by the FDA as an orphan drug for the treatment of cataplexy in patients with narcolepsy as Xyrem(sodium oxybate) oral solution. To promote the safe use of sodium oxybate, as well as alleviate concerns over possible diversion and abuse following product approval, a proprietary restricted drug distribution system was created, called the Xyrem Success Program. Components of the programme include a centralised distribution and dispensing system, a physician and patient registry, compulsory educational materials for patients and physicians, a specially trained pharmacy staff, a method for tracking prescription shipments, and an initial post-marketing surveillance programme. The system has created a unique opportunity to provide both physician and patient education and ongoing patient counselling, promoting greater drug safety and enhanced patient compliance.

miRNA Profiles in Plasma from Patients with Sleep Disorders Reveal Dysregulation of miRNAs in Narcolepsy and Other Central Hypersomnias

PubMed Central

Holm, Anja; Bang-Berthelsen, Claus Heiner; Knudsen, Stine; Kornum, Birgitte R.; Modvig, Signe; Jennum, Poul; Gammeltoft, Steen

2014-01-01

Study Objectives: MicroRNAs (miRNAs) have been implicated in the pathogenesis of human diseases including neurological disorders. The aim is to address the involvement of miRNAs in the pathophysiology of central hypersomnias including autoimmune narcolepsy with cataplexy and hypocretin deficiency (type 1 narcolepsy), narcolepsy without cataplexy (type 2 narcolepsy), and idiopathic hypersomnia. Design: We conducted high-throughput analysis of miRNA in plasma from three groups of patients—with type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia, respectively—in comparison with healthy controls using quantitative real-time polymerase chain reaction (qPCR) panels. Setting: University hospital based sleep clinic and research laboratories. Patients: Twelve patients with type 1 narcolepsy, 12 patients with type 2 narcolepsy, 12 patients with idiopathic hypersomnia, and 12 healthy controls. Measurements and Results: By analyzing miRNA in plasma with qPCR we identified 50, 24, and 6 miRNAs that were different in patients with type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia, respectively, compared with healthy controls. Twenty miRNA candidates who fulfilled the criteria of at least two-fold difference and p-value < 0.05 were selected to validate the miRNA changes in an independent cohort of patients. Four miRNAs differed significantly between type 1 narcolepsy patients and healthy controls. Levels of miR-30c, let-7f, and miR-26a were higher, whereas the level of miR-130a was lower in type 1 narcolepsy than healthy controls. The miRNA differences were not specific for type 1 narcolepsy, since the levels of the four miRNAs were also altered in patients with type 2 narcolepsy and idiopathic hypersomnia compared with healthy controls. Conclusion: The levels of four miRNAs differed in plasma from patients with type 1 narcolepsy, type 2 narcolepsy and idiopathic hypersomnia suggesting that alterations of miRNAs may be involved in the pathophysiology of central hypersomnias. Citation: Holm A, Bang-Berthelsen CH, Knudsen S, Kornum BR, Modvig S, Jennum P, Gammeltoft S. miRNA profiles in plasma from patients with sleep disorders reveal dysregulation of miRNAs in narcolepsy and other central hypersomnias. SLEEP 2014;37(9):1525-1533. PMID:25142559
Attention-Deficit/Hyperactivity Disorder (ADHD) Symptoms in Pediatric Narcolepsy: A Cross-Sectional Study

PubMed Central

Lecendreux, Michel; Lavault, Sophie; Lopez, Régis; Inocente, Clara Odilia; Konofal, Eric; Cortese, Samuele; Franco, Patricia; Arnulf, Isabelle; Dauvilliers, Yves

2015-01-01

Study Objectives: To evaluate the frequency, severity, and associations of symptoms of attention-deficit/hyperactivity disorder (ADHD) in children with narcolepsy with and without cataplexy. Design: Cross-sectional survey. Setting: Four French national reference centers for narcolepsy. Patients: One hundred eight consecutively referred children aged younger than 18 y with narcolepsy, with (NwC, n = 86) or without cataplexy (NwoC, n = 22), and 67 healthy controls. Interventions: The participants, their families, and sleep specialists completed a structured interview and questionnaires about sleep, daytime sleepiness, fatigue, and ADHD symptoms (ADHD-rating scale based upon Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] symptoms), and use of psychostimulants for the treatment of narcolepsy (administered in 68.2%). Polysomnographic measures were collected. Measurements and Results: Clinically significant levels of ADHD symptoms were found in 4.8% of controls compared with 35.3% in patients with NwoC (P < 0.001) and 19.7% in patients with NwC (P < 0.01). Total ADHD scores were 6.4 (95% confidence interval [CI]: 4.5, 9.0) in controls compared with 14.2 (95% CI: 10.6, 18.9; P < 0.001), in patients with NwoC and 12.2 (95% CI: 9.8, 15.3; P < 0.01) in patients with NwC; subscores of inattention and hyperactivity/impulsivity were also significantly higher in both narcolepsy groups compared with controls. No difference was found between the NwC and NwoC groups for any ADHD measure. ADHD symptom severity was associated with increased levels of sleepiness, fatigue, and insomnia. Compared with the 34 untreated patients, the 73 patients treated with psychostimulants (modafinil in 91%) showed a trend toward lower narcolepsy symptoms but not lower ADHD symptoms. Conclusions: Pediatric patients with narcolepsy have high levels of treatment-resistant attention-deficit/hyperactivity disorder (ADHD) symptoms. The optimal treatment for ADHD symptoms in these patients warrants further evaluation in longitudinal intervention studies. Citation: Lecendreux M, Lavault S, Lopez R, Inocente CO, Konofal E, Cortese S, Franco P, Arnulf I, Dauvilliers Y. Attention-deficit/hyperactivity disorder (adhd) symptoms in pediatric narcolepsy: a cross-sectional study. SLEEP 2015;38(8):1285–1295. PMID:26118560
[Clinical effect of atomoxetine hydrochloride in 66 children with narcolepsy].

PubMed

Zhang, Shen; Ding, Changhong; Wu, Husheng; Fang, Fang; Wang, Xiaohui; Ren, Xiaotun

2015-10-01

To observe the efficacy and safety of atomoxetine hydrochloride in children with narcolepsy. Totally 66 patients with narcolepsy who were conformed international classification of sleep disturbances (ICSD-2) diagnostic criteria treated with atomoxetine hydrochloride seen from November 2010 to December 2014 were enrolled into this study, 42 of them were male and 24 female, mean age of onset was 7.5 years (3.75-13.00 years), mean duration before diagnosis was 1.75 years (0.25-5.00 years). Complete blood count, liver and kidney function, multiple sleep latency test (MSLT), polysomnography (PGS), neuroimaging and electroencephalography (EEG) were performed for each patient. For some of the children HLA-DR2 gene and serum markers of infection were tested. The 66 cases were followed up from 2 to 49 months (average 18 months) to observe the clinical efficacy and adverse reactions. In 62 cases excessive daytime sleepiness was improved, in 11 cases (16.7%) it was controlled (16.7%), in 29 cases (43.9%) the treatment was obviously effective and in 22 (33.3%) it was effective; cataplexy occurred in 54 cases, in 18 (33.3%) it was controlled, in 19 (35.2%) the treatment was obviously effective and in 10 (18.5%) effective; night sleep disorders existed in 55 cases, in 47 cases it was improved, in 14 (25.5%) it was controlled, in 20 (36.4%) the treatment was obviously effective and in 13 (23.6%) effective; hypnagogic or hypnopompic hallucination was present in 13 cases, in only 4 these symptoms were controlled. Sleep paralysis existed in 4 cases, it was controlled in only 1 case. In 18 cases attention and learning efficiency improved.Anorexia occurred in 18 cases, mood disorder in 5 cases, depression in 2 cases, nocturia, muscle tremors, involuntary tongue movement each occurred in 1 case. P-R interval prolongation and atrial premature contraction were found in 1 case. Atomoxetine hydrochloride showed good effects in patients with narcolepsy on excessive daytime sleepiness, cataplexy and night sleep disorders, the effects on hallucinations and sleep paralysis were not significant. Adverse reactions were slight, anorexia and mood disorder were common. As a non-central nervous system stimulant, atomoxetine hydrochloride does not induce drug dependence and has no prescription limits; it has good tolerability, safety and effectiveness, it can be a good alternative in treatment of children with narcolepsy.
Melanin-concentrating hormone neurons discharge in a reciprocal manner to orexin neurons across the sleep–wake cycle

PubMed Central

Hassani, Oum Kaltoum; Lee, Maan Gee; Jones, Barbara E.

2009-01-01

Neurons containing melanin-concentrating hormone (MCH) are codistributed with neurons containing orexin (Orx or hypocretin) in the lateral hypothalamus, a peptide and region known to be critical for maintaining wakefulness. Evidence from knockout and c-Fos studies suggests, however, that the MCH neurons might play a different role than Orx neurons in regulating activity and sleep–wake states. To examine this possibility, neurons were recorded across natural sleep–wake states in head-fixed rats and labeled by using the juxtacellular technique for subsequent immunohistochemical identification. Neurons identified as MCH+ did not fire during wake (W); they fired selectively during sleep, occasionally during slow wave sleep (SWS) and maximally during paradoxical sleep (PS). As W-Off/Sleep-On, the MCH neurons discharged in a reciprocal manner to the W-On/Sleep-Off Orx neurons and could accordingly play a complementary role to Orx neurons in sleep–wake state regulation and contribute to the pathophysiology of certain sleep disorders, such as narcolepsy with cataplexy. PMID:19188611
Recurrent laughter-induced syncope.

PubMed

Gaitatzis, Athanasios; Petzold, Axel

2012-07-01

Syncope is a common presenting complaint in Neurology clinics or Emergency departments, but its causes are sometimes difficult to diagnose. Apart from vasovagal attacks, other benign, neurally mediated syncopes include "situational" syncopes, which occur after urination, coughing, swallowing, or defecation. A healthy 42-year-old male patient presented to the neurology clinic with a long history of faints triggered by spontaneous laughter, especially after funny jokes. Physical and neurological examination, and electroencephalography and magnetic resonance imaging were unremarkable. There was no evidence to suggest cardiogenic causes, epilepsy, or cataplexy and a diagnosis of laughing syncope was made. Laughter-induced syncope is usually a single event in the majority of cases, but may present as recurrent attacks as in our case. Some cases occur in association with underlying neurological conditions. Prognosis is good in the case of neurally mediated attacks. Laughter may not be recognized by physicians as a cause of syncope, which may lead to unnecessary investigations or misdiagnosis, and affect patients' quality of life.
Genetic factors in human sleep disorders with special reference to Norrie disease, Prader-Willi syndrome and Moebius syndrome.

PubMed

Parkes, J D

1999-06-01

Sleep-wake problems are common in specific inborn errors of metabolism and structure of the central nervous system. Psychological factors, behavioural difficulties, metabolic disturbances, and widespread rather than focal damage to the nervous system are present in many of these diseases and all influence the sleep-wake cycle. However, a number of conditions cause relatively focal damage to the neuroanatomical substrate of sleeping and waking. These include fatal familial insomnia, with involvement of the prion protein gene on chromosome 20, Norrie disease, the Prader-Willi syndrome and the Moebius syndrome. The last three important conditions, although rare, are considered in detail in this review. They result in sensory deprivation, hypothalamic and mid-brain damage, and involve the X-chromosome, chromosome 15, and chromosome 13, respectively. These conditions cause a wide variety of sleep disturbance, including parasomnias, daytime sleepiness, and a condition like cataplexy. The place of the relevant gene products in normal sleep regulation needs further exploration.
Case report of narcolepsy in a six-year-old child initially misdiagnosed as atypical epilepsy

PubMed Central

ZHOU, Jinquan; ZHANG, Xi; DONG, Zaiwen

2014-01-01

Summary This report describes a case of first-onset narcolepsy in a six-year-old female that was misdiagnosed as atypical epilepsy and other diagnoses at eight different hospitals over a period of 10 months before the correct diagnosis was made. The diagnosis of narcolepsy is more difficult in children because very few of them experience all four cardinal symptoms of narcolepsy – paroxysmal sleep, cataplexy, hypnagogic hallucination, and sleep paralysis – and they often have a more prolonged onset and diverse symptoms. To decrease the time lag between initial presentation and accurate diagnosis, we recommend that in all cases in which children report excessive sleep of unknown etiology – regardless of the associated symptoms – that sleep monitoring and sleep latency tests be conducted to rule out the possibility of narcolepsy. The case highlights the wide variety of presentations of uncommon psychiatric conditions, particularly in children, and the need for clinicians to be aware of the atypical presentations of these conditions when collecting medical histories. PMID:25317010
ApoE polymorphisms in narcolepsy

PubMed Central

Gencik, Martin; Dahmen, Norbert; Wieczorek, Stefan; Kasten, Meike; Gencikova, Alexandra; Epplen, Jorg T

2001-01-01

Background Narcolepsy is a common neuropsychiatric disorder characterized by increased daytime sleepiness, cataplexy and hypnagogic hallucinations. Deficiency of the hypocretin neurotransmitter system was shown to be involved in the pathogenesis of narcolepsy in animals and men. There are several hints that neurodegeneration of hypocretin producing neurons in the hypothalamus is the pathological correlate of narcolepsy. The ApoE4 allele is a major contributing factor to early-onset neuronal degeneration in Alzheimer disease and other neurodegenerative diseases as well. Methods To clarify whether the ApoE4 phenotype predisposes to narcolepsy or associates with an earlier disease onset, we have genotyped the ApoE gene in 103 patients with narcolepsy and 101 healthy controls. Results The frequency of the E4 allele of the ApoE gene was 11% in the patient and 15% in the control groups. Furthermore, the mean age of onset did not differ between the ApoE4+ and ApoE4- patient groups. Conclusion Our results exclude the ApoE4 allele as a major risk factor for narcolepsy. PMID:11560764
Case report of narcolepsy in a six-year-old child initially misdiagnosed as atypical epilepsy.

PubMed

Zhou, Jinquan; Zhang, Xi; Dong, Zaiwen

2014-08-01

This report describes a case of first-onset narcolepsy in a six-year-old female that was misdiagnosed as atypical epilepsy and other diagnoses at eight different hospitals over a period of 10 months before the correct diagnosis was made. The diagnosis of narcolepsy is more difficult in children because very few of them experience all four cardinal symptoms of narcolepsy - paroxysmal sleep, cataplexy, hypnagogic hallucination, and sleep paralysis - and they often have a more prolonged onset and diverse symptoms. To decrease the time lag between initial presentation and accurate diagnosis, we recommend that in all cases in which children report excessive sleep of unknown etiology - regardless of the associated symptoms - that sleep monitoring and sleep latency tests be conducted to rule out the possibility of narcolepsy. The case highlights the wide variety of presentations of uncommon psychiatric conditions, particularly in children, and the need for clinicians to be aware of the atypical presentations of these conditions when collecting medical histories.
Treatment of Narcolepsy and other Hypersomnias of Central Origin

PubMed Central

Wise, Merrill S.; Arand, Donna L.; Auger, R. Robert; Brooks, Stephen N.; Watson, Nathaniel F.

2007-01-01

Objective: The purpose of this paper is to summarize current knowledge about treatment of narcolepsy and other hypersomnias of central origin. Methods: The task force performed a systematic and comprehensive review of the relevant literature and graded the evidence using the Oxford grading system. This paper discusses the strengths and limitations of the available evidence regarding treatment of these conditions, and summarizes key information about safety of these medications. Our findings provide the foundation for development of evidence-based practice parameters on this topic by the Standards of Practice Committee of the American Academy of Sleep Medicine. Results: The majority of recent papers in this field provide information about use of modafinil or sodium oxybate for treatment of sleepiness associated with narcolepsy. Several large randomized, placebo-controlled studies indicate that modafinil and sodium oxybate are effective for treatment of hypersomnia due to narcolepsy. We identified no studies that report direct comparison of these newer medications versus traditional stimulants, or that indicate what proportion of patients treated initially with these medications require transition to traditional stimulants or to combination therapy to achieve adequate alertness. As with the traditional stimulants, modafinil and sodium oxybate provide, at best, only moderate improvement in alertness rather than full restoration of alertness in patients with narcolepsy. Several large randomized placebo-controlled studies demonstrate that sodium oxybate is effective for treatment of cataplexy associated with narcolepsy, and earlier studies provide limited data to support the effectiveness of fluoxetine and tricyclic antidepressants for treatment of cataplexy. Our findings indicate that very few reports provide information regarding treatment of special populations such as children, older adults, and pregnant or breastfeeding women. The available literature provides a modest amount of information about improvement in quality of life in association with treatment, patient preferences among the different medications, or patient compliance. Conclusion: Several recent studies provide evidence that modafinil and sodium oxybate are effective for treatment of hypersomnia due to narcolepsy. No studies were identified that report direct comparison of these newer medications with traditional stimulants. Despite significant advances in understanding the pathophysiology of narcolepsy, we do not have an ideal treatment to restore full and sustained alertness. Future investigations should be directed toward development of more effective and better tolerated therapies, and primary prevention. Citation: Wise MS; Arand DL; Auger RR; Brooks SN; Watson NF. Treatment of Narcolepsy and other Hypersomnias of Central Origin. SLEEP 2007;30(12):1712-1727. PMID:18246981
Altered Baseline and Nicotine-Mediated Behavioral and Cholinergic Profiles in ChAT-Cre Mouse Lines.

PubMed

Chen, Edison; Lallai, Valeria; Sherafat, Yasmine; Grimes, Nickolas P; Pushkin, Anna N; Fowler, J P; Fowler, Christie D

2018-02-28

The recent development of transgenic rodent lines expressing cre recombinase in a cell-specific manner, along with advances in engineered viral vectors, has permitted in-depth investigations into circuit function. However, emerging evidence has begun to suggest that genetic modifications may introduce unexpected caveats. In the current studies, we sought to extensively characterize male and female mice from both the ChAT (BAC) -Cre mouse line, created with the bacterial artificial chromosome (BAC) method, and ChAT (IRES) -Cre mouse line, generated with the internal ribosome entry site (IRES) method. ChAT (BAC) -Cre transgenic and wild-type mice did not differ in general locomotor behavior, anxiety measures, drug-induced cataplexy, nicotine-mediated hypolocomotion, or operant food training. However, ChAT (BAC) -Cre transgenic mice did exhibit significant deficits in intravenous nicotine self-administration, which paralleled an increase in vesicular acetylcholine transporter and choline acetyltransferase (ChAT) hippocampal expression. For the ChAT (IRES) -Cre line, transgenic mice exhibited deficits in baseline locomotor, nicotine-mediated hypolocomotion, and operant food training compared with wild-type and hemizygous littermates. No differences among ChAT (IRES) -Cre wild-type, hemizygous, and transgenic littermates were found in anxiety measures, drug-induced cataplexy, and nicotine self-administration. Given that increased cre expression was present in the ChAT (IRES) -Cre transgenic mice, as well as a decrease in ChAT expression in the hippocampus, altered neuronal function may underlie behavioral phenotypes. In contrast, ChAT (IRES) -Cre hemizygous mice were more similar to wild-type mice in both protein expression and the majority of behavioral assessments. As such, interpretation of data derived from ChAT-Cre rodents must consider potential limitations dependent on the line and/or genotype used in research investigations. SIGNIFICANCE STATEMENT Altered baseline and/or nicotine-mediated behavioral profiles were discovered in transgenic mice from the ChAT (BAC) -Cre and ChAT (IRES) -Cre lines. Given that these cre-expressing mice have become increasingly used by the scientific community, either independently with chemicogenetic and optogenetic viral vectors or crossed with other transgenic lines, the current studies highlight important considerations for the interpretation of data from previous and future experimental investigations. Moreover, the current findings detail the behavioral effects of either increased or decreased baseline cholinergic signaling mechanisms on locomotor, anxiety, learning/memory, and intravenous nicotine self-administration behaviors. Copyright © 2018 the authors 0270-6474/18/382177-12$15.00/0.
Evaluation of polygenic risks for narcolepsy and essential hypersomnia.

PubMed

Yamasaki, Maria; Miyagawa, Taku; Toyoda, Hiromi; Khor, Seik-Soon; Liu, Xiaoxi; Kuwabara, Hitoshi; Kano, Yukiko; Shimada, Takafumi; Sugiyama, Toshiro; Nishida, Hisami; Sugaya, Nagisa; Tochigi, Mamoru; Otowa, Takeshi; Okazaki, Yuji; Kaiya, Hisanobu; Kawamura, Yoshiya; Miyashita, Akinori; Kuwano, Ryozo; Kasai, Kiyoto; Tanii, Hisashi; Sasaki, Tsukasa; Honda, Yutaka; Honda, Makoto; Tokunaga, Katsushi

2016-10-01

In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (P HLA-DQB1*06:02 =2.30 × 10 -48 , P whole genome without HLA-DQB1*06:02 =6.73 × 10 -2 ) including HLA-DQB1*06:02 effects and 1.3% (P whole genome without HLA-DQB1*06:02 =2.43 × 10 -2 ) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (P whole genome without HLA-DQB1*06:02 =9.74 × 10 -2 ). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA-DQB1*06:02: 40.4%, P HLA-DQB1*06:02 =7.02 × 10 - 14 , P whole genome without HLA-DQB1*06:02 =1.34 × 10 - 1 , EHS without HLA-DQB1*06:02: 0.4%, P whole genome without HLA-DQB1*06:02 =3.06 × 10 - 1 ). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.
Positive Effects of Massage Therapy on a Patient with Narcolepsy

PubMed Central

Hill, Robyn; Baskwill, Amanda

2013-01-01

Purpose The purpose of this case report was to investigate the effects of massage therapy on the sleep patterns of a woman with narcolepsy. Participant The 23-year-old woman’s primary symptoms included excessive daytime sleepiness and periodic leg movements (PLM), which were associated with her diagnoses of both narcolepsy and cataplexy. Intervention Five 45-minute massage therapy treatments were administered over a five-week period. The patient’s sleep patterns were recorded each week before the treatment. A final measurement was recorded in the sixth week. The sleep patterns were monitored using the Leeds Sleep Evaluation Questionnaire, which included ten visual analogue scales. Results The results of this case report included an improvement in getting to sleep by 148%, an improvement in quality of sleep by 1100%, an improvement in awake following sleep by 121%, and an improvement in behaviour following wakening by 28% using the Leeds Sleep Evaluation Questionnaire. Conclusion This case report suggests that massage therapy had a positive effect on this patient with narcolepsy. Further research is needed to investigate the effects of massage therapy on narcolepsy and sleep patterns. PMID:23730398
Positive effects of massage therapy on a patient with narcolepsy.

PubMed

Hill, Robyn; Baskwill, Amanda

2013-01-01

The purpose of this case report was to investigate the effects of massage therapy on the sleep patterns of a woman with narcolepsy. The 23-year-old woman's primary symptoms included excessive daytime sleepiness and periodic leg movements (PLM), which were associated with her diagnoses of both narcolepsy and cataplexy. Five 45-minute massage therapy treatments were administered over a five-week period. The patient's sleep patterns were recorded each week before the treatment. A final measurement was recorded in the sixth week. The sleep patterns were monitored using the Leeds Sleep Evaluation Questionnaire, which included ten visual analogue scales. The results of this case report included an improvement in getting to sleep by 148%, an improvement in quality of sleep by 1100%, an improvement in awake following sleep by 121%, and an improvement in behaviour following wakening by 28% using the Leeds Sleep Evaluation Questionnaire. This case report suggests that massage therapy had a positive effect on this patient with narcolepsy. Further research is needed to investigate the effects of massage therapy on narcolepsy and sleep patterns.
Polysomnographic study of nocturnal sleep in idiopathic hypersomnia without long sleep time.

PubMed

Pizza, Fabio; Ferri, Raffaele; Poli, Francesca; Vandi, Stefano; Cosentino, Filomena I I; Plazzi, Giuseppe

2013-04-01

We investigated nocturnal sleep abnormalities in 19 patients with idiopathic hypersomnia without long sleep time (IH) in comparison with two age- and sex- matched control groups of 13 normal subjects (C) and of 17 patients with narcolepsy with cataplexy (NC), the latter considered as the extreme of excessive daytime sleepiness (EDS). Sleep macro- and micro- (i.e. cyclic alternating pattern, CAP) structure as well as quantitative analysis of EEG, of periodic leg movements during sleep (PLMS), and of muscle tone during REM sleep were compared across groups. IH and NC patients slept more than C subjects, but IH showed the highest levels of sleep fragmentation (e.g. awakenings), associated with a CAP rate higher than NC during lighter sleep stages and lower than C during slow wave sleep respectively, and with the highest relative amount of A3 and the lowest of A1 subtypes. IH showed a delta power in between C and NC groups, whereas muscle tone and PLMS had normal characteristics. A peculiar profile of microstructural sleep abnormalities may contribute to sleep fragmentation and, possibly, EDS in IH. © 2012 European Sleep Research Society.
Hypocretin-1 Levels Associate with Fragmented Sleep in Patients with Narcolepsy Type 1.

PubMed

Alakuijala, Anniina; Sarkanen, Tomi; Partinen, Markku

2016-05-01

We aimed to analyze nocturnal sleep characteristics of patients with narcolepsy type 1 (narcolepsy with cataplexy) measured by actigraphy in respect to cerebrospinal fluid hypocretin-1 levels of the same patients. Actigraphy recording of 1-2 w and hypocretin-1 concentration analysis were done to thirty-six unmedicated patients, aged 7 to 63 y, 50% female. Twenty-six of them had hypocretin-1 levels under 30 pg/mL and the rest had levels of 31-79 pg/mL. According to actigraphy, patients with very low hypocretin levels had statistically significantly longer sleep latency (P = 0.033) and more fragmented sleep, indicated by both the number of immobile phases of 1 min (P = 0.020) and movement + fragmentation index (P = 0.049). There were no statistically significant differences in the actual sleep time or circadian rhythm parameters measured by actigraphy. Actigraphy gives additional information about the stabilization of sleep in patients with narcolepsy type 1. Very low hypocretin levels associate with more wake intruding into sleep. © 2016 Associated Professional Sleep Societies, LLC.
Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice

PubMed Central

Liu, Meng; Thankachan, Stephen; Kaur, Satvinder; Begum, Suraiya; Blanco-Centurion, Carlos; Sakurai, Takeshi; Yanagisawa, Masashi; Neve, Rachael; Shiromani, Priyattam J.

2008-01-01

Gene transfer has proven to be an effective neurobiological tool in a number of neurodegenerative diseases, but it is not known if it can correct a sleep disorder. Narcolepsy is a neurodegenerative sleep disorder linked to the loss of neurons containing the neuropeptide orexin, also known as hypocretin. Here, a replication-defective herpes simplex virus-1 amplicon-based vector was constructed to transfer the gene for mouse prepro-orexin into mice with a genetic deletion of the orexin gene. After in vitro tests confirmed successful gene transfer into cells, the gene vector was delivered to the lateral hypothalamus of orexin knockout (KO) mice where the orexin peptide was robustly expressed in the somata and processes of numerous neurons, and the peptide product was detected in the cerebrospinal fluid. During the 4-day life-span of the vector the incidence of cataplexy declined by 60%, and the levels of rapid eye movement sleep during the second half of the night were similar to levels in wild-type mice, indicating that narcoleptic sleep–wake behavior in orexin KO mice can be improved by targeted gene transfer. PMID:18973565
The spectrum of REM sleep-related episodes in children with type 1 narcolepsy.

PubMed

Antelmi, Elena; Pizza, Fabio; Vandi, Stefano; Neccia, Giulia; Ferri, Raffaele; Bruni, Oliviero; Filardi, Marco; Cantalupo, Gaetano; Liguori, Rocco; Plazzi, Giuseppe

2017-06-01

Type 1 narcolepsy is a central hypersomnia due to the loss of hypocretin-producing neurons and characterized by cataplexy, excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. In children, close to the disease onset, type 1 narcolepsy has peculiar clinical features with severe cataplexy and a complex admixture of movement disorders occurring while awake. Motor dyscontrol during sleep has never been systematically investigated. Suspecting that abnormal motor control might affect also sleep, we systematically analysed motor events recorded by means of video polysomnography in 40 children with type 1 narcolepsy (20 females; mean age 11.8 ± 2.6 years) and compared these data with those recorded in 22 age- and sex-matched healthy controls. Motor events were classified as elementary movements, if brief and non-purposeful and complex behaviours, if simulating purposeful behaviours. Complex behaviours occurring during REM sleep were further classified as 'classically-defined' and 'pantomime-like' REM sleep behaviour disorder episodes, based on their duration and on their pattern (i.e. brief and vivid-energetic in the first case, longer and with subcontinuous gesturing mimicking daily life activity in the second case). Elementary movements emerging either from non-REM or REM sleep were present in both groups, even if those emerging from REM sleep were more numerous in the group of patients. Conversely, complex behaviours could be detected only in children with type 1 narcolepsy and were observed in 13 patients, with six having 'classically-defined' REM sleep behaviour disorder episodes and seven having 'pantomime-like' REM sleep behaviour disorder episodes. Complex behaviours during REM sleep tended to recur in a stereotyped fashion for several times during the night, up to be almost continuous. Patients displaying a more severe motor dyscontrol during REM sleep had also more severe motor disorder during daytime (i.e. status cataplecticus) and more complaints of disrupted nocturnal sleep and of excessive daytime sleepiness. The neurophysiological hallmark of this severe motor dyscontrol during REM sleep was a decreased atonia index. The present study reports for the first time the occurrence of a severe and peculiar motor disorder during REM sleep in paediatric type 1 narcolepsy and confirms the presence of a severe motor dyscontrol in these patients, emerging not only from wakefulness (i.e. status cataplecticus), but also from sleep (i.e. complex behaviours during REM sleep). This is probably related to the acute imbalance of the hypocretinergic system, which physiologically acts by promoting movements during wakefulness and suppressing them during sleep. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Delusional Confusion of Dreaming and Reality in Narcolepsy

PubMed Central

Wamsley, Erin; Donjacour, Claire E.H.M.; Scammell, Thomas E.; Lammers, Gert Jan; Stickgold, Robert

2014-01-01

Study Objectives: We investigated a generally unappreciated feature of the sleep disorder narcolepsy, in which patients mistake the memory of a dream for a real experience and form sustained delusions about significant events. Design: We interviewed patients with narcolepsy and healthy controls to establish the prevalence of this complaint and identify its predictors. Setting: Academic medical centers in Boston, Massachusetts and Leiden, The Netherlands. Participants: Patients (n = 46) with a diagnosis of narcolepsy with cataplexy, and age-matched healthy healthy controls (n = 41). Interventions: N/A. Measurements and Results: “Dream delusions” were surprisingly common in narcolepsy and were often striking in their severity. As opposed to fleeting hypnagogic and hypnopompic hallucinations of the sleep/wake transition, dream delusions were false memories induced by the experience of a vivid dream, which led to false beliefs that could persist for days or weeks. Conclusions: The delusional confusion of dreamed events with reality is a prominent feature of narcolepsy, and suggests the possibility of source memory deficits in this disorder that have not yet been fully characterized. Citation: Wamsley E; Donjacour CE; Scammell TE; Lammers GJ; Stickgold R. Delusional confusion of dreaming and reality in narcolepsy. SLEEP 2014;37(2):419-422. PMID:24501437
A novel DNMT1 mutation associated with early onset hereditary sensory and autonomic neuropathy, cataplexy, cerebellar atrophy, scleroderma, endocrinopathy, and common variable immune deficiency.

PubMed

Fox, Robin; Ealing, John; Murphy, Helen; Gow, David P; Gosal, David

2016-09-01

DNA methyltransferase 1 (DNMT1) is an enzyme which has a role in methylation of DNA, gene regulation, and chromatin stability. Missense mutations in the DNMT1 gene have been previously associated with two neurological syndromes: hereditary sensory and autonomic neuropathy type 1 with dementia and deafness (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). We report a case showing overlap of both of these syndromes plus associated clinical features of common variable immune deficiency, scleroderma, and endocrinopathy that could also be mutation associated. Our patient was found to be heterozygous for a previously unreported frameshift mutation, c.1635_1637delCAA p.(Asn545del) in the DNMT1 gene exon 20. This case displays both the first frameshift mutation described in the literature which is associated with a phenotype with a high degree of overlap between HSAN1E and ADCA-DN and early age of onset (c. 8 years). Our case is also of interest as the patient displays a number of new non-neurological features, which could also be DNMT1 mutation related. © 2016 Peripheral Nerve Society.

Orexinergic system and pathophysiology of epilepsy.

PubMed

Doreulee, N; Alania, M; Vashalomidze, G; Skhirtladze, E; Kapanadze, Ts

2010-11-01

Neuropeptids orexins, also known as the hypocretins, are expressed in the lateral hypothalamus. Orexin-containing cells project widely throughout the brains, are crucial for the regulation of wakefulness and dysfunction of this system is associated with pathophysiology of narcolepsy-cataplexy. Orexin neurons play an important role in motivation, feeding and adaptive behaviors. Distribution of orexinergic receptors in the hippocampus tended to the ideas that orexins might be involved in the functions relating to the hippocampus. Effects of neuropeptide orexin-A on epileptiform activity in hippocampal slices were investigated. 500 µm thick hippocampal slices from 8-10 week-old rodents were used. Field excitatory postsynaptic potential (pop-fEPSP) and population spike in CA1 of hippocamopus were registered using standard protocol of in vitro electrophysiological experiments. Initial slope of the fEPSP and amplitude of II pop-spike were measured. Bursting neurons in CA3 were recorded in modified saline. We have found that orexin-A decreases duration/amplitude of multiple discharges of pop-spikes and inhibits spontaneous epileptiform afterdischarges induced by bicuculline methiodide in CA1. Orexin-A also modulates the frequency of discharges of bursting neurons in CA3. Our results suggest possible involvement of orexinergic system in antiepileptic action. Supported by ISTC Grant G-1318.
The anatomical, cellular and synaptic basis of motor atonia during rapid eye movement sleep

PubMed Central

Chen, Michael C.

2016-01-01

Abstract Rapid eye movement (REM) sleep is a recurring part of the sleep–wake cycle characterized by fast, desynchronized rhythms in the electroencephalogram (EEG), hippocampal theta activity, rapid eye movements, autonomic activation and loss of postural muscle tone (atonia). The brain circuitry governing REM sleep is located in the pontine and medullary brainstem and includes ascending and descending projections that regulate the EEG and motor components of REM sleep. The descending signal for postural muscle atonia during REM sleep is thought to originate from glutamatergic neurons of the sublaterodorsal nucleus (SLD), which in turn activate glycinergic pre‐motor neurons in the spinal cord and/or ventromedial medulla to inhibit motor neurons. Despite work over the past two decades on many neurotransmitter systems that regulate the SLD, gaps remain in our knowledge of the synaptic basis by which SLD REM neurons are regulated and in turn produce REM sleep atonia. Elucidating the anatomical, cellular and synaptic basis of REM sleep atonia control is a critical step for treating many sleep‐related disorders including obstructive sleep apnoea (apnea), REM sleep behaviour disorder (RBD) and narcolepsy with cataplexy. PMID:27060683
Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice.

PubMed

Mochizuki, Takatoshi; Arrigoni, Elda; Marcus, Jacob N; Clark, Erika L; Yamamoto, Mihoko; Honer, Michael; Borroni, Edilio; Lowell, Bradford B; Elmquist, Joel K; Scammell, Thomas E

2011-03-15

Narcolepsy is caused by a loss of orexin/hypocretin signaling, resulting in chronic sleepiness, fragmented non-rapid eye movement sleep, and cataplexy. To identify the neuronal circuits underlying narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase. Mice lacking OX2R signaling had poor maintenance of wakefulness indicative of sleepiness and fragmented sleep and lacked any electrophysiological response to orexin-A in the wake-promoting neurons of the tuberomammillary nucleus. These defects were completely recovered by crossing them with mice that express Cre in the female germline, thus globally deleting the transcription-disrupter cassette. Then, by using an adeno-associated viral vector coding for Cre recombinase, we found that focal restoration of OX2R in neurons of the tuberomammillary nucleus and adjacent parts of the posterior hypothalamus completely rescued the sleepiness of these mice, but their fragmented sleep was unimproved. These observations demonstrate that the tuberomammillary region plays an essential role in the wake-promoting effects of orexins, but orexins must stabilize sleep through other targets.
Primary hypersomnias of central origin.

PubMed

Frenette, Eric; Kushida, Clete A

2009-09-01

Hypersomnia is a frequently encountered symptom in clinical practice. The cardinal manifestation is inappropriate daytime sleepiness, common to all types of hypersomnias. Hypersomnias of central origin are a rare cause of excessive daytime sleepiness, much rarer than the hypersomnia related to other pathologies, such as sleep-disordered breathing. Narcolepsy, with or without cataplexy, remains the most well studied of the primary hypersomnias. Although recognized more than a century ago, it was not until the end of the 20th century that major breakthroughs led to a better understanding of the disease, with hope of more specific therapies. The authors review the major aspects of this disorder, including the newer treatment modalities. Idiopathic hypersomnia is also part of the primary hypersomnias. Although difficult to diagnose, certain peculiarities stand out to help us differentiate it from the more commonly seen narcolepsy. The recurrent hypersomnias, particularly the Kleine-Levin syndrome, will be discussed. This rare disorder has been studied more closely in the last few years with abundant epidemiologic data assembled through literature and worldwide case reviews. Understanding the primary central hypersomnias warrants a thorough look from the original description, as well as a peek at the future, while more efficacious diagnostic and therapeutic interventions are currently being developed. Thieme Medical Publishers.
An overview of hypocretin based therapy in narcolepsy.

PubMed

Takenoshita, Shinichi; Sakai, Noriaki; Chiba, Yuhei; Matsumura, Mari; Yamaguchi, Mai; Nishino, Seiji

2018-04-01

Narcolepsy with cataplexy is most commonly caused by a loss of hypocretin/orexin peptide-producing neurons in the hypothalamus (i.e., Narcolepsy Type 1). Since hypocretin deficiency is assumed to be the main cause of narcoleptic symptoms, hypocretin replacement will be the most essential treatment for narcolepsy. Unfortunately, this option is still not available clinically. There are many potential approaches to replace hypocretin in the brain for narcolepsy such as intranasal administration of hypocretin peptides, developing small molecule hypocretin receptor agonists, hypocretin neuronal transplantation, transforming hypocretin stem cells into hypothalamic neurons, and hypocretin gene therapy. Together with these options, immunotherapy treatments to prevent hypocretin neuronal death should also be developed. Areas covered: In this review, we overview the pathophysiology of narcolepsy and the current and emerging treatments of narcolepsy especially focusing on hypocretin receptor based treatments. Expert opinion: Among hypocretin replacement strategies, developing non-peptide hypocretin receptor agonists is currently the most encouraging since systemic administration of a newly synthesized, selective hypocretin receptor 2 agonist (YNT-185) has been shown to ameliorate symptoms of narcolepsy in murine models. If this option is effective in humans, hypocretin cell transplants or gene therapy technology may become realistic in the future.
Transient Impact of Rituximab in H1N1 Vaccination-associated Narcolepsy With Severe Psychiatric Symptoms.

PubMed

Sarkanen, Tomi; Alén, Reija; Partinen, Markku

2016-09-01

Narcolepsy type 1 is an organic sleep disorder caused by the destruction of hypocretin producing neurons in hypothalamus. In addition to daytime sleepiness, the spectrum and severity of symptoms are very variable. Psychiatric comorbidity and phenomena resembling psychotic symptoms are also common. Current treatment options for narcolepsy are symptomatic but there are few case reports of positive effect of immunotherapy. We report a very severely affected young boy treated with rituximab (RXB). A 12-year-old boy developed narcolepsy after Pandemrix H1N1 vaccination in 2010. He started to express severe psychiatric symptoms shortly after the onset. Cataplexy and sleepiness were devastatingly disabling. Conventional treatments did not have any effect on symptoms so we decided to try RXB, chimeric human monoclonal antibody against CD20 expressed in B lymphocytes. After the first treatment his condition ameliorated dramatically. Unfortunately, the effect lasted only for 2 months. Following attempts did not show any effect. Effect of RXB on narcolepsy has not been reported before. Remarkable but short-lasting effect of RXB in narcolepsy is intriguing as it could imply that there is still ongoing B cell-mediated autoimmune response possible contributing to symptoms in narcolepsy.
Juvenile myoclonic epilepsy and narcolepsy: A series of three cases.

PubMed

Joshi, Puja Aggarwal; Poduri, Annapurna; Kothare, Sanjeev V

2015-10-01

This paper sets out to demonstrate the coexistence of juvenile myoclonic epilepsy (JME) and narcolepsy that raises the possibility of a shared genetic predisposition to both conditions. The electronic medical records (EMRs) were searched for narcolepsy and JME over 10years. We identified three young adult women diagnosed with JME in their teenage years, with myoclonic, generalized tonic-clonic, and absence seizure semiologies, along with psychiatric comorbidity, well managed on lamotrigine and/or levetiracetam. Our patients were also found to have disturbed sleep preceding the diagnosis of JME by many years, including excessive daytime sleepiness (EDS), fragmented nocturnal sleep, hypnagogic vivid hallucinations, and REM behavior disorder along with daytime cataplexy. They were ultimately diagnosed with coexisting narcolepsy, confirmed by sleep studies and multiple sleep latency testing, along with positive genetic testing for HLA-DQB1*0602 in all three patients. Stimulants, selective serotonin receptor inhibitors, and/or sodium oxybate were used to successfully treat their narcolepsy. The coexistence of JME and narcolepsy has not been well recognized and may be clinically relevant. In addition, it raises the possibility of a shared genetic predisposition to both conditions. Copyright © 2015 Elsevier Inc. All rights reserved.
Investigational therapies for the treatment of narcolepsy.

PubMed

de Biase, Stefano; Nilo, Annacarmen; Gigli, Gian Luigi; Valente, Mariarosaria

2017-08-01

Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. While non-pharmacological treatments are sometimes helpful, more than 90% of narcoleptic patients require a pharmacological treatment. Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 to 2017. It is focused on drugs currently in development for the treatment of narcolepsy. Expert opinion: Currently there is no cure for narcolepsy, with treatment focusing on symptoms control. However, these symptomatic treatments are often unsatisfactory. The research is leading to a better understanding of narcolepsy and its symptoms. New classes of compounds with possible applications in the development of novel stimulant/anticataplectic medications are described. H3 receptor antagonists represent a new therapeutic option for EDS in narcolepsy. JZP-110, with its distinct mechanism of action, would be a new therapeutic option for the treatment of EDS in the coming years. In the future, hypocretin-based therapies and immune-based therapies, could modify the clinical course of the disease. However, more information would be necessary to completely understand the autoimmune process and also how this process can be altered for therapeutic benefits.
Polysomnographic findings in craniopharyngioma patients.

PubMed

Pickering, Line; Klose, Marianne; Feldt-Rasmussen, Ulla; Jennum, Poul

2017-12-01

The purpose of this study is to evaluate whether damage to the hypothalamus due to craniopharyngioma or consequent surgery may involve the sleep-wake regulatory system, resulting in sleep disturbances and sleepiness. Seven craniopharyngioma patients and 10 healthy controls were evaluated with sleep questionnaires including the Epworth Sleepiness Scale, polysomnography, and a multiple sleep latency test (MSLT). Five patients and eight controls had lumbar puncture performed to determine hypocretin-1 levels. Patients tended to feel sleepier than control individuals of the same age (p = 0.09). No subjects had symptoms of hypnagogic hallucinations, sleep paralyses, or cataplexies. Four patients and one control had periodic leg movements (PLMs). One patient had fragmented sleep pattern, rapid eye movement (REM) sleep without atonia, and PLMs. One patient had short sleep periods during the daytime. Four patients had fragmented sleep pattern. With the MSLT, four patients and two controls had mean sleep latency of < 8 min. One patient and three controls had sudden onset of REM sleep in 2/5 and 3/5 sleep periods, respectively. All subjects showed normal hypocretin-1 levels. Four patients had electrophysiological findings indicative of central hypersomnia including one patient meeting the criteria of narcolepsy. The sleep-wake regulatory system may be involved in craniopharyngioma patients.
Low-carb diets, fasting and euphoria: Is there a link between ketosis and gamma-hydroxybutyrate (GHB)?

PubMed

Brown, Andrew J

2007-01-01

Anecdotal evidence links the initial phase of fasting or a low-carbohydrate diet with feelings of well-being and mild euphoria. These feelings have often been attributed to ketosis, the production of ketone bodies which can replace glucose as an energy source for the brain. One of these ketone bodies, beta-hydroxybutyrate (BHB), is an isomer of the notorious drug of abuse, GHB (gamma-hydroxybutyrate). GHB is also of interest in relation to its potential as a treatment for alcohol and opiate dependence and narcolepsy-associated cataplexy. Here I hypothesize that, the mild euphoria often noted with fasting or low-carbohydrate diets may be due to shared actions of BHB and GHB on the brain. Specifically, I propose that BHB, like GHB, induces mild euphoria by being a weak partial agonist for GABA(B) receptors. I outline several approaches that would test the hypothesis, including receptor binding studies in cultured cells, perception studies in trained rodents, and psychometric testing and functional magnetic resonance imaging in humans. These and other studies investigating whether BHB and GHB share common effects on brain chemistry and mood are timely and warranted, especially when considering their structural similarities and the popularity of ketogenic diets and GHB as a drug of abuse.
Characterization of Sleep in Zebrafish and Insomnia in Hypocretin Receptor Mutants

PubMed Central

Yokogawa, Tohei; Marin, Wilfredo; Faraco, Juliette; Pézeron, Guillaume; Appelbaum, Lior; Zhang, Jian; Rosa, Frédéric; Mourrain, Philippe; Mignot, Emmanuel

2007-01-01

Sleep is a fundamental biological process conserved across the animal kingdom. The study of how sleep regulatory networks are conserved is needed to better understand sleep across evolution. We present a detailed description of a sleep state in adult zebrafish characterized by reversible periods of immobility, increased arousal threshold, and place preference. Rest deprivation using gentle electrical stimulation is followed by a sleep rebound, indicating homeostatic regulation. In contrast to mammals and similarly to birds, light suppresses sleep in zebrafish, with no evidence for a sleep rebound. We also identify a null mutation in the sole receptor for the wake-promoting neuropeptide hypocretin (orexin) in zebrafish. Fish lacking this receptor demonstrate short and fragmented sleep in the dark, in striking contrast to the excessive sleepiness and cataplexy of narcolepsy in mammals. Consistent with this observation, we find that the hypocretin receptor does not colocalize with known major wake-promoting monoaminergic and cholinergic cell groups in the zebrafish. Instead, it colocalizes with large populations of GABAergic neurons, including a subpopulation of Adra2a-positive GABAergic cells in the anterior hypothalamic area, neurons that could assume a sleep modulatory role. Our study validates the use of zebrafish for the study of sleep and indicates molecular diversity in sleep regulatory networks across vertebrates. PMID:17941721
[Physiopathology of idiopathic hypersomnia. Current studies and new orientations].

PubMed

Billiard, M; Rondouin, G; Espa, F; Dauvilliers, Y; Besset, A

2001-11-01

In 1976 Bedrich Roth coined the term "idiopathic hypersomnia" and described two forms of the disease, one monosymptomatic, manifested only by excessive daytime sleepiness, and one polysymptomatic, characterized by excessive daytime sleepiness, nocturnal sleep of abnormally long duration and signs of "sleep drunkenness" on awakening. In comparison with that of narcolepsy, the pathophysiology of idiopathic hypersomnia remains poorly known. There are two main reasons for that: the absence of clinical and polysomnographic criteria pathognomonic or at least characteristic of the condition, as the cataplexies and the sleep onset REM periods of narcolepsy, and also the absence of a natural animal model comparable with the canine model of narcolepsy. The first investigations have stressed the frequent familial pattern of idiopathic hypersomnia. Later on biochemical assays have been performed in the CSF with results in favour of a dysfunction of noradrenergic systems. In the light of the two process model of sleep regulation in which sleep propensity is determined by a homeostatic process S and a circadian process C and of the later three-process model of regulation in which sleepiness/alertness are simulated by the combined action of a homeostatic process, a circadian process and sleep inertia, we suggest that idiopathic hypersomnia is not a pathological entity in itself, but rather the consequence of chronic sleep deprivation in very long sleepers.
Sleep-dependent memory consolidation in patients with sleep disorders.

PubMed

Cipolli, Carlo; Mazzetti, Michela; Plazzi, Giuseppe

2013-04-01

Sleep can improve the off-line memory consolidation of new items of declarative and non-declarative information in healthy subjects, whereas acute sleep loss, as well as sleep restriction and fragmentation, impair consolidation. This suggests that, by modifying the amount and/or architecture of sleep, chronic sleep disorders may also lead to a lower gain in off-line consolidation, which in turn may be responsible for the varying levels of impaired performance at memory tasks usually observed in sleep-disordered patients. The experimental studies conducted to date have shown specific impairments of sleep-dependent consolidation overall for verbal and visual declarative information in patients with primary insomnia, for verbal declarative information in patients with obstructive sleep apnoeas, and for visual procedural skills in patients with narcolepsy-cataplexy. These findings corroborate the hypothesis that impaired consolidation is a consequence of the chronically altered organization of sleep. Moreover, they raise several novel questions as to: a) the reversibility of consolidation impairment in the case of effective treatment, b) the possible negative influence of altered prior sleep also on the encoding of new information, and c) the relationships between altered sleep and memory impairment in patients with other (medical, psychiatric or neurological) diseases associated with quantitative and/or qualitative changes of sleep architecture. Copyright © 2012 Elsevier Ltd. All rights reserved.
Circadian Rest-Activity Rhythm in Pediatric Type 1 Narcolepsy.

PubMed

Filardi, Marco; Pizza, Fabio; Bruni, Oliviero; Natale, Vincenzo; Plazzi, Giuseppe

2016-06-01

Pediatric type 1 narcolepsy is often challenging to diagnose and remains largely undiagnosed. Excessive daytime sleepiness, disrupted nocturnal sleep, and a peculiar phenotype of cataplexy are the prominent features. The knowledge available about the regulation of circadian rhythms in affected children is scarce. This study compared circadian rest-activity rhythm and actigraphic estimated sleep measures of children with type 1 narcolepsy versus healthy controls. Twenty-two drug-naïve type 1 narcolepsy children and 21 age- and sex- matched controls were monitored for seven days during the school week by actigraphy. Circadian activity rhythms were analyzed through functional linear modeling; nocturnal and diurnal sleep measures were estimated from activity using a validated algorithm. Children with type 1 narcolepsy presented an altered rest-activity rhythm characterized by enhanced motor activity throughout the night and blunted activity in the first afternoon. No difference was found between children with type 1 narcolepsy and controls in the timing of the circadian phase. Actigraphic sleep measures showed good discriminant capabilities in assessing type 1 narcolepsy nycthemeral disruption. Actigraphy reliably renders the nycthemeral disruption typical of narcolepsy type 1 in drug-naïve children with recent disease onset, indicating the sensibility of actigraphic assessment in the diagnostic work-up of childhood narcolepsy type 1. © 2016 Associated Professional Sleep Societies, LLC.
A Global View on Narcolepsy - A Review Study.

PubMed

Klimova, Blanka; Maresova, Petra; Novotny, Michal; Kuca, Kamil

2018-02-14

Narcolepsy is an incurable neurological disorder when the brain is not able to regulate a sleep and wakefulness cycle correctly. The affected person suddenly falls asleep during the day or he/she suffers from excessive day sleepiness. In addition, people may also suffer from cataplexy, hypnagogic hallucinations, sleep paralysis, and disturbed nighttime sleep. The purpose of this review study is to provide the latest information on both clinical and socioeconomic issues in the field of narcolepsy treatment and emphasize its benefits and limitations. The methodological approaches include a method of literature review of available sources exploring the issue of narcolepsy, both from a global and specific perspective point of view. On the basis of evaluation of these literature sources, the researched issue is examined. The main benefits (e.g., new drugs are being tested or non-invasive cognitive behavioral therapies are being applied) and limitations (e.g., late diagnosis of the disease or lifelong and costly treatment) of the treatment of narcolepsy are highlighted. The findings call for more research in the field of the development of novel drugs reflecting understanding of the neurological basis of narcolepsy and early diagnosis in order to eliminate the symptoms of narcolepsy and prevent the development of this disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Modafinil : A Review of its Pharmacology and Clinical Efficacy in the Management of Narcolepsy.

PubMed

McClellan, K J; Spencer, C M

1998-04-01

Modafinil promotes wakefulness through an as yet unknown mechanism of action. It significantly increases daytime sleep latency and reduces excessive daytime sleepiness (EDS) compared with placebo in patients with narcolepsy. However, the drug does not suppress cataplexy. Although direct comparative data are lacking, modafinil offers advantages over amphetamines and methylphenidate in patients with narcolepsy because of its lack of rebound phenomena after treatment withdrawal and its low abuse potential. Clinical trials have shown modafinil to be well tolerated in patients with narcolepsy. Except for headache, which was reported with a significantly greater frequency in modafinil recipients, the tolerability profile of modafinil 200 to 400 mg/day was similar to that of placebo in patients treated for 9 weeks. Preliminary data suggest that the tolerability of modafinil is maintained long term (40 weeks). Thus, modafinil is effective in the treatment of EDS in patients with narcolepsy, although it is not effective against cataplexy. Preliminary findings indicate that, unlike other psychostimulants, the drug is unlikely to be abused and is not associated with withdrawal phenomena. Therefore, modafinil is likely to be an effective therapeutic option for the treatment of EDS in patients with narcolepsy. The mechanism of action of modafinil has not been clearly established. However, it may indirectly increase wakefulness, at least in part, through inhibition of cortical γ-aminobutyric acid (GABA) release via serotonergic mechanisms. Modafinil induces wakefulness and increases locomotor activity in a variety of animal species without causing stereotyped behaviour. In rhesus monkeys, the effects of oral modafinil were not associated with changes in blood pressure or heart rate. In contrast to dexamphetamine 20mg, single night-time doses of modafinil 100 or 200mg had no significant effects on objective sleep variables or sleep structure in young or elderly healthy volunteers. Modafinil reduced the impairment of cognitive performance induced by sleep deprivation in volunteers, suppressed microsleeps and reduced the length of recovery sleep required. However, volunteers treated with modafinil reported recovery sleep patterns which were similar to those of placebo recipients. Studies in volunteers indicate that modafinil has less abuse potential than dexamphetamine or methylphenidate. Peak plasma concentrations of modafinil (mean 4.82 mg/L) were reached 2.3 hours after a single 200mg oral dose in healthy volunteers. Over the dose range 200 to 600mg, the pharmacokinetics of modafinil were linear and dose dependent. Orally administered modafinil is extensively biotransformed in the liver to the inactive metabolites modafinil acid and modafinil sulphone, before being eliminated primarily in the urine (elimination half-life 9 to 14 hours). The pharmacokinetics of modafinil are not affected to a clinically significant extent by volunteer age or food intake, but both the maximum plasma concentration and the elimination half-life of the drug are increased in patients with hepatic or renal impairment. The efficacy of modafinil 200 or 400 mg/day was rated as good or excellent (using a 4-point scale) in 84 of 131 evaluable patients (64%) with excessive daytime sleepiness treated for 1 to 114 months in a noncomparative study. 53 patients withdrew from the study (43 because of loss of efficacy). In another study, 1 or 2 months' treatment with modafinil reduced or eliminated symptoms of excessive daytime sleepiness in 17 of 24 patients with narcolepsy. Modafinil 200 or 400 mg/day for 9 weeks significantly increased daytime sleep latency and reduced daytime sleepiness compared with placebo in patients with narcolepsy, but did not suppress cataplexy. It tended to improve psychomotor performance, although this effect was variable. Importantly, modafinil did not affect patients' nocturnal sleep parameters, ability to nap when necessary or feelings on awakening. There was no evidence of a withdrawal phenomenon (e.g. fatigue, vivid or unpleasant dreams, insomnia or hypersomnia) after treatment cessation. Clinical data comparing the efficacy of modafinil with that of other stimulants in patients with narcolepsy are limited. Although tolerability data for modafinil are limited, the drug appears to be well tolerated in patients with narcolepsy. A study in 283 evaluable patients showed that 9 weeks' treatment with modafinil 200 or 400 mg/day was as well tolerated as placebo, with only headache reported with significantly greater frequency (52 and 51 vs 36% of patients; p < 0.05). Nausea and nervousness also tended to occur more frequently in modafinil than in placebo recipients, but this difference did not reach statistical significance. The incidence or severity of adverse events associated with the use of modafinil did not appear to be dose related. Preliminary data showed that open-label modafinil was well tolerated for up to 40 weeks. The recommended dosage of modafinil is 200 or 400 mg/day, given once or twice daily (morning and midday) to patients with narcolepsy. Modafinil is contraindicated in patients with moderate to severe hypertension and may reduce the efficacy of low dose oral contraceptives via enzymatic induction.
Laughter and MIRTH (Methodical Investigation of Risibility, Therapeutic and Harmful): narrative synthesis.

PubMed

Ferner, R E; Aronson, J K

2013-12-12

To review the beneficial and harmful effects of laughter. Narrative synthesis. We searched Medline (1946 to June 2013) and Embase (1974 to June 2013) for reports of benefits or harms from laughter in humans, and counted the number of papers in each category. Benefits of laughter include reduced anger, anxiety, depression, and stress; reduced tension (psychological and cardiovascular); increased pain threshold; reduced risk of myocardial infarction (presumably requiring hearty laughter); improved lung function; increased energy expenditure; and reduced blood glucose concentration. However, laughter is no joke-dangers include syncope, cardiac and oesophageal rupture, and protrusion of abdominal hernias (from side splitting laughter or laughing fit to burst), asthma attacks, interlobular emphysema, cataplexy, headaches, jaw dislocation, and stress incontinence (from laughing like a drain). Infectious laughter can disseminate real infection, which is potentially preventable by laughing up your sleeve. As a side effect of our search for side effects, we also list pathological causes of laughter, among them epilepsy (gelastic seizures), cerebral tumours, Angelman's syndrome, strokes, multiple sclerosis, and amyotrophic lateral sclerosis or motor neuron disease. Laughter is not purely beneficial. The harms it can cause are immediate and dose related, the risks being highest for Homeric (uncontrollable) laughter. The benefit-harm balance is probably favourable. It remains to be seen whether sick jokes make you ill or jokes in bad taste cause dysgeusia, and whether our views on comedians stand up to further scrutiny.
Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant

NASA Astrophysics Data System (ADS)

Yin, Jie; Mobarec, Juan Carlos; Kolb, Peter; Rosenbaum, Daniel M.

2015-03-01

The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the β branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 Å resolution. The structure reveals how suvorexant adopts a π-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous π-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.
Improvement in daytime sleepiness with clarithromycin in patients with GABA-related hypersomnia: Clinical experience.

PubMed

Trotti, Lynn Marie; Saini, Prabhjyot; Freeman, Amanda A; Bliwise, Donald L; García, Paul S; Jenkins, Andrew; Rye, David B

2014-07-01

The macrolide antibiotic clarithromycin can enhance central nervous system excitability, possibly by antagonism of GABA-A receptors. Enhancement of GABA signaling has recently been demonstrated in a significant proportion of patients with central nervous system hypersomnias, so we sought to determine whether clarithromycin might provide symptomatic benefit in these patients. We performed a retrospective review of all patients treated with clarithromycin for hypersomnia, in whom cerebrospinal fluid enhanced GABA-A receptor activity in vitro in excess of controls, excluding those with hypocretin deficiency or definite cataplexy. Subjective reports of benefit and objective measures of psychomotor vigilance were collected to assess clarithromycin's effects. Clinical and demographic characteristics were compared in responders and non-responders. In total, 53 patients (38 women, mean age 35.2 (SD 12.8 years)) were prescribed clarithromycin. Of these, 34 (64%) reported improvement in daytime sleepiness, while 10 (19%) did not tolerate its side effects, and nine (17%) found it tolerable but without symptomatic benefit. In those who reported subjective benefit, objective corroboration of improved vigilance was evident on the psychomotor vigilance task. Twenty patients (38%) elected to continue clarithromycin therapy. Clarithromycin responders were significantly younger than non-responders. Clarithromycin may be useful in the treatment of hypersomnia associated with enhancement of GABA-A receptor function. Further evaluation of this novel therapy is needed. © The Author(s) 2013.
Misdiagnosis of narcolepsy.

PubMed

Dunne, Laura; Patel, Pallavi; Maschauer, Emily L; Morrison, Ian; Riha, Renata L

2016-12-01

Narcolepsy is a chronic primary sleep disorder, characterized by excessive daytime sleepiness and sleep dysfunction with or without cataplexy. Narcolepsy is uncommon, with a low prevalence rate which makes it difficult to diagnose definitively without a complex series of tests and a detailed history. The aim of this study was to review patients referred to a tertiary sleep centre who had been labelled with a diagnosis of narcolepsy prior to referral in order to assess if the diagnosis was accurate, and if not, to determine the cause of diagnostic misattribution. All patients seen at a sleep centre from 2007-2013 (n = 551) who underwent detailed objective testing including an MSLT PSG, as well as wearing an actigraphy watch and completing a sleep diary for 2 weeks, were assessed for a pre-referral and final diagnosis of narcolepsy. Of the 41 directly referred patients with a diagnostic label of narcolepsy, 19 (46 %) were subsequently confirmed to have narcolepsy on objective testing and assessment by a sleep physician using ICSD-2 criteria. The diagnosis of narcolepsy was incorrectly attributed to almost 50 % of patients labelled with a diagnosis of narcolepsy who were referred for further opinion by a variety of specialists and generalists. Accurate diagnosis of narcolepsy is critical for many reasons, such as the impact it has on quality of life, driving, employment, insurance and pregnancy in women as well as medication management.

From state dissociation to status dissociatus.

PubMed

Antelmi, Elena; Ferri, Raffaele; Iranzo, Alex; Arnulf, Isabelle; Dauvilliers, Yves; Bhatia, Kailash P; Liguori, Rocco; Schenck, Carlos H; Plazzi, Giuseppe

2016-08-01

The states of being are conventionally defined by the simultaneous occurrence of behavioral, neurophysiological and autonomic descriptors. State dissociation disorders are due to the intrusion of features typical of a different state into an ongoing state. Disorders related to these conditions are classified according to the ongoing main state and comprise: 1) Dissociation from prevailing wakefulness as seen in hypnagogic or hypnopompic hallucinations, automatic behaviors, sleep drunkenness, cataplexy and sleep paralysis 2) Dissociation from rapid eye movement (REM) sleep as seen in REM sleep behavior disorder and lucid dreaming and 3) Dissociation from NREM sleep as seen in the disorders of arousal. The extreme expression of states dissociation is characterized by the asynchronous occurrence of the various components of the different states that prevents the recognition of any state of being. This condition has been named status dissociatus. According to the underlying disorders/diseases and to their severity, among status dissociatus we may recognize disorders in which such an extreme dissociation occurs only at night time or intermittently (i.e., autoimmune encephalopathies, narcolepsy type 1 and IgLON5 parasomnia), and others in which it occurs nearly continuously with complete loss of any conventionally defined state of being, and of the circadian pattern (agrypnia excitata). Here, we render a comprehensive review of all diseases/disorders associated with state dissociation and status dissociatus and propose a critical classification of this complex scenario. Copyright © 2015 Elsevier Ltd. All rights reserved.
Psychosis in patients with narcolepsy as an adverse effect of sodium oxybate.

PubMed

Sarkanen, Tomi; Niemelä, Valter; Landtblom, Anne-Marie; Partinen, Markku

2014-01-01

Hypnagogic and hypnopompic hallucinations are characteristic symptoms of narcolepsy, as are excessive daytime sleepiness, cataplexy, and sleep paralysis. Narcolepsy patients may also experience daytime hallucinations unrelated to sleep-wake transitions. The effect of medication on hallucinations is of interest since treatment of narcolepsy may provoke psychotic symptoms. We aim to analyze the relation between sodium oxybate (SXB) treatment and psychotic symptoms in narcolepsy patients. Furthermore, we analyze the characteristics of hallucinations to determine their nature as mainly psychotic or hypnagogic and raise a discussion about whether SXB causes psychosis or if psychosis occurs as an endogenous complication in narcolepsy. We present altogether four patients with narcolepsy who experienced psychotic symptoms during treatment with SXB. In addition, we searched the literature for descriptions of hallucinations in narcolepsy and similarities and differences with psychotic symptoms in schizophrenia. Three out of four patients had hallucinations typical for psychosis and one had symptoms that resembled aggravated hypnagogic hallucinations. Two patients also had delusional symptoms primarily associated with mental disorders. Tapering down SXB was tried and helped in two out of four cases. Adding antipsychotic treatment (risperidone) alleviated psychotic symptoms in two cases. Psychotic symptoms in narcolepsy may appear during SXB treatment. Hallucinations resemble those seen in schizophrenia; however, the insight that symptoms are delusional is usually preserved. In case of SXB-induced psychotic symptoms or hallucinations, reducing SXB dose or adding antipsychotic medication can be tried.
Measurement of narcolepsy symptoms: The Narcolepsy Severity Scale.

PubMed

Dauvilliers, Yves; Beziat, Severine; Pesenti, Carole; Lopez, Regis; Barateau, Lucie; Carlander, Bertrand; Luca, Gianina; Tafti, Mehdi; Morin, Charles M; Billiard, Michel; Jaussent, Isabelle

2017-04-04

To validate the Narcolepsy Severity Scale (NSS), a brief clinical instrument to evaluate the severity and consequences of symptoms in patients with narcolepsy type 1 (NT1). A 15-item scale to assess the frequency and severity of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted nighttime sleep was developed and validated by sleep experts with patients' feedback. Seventy untreated and 146 treated adult patients with NT1 were evaluated and completed the NSS in a single reference sleep center. The NSS psychometric properties, score changes with treatment, and convergent validity with other clinical parameters were assessed. The NSS showed good psychometric properties with significant item-total score correlations. The factor analysis indicated a 3-factor solution with good reliability, expressed by satisfactory Cronbach α values. The NSS total score temporal stability was good. Significant NSS score differences were observed between untreated and treated patients (dependent sample, 41 patients before and after sleep therapy; independent sample, 29 drug-free and 105 treated patients). Scores were lower in the treated populations (10-point difference between groups), without ceiling effect. Significant correlations were found among NSS total score and daytime sleepiness (Epworth Sleepiness Scale, Mean Sleep Latency Test), depressive symptoms, and health-related quality of life. The NSS can be considered a reliable and valid clinical tool for the quantification of narcolepsy symptoms to monitor and optimize narcolepsy management. © 2017 American Academy of Neurology.
Circadian Rest-Activity Rhythm in Pediatric Type 1 Narcolepsy

PubMed Central

Filardi, Marco; Pizza, Fabio; Bruni, Oliviero; Natale, Vincenzo; Plazzi, Giuseppe

2016-01-01

Study Objectives: Pediatric type 1 narcolepsy is often challenging to diagnose and remains largely undiagnosed. Excessive daytime sleepiness, disrupted nocturnal sleep, and a peculiar phenotype of cataplexy are the prominent features. The knowledge available about the regulation of circadian rhythms in affected children is scarce. This study compared circadian rest-activity rhythm and actigraphic estimated sleep measures of children with type 1 narcolepsy versus healthy controls. Methods: Twenty-two drug-naïve type 1 narcolepsy children and 21 age- and sex- matched controls were monitored for seven days during the school week by actigraphy. Circadian activity rhythms were analyzed through functional linear modeling; nocturnal and diurnal sleep measures were estimated from activity using a validated algorithm. Results: Children with type 1 narcolepsy presented an altered rest-activity rhythm characterized by enhanced motor activity throughout the night and blunted activity in the first afternoon. No difference was found between children with type 1 narcolepsy and controls in the timing of the circadian phase. Actigraphic sleep measures showed good discriminant capabilities in assessing type 1 narcolepsy nycthemeral disruption. Conclusions: Actigraphy reliably renders the nycthemeral disruption typical of narcolepsy type 1 in drug-naïve children with recent disease onset, indicating the sensibility of actigraphic assessment in the diagnostic work-up of childhood narcolepsy type 1. Citation: Filardi M, Pizza F, Bruni O, Natale V, Plazzi G. Circadian rest-activity rhythm in pediatric type 1 narcolepsy. SLEEP 2016;39(6):1241–1247. PMID:27091539
Descending projections from the basal forebrain to the orexin neurons in mice.

PubMed

Agostinelli, Lindsay J; Ferrari, Loris L; Mahoney, Carrie E; Mochizuki, Takatoshi; Lowell, Bradford B; Arrigoni, Elda; Scammell, Thomas E

2017-05-01

The orexin (hypocretin) neurons play an essential role in promoting arousal, and loss of the orexin neurons results in narcolepsy, a condition characterized by chronic sleepiness and cataplexy. The orexin neurons excite wake-promoting neurons in the basal forebrain (BF), and a reciprocal projection from the BF back to the orexin neurons may help promote arousal and motivation. The BF contains at least three different cell types (cholinergic, glutamatergic, and γ-aminobutyric acid (GABA)ergic neurons) across its different regions (medial septum, diagonal band, magnocellular preoptic area, and substantia innominata). Given the neurochemical and anatomical heterogeneity of the BF, we mapped the pattern of BF projections to the orexin neurons across multiple BF regions and neuronal types. We performed conditional anterograde tracing using mice that express Cre recombinase only in neurons producing acetylcholine, glutamate, or GABA. We found that the orexin neurons are heavily apposed by axon terminals of glutamatergic and GABAergic neurons of the substantia innominata (SI) and magnocellular preoptic area, but there was no innervation by the cholinergic neurons. Channelrhodopsin-assisted circuit mapping (CRACM) demonstrated that glutamatergic SI neurons frequently form functional synapses with the orexin neurons, but, surprisingly, functional synapses from SI GABAergic neurons were rare. Considering their strong reciprocal connections, BF and orexin neurons likely work in concert to promote arousal, motivation, and other behaviors. J. Comp. Neurol. 525:1668-1684, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Orexin neurons are necessary for the circadian control of REM sleep.

PubMed

Kantor, Sandor; Mochizuki, Takatoshi; Janisiewicz, Agnieszka M; Clark, Erika; Nishino, Seiji; Scammell, Thomas E

2009-09-01

The orexin-producing neurons are hypothesized to be essential for the circadian control of sleep/wake behavior, but it remains unknown whether these rhythms are mediated by the orexin peptides or by other signaling molecules released by these neurons such as glutamate or dynorphin. To determine the roles of these neurotransmitters, we examined the circadian rhythms of sleep/wake behavior in mice lacking the orexin neurons (ataxin-3 [Atx] mice) and mice lacking just the orexin neuropeptides (orexin knockout [KO] mice). We instrumented mice for recordings of sleep-wake behavior, locomotor activity (LMA), and body temperature (Tb) and recorded behavior after 6 days in constant darkness. The amplitude of the rapid eye movement (REM) sleep rhythm was substantially reduced in Atx mice but preserved in orexin KO mice. This blunted rhythm in Atx mice was caused by an increase in the amount of REM sleep during the subjective night (active period) due to more transitions into REM sleep and longer REM sleep episodes. In contrast, the circadian variations of Tb, LMA, Wake, non-REM sleep, and cataplexy were normal, suggesting that the circadian timekeeping system and other output pathways are intact in both Atx and KO mice. These results indicate that the orexin neurons are necessary for the circadian suppression of REM sleep. Blunting of the REM sleep rhythm in Atx mice but not in orexin KO mice suggests that other signaling molecules such as dynorphin or glutamate may act in concert with orexins to suppress REM sleep during the active period.
Abnormal sleep/wake dynamics in orexin knockout mice.

PubMed

Diniz Behn, Cecilia G; Klerman, Elizabeth B; Mochizuki, Takatoshi; Lin, Shih-Chieh; Scammell, Thomas E

2010-03-01

Narcolepsy with cataplexy is caused by a loss of orexin (hypocretin) signaling, but the physiologic mechanisms that result in poor maintenance of wakefulness and fragmented sleep remain unknown. Conventional scoring of sleep cannot reveal much about the process of transitioning between states or the variations within states. We developed an EEG spectral analysis technique to determine whether the state instability in a mouse model of narcolepsy reflects abnormal sleep or wake states, faster movements between states, or abnormal transitions between states. We analyzed sleep recordings in orexin knockout (OXKO) mice and wild type (WT) littermates using a state space analysis technique. This non-categorical approach allows quantitative and unbiased examination of sleep/wake states and state transitions. OXKO mice spent less time in deep, delta-rich NREM sleep and in active, theta-rich wake and instead spent more time near the transition zones between states. In addition, while in the midst of what should be stable wake, OXKO mice initiated rapid changes into NREM sleep with high velocities normally seen only in transition regions. Consequently, state transitions were much more frequent and rapid even though the EEG progressions during state transitions were normal. State space analysis enables visualization of the boundaries between sleep and wake and shows that narcoleptic mice have less distinct and more labile states of sleep and wakefulness. These observations provide new perspectives on the abnormal state dynamics resulting from disrupted orexin signaling and highlight the usefulness of state space analysis in understanding narcolepsy and other sleep disorders.
The European Narcolepsy Network (EU-NN) database.

PubMed

Khatami, Ramin; Luca, Gianina; Baumann, Christian R; Bassetti, Claudio L; Bruni, Oliviero; Canellas, Francesca; Dauvilliers, Yves; Del Rio-Villegas, Rafael; Feketeova, Eva; Ferri, Raffaele; Geisler, Peter; Högl, Birgit; Jennum, Poul; Kornum, Birgitte R; Lecendreux, Michel; Martins-da-Silva, Antonio; Mathis, Johannes; Mayer, Geert; Paiva, Teresa; Partinen, Markku; Peraita-Adrados, Rosa; Plazzi, Guiseppe; Santamaria, Joan; Sonka, Karel; Riha, Renata; Tafti, Mehdi; Wierzbicka, Aleksandra; Young, Peter; Lammers, Gert Jan; Overeem, Sebastiaan

2016-06-01

Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply. Similar to other rare diseases, only a few European countries have registered narcolepsy cases in databases of the International Classification of Diseases or in registries of the European health authorities. A promising approach to identify disease-specific adverse health effects and needs in healthcare delivery in the field of rare diseases is to establish a distributed expert network. A first and important step is to create a database that allows collection, storage and dissemination of data on narcolepsy in a comprehensive and systematic way. Here, the first prospective web-based European narcolepsy database hosted by the European Narcolepsy Network is introduced. The database structure, standardization of data acquisition and quality control procedures are described, and an overview provided of the first 1079 patients from 18 European specialized centres. Due to its standardization this continuously increasing data pool is most promising to provide a better insight into many unsolved aspects of narcolepsy and related disorders, including clear phenotype characterization of subtypes of narcolepsy, more precise epidemiological data and knowledge on the natural history of narcolepsy, expectations about treatment effects, identification of post-marketing medication side-effects, and will contribute to improve clinical trial designs and provide facilities to further develop phase III trials. © 2016 European Sleep Research Society.
Laughter and MIRTH (Methodical Investigation of Risibility, Therapeutic and Harmful): narrative synthesis

PubMed Central

Aronson, J K

2013-01-01

Objective To review the beneficial and harmful effects of laughter. Design Narrative synthesis. Data sources and review methods We searched Medline (1946 to June 2013) and Embase (1974 to June 2013) for reports of benefits or harms from laughter in humans, and counted the number of papers in each category. Results Benefits of laughter include reduced anger, anxiety, depression, and stress; reduced tension (psychological and cardiovascular); increased pain threshold; reduced risk of myocardial infarction (presumably requiring hearty laughter); improved lung function; increased energy expenditure; and reduced blood glucose concentration. However, laughter is no joke—dangers include syncope, cardiac and oesophageal rupture, and protrusion of abdominal hernias (from side splitting laughter or laughing fit to burst), asthma attacks, interlobular emphysema, cataplexy, headaches, jaw dislocation, and stress incontinence (from laughing like a drain). Infectious laughter can disseminate real infection, which is potentially preventable by laughing up your sleeve. As a side effect of our search for side effects, we also list pathological causes of laughter, among them epilepsy (gelastic seizures), cerebral tumours, Angelman’s syndrome, strokes, multiple sclerosis, and amyotrophic lateral sclerosis or motor neuron disease. Conclusions Laughter is not purely beneficial. The harms it can cause are immediate and dose related, the risks being highest for Homeric (uncontrollable) laughter. The benefit-harm balance is probably favourable. It remains to be seen whether sick jokes make you ill or jokes in bad taste cause dysgeusia, and whether our views on comedians stand up to further scrutiny. PMID:24336308
Patient-Reported Measures of Narcolepsy: The Need for Better Assessment.

PubMed

Kallweit, Ulf; Schmidt, Markus; Bassetti, Claudio L

2017-05-15

Narcolepsy, a chronic disorder of the central nervous system, is clinically characterized by a symptom pentad that includes excessive daytime sleepiness, cataplexy, sleep paralysis, hypnopompic/hypnagogic hallucinations, and disrupted nighttime sleep. Ideally, screening and diagnosis instruments that assist physicians in evaluating a patient for type 1 or type 2 narcolepsy would be brief, easy for patients to understand and physicians to score, and would identify or rule out the need for electrophysiological testing. A search of the literature was conducted to review patient-reported measures used for the assessment of narcolepsy, mainly in clinical trials, with the goal of summarizing existing scales and identifying areas that may require additional screening questions and clinical practice scales. Of the seven scales reviewed, the Epworth Sleepiness Scale continues to be an important outcome measure to screen adults for excessive daytime sleepiness, which may be associated with narcolepsy. Several narcolepsy-specific scales have demonstrated utility, such as the Ullanlinna Narcolepsy Scale, Swiss Narcolepsy Scale, and Narcolepsy Symptom Assessment Questionnaire, but further validation is required. Although the narcolepsy-specific scales currently in use may identify type 1 narcolepsy, there are no validated questionnaires to identify type 2 narcolepsy. Thus, there remains a need for short, easily understood, and well-validated instruments that can be readily used in clinical practice to distinguish narcolepsy subtypes, as well as other hypersomnias, and for assessing symptoms of these conditions during treatment. © 2017 American Academy of Sleep Medicine
Diurnal and nocturnal cardiovascular variability and heart rate arousal response in idiopathic hypersomnia.

PubMed

Sforza, Emilia; Roche, Frédéric; Barthélémy, Jean Claude; Pichot, Vincent

2016-08-01

Autonomic nervous system dysfunction has been described in narcolepsy with cataplexy affecting sympathetic functions. In this study we analyzed whether altered diurnal and nocturnal cardiovascular control is present in idiopathic hypersomnia (IH). Fourteen drug-free patients aged 26.2 ± 7 years and 14 age-matched controls were examined. Clinical data, 24-h polysomnography, heart rate (HR) variability, and the HR response to spontaneous arousal were available. Sleep macrostructure was comparable between controls and patients, with the latter having significantly longer sleep time, a higher number of sleep cycles (p < 0.0001), and low sleep efficiency (p < 0.01). The HR variability indices did not differ between groups, except for the rise of high frequency (HF) and HFnu in patients (p < 0.05) associated with blunted sympathetic indices (p < 0.01). These parasympathetic alterations were present for light, slow wave, and rapid eye-movement sleep and persisted for all sleep cycles. Compared to controls, the HR arousal response was significantly higher (p < 0.01) in patients starting before the arousal onset and persisting into the post-arousal period. In IH patients a dysfunction of the parasympathetic activity during awake and sleep and an altered autonomic response to arousals are present. These findings suggest an impaired parasympathetic function that may explain some vegetative symptoms present in this type of central hypersomnia. Copyright © 2016 Elsevier B.V. All rights reserved.
Hypothalamic hypocretinergic/orexinergic neurons projecting to the oral pontine rapid eye movement sleep inducing site in the cat.

PubMed

García-García, Berta; Reinoso-Suárez, Fernando; Rodrigo-Angulo, Margarita L

2013-05-01

The cat ventral oral pontine reticular nucleus (vRPO) is responsible for the generation and maintenance of rapid eye movement (REM) sleep. Hypothalamic neurons containing the peptide hypocretin-1 (also called orexin-A) which will be herewith defined as orexinergic (Orx) neurons, occupy a pre-eminent place in the integration and stabilization of arousal networks as well as in the physiopathology of narcolepsy/cataplexy. In the previous investigations, low-volume and dose microinjections of hypocretin-1 in cat vRPO produced a specific and significant suppression of REM sleep. The aim of this study is to map the hypothalamic Orx neurons that project to the vRPO and suppress REM sleep generation in the cat. Five adult cats received microinjections of the retrograde tracer cholera toxin (CTb) into the vRPO. Brains were processed employing both CTb staining and antiorexin-A immunocytochemistry techniques. A large number of double-labeled neurons (Orx-CTb) intermingled with the single CTb-positive and single Orx neurons were detected in the ipsilateral lateral, perifornical, dorsal, anterior, perimammillothalamic, and posterior hypothalamic areas but were very scarce in the paraventricular, dorsomedial, ventromedial, and periventricular hypothalamic nuclei. A considerable number of double-labeled neurons were also observed in both the dorsal and the lateral hypothalamic areas in the contralateral hypothalamus. Our results suggest that the widely distributed Orx neuronal hypothalamic groups could physiologically inhibit REM sleep generation in vRPO. Copyright © 2013 Wiley Periodicals, Inc.
Psychosis in Patients with Narcolepsy as an Adverse Effect of Sodium Oxybate

PubMed Central

Sarkanen, Tomi; Niemelä, Valter; Landtblom, Anne-Marie; Partinen, Markku

2014-01-01

Aim: Hypnagogic and hypnopompic hallucinations are characteristic symptoms of narcolepsy, as are excessive daytime sleepiness, cataplexy, and sleep paralysis. Narcolepsy patients may also experience daytime hallucinations unrelated to sleep–wake transitions. The effect of medication on hallucinations is of interest since treatment of narcolepsy may provoke psychotic symptoms. We aim to analyze the relation between sodium oxybate (SXB) treatment and psychotic symptoms in narcolepsy patients. Furthermore, we analyze the characteristics of hallucinations to determine their nature as mainly psychotic or hypnagogic and raise a discussion about whether SXB causes psychosis or if psychosis occurs as an endogenous complication in narcolepsy. Method: We present altogether four patients with narcolepsy who experienced psychotic symptoms during treatment with SXB. In addition, we searched the literature for descriptions of hallucinations in narcolepsy and similarities and differences with psychotic symptoms in schizophrenia. Results: Three out of four patients had hallucinations typical for psychosis and one had symptoms that resembled aggravated hypnagogic hallucinations. Two patients also had delusional symptoms primarily associated with mental disorders. Tapering down SXB was tried and helped in two out of four cases. Adding antipsychotic treatment (risperidone) alleviated psychotic symptoms in two cases. Conclusion: Psychotic symptoms in narcolepsy may appear during SXB treatment. Hallucinations resemble those seen in schizophrenia; however, the insight that symptoms are delusional is usually preserved. In case of SXB-induced psychotic symptoms or hallucinations, reducing SXB dose or adding antipsychotic medication can be tried. PMID:25191304
Narcolepsy and Orexins: An Example of Progress in Sleep Research

PubMed Central

De la Herrán-Arita, Alberto K.; Guerra-Crespo, Magdalena; Drucker-Colín, René

2011-01-01

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. PMID:21541306
A 2-week, polysomnographic, safety study of sodium oxybate in obstructive sleep apnea syndrome.

PubMed

George, Charles F P; Feldman, Neil; Zheng, Yanping; Steininger, Teresa L; Grzeschik, Susanna M; Lai, Chinglin; Inhaber, Neil

2011-01-01

Sodium oxybate (SXB) is approved for cataplexy and excessive daytime sleepiness in narcolepsy. Obstructive sleep apnea syndrome (OSAS) affects ∼9-50% of narcoleptics. Effects of 2-week SXB administration on apnea-hypopnea index (AHI), oxygen saturation (SaO(2)), and sleep architecture were investigated in OSAS patients. OSAS patients (n = 48) received 2-week SXB or placebo (PBO) treatment with polysomnography at baseline and day 14. The primary outcome measure was change from baseline in mean AHI. Secondary outcomes included changes from baseline in SaO(2), and sleep architecture. Compared with PBO, SXB significantly increased reduction in mean AHI and obstructive apnea index with SXB (-0.8 ± 13.3 vs. -8.2 ± 10.0; p = 0.0327 and 3.54 ± 11.1 vs. -4.72 ± 7.7; p = 0.0054, respectively) and significantly increased change in slow wave sleep duration (5.2 ± 25.0 min vs. 29.4 ± 37.0 min; p = 0.0038). There were no differences between treatments in SaO2, central apneic events, or other measures. Adverse events, most commonly headache, were noted in nine of 27 (33%) and six of 23 (26%) patients receiving SXB and PBO, respectively. Short-term use of 4.5 g/night SXB did not generate respiratory depressant effects in OSAS patients as measured by AHI, obstructive apnea events, central apneas, and SaO2. Extended use of SXB in higher therapeutic doses in OSAS has not been studied, and merits caution.
Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C.

PubMed

Yanjanin, Nicole M; Vélez, Jorge I; Gropman, Andrea; King, Kelly; Bianconi, Simona E; Conley, Sandra K; Brewer, Carmen C; Solomon, Beth; Pavan, William J; Arcos-Burgos, Mauricio; Patterson, Marc C; Porter, Forbes D

2010-01-05

Niemann-Pick disease, type C is a neurodegenerative, lysosomal storage disorder with a broad clinical spectrum and a variable age of onset. The absence of a universally accepted clinical outcome measure is an impediment to the design of a therapeutic trial for NPC. Thus, we developed a clinical severity scale to characterize and quantify disease progression. Clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, and swallowing) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, and respiratory problems) domains were scored. Data were collected from 18 current NPC patients and were extracted from records of 19 patients. Both patient cohorts showed a linear increase in severity scores over time. Cross-sectional evaluation of current patients showed a linear increase in the severity score. Longitudinal chart review of historical data demonstrated that although age of onset varied significantly, the rate of progression appeared linear, independent of age of onset, and similar in all patients. Combining the data from both cohorts, disease progression could be modeled by the following equation: ŝ(t0+x) = ŝ(t0) + 1.87x; where ŝ(t0) is the initial score and ŝ(t0+x) is the predicted future score after x years. Our observation that disease progression is similar across patients and independent of age of onset is consistent with a biphasic pathological model for NPC. This scale may prove useful in the characterization of potential biomarkers, and as an outcome measure to monitor disease progression in NPC patients. (c) 2009 Wiley-Liss, Inc.
Genetic ablation of hypocretin neurons alters behavioral state transitions in zebrafish.

PubMed

Elbaz, Idan; Yelin-Bekerman, Laura; Nicenboim, Julian; Vatine, Gad; Appelbaum, Lior

2012-09-12

Sleep is an essential biological need of all animals studied to date. The sleep disorder narcolepsy is characterized by excessive daytime sleepiness, fragmentation of nighttime sleep, and cataplexy. Narcolepsy is caused by selective degeneration of hypothalamic hypocretin/orexin (HCRT) neurons. In mammals, HCRT neurons primarily regulate the sleep/wake cycle, feeding, reward-seeking, and addiction. The role of HCRT neurons in zebrafish is implicated in both sleep and wake regulation. We established a transgenic zebrafish model enabling inducible ablation of HCRT neurons and used these animals to understand the function of HCRT neurons and narcolepsy. Loss of HCRT neurons increased the expression of the HCRT receptor (hcrtr). Behavioral assays revealed that HCRT neuron-ablated larvae had normal locomotor activity, but demonstrated an increase in sleep time during the day and an increased number of sleep/wake transitions during both day and night. Mild sleep disturbance reduced sleep and increased c-fos expression in HCRT neuron-ablated larvae. Furthermore, ablation of HCRT neurons altered the behavioral response to external stimuli. Exposure to light during the night decreased locomotor activity of wild-type siblings, but induced an opposite response in HCRT neuron-ablated larvae. Sound stimulus during the day reduced the locomotor activity of wild-type sibling larvae, while HCRT neuron-ablated larvae demonstrated a hyposensitive response. This study establishes zebrafish as a model for narcolepsy, and indicating a role of HCRT neurons in regulation of sleep/wake transitions during both day and night. Our results further suggest a key role of HCRT neurons in mediating behavioral state transitions in response to external stimuli.
Halothane-induced Hypnosis Is Not Accompanied by Inactivation of Orexinergic Output in Rodents

PubMed Central

Gompf, Heinrich; Chen, Jingqiu; Sun, Yi; Yanagisawa, Masashi; Aston-Jones, Gary; Kelz, Max B.

2009-01-01

Background One underexploited property of anesthetics is their ability to probe neuronal regulation of arousal. At appropriate doses, anesthetics reversibly obtund conscious perception. However, individual anesthetic agents may accomplish this by altering the function of distinct neuronal populations. Previously we showed that isoflurane and sevoflurane inhibit orexinergic neurons, delaying reintegration of sensory perception as denoted by emergence. Herein we study the effects of halothane. As a halogenated alkane, halothane differs structurally, has a nonoverlapping series of molecular binding partners, and differentially modulates electrophysiologic properties of several ion channels when compared with its halogenated ether relatives. Methods c-Fos immunohistochemistry and in vivo electrophysiology were used to assess neuronal activity. Anesthetic induction and emergence were determined behaviorally in narcoleptic orexin/ataxin-3 mice and control siblings exposed to halothane. Results Halothane-induced hypnosis occurred despite lack of inhibition of orexinergic neurons in mice. In rats, extracellular single-unit recordings within the locus coeruleus showed significantly greater activity during halothane than during a comparable dose of isoflurane. Microinjection of the orexin-1 receptor antagonist, SB-334867-A during the active period slowed firing rates of locus coeruleus neurons in halothane-anesthetized rats, but had no effect on isoflurane-anesthetized rats. Surprisingly, orexin/ataxin-3 transgenic mice, which develop narcolepsy with cataplexy due to loss of orexinergic neurons, did not show delayed emergence from halothane. Conclusion Coordinated inhibition of hypothalamic orexinergic and locus coeruleus noradrenergic neurons is not required for anesthetic induction. Normal emergence from halothane-induced hypnosis in orexin-deficient mice suggests that additional wake-promoting systems likely remain active during general anesthesia produced by halothane. PMID:19809293
Activation of the Basal Forebrain by the Orexin/Hypocretin Neurons: Orexin International Symposium

PubMed Central

Arrigoni, Elda; Mochizuki, Takatoshi; Scammell, Thomas E.

2010-01-01

The orexin neurons play an essential role in driving arousal and in maintaining normal wakefulness. Lack of orexin neurotransmission produces a chronic state of hypoarousal characterized by excessive sleepiness, frequent transitions between wake and sleep, and episodes of cataplexy. A growing body of research now suggests that the basal forebrain (BF) may be a key site through which the orexin-producing neurons promote arousal. Here we review anatomical, pharmacological and electrophysiological studies on how the orexin neurons may promote arousal by exciting cortically-projecting neurons of the BF. Orexin fibers synapse on BF cholinergic neurons and orexin-A is released in the BF during waking. Local application of orexins excites BF cholinergic neurons, induces cortical release of acetylcholine, and promotes wakefulness. The orexin neurons also contain and probably co-release the inhibitory neuropeptide dynorphin. We found that orexin-A and dynorphin have specific effects on different classes of BF neurons that project to the cortex. Cholinergic neurons were directly excited by orexin-A, but did not respond to dynorphin. Non-cholinergic BF neurons that project to the cortex seem to comprise at least two populations with some directly excited by orexin that may represent wake-active, GABAergic neurons, whereas others did not respond to orexin but were inhibited by dynorphin and may be sleep-active, GABAergic neurons. This evidence suggests that the BF is a key site through which orexins activate the cortex and promotes behavioral arousal. In addition, orexins and dynorphin may act synergistically in the BF to promote arousal and improve cognitive performance. PMID:19723027
Narcolepsy in Southern Chinese patients: clinical characteristics, HLA typing and seasonality of birth.

PubMed

Wing, Y K; Chen, L; Fong, S Y Y; Ng, M H L; Ho, C K W; Cheng, S H; Tang, N L S; Li, A M

2008-11-01

To report clinical characteristics, human leukocyte antigen (HLA) typing and seasonality of birth of a series of 54 Southern Chinese patients suffering from narcolepsy. All subjects underwent detailed medical and psychiatric interviews and a standardised nocturnal polysomnogram followed by a daytime Multiple Sleep Latency Test. Each subject also completed a set of sleep questionnaires. HLA typing was performed in 91% of subjects. A total of 78% and 22% of patients were diagnosed with suffering from cataplectic and non-cataplectic narcolepsy, respectively. The majority (n = 47, 87%) of patients were referred to our sleep clinic for excessive daytime sleepiness (EDS). The cataplectic narcolepsy differed from non-cataplectic narcolepsy by having more rapid eye movement (REM)-related clinical symptoms (more sleep paralysis and sleep-related hallucination) and sleep disturbances (shorter REM latency), as well as tighter association with HLA DQB1*0602. A bi-modal peak pattern was observed at 11 and 39 years old. A similar bi-modal pattern also occurred for EDS and cataplexy. Excess winter births were observed for this series of patients. 81% of patients with cataplectic narcolepsy were DQB1*0602-positive. There were no differences between early- and late-onset cases in the association with positive DQB1*0602 (71.4% vs 60%). Narcolepsy had prominent pernicious effects on various social, academic, family and mental aspects in our patients. In our Southern Chinese narcolepsy series, bi-modal peak pattern of age of onset, excess winter birth and tight association of HLA DQB1*0602 with cataplectic narcolepsy were found.

Lucid dreaming in narcolepsy.

PubMed

Dodet, Pauline; Chavez, Mario; Leu-Semenescu, Smaranda; Golmard, Jean-Louis; Arnulf, Isabelle

2015-03-01

To evaluate the frequency, determinants and sleep characteristics of lucid dreaming in narcolepsy. University hospital sleep disorder unit. Case-control study. Consecutive patients with narcolepsy and healthy controls. Participants were interviewed regarding the frequency and determinants of lucid dreaming. Twelve narcolepsy patients and 5 controls who self-identified as frequent lucid dreamers underwent nighttime and daytime sleep monitoring after being given instructions regarding how to give an eye signal when lucid. Compared to 53 healthy controls, the 53 narcolepsy patients reported more frequent dream recall, nightmares and recurrent dreams. Lucid dreaming was achieved by 77.4% of narcoleptic patients and 49.1% of controls (P < 0.05), with an average of 7.6±11 vs. 0.3±0.8 lucid dreams/ month (P < 0.0001). The frequency of cataplexy, hallucinations, sleep paralysis, dyssomnia, HLA positivity, and the severity of sleepiness were similar in narcolepsy with and without lucid dreaming. Seven of 12 narcoleptic (and 0 non-narcoleptic) lucid dreamers achieved lucid REM sleep across a total of 33 naps, including 14 episodes with eye signal. The delta power in the electrode average, in delta, theta, and alpha powers in C4, and coherences between frontal electrodes were lower in lucid than non-lucid REM sleep in spectral EEG analysis. The duration of REM sleep was longer, the REM sleep onset latency tended to be shorter, and the percentage of atonia tended to be higher in lucid vs. non-lucid REM sleep; the arousal index and REM density and amplitude were unchanged. Narcolepsy is a novel, easy model for studying lucid dreaming. © 2015 Associated Professional Sleep Societies, LLC.
Urine Toxicology in Adults Evaluated for a Central Hypersomnia and How the Results Modify the Physician's Diagnosis.

PubMed

Kosky, Christopher A; Bonakis, Anastasios; Yogendran, Arthee; Hettiarachchi, Gihan; Dargan, Paul I; Williams, Adrian J

2016-11-15

Drugs and psychoactive substances can cause sleepiness and when undetected, may lead to over diagnosis of central hypersomnias. We performed urine drug testing using gas chromatography-mass spectrometry in adults undergoing multiple sleep latency testing (MSLT) for a suspected central hypersomnia. We examined how the drug test results modified the treating physician's diagnosis. One hundred eighty-six consecutive patients with a suspected central hypersomnia who underwent clinical assessment, MSLT and urine drug testing by gas chromatography-mass spectrometry were retrospectively studied. Physicians made a diagnosis after clinical assessment and MSLT and were initially blinded to the urine drug test results. A third of patients assessed for subjective hypersomnia had a positive urine drug test for a substance affecting sleep. Opioids, cannabis, and amphetamines were the commonest drugs detected. Using MSLT, 35 (18.8%) of 186 patients had objective hypersomnia that may have been due to a drug or substance. Drugs or substances may have confounded the MSLT in 11 (20.1%) of 53 patients who fulfilled diagnostic criteria for idiopathic hypersomnia, and 12 (52%) of 23 of those who fulfilled diagnostic criteria for narcolepsy without cataplexy. Of the 75 positive urine drug samples, 61 (81%) were substances or medications not revealed in the physician interview. The treating physician had not suspected drugs or substances as a possible cause of objective hypersomnia in 34 (97%) of the 35 patients. Drugs and psychoactive substances can confound the results of the MSLT and when undetected could lead to over diagnosis of central hypersomnias. © 2016 American Academy of Sleep Medicine
Myotonic dystrophy type 1, daytime sleepiness and REM sleep dysregulation.

PubMed

Dauvilliers, Yves A; Laberge, Luc

2012-12-01

Myotonic dystrophy type 1 (DM1), or Steinert's disease, is the most common adult-onset form of muscular dystrophy. DM1 also constitutes the neuromuscular condition with the most significant sleep disorders including excessive daytime sleepiness (EDS), central and obstructive sleep apneas, restless legs syndrome (RLS), periodic leg movements in wake (PLMW) and periodic leg movements in sleep (PLMS) as well as nocturnal and diurnal rapid eye movement (REM) sleep dysregulation. EDS is the most frequent non-muscular complaint in DM1, being present in about 70-80% of patients. Different phenotypes of sleep-related problems may mimic several sleep disorders, including idiopathic hypersomnia, narcolepsy without cataplexy, sleep apnea syndrome, and periodic leg movement disorder. Subjective and objective daytime sleepiness may be associated with the degree of muscular impairment. However, available evidence suggests that DM1-related EDS is primarily caused by a central dysfunction of sleep regulation rather than by sleep fragmentation, sleep-related respiratory events or periodic leg movements. EDS also tends to persist despite successful treatment of sleep-disordered breathing in DM1 patients. As EDS clearly impacts on physical and social functioning of DM1 patients, studies are needed to identify the best appropriate tools to identify hypersomnia, and clarify the indications for polysomnography (PSG) and multiple sleep latency test (MSLT) in DM1. In addition, further structured trials of assisted nocturnal ventilation and randomized trials of central nervous system (CNS) stimulant drugs in large samples of DM1 patients are required to optimally treat patients affected by this progressive, incurable condition. Copyright © 2012 Elsevier Ltd. All rights reserved.
Examining the Frequency of Stimulant Misuse among Patients with Primary Disorders of Hypersomnolence: A Retrospective Cohort Study.

PubMed

Mantyh, William G; Auger, R Robert; Morgenthaler, Timothy I; Silber, Michael H; Moore, Wendy R

2016-05-15

Narcolepsy and idiopathic hypersomnia are commonly treated by sleep specialists and encountered by other medical providers. Although pharmacotherapy with modafinil and traditional stimulants is considered the mainstay of treatment, physicians are often uncomfortable with their prescription because of concerns regarding misuse. The goal of this study was to assess the frequency of stimulant misuse in this population. A retrospective cohort study was performed evaluating patients 18 years and older diagnosed with narcolepsy with and without cataplexy and idiopathic hypersomnia with and without long sleep between 2003-2008. Patients were included if they obtained stimulant prescriptions from and had at least one follow-up visit subsequent to initial diagnosis at our center. Stimulant misuse was defined by multiple prescription sources or early refill requests, which are systematically entered into the record by nursing staff. A total of 105 patients met inclusion criteria for the study; 45 (42%) were male. Mean age at multiple sleep latency test was 42 (± 16). Twelve (11%) patients had a history of illicit substance misuse, and one (1%) patient demonstrated previous stimulant misuse. Fifty-seven (54%) patients carried psychiatric diagnoses, 88% of whom reported depression. Median duration of monitored stimulant therapy was 26 months (range 1-250). None of the 105 patients was found to have evidence of stimulant misuse. This study suggests that the frequency of stimulant misuse in patients with narcolepsy and idiopathic hypersomnia is extremely low. Concerns regarding drug misuse should not leverage decisions to provide long-term therapy. © 2016 American Academy of Sleep Medicine.
Listening to the Patient Voice in Narcolepsy: Diagnostic Delay, Disease Burden, and Treatment Efficacy.

PubMed

Maski, Kiran; Steinhart, Erin; Williams, David; Scammell, Thomas; Flygare, Julie; McCleary, Kimberly; Gow, Monica

2017-03-15

Describe common symptoms, comorbidities, functional limitations, and treatment responsiveness among patients with narcolepsy. Investigate the effect of pediatric onset of narcolepsy symptoms on time to diagnosis of narcolepsy and presence of comorbid depression. Cross-sectional survey of 1,699 people in the United States with self-reported diagnosis of narcolepsy. We utilized mixed-methods data analyses to report study findings. Most participants reported receiving a diagnosis of narcolepsy more than 1 y after symptom onset. We found that the strongest predictor of this delayed diagnosis was pediatric onset of symptoms (odds ratio = 2.4, p < 0.0005). Depression was the most common comorbidity but we detected no association with pediatric onset of narcolepsy symptoms. Overall, participants reported that fatigue and cognitive difficulties were their most burdensome symptoms in addition to sleepiness and cataplexy. The majority of participants reported residual daytime fatigue and/or sleepiness despite treatment. Most participants reported they could not perform at work or school as well as they would like because of narcolepsy symptoms. This study provides unique insight into the narcolepsy disease experience. The study quantifies the problem of diagnostic delay for narcolepsy patients in the United States and highlights that symptoms are more likely to be missed if they develop before 18 y of age. These results suggest that narcolepsy awareness efforts should be aimed at parents, pediatric health care providers, school professionals, and children/adolescents themselves. Disease burden is high because of problems with fatigue, cognition, and persistence of residual symptoms despite treatment. © 2017 American Academy of Sleep Medicine
The relationship between orexin levels and blood pressure changes in patients with narcolepsy.

PubMed

Sieminski, Mariusz; Chwojnicki, Kamil; Sarkanen, Tomi; Partinen, Markku

2017-01-01

Narcolepsy type 1 (NT1) is caused by a deficiency or absence of the neurotransmitter orexin. NT1 is also associated with a reduced nocturnal "dipping" of blood pressure (BP). The study objective was to analyze whether nocturnal BP values differed in patients depleted of orexin, versus those in whom production was preserved. We performed a retrospective analysis of the polysomnographic recordings, orexin levels, and BP values of patients with NT1. Data was collected from a total of 21 patients, divided into two groups as follows: those with a complete depletion of orexin (n = 11) (Group1), and those with a remaining, limited presence of orexin (n = 10) (Group 2). The groups did not differ in terms of the clinical features of NT1 or sleep characteristics, with an exception of increased number of cataplexy episodes and increased percentage of sleep stage 2 in the Group 1. Daytime and nocturnal BP did not differ between the groups. Most patients, regardless of group, had a non-dipping blood pressure pattern, and no difference in dipping prevalence was observed between groups. The amplitude of the daytime to nighttime change in BP did not differ between the groups. Non-dipping BP patterns are frequent among patients with narcolepsy type 1, but we saw no evidence that they depended on whether orexin levels were above or below the assay detection threshold. Therefore, our results do not support the hypothesis that in patients with narcolepsy type 1 residual orexin levels play a role in the control of nocturnal BP dipping.
Patient-Reported Measures of Narcolepsy: The Need for Better Assessment

PubMed Central

Kallweit, Ulf; Schmidt, Markus; Bassetti, Claudio L.

2017-01-01

Study Objectives: Narcolepsy, a chronic disorder of the central nervous system, is clinically characterized by a symptom pentad that includes excessive daytime sleepiness, cataplexy, sleep paralysis, hypnopompic/hypnagogic hallucinations, and disrupted nighttime sleep. Ideally, screening and diagnosis instruments that assist physicians in evaluating a patient for type 1 or type 2 narcolepsy would be brief, easy for patients to understand and physicians to score, and would identify or rule out the need for electrophysiological testing. Methods: A search of the literature was conducted to review patient-reported measures used for the assessment of narcolepsy, mainly in clinical trials, with the goal of summarizing existing scales and identifying areas that may require additional screening questions and clinical practice scales. Results: Of the seven scales reviewed, the Epworth Sleepiness Scale continues to be an important outcome measure to screen adults for excessive daytime sleepiness, which may be associated with narcolepsy. Several narcolepsy-specific scales have demonstrated utility, such as the Ullanlinna Narcolepsy Scale, Swiss Narcolepsy Scale, and Narcolepsy Symptom Assessment Questionnaire, but further validation is required. Conclusions: Although the narcolepsy-specific scales currently in use may identify type 1 narcolepsy, there are no validated questionnaires to identify type 2 narcolepsy. Thus, there remains a need for short, easily understood, and well-validated instruments that can be readily used in clinical practice to distinguish narcolepsy subtypes, as well as other hypersomnias, and for assessing symptoms of these conditions during treatment. Citation: Kallweit U, Schmidt M, Bassetti CL. Patient-reported measures of narcolepsy: the need for better assessment. J Clin Sleep Med. 2017;13(5):737–744. PMID:28162143
Sleep Related Changes in Blood Pressure in Hypocretin-Deficient Narcoleptic Mice

PubMed Central

Bastianini, Stefano; Silvani, Alessandro; Berteotti, Chiara; Elghozi, Jean-Luc; Franzini, Carlo; Lenzi, Pierluigi; Lo, Martire Viviana; Zoccoli, Giovanna

2011-01-01

Study Objectives: Although blood pressure during sleep and the difference in blood pressure between sleep and wakefulness carry prognostic information, little is known on their central neural mechanisms. Hypothalamic neurons releasing hypocretin (orexin) peptides control wake-sleep behavior and autonomic functions and are lost in narcolepsy-cataplexy. We investigated whether chronic lack of hypocretin signaling alters blood pressure during sleep. Design: Comparison of blood pressure as a function of the wake-sleep behavior between 2 different hypocretin-deficient mouse models and control mice with the same genetic background. Setting: N/A. Subjects: Hypocretin-ataxin3 transgenic mice with genetic ablation of hypocretin neurons (TG, n = 12); hypocretin gene knock-out mice (KO, n = 8); congenic wild-type controls (WT, n = 10). Interventions: Instrumentation with electrodes for sleep recordings and a telemetric blood pressure transducer. Measurements and Results: Blood pressure was significantly higher in either TG or KO than in WT during non–rapid eye movement sleep (NREMS; 4 ± 2 and 7 ± 2 mm Hg, respectively) and rapid eye movement sleep (REMS; 11 ± 2 and 12 ± 3 mm Hg, respectively), whereas it did not differ significantly between groups during wakefulness. Accordingly, the decrease in blood pressure between either NREMS or REMS and wakefulness was significantly blunted in TG and KO with respect to WT. Conclusions: Chronic lack of hypocretin signaling may entail consequences on blood pressure that are potentially adverse and that vary widely among wake-sleep states. Citation: Bastianini S; Silvani A; Berteotti C; Elghozi JL; Franzini C; Lenzi P; Lo Martire V; Zoccoli G. Sleep related changes in blood pressure in hypocretin-deficient narcoleptic mice. SLEEP 2011;34(2):213-218. PMID:21286242
Effects of Oral L-Carnitine Administration in Narcolepsy Patients: A Randomized, Double-Blind, Cross-Over and Placebo-Controlled Trial

PubMed Central

Miyagawa, Taku; Kawamura, Hiromi; Obuchi, Mariko; Ikesaki, Asuka; Ozaki, Akiko; Tokunaga, Katsushi; Inoue, Yuichi; Honda, Makoto

2013-01-01

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities. A genome-wide association study (GWAS) identified a novel narcolepsy-related single nucleotide polymorphism (SNP), which is located adjacent to the carnitine palmitoyltransferase 1B (CPT1B) gene encoding an enzyme involved in β-oxidation of long-chain fatty acids. The mRNA expression levels of CPT1B were associated with this SNP. In addition, we recently reported that acylcarnitine levels were abnormally low in narcolepsy patients. To assess the efficacy of oral l-carnitine for the treatment of narcolepsy, we performed a clinical trial administering l-carnitine (510 mg/day) to patients with the disease. The study design was a randomized, double-blind, cross-over and placebo-controlled trial. Thirty narcolepsy patients were enrolled in our study. Two patients were withdrawn and 28 patients were included in the statistical analysis (15 males and 13 females, all with HLA-DQB1*06:02). l-carnitine treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. l-carnitine efficiently increased serum acylcarnitine levels, and reduced serum triglycerides concentration. Differences in the Japanese version of the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) vitality and mental health subscales did not reach statistical significance between l-carnitine and placebo. This study suggests that oral l-carnitine can be effective in reducing excessive daytime sleepiness in narcolepsy patients. Trial Registration University hospital Medical Information Network (UMIN) UMIN000003760 PMID:23349733
Knockdown of orexin type 2 receptor in the lateral pontomesencephalic tegmentum of rats increases REM sleep

PubMed Central

Chen, Lichao; McKenna, James T.; Bolortuya, Yunren; Brown, Ritchie E.

2012-01-01

Dysfunction of the orexin/hypocretin neurotransmitter system causes the sleep disorder narcolepsy, characterized by intrusion of rapid-eye-movement (REM) sleep-like events into normal wakefulness. The sites where orexins act to suppress REM sleep are incompletely understood. Previous studies suggested that the lateral pontomesencephalic tegmentum (lPMT) contains an important REM sleep inhibitory area, and proposed that orexins inhibit REM sleep via orexin type 2 receptors (OxR2) in this region. However, this hypothesis has heretofore not been tested. We thus performed bilateral injection of small interfering RNAs (siRNAs) targeting Ox2R into the lPMT on two consecutive days. This led to a ~30 % increase of time spent in REM sleep in both the dark and light periods for the first two days after injection, with a return to baseline over the next two post-injection days. This increase was mainly due to more longer (>120 s) REM episodes. Cataplexy-like episodes were not observed. The percentage of time spent in wakefulness and NREM sleep, as well as the power spectral profile of NREM and REM sleep, were unaffected. Control animals injected with scrambled siRNA had no sleep changes post-injection. Quantification of the knockdown revealed that unilateral microinjection of siRNAs targeting OxR2 into the lPMT induced a ~40% reduction of OxR2 mRNA two days following the injections when compared to the contralateral side receiving control (scrambled) siRNA. Orexin type 1 receptor (OxR1) mRNA level was unaffected. Our results indicate that removal of OxR2 neurotransmission in the lPMT enhances REM sleep by increasing the duration of REM episodes. PMID:23282008
Increase of histaminergic tuberomammillary neurons in narcolepsy.

PubMed

Valko, Philipp O; Gavrilov, Yury V; Yamamoto, Mihoko; Reddy, Hasini; Haybaeck, Johannes; Mignot, Emmanuel; Baumann, Christian R; Scammell, Thomas E

2013-12-01

Narcolepsy is caused by loss of the hypothalamic neurons producing the orexin/hypocretin neuropeptides. One key target of the orexin system is the histaminergic neurons of the tuberomammillary nucleus (TMN), an essential wake-promoting system. As cerebrospinal fluid histamine levels may be low in patients with narcolepsy, we examined histaminergic neurons in patients with narcolepsy and in 2 mouse models of narcolepsy. We counted the number of hypothalamic neurons producing orexin, melanin-concentrating hormone, and histamine in 7 narcolepsy patients and 12 control subjects using stereological techniques. We identified histaminergic neurons using immunostaining for histidine decarboxylase. We also examined these systems in 6 wild-type mice, 6 orexin/ataxin-3 transgenic mice, and 5 orexin ligand knockout mice. Compared to controls, narcolepsy patients had 94% more histaminergic TMN neurons (233,572 ± 49,476 vs 120,455 ± 10,665, p < 0.001). This increase was higher in 5 narcolepsy patients with >90% orexin neuron loss than in 2 patients with ≤75% orexin neuron loss (252,279 ± 46,264 vs 186,804 ± 1,256, p = 0.03). Similarly, the number of histaminergic TMN neurons was increased 53% in orexin ligand knockout mice compared to wild-type mice, whereas orexin/ataxin-3 transgenic mice showed an intermediate 28% increase. This surprising increase in histaminergic neurons in narcolepsy may be a compensatory response to loss of excitatory drive from the orexin neurons and may contribute to some of the symptoms of narcolepsy such as preserved consciousness during cataplexy and fragmented nighttime sleep. In addition, this finding may have therapeutic implications, as medications that enhance histamine signaling are now under development. © 2013 American Neurological Association.
Listening to the Patient Voice in Narcolepsy: Diagnostic Delay, Disease Burden, and Treatment Efficacy

PubMed Central

Maski, Kiran; Steinhart, Erin; Williams, David; Scammell, Thomas; Flygare, Julie; McCleary, Kimberly; Gow, Monica

2017-01-01

Study Objectives: Describe common symptoms, comorbidities, functional limitations, and treatment responsiveness among patients with narcolepsy. Investigate the effect of pediatric onset of narcolepsy symptoms on time to diagnosis of narcolepsy and presence of comorbid depression. Methods: Cross-sectional survey of 1,699 people in the United States with self-reported diagnosis of narcolepsy. We utilized mixed-methods data analyses to report study findings. Results: Most participants reported receiving a diagnosis of narcolepsy more than 1 y after symptom onset. We found that the strongest predictor of this delayed diagnosis was pediatric onset of symptoms (odds ratio = 2.4, p < 0.0005). Depression was the most common comorbidity but we detected no association with pediatric onset of narcolepsy symptoms. Overall, participants reported that fatigue and cognitive difficulties were their most burdensome symptoms in addition to sleepiness and cataplexy. The majority of participants reported residual daytime fatigue and/or sleepiness despite treatment. Most participants reported they could not perform at work or school as well as they would like because of narcolepsy symptoms. Conclusions: This study provides unique insight into the narcolepsy disease experience. The study quantifies the problem of diagnostic delay for narcolepsy patients in the United States and highlights that symptoms are more likely to be missed if they develop before 18 y of age. These results suggest that narcolepsy awareness efforts should be aimed at parents, pediatric health care providers, school professionals, and children/adolescents themselves. Disease burden is high because of problems with fatigue, cognition, and persistence of residual symptoms despite treatment. Citation: Maski K, Steinhart E, Williams D, Scammell T, Flygare J, McCleary K, Gow M. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden and treatment efficacy. J Clin Sleep Med. 2017;13(3):419–425. PMID:27923434
Orexin Neurons Are Necessary for the Circadian Control of REM Sleep

PubMed Central

Kantor, Sandor; Mochizuki, Takatoshi; Janisiewicz, Agnieszka M.; Clark, Erika; Nishino, Seiji; Scammell, Thomas E.

2009-01-01

Study Objectives: The orexin-producing neurons are hypothesized to be essential for the circadian control of sleep/wake behavior, but it remains unknown whether these rhythms are mediated by the orexin peptides or by other signaling molecules released by these neurons such as glutamate or dynorphin. To determine the roles of these neurotransmitters, we examined the circadian rhythms of sleep/wake behavior in mice lacking the orexin neurons (ataxin-3 [Atx] mice) and mice lacking just the orexin neuropeptides (orexin knockout [KO] mice). Design: We instrumented mice for recordings of sleep-wake behavior, locomotor activity (LMA), and body temperature (Tb) and recorded behavior after 6 days in constant darkness. Results: The amplitude of the rapid eye movement (REM) sleep rhythm was substantially reduced in Atx mice but preserved in orexin KO mice. This blunted rhythm in Atx mice was caused by an increase in the amount of REM sleep during the subjective night (active period) due to more transitions into REM sleep and longer REM sleep episodes. In contrast, the circadian variations of Tb, LMA, Wake, non-REM sleep, and cataplexy were normal, suggesting that the circadian timekeeping system and other output pathways are intact in both Atx and KO mice. Conclusions: These results indicate that the orexin neurons are necessary for the circadian suppression of REM sleep. Blunting of the REM sleep rhythm in Atx mice but not in orexin KO mice suggests that other signaling molecules such as dynorphin or glutamate may act in concert with orexins to suppress REM sleep during the active period. Citation: Kantor S; Mochizuki T; Janisiewicz AM; Clark E; Nishino S; Scammell TE. Orexin neurons are necessary for the circadian control of REM sleep. SLEEP 2009;32(9):1127-1134. PMID:19750917
Abnormal Sleep/Wake Dynamics in Orexin Knockout Mice

PubMed Central

Diniz Behn, Cecilia G.; Klerman, Elizabeth B.; Mochizuki, Takatoshi; Lin, Shih-Chieh; Scammell, Thomas E.

2010-01-01

Study Objectives: Narcolepsy with cataplexy is caused by a loss of orexin (hypocretin) signaling, but the physiologic mechanisms that result in poor maintenance of wakefulness and fragmented sleep remain unknown. Conventional scoring of sleep cannot reveal much about the process of transitioning between states or the variations within states. We developed an EEG spectral analysis technique to determine whether the state instability in a mouse model of narcolepsy reflects abnormal sleep or wake states, faster movements between states, or abnormal transitions between states. Design: We analyzed sleep recordings in orexin knockout (OXKO) mice and wild type (WT) littermates using a state space analysis technique. This non-categorical approach allows quantitative and unbiased examination of sleep/wake states and state transitions. Measurements and Results: OXKO mice spent less time in deep, delta-rich NREM sleep and in active, theta-rich wake and instead spent more time near the transition zones between states. In addition, while in the midst of what should be stable wake, OXKO mice initiated rapid changes into NREM sleep with high velocities normally seen only in transition regions. Consequently, state transitions were much more frequent and rapid even though the EEG progressions during state transitions were normal. Conclusions: State space analysis enables visualization of the boundaries between sleep and wake and shows that narcoleptic mice have less distinct and more labile states of sleep and wakefulness. These observations provide new perspectives on the abnormal state dynamics resulting from disrupted orexin signaling and highlight the usefulness of state space analysis in understanding narcolepsy and other sleep disorders. Citation: Diniz Behn CG; Klerman EB; Mochizuki T; Lin S; Scammell TE. Abnormal sleep/wake dynamics in orexin knockout mice. SLEEP 2010;33(3):297-306. PMID:20337187
The Medical and Economic Burden of Narcolepsy: Implications for Managed Care

PubMed Central

Thorpy, Michael J.; Hiller, George

2017-01-01

Background The neurologic disorder narcolepsy results from dysregulation of the sleep-wake cycle and is primarily characterized by chronic, severely excessive daytime sleepiness and cataplexy, an emotionally induced muscle weakness. The prevalence of narcolepsy is approximately 0.05%, and onset generally occurs during the first 2 decades of life. Narcolepsy is believed to be an autoimmune disorder with destruction of hypocretin-producing neurons in the lateral hypothalamus. Objectives To provide an enhanced understanding of narcolepsy and establish the need for early diagnosis and rapid initiation of effective treatment for patients with narcolepsy. Discussion Narcolepsy reduces daily functioning and is associated with a substantial medical and economic burden, with many patients being on full disability. The annual direct medical costs are approximately 2-fold higher in patients with narcolepsy than in matched controls without this condition ($11,702 vs $5261, respectively; P <.0001). Further contributing to the overall burden is a lack of recognition of the signs and symptoms of narcolepsy and an absence of easily measurable biomarkers, resulting in a diagnostic delay that often exceeds 10 years and may be associated with misdiagnosis and inappropriate resource utilization. Because narcolepsy generally has an onset in childhood or in adolescence, is often misdiagnosed, has no known cure, and requires lifelong treatment, it is an important disease from a managed care perspective. Clinical features, as well as objective testing, should be used to ensure the timely diagnosis and treatment of patients with narcolepsy. Conclusion Policies for the diagnosis and treatment of narcolepsy should be based on the current treatment guidelines, but they should also encourage shared decisions between clinicians and patients to allow for individualized diagnostic and treatment choices, as suggested in best practice recommendations. PMID:28975007
Sustained attention to response task (SART) shows impaired vigilance in a spectrum of disorders of excessive daytime sleepiness.

PubMed

Van Schie, Mojca K M; Thijs, Roland D; Fronczek, Rolf; Middelkoop, Huub A M; Lammers, Gert Jan; Van Dijk, J Gert

2012-08-01

The sustained attention to response task comprises withholding key presses to one in nine of 225 target stimuli; it proved to be a sensitive measure of vigilance in a small group of narcoleptics. We studied sustained attention to response task results in 96 patients from a tertiary narcolepsy referral centre. Diagnoses according to ICSD-2 criteria were narcolepsy with (n=42) and without cataplexy (n=5), idiopathic hypersomnia without long sleep time (n=37), and obstructive sleep apnoea syndrome (n=12). The sustained attention to response task was administered prior to each of five multiple sleep latency test sessions. Analysis concerned error rates, mean reaction time, reaction time variability and post-error slowing, as well as the correlation of sustained attention to response task results with mean latency of the multiple sleep latency test and possible time of day influences. Median sustained attention to response task error scores ranged from 8.4 to 11.1, and mean reaction times from 332 to 366ms. Sustained attention to response task error score and mean reaction time did not differ significantly between patient groups. Sustained attention to response task error score did not correlate with multiple sleep latency test sleep latency. Reaction time was more variable as the error score was higher. Sustained attention to response task error score was highest for the first session. We conclude that a high sustained attention to response task error rate reflects vigilance impairment in excessive daytime sleepiness irrespective of its cause. The sustained attention to response task and the multiple sleep latency test reflect different aspects of sleep/wakefulness and are complementary. © 2011 European Sleep Research Society.
Examining the Frequency of Stimulant Misuse among Patients with Primary Disorders of Hypersomnolence: A Retrospective Cohort Study

PubMed Central

Mantyh, William G.; Auger, R. Robert; Morgenthaler, Timothy I.; Silber, Michael H.; Moore, Wendy R.

2016-01-01

Study Objectives: Narcolepsy and idiopathic hypersomnia are commonly treated by sleep specialists and encountered by other medical providers. Although pharmacotherapy with modafinil and traditional stimulants is considered the mainstay of treatment, physicians are often uncomfortable with their prescription because of concerns regarding misuse. The goal of this study was to assess the frequency of stimulant misuse in this population. Methods: A retrospective cohort study was performed evaluating patients 18 years and older diagnosed with narcolepsy with and without cataplexy and idiopathic hypersomnia with and without long sleep between 2003–2008. Patients were included if they obtained stimulant prescriptions from and had at least one follow-up visit subsequent to initial diagnosis at our center. Stimulant misuse was defined by multiple prescription sources or early refill requests, which are systematically entered into the record by nursing staff. Results: A total of 105 patients met inclusion criteria for the study; 45 (42%) were male. Mean age at multiple sleep latency test was 42 (± 16). Twelve (11%) patients had a history of illicit substance misuse, and one (1%) patient demonstrated previous stimulant misuse. Fifty-seven (54%) patients carried psychiatric diagnoses, 88% of whom reported depression. Median duration of monitored stimulant therapy was 26 months (range 1–250). None of the 105 patients was found to have evidence of stimulant misuse. Conclusion: This study suggests that the frequency of stimulant misuse in patients with narcolepsy and idiopathic hypersomnia is extremely low. Concerns regarding drug misuse should not leverage decisions to provide long-term therapy. Citation: Mantyh WG, Auger RR, Morgenthaler TI, Silber MH, Moore WR. Examining the frequency of stimulant misuse among patients with primary disorders of hypersomnolence: a retrospective cohort study. J Clin Sleep Med 2016;12(5):659–662. PMID:26943713
A polymorphism in CCR1/CCR3 is associated with narcolepsy.

PubMed

Toyoda, Hiromi; Miyagawa, Taku; Koike, Asako; Kanbayashi, Takashi; Imanishi, Aya; Sagawa, Yohei; Kotorii, Nozomu; Kotorii, Tatayu; Hashizume, Yuji; Ogi, Kimihiro; Hiejima, Hiroshi; Kamei, Yuichi; Hida, Akiko; Miyamoto, Masayuki; Imai, Makoto; Fujimura, Yota; Tamura, Yoshiyuki; Ikegami, Azusa; Wada, Yamato; Moriya, Shunpei; Furuya, Hirokazu; Takeuchi, Masaki; Kirino, Yohei; Meguro, Akira; Remmers, Elaine F; Kawamura, Yoshiya; Otowa, Takeshi; Miyashita, Akinori; Kashiwase, Koichi; Khor, Seik-Soon; Yamasaki, Maria; Kuwano, Ryozo; Sasaki, Tsukasa; Ishigooka, Jun; Kuroda, Kenji; Kume, Kazuhiko; Chiba, Shigeru; Yamada, Naoto; Okawa, Masako; Hirata, Koichi; Mizuki, Nobuhisa; Uchimura, Naohisa; Shimizu, Tetsuo; Inoue, Yuichi; Honda, Yutaka; Mishima, Kazuo; Honda, Makoto; Tokunaga, Katsushi

2015-10-01

Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function. Copyright © 2015 Elsevier Inc. All rights reserved.
Sleep-stage sequencing of sleep-onset REM periods in MSLT predicts treatment response in patients with narcolepsy.

PubMed

Drakatos, Panagis; Patel, Kishankumar; Thakrar, Chiraag; Williams, Adrian J; Kent, Brian D; Leschziner, Guy D

2016-04-01

Current treatment recommendations for narcolepsy suggest that modafinil should be used as a first-line treatment ahead of conventional stimulants or sodium oxybate. In this study, performed in a tertiary sleep disorders centre, treatment responses were examined following these recommendations, and the ability of sleep-stage sequencing of sleep-onset rapid eye movement periods in the multiple sleep latency test to predict treatment response. Over a 3.5-year period, 255 patients were retrospectively identified in the authors' database as patients diagnosed with narcolepsy, type 1 (with cataplexy) or type 2 (without) using clinical and polysomnographic criteria. Eligible patients were examined in detail, sleep study data were abstracted and sleep-stage sequencing of sleep-onset rapid eye movement periods were analysed. Response to treatment was graded utilizing an internally developed scale. Seventy-five patients were included (39% males). Forty (53%) were diagnosed with type 1 narcolepsy with a mean follow-up of 2.37 ± 1.35 years. Ninety-seven percent of the patients were initially started on modafinil, and overall 59% reported complete response on the last follow-up. Twenty-nine patients (39%) had the sequence of sleep stage 1 or wake to rapid eye movement in all of their sleep-onset rapid eye movement periods, with most of these diagnosed as narcolepsy type 1 (72%). The presence of this specific sleep-stage sequence in all sleep-onset rapid eye movement periods was associated with worse treatment response (P = 0.0023). Sleep-stage sequence analysis of sleep-onset rapid eye movement periods in the multiple sleep latency test may aid the prediction of treatment response in narcoleptics and provide a useful prognostic tool in clinical practice, above and beyond their classification as narcolepsy type 1 or 2. © 2015 European Sleep Research Society.
Risk of Narcolepsy after AS03 Adjuvanted Pandemic A/H1N1 2009 Influenza Vaccine in Adults: A Case-Coverage Study in England.

PubMed

Stowe, Julia; Andrews, Nicholas; Kosky, Christopher; Dennis, Gary; Eriksson, Sofia; Hall, Andrew; Leschziner, Guy; Reading, Paul; Shneerson, John M; Donegan, Katherine; Miller, Elizabeth

2016-05-01

An increased risk of narcolepsy has been observed in children following ASO3-adjuvanted pandemic A/H1N1 2009 (Pandemrix) vaccine. We investigated whether this risk extends to adults in England. Six adult sleep centers in England were visited between November 2012 and February 2014 and vaccination/clinical histories obtained from general practitioners. Suspected narcolepsy cases aged older than 17 y were selected. The risk of narcolepsy following Pandemrix was calculated using cases diagnosed by the time of the center visits and those with a diagnosis by November 30, 2011 after which there was increased awareness of the risk in children. The odds of vaccination in cases and in matched population data were compared using a case-coverage design. Of 1,446 possible cases identified, most had onset before 2009 or were clearly not narcolepsy. Of the 60 remaining cases, 20 were excluded after expert review, leaving 40 cases with narcolepsy; 5 had received Pandemrix between 3 and 18 mo before onset. All the vaccinated cases had cataplexy, two received a diagnosis by November 2011 and two were aged 40 y or older. The odds ratio for vaccination in cases compared to the population was 4.24 (95% confidence interval 1.45-12.38) using all cases and 9.06 (1.90-43.17) using cases with a diagnosis by November 2011, giving an attributable risk of 0.59 cases per 100,000 doses. We found a significantly increased risk of narcolepsy in adults following Pandemrix vaccination in England. The risk was lower than that seen in children using a similar study design. © 2016 Associated Professional Sleep Societies, LLC.

Genetic association, seasonal infections and autoimmune basis of narcolepsy

PubMed Central

Singh, Abinav Kumar; Mahlios, Josh; Mignot, Emmanuel

2014-01-01

In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky’s criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers. PMID:23497937
Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update.

PubMed

Patterson, Marc C; Hendriksz, Christian J; Walterfang, Mark; Sedel, Frederic; Vanier, Marie T; Wijburg, Frits

2012-07-01

Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the brain and other tissues. Characteristic neurological manifestations of NP-C include saccadic eye movement (SEM) abnormalities or vertical supranuclear gaze palsy (VSGP), cerebellar signs (ataxia, dystonia/dysmetria, dysarthria and dysphagia) and gelastic cataplexy. Epileptic seizures are also common in affected patients. Typically, neurological disease onset occurs during childhood, although an increasing number of cases are being detected and diagnosed during adulthood based on late-onset neurological signs and psychiatric manifestations. Categorization of patients according to age at onset of neurological manifestations (i.e. early-infantile, late-infantile, juvenile and adolescent/adult-onset) can be useful for the evaluation of disease course and treatment responses. The first international guidelines for the clinical management of NP-C in children and adults were published in 2009. Since that time a significant amount of data regarding the epidemiology, detection/diagnosis, and treatment of NP-C has been published. Here, we report points of consensus among experts in the diagnosis and treatment of NP-C based on a follow-up meeting in Paris, France in September 2011. This article serves as an update to the original guidelines providing, among other things, further information on detection/diagnostic methods, potential new methods of monitoring disease progression, and therapy. Treatment goals and the application of disease-specific therapy with miglustat are also re-evaluated. Copyright © 2012 Elsevier Inc. All rights reserved.
The Nightly Use of Sodium Oxybate Is Associated with a Reduction in Nocturnal Sleep Disruption: A Double-Blind, Placebo-Controlled Study in Patients with Narcolepsy

PubMed Central

Black, Jed; Pardi, Daniel; Hornfeldt, Carl S.; Inhaber, Neil

2010-01-01

Objective: To further explore the effects of sodium oxybate (SXB) administration on nocturnal sleep in narcolepsy patients during a double-blind, placebo-controlled, parallel group study conducted with 228 adult patients with narcolepsy/cataplexy in the United States, Canada, and Europe. Method: Patients were withdrawn from antidepressants and sedative/hypnotics, and then randomized to receive 4.5, 6, or 9 g SXB or placebo nightly for 8 weeks. Patients receiving 6 and 9 g/night doses were titrated to their final dose in weekly 1.5 g increments, while patients receiving placebo were randomized to undergo a similar mock dose titration. The use of stimulant therapy continued unchanged. Changes in sleep architecture were measured using centrally scored nocturnal polysomnograms. Daily diaries were used to record changes in narcolepsy symptoms and adverse events. Results: Following 8 weeks of SXB treatment, study patients demonstrated significant dose-related increases in the duration of stage 3 and 4 sleep, reaching a median increase of 52.5 minutes in patients receiving 9 g nightly. Compared to placebo-treated patients, delta power was significantly increased in all dose groups. Stage 1 sleep and the frequency of nocturnal awakenings were each significantly decreased at the 6 and 9 g/night doses. The changes in nocturnal sleep coincided with significant decreases in the severity and frequency of narcolepsy symptoms. Conclusions: The nightly administration of SXB to narcolepsy patients significantly impacts measures of slow wave sleep, wake after sleep onset, awakenings, total sleep time, and stage 1 sleep in a dose-related manner. The frequency and severity of narcolepsy symptoms decreased with treatment. Citation: Black J; Pardi D; Hornfeldt CS; Inhaber N. The nightly use of sodium oxybate is associated with a reduction in nocturnal sleep disruption: a double-blind, placebo-controlled study in patients with narcolepsy. J Clin Sleep Med 2010;6(6):596-602. PMID:21206549
MX2 Gene Expression Tends to be Downregulated in Subjects with HLA-DQB1*0602

PubMed Central

Tanaka, Susumu; Honda, Yutaka; Honda, Makoto

2008-01-01

Objective: There is a close association between narcolepsy and the human leukocyte antigen (HLA)-DQB1*0602. The detailed influence and function of this specific HLA allele with regard to narcolepsy have not yet been elucidated. Our previous report identified the myxovirus resistance 2 (MX2) gene as a narcolepsy-specific dysregulated gene; however, the report had a limitation—the control groups were not HLA matched. In this study, we examined the possibility of an association between MX2 expression and HLA haplotypes. Designs: The expression levels of the MX2 gene in 3 groups (24 narcolepsy with cataplexy patients; 24 age-, sex-, and HLA-DQB1 genotype-matched controls; and 24 age- and sex-matched controls without the HLA-DQB1*0602 allele) were measured by quantitative real-time RT-PCR. Results: The expression level of the MX2 gene tended to be downregulated in subjects carrying HLA-DQB1*0602, compared with that of the control subjects without this allele. There was no difference in the MX2 expression level between the narcolepsy subjects and the HLA-DQB1 genotype-matched control subjects. Conclusion: Our previous finding—the narcolepsy-specific reduction of MX2 gene expression—was not replicated in this follow-up study. The expression level of the MX2 gene in white blood cells was found to be lower in subjects with the HLA-DQB1*0602 than in subjects without this allele, suggesting that there exists a relationship between the HLA-DQB1*0602 allele and MX2 gene expression. This might be a possible explanation for the strong HLA association observed in narcolepsy. Citation: Tanaka S; Honda Y; Honda M. MX2 gene expression tends to be downregulated in subjects with HLA-DQB1*0602. SLEEP 2008;31(5):749-751. PMID:18517045
Lucid Dreaming in Narcolepsy

PubMed Central

Dodet, Pauline; Chavez, Mario; Leu-Semenescu, Smaranda; Golmard, Jean-Louis; Arnulf, Isabelle

2015-01-01

Objective: To evaluate the frequency, determinants and sleep characteristics of lucid dreaming in narcolepsy Settings: University hospital sleep disorder unit Design: Case-control study Participants: Consecutive patients with narcolepsy and healthy controls Methods: Participants were interviewed regarding the frequency and determinants of lucid dreaming. Twelve narcolepsy patients and 5 controls who self-identified as frequent lucid dreamers underwent nighttime and daytime sleep monitoring after being given instructions regarding how to give an eye signal when lucid. Results: Compared to 53 healthy controls, the 53 narcolepsy patients reported more frequent dream recall, nightmares and recurrent dreams. Lucid dreaming was achieved by 77.4% of narcoleptic patients and 49.1% of controls (P < 0.05), with an average of 7.6 ± 11 vs. 0.3 ± 0.8 lucid dreams/month (P < 0.0001). The frequency of cataplexy, hallucinations, sleep paralysis, dyssomnia, HLA positivity, and the severity of sleepiness were similar in narcolepsy with and without lucid dreaming. Seven of 12 narcoleptic (and 0 non-narcoleptic) lucid dreamers achieved lucid REM sleep across a total of 33 naps, including 14 episodes with eye signal. The delta power in the electrode average, in delta, theta, and alpha powers in C4, and coherences between frontal electrodes were lower in lucid than non-lucid REM sleep in spectral EEG analysis. The duration of REM sleep was longer, the REM sleep onset latency tended to be shorter, and the percentage of atonia tended to be higher in lucid vs. non-lucid REM sleep; the arousal index and REM density and amplitude were unchanged. Conclusion: Narcoleptics have a high propensity for lucid dreaming without differing in REM sleep characteristics from people without narcolepsy. This suggests narcolepsy patients may provide useful information in future studies on the nature of lucid dreaming. Citation: Dodet P, Chavez M, Leu-Semenescu S, Golmard JL, Arnulf I. Lucid dreaming in narcolepsy. SLEEP 2015;38(3):487–497. PMID:25348131
"Did You Climax or Are You Just Laughing at Me?" Rare Phenomena Associated With Orgasm.

PubMed

Reinert, Anna E; Simon, James A

2017-07-01

The study of the human orgasm has shown a core set of physiologic and psychological symptoms experienced by most individuals. The study of normal sheds light on the abnormal and has spotlighted rare physical and psychological symptoms experienced by some individuals in association with orgasm. These phenomena are rare and, as is typical of rare phenomena, their documentation in the medical literature is largely confined to case studies. To identify peri-orgasmic phenomena, defined as unusual physical or psychological symptoms subjectively experienced by some individuals as part of the orgasm response, distinct from the usual or normal orgasm response. A list of peri-orgasmic phenomena was made with help from sexual health colleagues and, using this list as a foundation, a literature search was performed of articles published in English. Publications included in this review report on physical or psychological phenomena at the time of orgasm that are distinct from psychological, whole-body, and genito-pelvic sensations commonly experienced at the time of orgasm. Cases of physical symptoms related to the physiology of sexual intercourse and not specifically to orgasm were excluded. Case studies of peri-orgasmic phenomena were reviewed, including cases describing cataplexy (weakness), crying, dysorgasmia, dysphoria, facial and/or ear pain, foot pain, headache, pruritus, laughter, panic attack, post-orgasm illness syndrome, seizures, and sneezing. The literature review confirms the existence of diverse and frequently replicated peri-orgasmic phenomena. The value of case studies is in the collection and recording of observations so that hypotheses can be formed about the observed phenomena. Accordingly, this review could inspire further research on the neurophysiologic mechanisms of orgasm. Reinert AE, Simon JA. "Did You Climax or Are You Just Laughing at Me?" Rare Phenomena Associated With Orgasm. Sex Med Rev 2017;5:275-281. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells.

PubMed

Lecendreux, Michel; Churlaud, Guillaume; Pitoiset, Fabien; Regnault, Armelle; Tran, Tu Anh; Liblau, Roland; Klatzmann, David; Rosenzwajg, Michelle

2017-01-01

Narcolepsy is a rare neurologic disorder characterized by excessive daytime sleepiness, cataplexy and disturbed nocturnal sleep patterns. Narcolepsy type 1 (NT1) has been shown to result from a selective loss of hypothalamic hypocretin-secreting neurons with patients typically showing low CSF-hypocretin levels (<110 pg/ml). This specific loss of hypocretin and the strong association with the HLA-DQB1*06:02 allele led to the hypothesis that NT1 could be an immune-mediated pathology. Moreover, susceptibility to NT1 has recently been associated with several pathogens, particularly with influenza A H1N1 virus either through infection or vaccination. The goal of this study was to compare peripheral blood immune cell populations in recent onset pediatric NT1 subjects (post or non-post 2009-influenza A H1N1 vaccination) to healthy donors. We demonstrated an increased number of central memory CD4+ T cells (CD62L+ CD45RA-) associated to an activated phenotype (increase in CD69 and CD25 expression) in NT1 patients. Percentage and absolute count of regulatory T cells (Tregs) in NT1 patients were increased associated with an activated phenotype (increase in GITR and LAP expression), and of activated memory phenotype. Cytokine production by CD4+ and CD8+ T cells after activation was not modified in NT1 patients. In H1N1 vaccinated NT1 patients, absolute counts of CD3+, CD8+ T cells, and B cells were increased compared to non-vaccinated NT1 patients. These results support a global T cell activation in NT1 patients and thus support a T cell-mediated autoimmune origin of NT1, but do not demonstrate the pathological role of H1N1 prophylactic vaccination. They should prompt further studies of T cells, particularly of Tregs (such as suppression and proliferation antigen specific assays, and also T-cell receptor sequencing), in NT1.
Safety of quadrivalent live attenuated influenza vaccine in subjects aged 2-49years.

PubMed

Baxter, Roger; Eaton, Abigail; Hansen, John; Aukes, Laurie; Caspard, Herve; Ambrose, Christopher S

2017-03-01

Quadrivalent live attenuated influenza vaccine (Q/LAIV) was licensed in 2012 and replaced trivalent live attenuated influenza vaccine in the United States during the 2013-2014 influenza season. This study assessed the safety of Q/LAIV in children and adults aged 2-49years. This was a prospective observational cohort study using data collected from Kaiser Permanente Northern California. Post-vaccination events of interest were any hospitalization, hospitalization for lower respiratory tract infection, and the following medically attended events: hypersensitivity, seizures/convulsions, lower respiratory tract infection, wheezing, Guillain-Barré syndrome, Bell's palsy, encephalitis, neuritis, vasculitis, and narcolepsy/cataplexy. The rates of these events during the risk interval post-vaccination were compared with rates observed during reference periods later in the follow-up (within-cohort analysis) and with rates observed in frequency-matched unvaccinated controls and inactivated influenza vaccine (IIV) recipients. A total of 62,040 eligible Q/LAIV recipients were identified during the 2013-2014 influenza season. Within-cohort comparisons of all Q/LAIV recipients as well as comparisons between Q/LAIV recipients and unvaccinated controls or IIV recipients did not show any significantly higher risk of hospitalizations or medically attended events following administration of Q/LAIV. Additional analyses by setting (clinic visits, emergency department visits, and hospital admissions) and age group (2-4, 5-8, 9-17, and 18-49years) also did not reveal clinically consistent findings that suggested any increased risk after administration of Q/LAIV. In this large population study of individuals aged 2-49years, no safety signals associated with the administration of Q/LAIV were observed. A much larger study population would be needed to confidently reject any association between Q/LAIV and very rare events, specifically those with an incidence of <1 event/10,000 person-years. ClinicalTrials.gov NCT01985997. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Urine Toxicology in Adults Evaluated for a Central Hypersomnia and How the Results Modify the Physician's Diagnosis

PubMed Central

Kosky, Christopher A.; Bonakis, Anastasios; Yogendran, Arthee; Hettiarachchi, Gihan; Dargan, Paul I.; Williams, Adrian J.

2016-01-01

Study Objectives: Drugs and psychoactive substances can cause sleepiness and when undetected, may lead to over diagnosis of central hypersomnias. We performed urine drug testing using gas chromatography-mass spectrometry in adults undergoing multiple sleep latency testing (MSLT) for a suspected central hypersomnia. We examined how the drug test results modified the treating physician's diagnosis. Methods: One hundred eighty-six consecutive patients with a suspected central hypersomnia who underwent clinical assessment, MSLT and urine drug testing by gas chromatography-mass spectrometry were retrospectively studied. Physicians made a diagnosis after clinical assessment and MSLT and were initially blinded to the urine drug test results. Results: A third of patients assessed for subjective hypersomnia had a positive urine drug test for a substance affecting sleep. Opioids, cannabis, and amphetamines were the commonest drugs detected. Using MSLT, 35 (18.8%) of 186 patients had objective hypersomnia that may have been due to a drug or substance. Drugs or substances may have confounded the MSLT in 11 (20.1%) of 53 patients who fulfilled diagnostic criteria for idiopathic hypersomnia, and 12 (52%) of 23 of those who fulfilled diagnostic criteria for narcolepsy without cataplexy. Of the 75 positive urine drug samples, 61 (81%) were substances or medications not revealed in the physician interview. The treating physician had not suspected drugs or substances as a possible cause of objective hypersomnia in 34 (97%) of the 35 patients. Conclusions: Drugs and psychoactive substances can confound the results of the MSLT and when undetected could lead to over diagnosis of central hypersomnias. Citation: Kosky CA, Bonakis A, Yogendran A, Hettiarachchi G, Dargan PI, Williams AJ. Urine toxicology in adults evaluated for a central hypersomnia and how the results modify the physician's diagnosis. J Clin Sleep Med 2016;12(11):1499–1505. PMID:27568897
IgG abnormality in narcolepsy and idiopathic hypersomnia.

PubMed

Tanaka, Susumu; Honda, Makoto

2010-03-05

A close association between narcolepsy and the Human Leukocyte Antigen (HLA)-DQB1*0602 allele suggests the involvement of the immune system, or possibly an autoimmune process. We investigated serum IgG levels in narcolepsy. We measured the serum total IgG levels in 159 Japanese narcolepsy-cataplexy patients positive for the HLA-DQB1*0602 allele, 28 idiopathic hypersomnia patients with long sleep time, and 123 healthy controls (the HLA-DQB1*0602 allele present in 45 subjects). The serum levels of each IgG subclass were subsequently measured. The distribution of serum IgG was significantly different among healthy controls negative for the HLA-DQB1*0602 allele (11.66+/-3.55 mg/ml), healthy controls positive for the HLA-DQB1*0602 allele (11.45+/-3.43), narcolepsy patients (9.67+/-3.38), and idiopathic hypersomnia patients (13.81+/-3.80). None of the following clinical variables, age, disease duration, Epworth Sleepiness Scale, smoking habit and BMI at the time of blood sampling, were associated with IgG levels in narcolepsy or idiopathic hypersomnia. Furthermore we found the decrease in IgG1 and IgG2 levels, stable expression of IgG3, and the increase in the proportion of IgG4 in narcolepsy patients with abnormally low IgG levels. The increase in the proportion of IgG4 levels was also found in narcolepsy patients with normal serum total IgG levels. Idiopathic hypersomnia patients showed a different pattern of IgG subclass distribution with high IgG3 and IgG4 level, low IgG2 level, and IgG1/IgG2 imbalance. Our study is the first to determine IgG abnormalities in narcolepsy and idiopathic hypersomnia by measuring the serum IgG levels in a large number of hypersomnia patients. The observed IgG abnormalities indicate humoral immune alterations in narcolepsy and idiopathic hypersomnia. Different IgG profiles suggest immunological differences between narcolepsy and idiopathic hypersomnia.
Increased GABA Levels in Medial Prefrontal Cortex of Young Adults with Narcolepsy

PubMed Central

Kim, Seog Ju; Lyoo, In Kyoon; Lee, Yujin S.; Sung, Young Hoon; Kim, Hengjun J.; Kim, Jihyun H.; Kim, Kye Hyun; Jeong, Do-Un

2008-01-01

Study Objectives: To explore absolute concentrations of brain metabolites including gamma amino-butyric acid (GABA) in the medial prefrontal cortex and basal ganglia of young adults with narcolepsy. Design: Proton magnetic resonance (MR) spectroscopy centered on the medial prefrontal cortex and the basal ganglia was acquired. The absolute concentrations of brain metabolites including GABA and glutamate were assessed and compared between narcoleptic patients and healthy comparison subjects. Setting: Sleep and Chronobiology Center at Seoul National University Hospital; A high strength 3.0 Tesla MR scanner in the Department of Radiology at Seoul National University Hospital. Patients or Participants: Seventeen young adults with a sole diagnosis of HLA DQB1 0602 positive narcolepsy with cataplexy (25.1 ± 4.6 years old) and 17 healthy comparison subjects (26.8 ± 4.8 years old). Interventions: N/A. Measurements and Results: Relative to comparison subjects, narcoleptic patients had higher GABA concentration in the medial prefrontal cortex (t = 4.10, P <0.001). Narcoleptic patients with nocturnal sleep disturbance had higher GABA concentration in the medial prefrontal cortex than those without nocturnal sleep disturbance (t = 2.45, P= 0.03), but had lower GABA concentration than comparison subjects (t = 2.30, P = 0.03). Conclusions: The current study reports that young adults with narcolepsy had a higher GABA concentration in the medial prefrontal cortex, which was more prominent in patients without nocturnal sleep disturbance. Our findings suggest that the medial prefrontal GABA level may be increased in narcolepsy, and the increased medial prefrontal GABA might be a compensatory mechanism to reduce nocturnal sleep disturbances in narcolepsy. Citation: Kim SJ; Lyoo IK; Lee YS; Sung YH; Kim HJ; Kim JH; Kim KH; Jeong DU. Increased GABA levels in medial prefrontal cortex of young adults with narcolepsy. SLEEP 2008;31(3):342-347. PMID:18363310
Patterns of spontaneous reports on narcolepsy following administration of pandemic influenza vaccine; a case series of individual case safety reports in Eudravigilance.

PubMed

Gadroen, Kartini; Straus, Sabine M J M; Pacurariu, Alexandra; Weibel, Daniel; Kurz, Xavier; Sturkenboom, Miriam C J M

2016-09-22

This study aims to describe the frequency and quality of spontaneous narcolepsy case reports following administration of pandemic influenza vaccine as captured in the Eudravigilance database. We conducted a retrospective descriptive study of spontaneous Individual Case Safety Reports (ICSRs), reporting narcolepsy following administration of pandemic influenza vaccine as received by Eudravigilance until July 2014. De-duplication was carried out by Eudravigilance. Frequency of reporting is described as number of ICSRs received per month over time. The quality of the ICSRs was evaluated by completeness of information and diagnostic certainty using the Automated Brighton Collaboration case definition tool (ABC-tool) for narcolepsy. After de-duplication, a total of 1333 ICSRs of narcolepsy and/or cataplexy following pandemic influenza vaccine were identified, originating from 18 countries worldwide. Most of the ICSRs (61.9%) originated from the signaling countries, Sweden and Finland. Although de-duplication of case reports was carried out, it is suspected that many duplicates exist, in particular from Sweden. The majority of the ICSRs (95.3%), reported exposure to Pandemrix®. Only few reports were received for Arepanrix® (1.6%) or Focetria® (0.5%), and Celvapan® (0.1%). Of those ICSRs reporting age, 73.1% concerned persons below age of 20years. When using the ABC-tool, all ICSRs were classified as having insufficient information to meet the Brighton Collaboration case definition of narcolepsy. An increase in reporting of narcolepsy appeared in Eudravigilance only after awareness was raised by the national authorities. Most narcolepsy reports were received from countries where the signal initially occurred, and were related to Pandemrix® in children/adolescents. Basic information about the patient and the exposure was present in most of the ICSRs. The ICSRs captured by Eudravigilance however, do not collect enough information to assess the diagnostic certainty according to the Brighton Collaboration case definition. Copyright © 2016 Elsevier Ltd. All rights reserved.
Clinical course of H1N1-vaccine-related narcolepsy.

PubMed

Sarkanen, Tomi; Alakuijala, Anniina; Partinen, Markku

2016-03-01

To follow and analyze the clinical course and quality of life of Pandemrix H1N1-vaccine-related narcolepsy (pNT1). Twenty-six drug-naïve confirmed pNT1 subjects completed Epworth Sleepiness Scale (ESS), Ullanlinna Narcolepsy Scale (UNS), Swiss Narcolepsy Scale (SNS), Rimon's Brief Depression scale (RDS), and WHO-5 Well-being index questionnaires near the disease onset and in a follow-up a minimum of two years later. The number of cataplexies and body mass index (BMI) were recorded. The effects of hypocretin-1 levels and sleep recording results were analyzed. The findings at the follow-up visit were compared with 25 non-vaccine-related type 1 narcolepsy (NT1) subjects. In pNT1, RDS score decreased significantly (mean 10.2, SD 4.7 vs mean 6.7, SD 4.5, p = 0.003). Median of BMI increased from 20.8 kg m(-2) to 23.4 kg m(-2), p <0.001. There were no significant differences in other sleep scores. However, deviation and range in questionnaire scores at the follow-up were wide. Subjects with very low or undetectable hypocretin-1 levels had worse scores in UNS (mean 26.4, SD 6.95 vs mean 19.1, SD 3.83, p = 0.006) and ESS (mean 17.9, SD = 4.29 vs mean 14.1, SD = 3.70, p = 0.047) than those with hypocretin-1 levels of 20-110 pg/mL. Most disabling symptoms were excessive daytime sleepiness and disturbed sleep. There were no significant differences between the scores in pNT1 and NT1. Clinical course of pNT1 is heterogeneous but the evolution of pNT1 seems similar to NT1. Lower hypocretin levels in pNT1 are associated with a more severe phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.
Profile of suvorexant in the management of insomnia

PubMed Central

Sutton, Eliza L

2015-01-01

Suvorexant, approved in late 2014 in the United States and Japan for the treatment of insomnia characterized by difficulty achieving and/or maintaining sleep, is a dual orexin receptor antagonist and the first drug in its class to reach the market. Its development followed from the 1998 discovery of orexins (also called hypocretins), excitatory neuropeptides originating from neurons in the hypothalamus involved in regulation of sleep and wake, feeding behavior and energy regulation, motor activity, and reward-seeking behavior. Suvorexant objectively improves sleep, shortening the time to achieve persistent sleep and reducing wake after sleep onset, although at approved doses (≤20 mg) the benefit was subjectively assessed as modest. Its half-life of 12 hours is relatively long for a modern hypnotic; however, at approved doses (≤20 mg) next-day sedation and driving impairment were much less apparent than at higher doses. Suvorexant is metabolized by the hepatic CYP3A system and should be avoided in combination with strong CYP3A inhibitors. Drug levels are higher in women and obese people; hence, dosing should be conservative in obese women. Administration with food delays drug absorption and is not advised. No dose adjustment is needed for advanced age, renal impairment, or mild-to-moderate hepatic impairment. Suvorexant in contraindicated in narcolepsy and has not been studied in children. In alignment with the changes begun in 2013 in the labeling of other hypnotics, the United States Food and Drug Administration advises that the lowest dose effective to treat symptoms be used and that patients be advised of the possibility of next-day impairment in function, including driving. Infrequent but notable side effects included abnormal dreams, sleep paralysis, and suicidal ideation that were dose-related and reported to be mild. Given its mechanism of action, cataplexy and rapid eye movement (REM) sleep behavior disorder could potentially occur in some patients taking this medication. PMID:26648692
Multiple sleep latency measures in narcolepsy and behaviourally induced insufficient sleep syndrome.

PubMed

Marti, Isabelle; Valko, Philipp O; Khatami, Ramin; Bassetti, Claudio L; Baumann, Christian R

2009-12-01

Short mean latencies to the first epoch of non-rapid eye movement sleep stage 1 (NREM1) and the presence of >or= 2 sleep onset REM (SOREM) periods on multiple sleep latency test (MSLT) occur in both narcolepsy-cataplexy (NC) and behaviourally induced insufficient sleep syndrome (BIISS). It is not known whether specific MSLT findings help differentiate the two disorders. We analyzed MSLT data including sleep latencies to and between different sleep stages of 60 age-, gender- and body mass index (BMI)-matched subjects (hypocretin-deficient NC, actigraphy-confirmed BIISS, healthy controls: each 20). Mean latency (in minutes) to NREM1 sleep was significantly shorter in NC (1.8+/-1.5) than in BIISS (4.7+/-2.1, p<0.001) and controls (11.4+/-3.3, p<0.001). Mean latency to NREM2 sleep was similar in NC (8.6+/-4.7) and BIISS (8.1+/-2.7, p=0.64); latency to either NREM2 or rapid eye movement (REM) sleep (i.e., the sum of the sleep latency to NREM1 and the duration of the first NREM1 sleep sequence), however, was shorter in NC (4.4+/-2.9) than in BIISS (7.9+/-3.5, p<0.001). Referring to all naps with SOREM periods, the sequence NREM1-REM-NREM2 was more common (71%) in NC than in BIISS (15%, p<0.001), reflecting the shorter latency from NREM1 to NREM2 in BIISS (3.7+/-2.5) than in NC (6.1+/-5.9, p<0.001). Our findings show that both sleepiness (as measured by NREM1 sleep latency) and REM sleep propensity are higher in NC than in BIISS. Furthermore, our finding of frequent REM sleep prior to NREM2 sleep in NC is in line with the recent assumption of an insufficient NREM sleep intensity in NC. Together with detailed clinical interviews, sleep logs, actigraphy, and nocturnal polysomnography, mean sleep latencies to NREM1
Ultra-high-performance liquid chromatography tandem mass spectrometry determination of GHB, GHB-glucuronide in plasma and cerebrospinal fluid of narcoleptic patients under sodium oxybate treatment.

PubMed

Tittarelli, Roberta; Pichini, Simona; Pedersen, Daniel S; Pacifici, Roberta; Moresco, Monica; Pizza, Fabio; Busardò, Francesco Paolo; Plazzi, Giuseppe

2017-05-01

Sodium oxybate (Xyrem ® ), the sodium salt of γ- hydroxybutyric acid (GHB), is a first-line treatment of the symptoms induced by type 1 narcolepsy (NT1) and it is highly effective in improving sleep architecture, decreasing excessive daytime sleepiness and the frequency of cataplexy attacks. Using an ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) validated method, GHB was determined together with its glucuronide (GHB-gluc), in plasma and cerebrospinal fluid (CSF) samples of NT1 patients under sodium oxybate treatment. To characterize the plasma pharmacokinetics of GHB, three subjects with NT1 were administered at time 0 and 4h with 1.25, 1.5 and 3.55g Xyrem ® , respectively and had their blood samples collected at 7 time points throughout an 8-h session. CSF specimens, collected for orexin A measurement from the same three subjects 6h after their second administration, were also tested. The results obtained suggested that GHB plasma values increased disproportionally with the rising doses, (C max0-4 : 12.53, 32.95 and 69.62μg/mL; C max4-8 : 44.93, 75.03 and 111.93μg/mL for total Xyrem ® dose of 2.5, 3 and 7g respectively) indicating non-linear dose-response. GHB-Gluc was present only in traces in all plasma samples from treated patients, not changing with increasing Xyrem ® doses. GHB values of 5.62, 6.10 and 17.74μg/mL for 2, 3 and 7g Xyrem ® were found in CSF with a significant difference from control values. GHB-Gluc was found in negligible concentrations with no differences to those of control individuals. In conclusion this simple and fast UHPLC-MS/MS method proved useful for pharmacokinetic studies and therapeutic drug monitoring of GHB in narcoleptic patients treated with sodium oxybate. Copyright © 2017 Elsevier B.V. All rights reserved.
Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

PubMed Central

Dugovic, Christine; Shelton, Jonathan E.; Yun, Sujin; Bonaventure, Pascal; Shireman, Brock T.; Lovenberg, Timothy W.

2014-01-01

In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R) and orexin-2 (OX2R) receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM) sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM) and REM sleep following oral dosing (10 and 30 mg/kg) at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion). When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg) increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg) did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic. PMID:24592208
Comparison of driving simulator performance and neuropsychological testing in narcolepsy.

PubMed

Kotterba, Sylvia; Mueller, Nicole; Leidag, Markus; Widdig, Walter; Rasche, Kurt; Malin, Jean-Pierre; Schultze-Werninghaus, Gerhard; Orth, Maritta

2004-09-01

Daytime sleepiness and cataplexy can increase automobile accident rates in narcolepsy. Several countries have produced guidelines for issuing a driving license. The aim of the study was to compare driving simulator performance and neuropsychological test results in narcolepsy in order to evaluate their predictive value regarding driving ability. Thirteen patients with narcolepsy (age: 41.5+/-12.9 years) and 10 healthy control patients (age: 55.1+/-7.8 years) were investigated. By computer-assisted neuropsychological testing, vigilance, alertness and divided attention were assessed. In a driving simulator patients and controls had to drive on a highway for 60 min (mean speed of 100 km/h). Different weather and daytime conditions and obstacles were presented. Epworth Sleepiness Scale-Scores were significantly raised (narcolepsy patients: 16.7+/-5.1, controls: 6.6+/-3.6, P < or = 0.001). The accident rate of the control patients increased (3.2+/-1.8 versus 1.3+/-1.5, P < or = 0.01). Significant differences in concentration lapses (e.g. tracking errors and deviation from speed limit) could not be revealed (9.8+/-3.5 versus 7.1+/-3.2, pns). Follow-up investigation in five patients after an optimising therapy could demonstrate the decrease in accidents due to concentration lapses (P < or = 0.05). Neuropsychological testing (expressed as percentage compared to a standardised control population) revealed deficits in alertness (32.3+/-28.6). Mean percentage scores of divided attention (56.9+/-25.4) and vigilance (58.7+/-26.8) were in a normal range. There was, however, a high inter-individual difference. There was no correlation between driving performance and neuropsychological test results or ESS Score. Neuropsychological test results did not significantly change in the follow-up. The difficulties encountered by the narcolepsy patient in remaining alert may account for sleep-related motor vehicle accidents. Driving simulator investigations are closely related to real traffic situations than isolated neuropsychological tests. At the present time the driving simulator seems to be a useful instrument judging driving ability especially in cases with ambiguous neuropsychological results.
GHB Pharmacology and Toxicology: Acute Intoxication, Concentrations in Blood and Urine in Forensic Cases and Treatment of the Withdrawal Syndrome

PubMed Central

Busardò, Francesco P.; Jones, Alan W.

2015-01-01

The illicit recreational drug of abuse, γ-hydroxybutyrate (GHB) is a potent central nervous system depressant and is often encountered during forensic investigations of living and deceased persons. The sodium salt of GHB is registered as a therapeutic agent (Xyrem®), approved in some countries for the treatment of narcolepsy-associated cataplexy and (Alcover®) is an adjuvant medication for detoxification and withdrawal in alcoholics. Trace amounts of GHB are produced endogenously (0.5-1.0 mg/L) in various tissues, including the brain, where it functions as both a precursor and a metabolite of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). Available information indicates that GHB serves as a neurotransmitter or neuromodulator in the GABAergic system, especially via binding to the GABA-B receptor subtype. Although GHB is listed as a controlled substance in many countries abuse still continues, owing to the availability of precursor drugs, γ-butyrolactone (GBL) and 1,4-butanediol (BD), which are not regulated. After ingestion both GBL and BD are rapidly converted into GHB (t½ ~1 min). The Cmax occurs after 20-40 min and GHB is then eliminated from plasma with a half-life of 30-50 min. Only about 1-5% of the dose of GHB is recoverable in urine and the window of detection is relatively short (3-10 h). This calls for expeditious sampling when evidence of drug use and/or abuse is required in forensic casework. The recreational dose of GHB is not easy to estimate and a concentration in plasma of ~100 mg/L produces euphoria and disinhibition, whereas 500 mg/L might cause death from cardiorespiratory depression. Effective antidotes to reverse the sedative and intoxicating effects of GHB do not exist. The poisoned patients require supportive care, vital signs should be monitored and the airways kept clear in case of emesis. After prolonged regular use of GHB tolerance and dependence develop and abrupt cessation of drug use leads to unpleasant withdrawal symptoms. There is no evidence-based protocol available to deal with GHB withdrawal, apart from administering benzodiazepines. PMID:26074743
Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells

PubMed Central

Pitoiset, Fabien; Regnault, Armelle; Tran, Tu Anh; Liblau, Roland; Klatzmann, David; Rosenzwajg, Michelle

2017-01-01

Narcolepsy is a rare neurologic disorder characterized by excessive daytime sleepiness, cataplexy and disturbed nocturnal sleep patterns. Narcolepsy type 1 (NT1) has been shown to result from a selective loss of hypothalamic hypocretin-secreting neurons with patients typically showing low CSF-hypocretin levels (<110 pg/ml). This specific loss of hypocretin and the strong association with the HLA-DQB1*06:02 allele led to the hypothesis that NT1 could be an immune-mediated pathology. Moreover, susceptibility to NT1 has recently been associated with several pathogens, particularly with influenza A H1N1 virus either through infection or vaccination. The goal of this study was to compare peripheral blood immune cell populations in recent onset pediatric NT1 subjects (post or non-post 2009-influenza A H1N1 vaccination) to healthy donors. We demonstrated an increased number of central memory CD4+ T cells (CD62L+ CD45RA-) associated to an activated phenotype (increase in CD69 and CD25 expression) in NT1 patients. Percentage and absolute count of regulatory T cells (Tregs) in NT1 patients were increased associated with an activated phenotype (increase in GITR and LAP expression), and of activated memory phenotype. Cytokine production by CD4+ and CD8+ T cells after activation was not modified in NT1 patients. In H1N1 vaccinated NT1 patients, absolute counts of CD3+, CD8+ T cells, and B cells were increased compared to non-vaccinated NT1 patients. These results support a global T cell activation in NT1 patients and thus support a T cell-mediated autoimmune origin of NT1, but do not demonstrate the pathological role of H1N1 prophylactic vaccination. They should prompt further studies of T cells, particularly of Tregs (such as suppression and proliferation antigen specific assays, and also T-cell receptor sequencing), in NT1. PMID:28107375

Orexin OX2 Receptor Antagonists as Sleep Aids.

PubMed

Jacobson, Laura H; Chen, Sui; Mir, Sanjida; Hoyer, Daniel

The discovery of the orexin system represents the single major progress in the sleep field of the last three to four decades. The two orexin peptides and their two receptors play a major role in arousal and sleep/wake cycles. Defects in the orexin system lead to narcolepsy with cataplexy in humans and dogs and can be experimentally reproduced in rodents. At least six orexin receptor antagonists have reached Phase II or Phase III clinical trials in insomnia, five of which are dual orexin receptor antagonists (DORAs) that target both OX 1 and OX 2 receptors (OX 2 Rs). All clinically tested DORAs induce and maintain sleep: suvorexant, recently registered in the USA and Japan for insomnia, represents the first hypnotic principle that acts in a completely different manner from the current standard medications. It is clear, however, that in the clinic, all DORAs promote sleep primarily by increasing rapid eye movement (REM) and are almost devoid of effects on slow-wave (SWS) sleep. At present, there is no consensus on whether the sole promotion of REM sleep has a negative impact in patients suffering from insomnia. However, sleep onset REM (SOREM), which has been documented with DORAs, is clearly an undesirable effect, especially for narcoleptic patients and also in fragile populations (e.g. elderly patients) where REM-associated loss of muscle tone may promote an elevated risk of falls. Debate thus remains as to the ideal orexin agent to achieve a balanced increase in REM and non-rapid eye movement (NREM) sleep. Here, we review the evidence that an OX 2 R antagonist should be at least equivalent, or perhaps superior, to a DORA for the treatment of insomnia. An OX 2 R antagonist may produce more balanced sleep than a DORA. Rodent sleep experiments show that the OX 2 R is the primary target of orexin receptor antagonists in sleep modulation. Furthermore, an OX 2 R antagonist should, in theory, have a lower narcoleptic/cataplexic potential. In the clinic, the situation remains equivocal, since OX 2 R antagonists are in early stages: MK-1064 has completed Phase I, and MIN202 is currently in clinical Phase II/III trials. However, data from insomnia patients have not yet been released. Promotional material suggests that balanced sleep is indeed induced by MIN-202, whereas in volunteers MK-1064 has been reported to act similarly to DORAs.
Anesthetic Management of Narcolepsy Patients During Surgery: A Systematic Review.

PubMed

Hu, Sally; Singh, Mandeep; Wong, Jean; Auckley, Dennis; Hershner, Shelley; Kakkar, Rahul; Thorpy, Michael J; Chung, Frances

2018-01-01

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness, sleep paralysis, and/or hypnagogic/hypnopompic hallucinations, and in some cases cataplexy. The response to anesthetic medications and possible interactions in narcolepsy patients is unclear in the perioperative period. In this systematic review, we aim to evaluate the current evidence on the perioperative outcomes and anesthetic considerations in narcolepsy patients. Electronic literature search of Medline, Medline in-process, Embase, Cochrane Database of Systematic Reviews databases, international conference proceedings, and abstracts was conducted in November 2015 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guideline. A total of 3757 articles were screened using a 2-stage strategy (title-abstract followed by full text). We included case studies/series, cohort studies, and randomized controlled trials of narcolepsy patients undergoing surgical procedures under anesthesia or sedation. Preoperative narcolepsy symptoms and sleep study data, anesthetic technique, and perioperative complications were extracted. Screening of articles, data extraction, and compilation were conducted by 2 independent reviewers and any conflict was resolved by the senior author. A total of 19 studies including 16 case reports and 3 case series were included and evaluated. The majority of these patients received general anesthesia, whereas a small percentage of patients received regional anesthesia. Reported complications of narcolepsy patients undergoing surgeries were mainly related to autonomic dysregulation, or worsening of narcolepsy symptoms intra/postoperatively. Narcolepsy symptoms worsened only in those patient populations where the preoperative medications were either discontinued or reduced (mainly in obstetric patients). In narcolepsy patients, use of depth of anesthesia monitoring and total intravenous technique may have some advantage in terms of safety profile. Several patients undergoing neurosurgery involving the hypothalamus or third or four ventricles developed new-onset narcolepsy. We found a paucity of prospective clinical trials in this patient population, as most of the studies were case reports or observational studies. Continuation of preoperative medications, depth of anesthesia monitoring, use of multimodal analgesia with short-acting agents and regional anesthesia techniques were associated with favorable outcomes. Obstetric patients may be at greater risk for worsening narcolepsy symptoms, possibly related to a reduction or discontinuation of medications. For neurosurgical procedures involving the hypothalamus or third and fourth ventricle, postoperative considerations should include monitoring for symptoms of narcolepsy. Future studies are needed to better define perioperative risks associated with anesthesia and surgery in this population of patients.
Clinical analysis of anti-Ma2-associated encephalitis.

PubMed

Dalmau, Josep; Graus, Francesc; Villarejo, Alberto; Posner, Jerome B; Blumenthal, Deborah; Thiessen, Brian; Saiz, Albert; Meneses, Patricio; Rosenfeld, Myrna R

2004-08-01

Increasing experience indicates that anti-Ma2-associated encephalitis differs from classical paraneoplastic limbic or brainstem encephalitis, and therefore may be unrecognized. To facilitate its diagnosis we report a comprehensive clinical analysis of 38 patients with anti-Ma2 encephalitis. Thirty-four (89%) patients presented with isolated or combined limbic, diencephalic or brainstem dysfunction, and four with other syndromes. Considering the clinical and MRI follow-up, 95% of the patients developed limbic, diencephalic or brainstem encephalopathy. Only 26% had classical limbic encephalitis. Excessive daytime sleepiness affected 32% of the patients, sometimes with narcolepsy-cataplexy and low CSF hypocretin. Additional hormonal or MRI abnormalities indicated diencephalic-hypothalamic involvement in 34% of the patients. Eye movement abnormalities were prominent in 92% of the patients with brainstem dysfunction, but those with additional limbic or diencephalic deficits were most affected; 60% of these patients had vertical gaze paresis that sometimes evolved to total external ophthalmoplegia. Three patients developed atypical parkinsonism, and two a severe hypokinetic syndrome with a tendency to eye closure and dramatic reduction of verbal output. Neurological symptoms preceded the tumour diagnosis in 62% of the patients. Brain MRI abnormalities were present in 74% of all patients and 89% of those with limbic or diencephalic dysfunction. Among the 34 patients with cancer, 53% had testicular germ-cell tumours. Two patients without evidence of cancer had testicular microcalcification and one cryptorchidism, risk factors for testicular germ-cell tumours. After neurological syndrome development, 17 of 33 patients received oncological treatment (nine also immunotherapy), 10 immunotherapy alone, and six no treatment. Overall, 33% of the patients had neurological improvement, three with complete recovery; 21% had long-term stabilization, and 46% deteriorated. Features significantly associated with improvement or stabilization included, male gender, age <45 years, testicular tumour with complete response to treatment, absence of anti-Ma1 antibodies and limited CNS involvement. Immunosuppression was not found to be associated with improvement but was clearly effective in some patients. Fifteen patients (10 women, five men) had additional antibodies to Ma1. These patients were more likely to have tumours other than testicular cancer and to develop ataxia, and had a worse prognosis than patients with only anti-Ma2 antibodies (two women, 21 men); 67% of deceased patients had anti-Ma1 antibodies. Anti-Ma2 encephalitis (with or without anti-Ma1 antibodies) should be suspected in patients with limbic, diencephalic or brainstem dysfunction, MRI abnormalities in these regions, and inflammatory changes in the CSF. In young male patients, the primary tumour is usually in the testis, in other patients the leading neoplasm is lung cancer.
Increased β-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases.

PubMed

Ambati, A; Poiret, T; Svahn, B-M; Valentini, D; Khademi, M; Kockum, I; Lima, I; Arnheim-Dahlström, L; Lamb, F; Fink, K; Meng, Q; Kumar, A; Rane, L; Olsson, T; Maeurer, M

2015-09-01

Type 1 narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy associated with the HLA allele DQB1*06:02. Genetic predisposition along with external triggering factors may drive autoimmune responses, ultimately leading to the selective loss of hypocretin-positive neurons. The aim of this study was to investigate potential aetiological factors in Swedish cases of postvaccination (Pandemrix) narcolepsy defined by interferon-gamma (IFNγ) production from immune cells in response to molecularly defined targets. Cellular reactivity defined by IFNγ production was examined in blood from 38 (HLA-DQB1*06:02(+) ) Pandemrix-vaccinated narcolepsy cases and 76 (23 HLA-DQB1*06:02(+) and 53 HLA-DQB1*06:02(-) ) control subjects, matched for age, sex and exposure, using a variety of different antigens: β-haemolytic group A streptococcal (GAS) antigens (M5, M6 and streptodornase B), influenza (the pandemic A/H1N1/California/7/09 NYMC X-179A and A/H1N1/California/7/09 NYMC X-181 vaccine antigens, previous Flu-A and -B vaccine targets, A/H1N1/Brisbane/59/2007, A/H1N1/Solomon Islands/3/2006, A/H3N2/Uruguay/716/2007, A/H3N2/Wisconsin/67/2005, A/H5N1/Vietnam/1203/2004 and B/Malaysia/2506/2004), noninfluenza viral targets (CMVpp65, EBNA-1 and EBNA-3) and auto-antigens (hypocretin peptide, Tribbles homolog 2 peptide cocktail and extract from rat hypothalamus tissue). IFN-γ production was significantly increased in whole blood from narcolepsy cases in response to streptococcus serotype M6 (P = 0.0065) and streptodornase B protein (P = 0.0050). T-cell recognition of M6 and streptodornase B was confirmed at the single-cell level by intracellular cytokine (IL-2, IFNγ, tumour necrosis factor-alpha and IL-17) production after stimulation with synthetic M6 or streptodornase B peptides. Significantly, higher (P = 0.02) titres of serum antistreptolysin O were observed in narcolepsy cases, compared to vaccinated controls. β-haemolytic GAS may be involved in triggering autoimmune responses in patients who developed narcolepsy symptoms after vaccination with Pandemrix in Sweden, characterized by a Streptococcus pyogenes M-type-specific IFN-γ cellular immune response. © 2015 The Association for the Publication of the Journal of Internal Medicine.
Prevalence and Clinical Correlates of a Short Onset REM Period (SOREMP) during Routine PSG

PubMed Central

Cairns, Alyssa; Bogan, Richard

2015-01-01

Study Objectives: The objectives of this study were to quantify the (1) sensitivity and specificity of nocturnal PSG SOREMP (REM latency ≤ 15 min) for narcolepsy in those being evaluated for hypersomnolence and (2) prevalence and predictors of SOREMP during baseline PSG for patients being evaluated for various sleep disorders. Design: This was a retrospective analysis of a large repository of de-identified PSG and MSLT test results from 2007 to 2013. Setting and Patients: Patient records were retrieved from a repository of studies completed at a variety of sleep laboratories across the USA. Included in the analyses were 79,651 general sleep clinic patients (without an MSLT; 48% male; 72% Caucasian) and an additional 3,059 patients (31.3% male; 72% Caucasian) being evaluated for hypersomnolence (with a consecutive MSLT). Interventions: NA. Measurements and Results: For patients being evaluated for hypersomnolence, the prevalence of PSG SOREMP increased in a dose-response fashion with the number of REM onsets that occurred on a consecutive MSLT (0.5% for no MSLT SOREMPs to > 33.0% for those with 5 MSLT SOREMPs). Overall, having a PSG SOREMP was highly specific (99.5%; 95% CI: 99.1–99.7%) but not sensitive (6.7%; 95% CI: 4.7–9.2%) for narcolepsy. The prevalence of PSG SOREMP for patients in the general sleep clinic sample (i.e., not being evaluated by a consecutive MSLT) was 0.8% and was much higher in those that work night/swing shift. In adjusted models, African American race contributed to the most variance in PSG SOREMP. Conclusions: A short onset rapid eye movement (REM) latency occurs rarely in general sleep clinic samples (< 1.0%), but is highly specific for the diagnosis of narcolepsy. Although rare, the prevalence of the phenomenon is much higher than the estimated prevalence of narcolepsy and may provide a critical opportunity for practitioners to identify narcolepsy in sleep clinic patients. These data also suggest that the utility of polysomnography (PSG) short onset REM peroid (SOREMP) for the diagnosis of narcolepsy may be altered by a history of shift/night work and/ or other factors that may allow for a rebound of REM sleep (e.g., undergoing a positive airway pressure titration), supporting published guidelines that other sleep disorders and insufficient and/or poorly timed sleep should be ruled out and/or adequately controlled for prior to conducting sleep testing. Further research is needed to understand racial differences in PSG SOREMP and narcolepsy. This study was limited in that data on cataplexy (with exception to that in final diagnosis) and habitual sleep duration were not available. Citation: Cairns A, Bogan R. Prevalence and clinical correlates of a short onset REM period (SOREMP) during routine PSG. SLEEP 2015;38(10):1575–1581. PMID:26039966
[Adult onset Niemann-Pick type C disease and psychosis: literature review].

PubMed

Maubert, A; Hanon, C; Metton, J-P

2013-10-01

Niemann-Pick type C disease (NPC) is a rare hereditary disease, which psychiatrists do not face often in France. Indeed, only a couple of articles specifically describing the psychiatric-disorders in the adult form have been published. And for the most part, they were not written by psychiatrists. This comprehensive international literature review aims at providing knowledge on this disease to French psychiatrists. To achieve this literature review, we used the "PubMed" search engine, looking for the following keywords: Niemann-Pick type C AND (schizophrenia OR psychosis). Niemann-Pick type C disease (NPC) is a rare, neurovisceral, autosomal recessive disease, with an extremely heterogeneous clinical presentation. It is characterized by a wide range of symptoms that are not specific, such as neurological, systemic or psychiatric symptoms. The adult form of the disease concerns a small proportion (5 %) of the people affected and is usually expressed as a neurological form. A variety of progressive and disabling symptoms are encountered, mainly cerebellar signs (cerebellar ataxia, impaired gait, dysarthria), but also movement disorders, cataplexy, seizures and dysphagia. Patients face constant cognitive deterioration, which can result in severe dementia. Abnormal saccadic eye movement is often the first manifestation of the disease. Supranuclear gaze palsy is considered to be a specific sign and should be systematically searched for. In terms of systemic signs, the usual infantile hepatosplenomegaly is very fickle in the adult form; if present, it is usually asymptomatic. Non-specific psychiatric symptoms are often associated with NPC disease. For one third of cases, it can also express as an isolated psychiatric-disorder form, such as schizophrenia-like psychosis (paranoid delusions, auditory hallucinations, interpretative thoughts, and disorganization), depression, bipolar disorder, obsessive-compulsive behaviour and behavioural problems (sleep disorders, hyperactivity, agitation, aggressiveness or self-mutilations). This psychiatric overview is mostly atypical and is accompanied by visual hallucinations, confusion, symptom fluctuations, treatment resistance or aggravation with neuroleptic drugs, catatonia, progressive cognitive decline, but also seizures. The late appearance of neurological manifestations is often wrongfully attributed to the effects of antipsychotic medication, which generates tardy diagnosis. Most of NPC affected patients die prematurely. NPC diagnosis is based on a filipin test on a fibroblast culture from a skin biopsy and also on a sequencing of the NPC1 and NPC2 genes. Routine laboratory biochemistry profiles are generally normal. The early diagnosis is fundamental to deploy the best follow-up care. The patient should therefore be in contact with a reference centre. Until recently, NPC treatment consisted in supportive therapies and symptomatic drugs, useful, however, with variable efficacy. The recent discovery of a medicine called Miglustat (N-butyldeoxynojirimycin; NB-DJN; Zavesca(®), Actelion Pharmaceuticals Ltd.) which improves the disease evolution, should encourage psychiatrists to look for it in every atypical psychosis. Copyright © 2013 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.
Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

ClinicalTrials.gov

2017-09-28

Rare Disorders; Undiagnosed Disorders; Disorders of Unknown Prevalence; Cornelia De Lange Syndrome; Prenatal Benign Hypophosphatasia; Perinatal Lethal Hypophosphatasia; Odontohypophosphatasia; Adult Hypophosphatasia; Childhood-onset Hypophosphatasia; Infantile Hypophosphatasia; Hypophosphatasia; Kabuki Syndrome; Bohring-Opitz Syndrome; Narcolepsy Without Cataplexy; Narcolepsy-cataplexy; Hypersomnolence Disorder; Idiopathic Hypersomnia Without Long Sleep Time; Idiopathic Hypersomnia With Long Sleep Time; Idiopathic Hypersomnia; Kleine-Levin Syndrome; Kawasaki Disease; Leiomyosarcoma; Leiomyosarcoma of the Corpus Uteri; Leiomyosarcoma of the Cervix Uteri; Leiomyosarcoma of Small Intestine; Acquired Myasthenia Gravis; Addison Disease; Hyperacusis (Hyperacousis); Juvenile Myasthenia Gravis; Transient Neonatal Myasthenia Gravis; Williams Syndrome; Lyme Disease; Myasthenia Gravis; Marinesco Sjogren Syndrome(Marinesco-Sjogren Syndrome); Isolated Klippel-Feil Syndrome; Frasier Syndrome; Denys-Drash Syndrome; Beckwith-Wiedemann Syndrome; Emanuel Syndrome; Isolated Aniridia; Beckwith-Wiedemann Syndrome Due to Paternal Uniparental Disomy of Chromosome 11; Beckwith-Wiedemann Syndrome Due to Imprinting Defect of 11p15; Beckwith-Wiedemann Syndrome Due to 11p15 Translocation/Inversion; Beckwith-Wiedemann Syndrome Due to 11p15 Microduplication; Beckwith-Wiedemann Syndrome Due to 11p15 Microdeletion; Axenfeld-Rieger Syndrome; Aniridia-intellectual Disability Syndrome; Aniridia - Renal Agenesis - Psychomotor Retardation; Aniridia - Ptosis - Intellectual Disability - Familial Obesity; Aniridia - Cerebellar Ataxia - Intellectual Disability; Aniridia - Absent Patella; Aniridia; Peters Anomaly - Cataract; Peters Anomaly; Potocki-Shaffer Syndrome; Silver-Russell Syndrome Due to Maternal Uniparental Disomy of Chromosome 11; Silver-Russell Syndrome Due to Imprinting Defect of 11p15; Silver-Russell Syndrome Due to 11p15 Microduplication; Syndromic Aniridia; WAGR Syndrome; Wolf-Hirschhorn Syndrome; 4p16.3 Microduplication Syndrome; 4p Deletion Syndrome, Non-Wolf-Hirschhorn Syndrome; Autosomal Recessive Stickler Syndrome; Stickler Syndrome Type 2; Stickler Syndrome Type 1; Stickler Syndrome; Mucolipidosis Type 4; X-linked Spinocerebellar Ataxia Type 4; X-linked Spinocerebellar Ataxia Type 3; X-linked Intellectual Disability - Ataxia - Apraxia; X-linked Progressive Cerebellar Ataxia; X-linked Non Progressive Cerebellar Ataxia; X-linked Cerebellar Ataxia; Vitamin B12 Deficiency Ataxia; Toxic Exposure Ataxia; Unclassified Autosomal Dominant Spinocerebellar Ataxia; Thyroid Antibody Ataxia; Sporadic Adult-onset Ataxia of Unknown Etiology; Spinocerebellar Ataxia With Oculomotor Anomaly; Spinocerebellar Ataxia With Epilepsy; Spinocerebellar Ataxia With Axonal Neuropathy Type 2; Spinocerebellar Ataxia Type 8; Spinocerebellar Ataxia Type 7; Spinocerebellar Ataxia Type 6; Spinocerebellar Ataxia Type 5; Spinocerebellar Ataxia Type 4; Spinocerebellar Ataxia Type 37; Spinocerebellar Ataxia Type 36; Spinocerebellar Ataxia Type 35; Spinocerebellar Ataxia Type 34; Spinocerebellar Ataxia Type 32; Spinocerebellar Ataxia Type 31; Spinocerebellar Ataxia Type 30; Spinocerebellar Ataxia Type 3; Spinocerebellar Ataxia Type 29; Spinocerebellar Ataxia Type 28; Spinocerebellar Ataxia Type 27; Spinocerebellar Ataxia Type 26; Spinocerebellar Ataxia Type 25; Spinocerebellar Ataxia Type 23; Spinocerebellar Ataxia Type 22; Spinocerebellar Ataxia Type 21; Spinocerebellar Ataxia Type 20; Spinocerebellar Ataxia Type 2; Spinocerebellar Ataxia Type 19/22; Spinocerebellar Ataxia Type 18; Spinocerebellar Ataxia Type 17; Spinocerebellar Ataxia Type 16; Spinocerebellar Ataxia Type 15/16; Spinocerebellar Ataxia Type 14; Spinocerebellar Ataxia Type 13; Spinocerebellar Ataxia Type 12; Spinocerebellar Ataxia Type 11; Spinocerebellar Ataxia Type 10; Spinocerebellar Ataxia Type 1 With Axonal Neuropathy; Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia - Unknown; Spinocerebellar Ataxia - Dysmorphism; Non Progressive Epilepsy and/or Ataxia With Myoclonus as a Major Feature; Spectrin-associated Autosomal Recessive Cerebellar Ataxia; Spasticity-ataxia-gait Anomalies Syndrome; Spastic Ataxia With Congenital Miosis; Spastic Ataxia - Corneal Dystrophy; Spastic Ataxia; Rare Hereditary Ataxia; Rare Ataxia; Recessive Mitochondrial Ataxia Syndrome; Progressive Epilepsy and/or Ataxia With Myoclonus as a Major Feature; Posterior Column Ataxia - Retinitis Pigmentosa; Post-Stroke Ataxia; Post-Head Injury Ataxia; Post Vaccination Ataxia; Polyneuropathy - Hearing Loss - Ataxia - Retinitis Pigmentosa - Cataract; Muscular Atrophy - Ataxia - Retinitis Pigmentosa - Diabetes Mellitus; Non-progressive Cerebellar Ataxia With Intellectual Disability; Non-hereditary Degenerative Ataxia; Paroxysmal Dystonic Choreathetosis With Episodic Ataxia and Spasticity; Olivopontocerebellar Atrophy - Deafness; NARP Syndrome; Myoclonus - Cerebellar Ataxia - Deafness; Multiple System Atrophy, Parkinsonian Type; Multiple System Atrophy, Cerebellar Type; Multiple System Atrophy; Maternally-inherited Leigh Syndrome; Machado-Joseph Disease Type 3; Machado-Joseph Disease Type 2; Machado-Joseph Disease Type 1; Lethal Ataxia With Deafness and Optic Atrophy; Leigh Syndrome; Leukoencephalopathy With Mild Cerebellar Ataxia and White Matter Edema; Leukoencephalopathy - Ataxia - Hypodontia - Hypomyelination; Leigh Syndrome With Nephrotic Syndrome; Leigh Syndrome With Leukodystrophy; Leigh Syndrome With Cardiomyopathy; Late-onset Ataxia With Dementia; Intellectual Disability-hyperkinetic Movement-truncal Ataxia Syndrome; Infection or Post Infection Ataxia; Infantile-onset Autosomal Recessive Nonprogressive Cerebellar Ataxia; Infantile Onset Spinocerebellar Ataxia; GAD Ataxia; Hereditary Episodic Ataxia; Gliadin/Gluten Ataxia; Friedreich Ataxia; Fragile X-associated Tremor/Ataxia Syndrome; Familial Paroxysmal Ataxia; Exposure to Medications Ataxia; Episodic Ataxia With Slurred Speech; Episodic Ataxia Unknown Type; Episodic Ataxia Type 7; Episodic Ataxia Type 6; Episodic Ataxia Type 5; Episodic Ataxia Type 4; Episodic Ataxia Type 3; Episodic Ataxia Type 1; Epilepsy and/or Ataxia With Myoclonus as Major Feature; Early-onset Spastic Ataxia-neuropathy Syndrome; Early-onset Progressive Neurodegeneration - Blindness - Ataxia - Spasticity; Early-onset Cerebellar Ataxia With Retained Tendon Reflexes; Early-onset Ataxia With Dementia; Childhood-onset Autosomal Recessive Slowly Progressive Spinocerebellar Ataxia; Dilated Cardiomyopathy With Ataxia; Cataract - Ataxia - Deafness; Cerebellar Ataxia, Cayman Type; Cerebellar Ataxia With Peripheral Neuropathy; Cerebellar Ataxia - Hypogonadism; Cerebellar Ataxia - Ectodermal Dysplasia; Cerebellar Ataxia - Areflexia - Pes Cavus - Optic Atrophy - Sensorineural Hearing Loss; Brain Tumor Ataxia; Brachydactyly - Nystagmus - Cerebellar Ataxia; Benign Paroxysmal Tonic Upgaze of Childhood With Ataxia; Autosomal Recessive Syndromic Cerebellar Ataxia; Autosomal Recessive Spastic Ataxia With Leukoencephalopathy; Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay; Autosomal Recessive Spastic Ataxia - Optic Atrophy - Dysarthria; Autosomal Recessive Spastic Ataxia; Autosomal Recessive Metabolic Cerebellar Ataxia; Autosomal Dominant Spinocerebellar Ataxia Due to Repeat Expansions That do Not Encode Polyglutamine; Autosomal Recessive Ataxia, Beauce Type; Autosomal Recessive Ataxia Due to Ubiquinone Deficiency; Autosomal Recessive Ataxia Due to PEX10 Deficiency; Autosomal Recessive Degenerative and Progressive Cerebellar Ataxia; Autosomal Recessive Congenital Cerebellar Ataxia Due to MGLUR1 Deficiency; Autosomal Recessive Congenital Cerebellar Ataxia Due to GRID2 Deficiency; Autosomal Recessive Congenital Cerebellar Ataxia; Autosomal Recessive Cerebellar Ataxia-pyramidal Signs-nystagmus-oculomotor Apraxia Syndrome; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to WWOX Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to TUD Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to KIAA0226 Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome; Autosomal Recessive Cerebellar Ataxia With Late-onset Spasticity; Autosomal Recessive Cerebellar Ataxia Due to STUB1 Deficiency; Autosomal Recessive Cerebellar Ataxia Due to a DNA Repair Defect; Autosomal Recessive Cerebellar Ataxia - Saccadic Intrusion; Autosomal Recessive Cerebellar Ataxia - Psychomotor Retardation; Autosomal Recessive Cerebellar Ataxia - Blindness - Deafness; Autosomal Recessive Cerebellar Ataxia; Autosomal Dominant Spinocerebellar Ataxia Due to a Polyglutamine Anomaly; Autosomal Dominant Spinocerebellar Ataxia Due to a Point Mutation; Autosomal Dominant Spinocerebellar Ataxia Due to a Channelopathy; Autosomal Dominant Spastic Ataxia Type 1; Autosomal Dominant Spastic Ataxia; Autosomal Dominant Optic Atrophy; Ataxia-telangiectasia Variant; Ataxia-telangiectasia; Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy; Autosomal Dominant Cerebellar Ataxia Type 4; Autosomal Dominant Cerebellar Ataxia Type 3; Autosomal Dominant Cerebellar Ataxia Type 2; Autosomal Dominant Cerebellar Ataxia Type 1; Autosomal Dominant Cerebellar Ataxia; Ataxia-telangiectasia-like Disorder; Ataxia-intellectual Disability-oculomotor Apraxia-cerebellar Cysts Syndrome; Ataxia-deafness-intellectual Disability Syndrome; Ataxia With Vitamin E Deficiency; Ataxia With Dementia; Ataxia Neuropathy Spectrum; Ataxia - Tapetoretinal Degeneration; Ataxia - Photosensitivity - Short Stature; Ataxia - Pancytopenia; Ataxia - Oculomotor Apraxia Type 1; Ataxia - Hypogonadism - Choroidal Dystrophy; Ataxia - Other; Ataxia - Genetic Diagnosis - Unknown; Acquired Ataxia; Adult-onset Autosomal Recessive Cerebellar Ataxia; Alcohol Related Ataxia; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type II; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2; Multiple Endocrine Neoplasia, Type IV; Multiple Endocrine Neoplasia, Type 3; Multiple Endocrine Neoplasia (MEN) Syndrome; Multiple Endocrine Neoplasia Type 2B; Multiple Endocrine Neoplasia Type 2A; Atypical Hemolytic Uremic Syndrome; Atypical HUS; Wiedemann-Steiner Syndrome; Breast Implant-Associated Anaplastic Large Cell Lymphoma; Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA); Hemophagocytic Lymphohistiocytosis; Behcet's Disease
Vaccines for preventing influenza in healthy children.

PubMed

Jefferson, Tom; Rivetti, Alessandro; Di Pietrantonj, Carlo; Demicheli, Vittorio

2018-02-01

The consequences of influenza in children and adults are mainly absenteeism from school and work. However, the risk of complications is greatest in children and people over 65 years of age. This is an update of a review published in 2011. Future updates of this review will be made only when new trials or vaccines become available. Observational data included in previous versions of the review have been retained for historical reasons but have not been updated because of their lack of influence on the review conclusions. To assess the effects (efficacy, effectiveness, and harm) of vaccines against influenza in healthy children. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 12), which includes the Cochrane Acute Respiratory Infections Group Specialised Register, MEDLINE (1966 to 31 December 2016), Embase (1974 to 31 December 2016), WHO International Clinical Trials Registry Platform (ICTRP; 1 July 2017), and ClinicalTrials.gov (1 July 2017). Randomised controlled trials comparing influenza vaccines with placebo or no intervention in naturally occurring influenza in healthy children under 16 years. Previous versions of this review included 19 cohort and 11 case-control studies. We are no longer updating the searches for these study designs but have retained the observational studies for historical purposes. Review authors independently assessed risk of bias and extracted data. We used GRADE to rate the certainty of evidence for the key outcomes of influenza, influenza-like illness (ILI), complications (hospitalisation, ear infection), and adverse events. Due to variation in control group risks for influenza and ILI, absolute effects are reported as the median control group risk, and numbers needed to vaccinate (NNVs) are reported accordingly. For other outcomes aggregate control group risks are used. We included 41 clinical trials (> 200,000 children). Most of the studies were conducted in children over the age of two and compared live attenuated or inactivated vaccines with placebo or no vaccine. Studies were conducted over single influenza seasons in the USA, Western Europe, Russia, and Bangladesh between 1984 and 2013. Restricting analyses to studies at low risk of bias showed that influenza and otitis media were the only outcomes where the impact of bias was negligible. Variability in study design and reporting impeded meta-analysis of harms outcomes.Live attenuated vaccinesCompared with placebo or do nothing, live attenuated influenza vaccines probably reduce the risk of influenza infection in children aged 3 to 16 years from 18% to 4% (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.11 to 0.41; 7718 children; moderate-certainty evidence), and they may reduce ILI by a smaller degree, from 17% to 12% (RR 0.69, 95% CI 0.60 to 0.80; 124,606 children; low-certainty evidence). Seven children would need to be vaccinated to prevent one case of influenza, and 20 children would need to be vaccinated to prevent one child experiencing an ILI. Acute otitis media is probably similar following vaccine or placebo during seasonal influenza, but this result comes from a single study with particularly high rates of acute otitis media (RR 0.98, 95% CI 0.95 to 1.01; moderate-certainty evidence). There was insufficient information available to determine the effect of vaccines on school absenteeism due to very low-certainty evidence from one study. Vaccinating children may lead to fewer parents taking time off work, although the CI includes no effect (RR 0.69, 95% CI 0.46 to 1.03; low-certainty evidence). Data on the most serious consequences of influenza complications leading to hospitalisation were not available. Data from four studies measuring fever following vaccination varied considerably, from 0.16% to 15% in children who had live vaccines, while in the placebo groups the proportions ranged from 0.71% to 22% (very low-certainty evidence). Data on nausea were not reported.Inactivated vaccinesCompared with placebo or no vaccination, inactivated vaccines reduce the risk of influenza in children aged 2 to 16 years from 30% to 11% (RR 0.36, 95% CI 0.28 to 0.48; 1628 children; high-certainty evidence), and they probably reduce ILI from 28% to 20% (RR 0.72, 95% CI 0.65 to 0.79; 19,044 children; moderate-certainty evidence). Five children would need to be vaccinated to prevent one case of influenza, and 12 children would need to be vaccinated to avoid one case of ILI. The risk of otitis media is probably similar between vaccinated children and unvaccinated children (31% versus 27%), although the CI does not exclude a meaningful increase in otitis media following vaccination (RR 1.15, 95% CI 0.95 to 1.40; 884 participants; moderate-certainty evidence). There was insufficient information available to determine the effect of vaccines on school absenteeism due to very low-certainty evidence from one study. We identified no data on parental working time lost, hospitalisation, fever, or nausea.We found limited evidence on secondary cases, requirement for treatment of lower respiratory tract disease, and drug prescriptions. One brand of monovalent pandemic vaccine was associated with a sudden loss of muscle tone triggered by the experience of an intense emotion (cataplexy) and a sleep disorder (narcolepsy) in children. Evidence of serious harms (such as febrile fits) was sparse. In children aged between 3 and 16 years, live influenza vaccines probably reduce influenza (moderate-certainty evidence) and may reduce ILI (low-certainty evidence) over a single influenza season. In this population inactivated vaccines also reduce influenza (high-certainty evidence) and may reduce ILI (low-certainty evidence). For both vaccine types, the absolute reduction in influenza and ILI varied considerably across the study populations, making it difficult to predict how these findings translate to different settings. We found very few randomised controlled trials in children under two years of age. Adverse event data were not well described in the available studies. Standardised approaches to the definition, ascertainment, and reporting of adverse events are needed. Identification of all global cases of potential harms is beyond the scope of this review.

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