Narcolepsy Research Articles

Research progress of immunologic mechanism of narcolepsy

Narcolepsy is a severe neurological sleep disorder, which is caused by the large loss of Hypocretin (Hcrt)/Orexin producing neurons in the hypothalamus in narcolepsy with cataplexy patients. It is likely the result of an autoimmune process that causes selective destruction of Hcrt neurons in the hypothalamus. It has been known that narcolepsy is associated with the human leukocyte antigens (HLA)-DR2 and HLA-DQB1*0602 . Recent epidemic data have shown a robust incidence of disease onset associated with pandemic H1N1-infection, H1N1 vaccination and streptococcus pyogenes infection. A genome-wide association variants in P2RY11 are associated with narcolepsy. Narcolepsy is associated with polymorphisms of the genes encoding T cell receptor-α (TCR-α) and tumor necrosis factor-α (TNF-α). Several cases report successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset, but the effects are not persistent. However, there is no significant evidence of narcolepsy specific antibodies or T cell reactions found, and the relations with cytokines and central nervous system inflammatory cells have not been elaborated well. It is still a big challenge for further study.

Evidence-based evaluation of therapeutic measures for sleep disorders

Objective To evaluate the therapeutic efficacy and side effects of various treatment for sleep disorders in order to provide the best therapeutic regimen for the evidence-based treatment of sleep disorders. Methods Sleep disorder, insomnia, restless legs syndrome or RLS, obstructive sleep apnea or OSA, narcolepsy, REM behaviour disorder or RBD, treatment or therapy were used as retrieval words. Cochrane Library, MEDLINE, ScienceDirect were used for retrieval, and manual searching was also used. Related clinical guidelines, systematic reviews, randomized controlled clinical trials, retrospective case analysis, case-observation studies and reviews were collected and evaluated by Jadad Scale. Results Forty related articles were selected as following: 6 clinical guidelines, 12 systematic reviews, 5 randomized controlled trials, 2 retrospective case analysis, 1 case-observation study and 14 reviews. Thirty-three were of high quality, while 7 were of low quality with score. According to the evaluation of therapeutic efficacy and side effects of various therapies, it is suggested as following: 1) insomnia is the most common in sleep disorders; the treatment methods of insomnia mainly include drug therapy and cognitive behavioral treatment (CBT); the two kinds of therapy have their own advantages and disadvantages, and the combination therapy of drugs and CBT is the best treatment plan. 2) The first-line treatment of primary RLS is dopamine agonists and anti-seizure drugs; however, the treatment of secondary RLS is mainly etiologic treatment. 3) The main treatments of OSAS are nasal continuous positive airway pressure (nCPAP), oral orthotics and surgery, and nCPAP is the first-line treatments. 4) The medication of narcolepsy is mainly modafinil, hydroxy butyric acid sodium and antidepressants, and the specific choosing should accord to clinical classifications. 5) The main treatments of RBD include general treatments such as avoiding triggers, insuring the safety of sleep environment, and drug therapy such as benzodiazepines and melatonin. Conclusion Evidence-based medicine can provide the best clinical evidence on sleep disorders' treatment.

Association between H1N1 vaccination and narcolepsy–cataplexy

After the beginning of the influenza A (H1N1 pdm09) pandemic in 2009, several monovalent pandemic H1N1 vaccines were licensed using fast track procedures, with limited safety data in children and adolescents.1 Nonadjuvant monovalent vaccines were used in the United States and Australia, and on a limited scale, in Europe (France, Spain) and other countries. Within the European Union (EU), 2 different vaccines with adjuvant were licensed, both containing a new generation of squalene-based adjuvant: Focetria (Novartis, Philadelphia, PA), with the MF59 adjuvant, and Pandemrix (GSK, Philadelphia, PA), containing AS03 (squalene and α-tocopherol). Arepanrix, similar to Pandemrix, was used in Canada and Brazil. The vaccine program started in the EU by September 2009; concurrently, the European Center for Disease Prevention & Control (ECDC), Vaccine Adverse Event Surveillance and Communication, and other agencies initiated an active surveillance program to monitor safety and adverse events associated with this vaccine.

Characteristics of rapid eye movement sleep behavior disorder in narcolepsy

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dreamenacting behavior and impaired motor inhibition during REM sleep (REM sleep without atonia, RSWA). RBD is commonly associated with Parkinsonian disorders, but is also reported in narcolepsy. Most patients with narcolepsy with cataplexy lack the hypocretin neurons in the lateral hypothalamus. In contrast, RBD, RSWA, and hypocretin deficiency are rare in narcolepsy without cataplexy. Phasic motor activity in REM and non-REM (NREM) and dreamenacting behavior (RBD) coexist with cataplexy in narcolepsy because of hypocretin deficiency. Thus, hypocretin deficiency is linked to the two major disturbances of REM sleep motor regulation in narcolepsy: RBD and cataplexy. Moreover, it is likely that hypocretin deficiency independently predicts periodic limb movements in REM and NREM sleep, probably via involvement of the dopaminergic system. This supports the hypothesis that an impaired hypocretin system causes general instability of motor regulation during wakefulness, REM and NREM sleep in human narcolepsy. We propose that hypocretin neurons are centrally involved in motor tone control during wakefulness and sleep in humans and that hypocretin deficiency causes a functional defect in the motor control involved in the development of cataplexy during wakefulness and RBD/RSWA/ phasic motor activity during REM sleep.

HPA data support Pandemrix link with narcolepsy

HPA data support Pandemrix link with narcolepsy

Modafinil as a Catecholaminergic Agent: Empirical Evidence and Unanswered Questions

Modafinil, in its two clinical formulations (Provigil® and Nuvigil®), is a widely prescribed wake-promoting therapeutic agent. It binds competitively to the cell-membrane dopamine (DA) transporter and is dependent on catecholaminergic (dopaminergic and adrenergic) signaling for its wake-promoting effects. The clinical spectrum of effects for modafinil is distinct from the effects seen with other catecholaminergic agents. Relative to other commonly used agents that act through catecholaminergic mechanisms, modafinil has a relatively low abuse potential, produces wakefulness with an attenuated compensatory sleep recovery thereafter, and does not ameliorate cataplexy in narcolepsy. These clinically relevant phenomenological differences between modafinil and agents such as amphetamines and cocaine do not eliminate catecholaminergic effects as a possible mediator of its wake-promoting action; they merely reflect its unique pharmacological profile. Modafinil is an exceptionally weak, but apparently very selective, DA transporter inhibitor. The pharmacodynamic response to modafinil, as measured by DA levels in brain microdialyzate, is protracted relative to other agents that act via catecholaminergic mechanisms. The conformational constraints on the interaction of modafinil with the DA transporter – and probably, as a consequence, its effects on trace amine receptor signaling in the catecholaminergic cell – are unique among catecholaminergic agents. These unique pharmacological properties of modafinil should be considered both in seeking to thoroughly understand its putatively elusive mechanism of action and in the design of novel therapeutic agents.

Sleep-dependent consolidation of motor skills in patients with narcolepsy-cataplexy.

This study investigated whether the altered organization of post-training sleep in patients with narcolepsy-cataplexy (NC) is associated with a lower off-line improvement in the consolidation of motor skills compared with normal subjects. Fourteen drug-naive NC patients, fulfilling the international clinical and polysomnographic diagnostic criteria, and 14 individually-matched controls underwent training at a sequential finger tapping task (FTT) and were re-tested on the next morning (after a night with polysomnographic recording) and after another six nights (spent at home). Training and retrieval sessions were performed in a controlled laboratory setting. FTT performance was worse in NC patients than controls at training and at both retrieval sessions and showed a fairly different time course (slower than in controls) of consolidation. Several sleep indices (lower values of stage-2 NREM sleep and SWS) were compatible with a lower effectiveness of sleep for consolidation of motor skills in NC patients, although no statistically significant relationship was found between such indices and improvement rate. The consolidation process of motor skills results less effective in NC patients since training and slower than in normal subjects over the week following training. The wider variations in performance scores and sleep parameters of post.-training night in NC patients relative to controls suggest that a) the lower initial consolidation may be due to a less effective encoding consequent to altered prior sleep, and b) the consolidation process over the 24 h following training is negatively influenced not only by the altered characteristics of post-training sleep, but also by the daytime sleepiness following training.

Sleepiness that cannot be overcome: Narcolepsy and cataplexy

Narcolepsy-cataplexy syndrome is characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. It is strongly associated with the genetic marker, human leucocyte antigen (HLA) DQB1*06:02. A deficit in the endogenous hypocretin/orexin system due to neuronal degeneration in the lateral hypothalamus, induced by an autoimmune-mediated process, is the primary pathophysiology associated with the human disease. The important finding of an association with hypocretin genes in animal models of narcolepsy has led to the establishment of cerebrospinal fluid hypocretin measurements as a new diagnostic test for human narcolepsy. This is a fascinating story of translation of basic science research into clinical practice in sleep medicine during the past decade. Recent advances have shed light on the associations between respiratory medicine and narcolepsy-cataplexy research. The first is that upper airway infections, including H1N1 and/or streptococcal infections, may initiate or reactivate an immune response that leads to loss of hypocretin-secreting cells and narcolepsy in genetically susceptible individuals. The second is that an increased incidence of sleep disordered breathing among narcoleptic subjects may relate to the impairment of central control of breathing, linked to hypocretin deficiency or carriage of HLADQB1*06:02, in animals and human subjects with narcolepsy, respectively, indicating neural dysfunction in an area where respiratory and sleep-wake systems are closely interrelated.

Narcolepsy: clinical differences and association with other sleep disorders in different age groups

Narcolepsy-cataplexy (N-C) is a focal neurodegenerative disease with a genetic predisposition and autoimmune etiology; the pathogenesis of narcolepsy without cataplexy (Nw/oC) is less clear. One hundred and forty eight patients underwent clinical face-to face interviews, polysomnography, multiple sleep latency testing and HLA-DQB1*0602 typing. The cohort was divided into four age groups: children and adolescents under 19years (N=31), adults aged 20-39years (N=51), 40-59years (N=28) and over 60years (N=38). N-C was found in 93 adults (79.5%) compared with 16 pediatric patients (51.6%) (p<0.01), suggesting that at least some of the children were candidates for developing cataplexy in the future. Statistical evaluation showed an increasing age-related proportion of associated sleep disorders-obstructive sleep apnea, periodic leg movements and restless leg syndrome (p<0.001). Nw/oC patients showed sleep comorbidities less frequently than N-C group. A close connection with N-C was found particularly in REM behavior disorder (RBD) (p<0.05). RBD affected a third of the patients in the youngest as well as in the oldest groups. However, association with other sleep disorders had no significant effect on nocturnal sleep (with the exception of obstructive sleep apnea), and the sleep comorbidities under study had no noticeable effect on daytime sleepiness.

The Pandemrix – narcolepsy tragedy: how it started and what we know today

The Pandemrix – narcolepsy tragedy: how it started and what we know today

Non-Dipping Blood Pressure Profile in Narcolepsy with Cataplexy

BackgroundPatients with narcolepsy-cataplexy (NC) mostly exhibit undetectable hypocretin levels. Hypocretin system is one of the key players in the complex interaction between sleep and the cardiovascular system. We tested the hypothesis that hypocretin deficiency affects cardiovascular risk factors by measuring nighttime and daytime ambulatory blood pressure (BP) and the night-to-day BP ratio as well as endothelial dysfunction by the digital pulse amplitude response in drug-free patients with NC compared to controls.MethodologySleep, clinical and biological cardiovascular risk factors, fingertip peripheral arterial tonometry, and 24-hour ambulatory BP monitoring were recorded in 50 drug-free patients with NC and 42 healthy control subjects, except for BP monitoring available in all controls but in 36 patients with NC.Principal FindingsMore patients than controls were smokers, obese and with dyslipidemia. One-third of patients with NC were “non-dippers” (defined as <10% drop in BP during sleep) compared to only 3% of controls. The diastolic non-dipper BP profile had up to 12-fold higher odds of being associated with NC. We noted negative correlations between mean diastolic BP fall during night, REM sleep percentage and number of sleep onset REM periods, and a positive correlation with mean sleep latency on the MSLT. The digital pulse amplitude response measured by fingertip was similar between NC and controls.ConclusionWe found a high percentage of non-dippers in patients with NC with association with REM sleep dysregulation. The blunted sleep-related BP dip in NC may be of clinical relevance, as it may indicate increased risk for cardiovascular events.

The use of sodium oxybate to treat narcolepsy

Narcolepsy is a life-long neurodegenerative disorder that causes considerable impairment to quality of life. Until the 1970s, the treatment for one of the main symptoms, excessive daytime sleepiness, was restricted to stimulants, whereas the second core symptom, cataplexy, was treated with antidepressants, and the resultant fragmented night-time sleep with hypnotics. Sodium oxybate (Xyrem®, UCB Pharma, Brussels, Belgium) is an efficacious drug for all three symptoms which improves the quality of life of narcoleptic patients. Owing to its metabolic pathway, there is very little pharmacokinetic interaction with other drugs. In combination with modafinil, some of its therapeutic benefits are enhanced. Adverse events and side effects are moderate when taken according to indication and as recommended. Essential limitations have to be considered before starting the treatment (sleep-related breathing disorders, alcohol intake, hypnotic and sedative comedication, and epilepsy). This article gives an overview of sodium oxybate, which has been US FDA approved for the treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy, and EMA approved for the treatment of narcolepsy–cataplexy.

Narcolepsy–cataplexy: deficient prepulse inhibition of blink reflex suggests pedunculopontine involvement

Hypocretin (orexin) deficiency plays a major role in the pathophysiology of narcolepsy-cataplexy. In animal models, hypocretinergic projections to the pedunculopontine nucleus are directly involved in muscle tone regulation mediating muscle atonia - a hallmark of cataplexy. We hypothesized that pedunculopontine nucleus function, tested with prepulse inhibition of the blink reflex, is altered in human narcolepsy-cataplexy. Twenty patients with narcolepsy-cataplexy and 20 healthy controls underwent a neurophysiological study of pedunculopontine nucleus function. Blink reflex, prepulse inhibition of the blink reflex and blink reflex excitability recovery were measured. Blink reflex characteristics (R1 latency and amplitude, and R2 and R2c latency and area under the curve) did not differ between patients and controls (P > 0.05). Prepulse stimulation significantly increased R2 and R2c latencies and reduced R2 and R2c areas in patients and controls. However, the R2 and R2c area suppression was significantly less in patients than in controls (to 69.8 ± 14.4 and 74.9 ± 12.6%, respectively, versus 34.5 ± 28.6 and 43.3 ± 29.5%, respectively; each P < 0.001). Blink reflex excitability recovery, as measured by paired-pulse stimulation, which is not mediated via the pedunculopontine nucleus, did not differ between patients and controls (P > 0.05). Our data showed that prepulse inhibition is reduced in narcolepsy-cataplexy, whereas unconditioned blink reflex and its excitability recovery are normal. Because the pedunculopontine nucleus is important for prepulse inhibition, these results suggest its functional involvement in narcolepsy-cataplexy.

Executive Control of Attention in Narcolepsy

BackgroundNarcolepsy 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.MethodologyTwenty-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 FindingsIrrespective 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.ConclusionsWe 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.

Sodium oxybate in the treatment of childhood narcolepsy–cataplexy: A retrospective study

To evaluate the efficacy and side effect profile of sodium oxybate in the treatment for narcolepsy-cataplexy in the pediatric age group. A retrospective study was conducted on 15 children and adolescents with narcolepsy-cataplexy who had been treated with sodium oxybate. The mean age at diagnosis of narcolepsy was 11 years (range 3-17 years). Subjects were followed for 3-90 months (mean 33) after starting sodium oxybate. During this period of time they were also maintained on other medications for sleepiness (n=14) and cataplexy (n=6). The charts were reviewed for documentation of improvement in sleepiness or cataplexy, side effects, and functioning in daily life. Subsequent to the addition of sodium oxybate, sleepiness improved in 13/15 patients. In patients who had Epworth Sleepiness Scale (ESS) assessments, the score fell from a baseline median of 18 to 12 (n=10, p=0.01). The number of cataplexy episodes estimated by parents decreased from a median of 38/week pre-treatment to <1/week post treatment (n=14, p<0.001). Cataplexy severity, measured on an arbitrary scale, fell from a median of 3 (severe) to 1 (mild) in all 15 subjects (p<0.001). Two of the 15 patients (13%) discontinued sodium oxybate, one for insurance reasons and the other due to constipation and dissociative feelings. A third patient stopped the medication temporarily due to body aches and dizziness, but then resumed treatment without recurrence of symptoms. Side effects in four others included tremor, blurring of vision, nocturnal awakenings, and increased nightmares. Overall, side effects occurred in 6/15 (40%) individuals. Improvement in social/academic spheres was noted in 11/15 (73%) subjects after starting sodium oxybate. The median BMI before and after treatment remained unchanged at 23 (n=14, p=0.99). Median values of height and weight before and after treatment also did not change significantly. The mean dose of sodium oxybate was 5 ± 2 g. Dose escalation owing to development of tolerance was not encountered. Sodium oxybate is effective in alleviating sleepiness and cataplexy in childhood onset narcolepsy-cataplexy. The therapeutic response was sustained over time, and without development of tolerance. Forty percent of the subjects experienced adverse effects.

Wake-up call: the battle to control sleep

Henry Nicholls discovers that knowledge about the condition he developed in his 20s is being used to induce narcolepsy rather than prevent it

An immersive simulation system for provoking and analyzing cataplexy.

Cataplexy, a sudden loss of voluntary muscle control, is one of the hallmark symptoms of narcolepsy, a sleep disorder characterized by excessive daytime sleepiness. Cataplexy is usually triggered by strong, spontaneous emotions, such as laughter, surprise, fear or anger, 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 use of immersive displays may help bypass patient defenses, and game-like "unreality" allows introduction of surprising, threatening, or humorous elements, with little risk of offending patients. The project is referred to as the "Cataplexy/Narcolepsy Activation Program", or CatNAP. We have developed an automobile driving simulation to allow the introduction of humorous, surprising, or stress-inducing events and objects as the patient attempts to navigate a simulated vehicle through a virtual town. The patient wears a stereoscopic head-mounted display, by which he views the virtual town through the windows of his simulated vehicle. The vehicle is controlled via a driving simulator steering wheel and pedal cluster. The patient is instructed to drive his vehicle to another location in town, given initial directions and street signs. As he attempts to accomplish the task, various objects, sounds or conditions occur which may distract, startle, frustrate or cause laughter; responses which may trigger a cataplectic episode. The patient can be monitored by reflex tests and EMG recordings during the driving experience. An evaluation phase with volunteer patients previously diagnosed with cataplexy has been completed. The goal of these trials was to gain insight from the volunteers as to improvements that could be made to the simulation. All patients that participated in the evaluation phase have been under a physician's care for a number of years and control their cataplexy with medication. We believe this is a novel and innovative approach to a difficult problem. CatNAP is a compelling example of the potentially effective application of virtual reality technology to an important clinical problem that has resisted previous approaches. Preliminary results suggest that an immersive simulation system like CatNAP will be able to reliably induce cataplexy in a controlled environment. The project is continuing through a final stage of refinement prior to conducting a full clinical study.

Narcolepsy: Past, present and future

Narcolepsy: Past, present and future

Post H1N1 vaccination narcolepsy–cataplexy with decreased CSF beta-amyloid

Post H1N1 vaccination narcolepsy–cataplexy with decreased CSF beta-amyloid

Motor events during REM sleep in patients with narcolepsy–cataplexy: A video-polysomnographic pilot study

We carried out a systematic video-polysomnographic analysis of the number and type of motor events during REM sleep in narcolepsy-cataplexy patients with REM sleep behavior disorder (NC + RBD) but not clinical RBD (NC-RBD). Twelve NC + RBD and 10 NC-RBD male patients underwent video-polysomnography (video-PSG). Motor events of different type and complexity (i.e., elementary and complex movements and vocalizations) occurring during REM sleep were visually assessed, and indices of their frequency per hour of REM sleep were calculated. Subsequently, the index values were compared in NC + RBD versus NC-RBD patients. Typical RBD behaviors observed in five NC + RBD patients were not included in any type of motor events. No objective conventional sleep parameter, including visual analysis of chin electromyographic (EMG) activity, significantly differed between the two groups of NC patients. NC + RBD patients showed higher occurrence of elementary movements (p = 0.034) during REM sleep compared with NC-RBD patients, but the occurrence of complex movements did not differ significantly. Video-analysis of motor events during REM sleep may improve the diagnosis of RBD in NC. RBD in NC patients is mainly characterized by elementary rather than complex movements, consistent with the view that RBD with NC patients displays a distinct phenotype with respect to other RBD patients.