Narcolepsy Research Articles

Tricks to rapidly terminate episodes of cataplexy in narcolepsy

Cataplexy is a distinctive symptom of narcolepsy type 1 and is characterized by episodes of sudden loss of muscle tone with preserved consciousness that are usually triggered by emotions [1]. Cataplectic attacks usually last from seconds to a fewminutes until, unpredictably, the muscle function is completely restored, which is normally within seconds [2]. To the best of our knowledge, this is the first description of two patients with narcolepsy type 1 in whom their relatives used a maneuver or trick to rapidly terminate the episodes of cataplexy.

Treatment paradigms for cataplexy in narcolepsy: past, present, and future.

Cataplexy is defined as episodes of sudden loss of voluntary muscle tone triggered by emotions generally lasting <2 minutes. Cataplexy is most commonly associated with and considered pathognomonic for narcolepsy, a sleep disorder affecting ~0.05% of the general population. Knowledge of the pathophysiology of cataplexy has advanced through study of canine, murine, and human models. It is now generally considered that loss of signaling by hypothalamic hypocretin/orexin-producing neurons plays a key role in the development of cataplexy. Although the cause of hypocretin/orexin neuron loss in narcolepsy with cataplexy is unknown, an autoimmune etiology is widely hypothesized. Despite these advances, a literature review shows that treatment of cataplexy remains limited. Multiple classes of antidepressants have been commonly used off-label for cataplexy in narcolepsy and are suggested for this use in expert consensus guidelines based on traditional practice, case reports, and small trials. However, systematic research evidence supporting antidepressants for cataplexy is lacking. The single pharmacotherapy indicated for cataplexy and the guideline-recommended first-line treatment in Europe and the US is sodium oxybate, the sodium salt of gamma-hydroxybutyrate. Clinical trial evidence of its efficacy and safety in cataplexy is robust, and it is hypothesized that its therapeutic effects may occur through gamma-aminobutyric acid receptor type B-mediated effects at noradrenergic, dopaminergic, and thalamocortical neurons. Additional possible mechanisms for cataplexy therapy suggested by preliminary research include antagonism of the histamine H3 autoreceptor with pitolisant and intravenous immunoglobulin therapy for amelioration of the presumed autoimmune-mediated hypocretin/orexin cell loss. Further research and development of therapeutic approaches to cataplexy are needed.

The relationship of narcolepsy and psychology

The relationship of narcolepsy and psychology

Post-Traumatic Narcolepsy Associated with Thalamic/Hypothalamic Injury

Post-Traumatic Narcolepsy Associated with Thalamic/Hypothalamic Injury

Relationship between brain image and neurocognitive functions in patients with narcolepsy–cataplexy

Relationship between brain image and neurocognitive functions in patients with narcolepsy–cataplexy

Clinical features of obese children with narcolepsy

Objective To analyze the clinical characteristics of narcolepsy in children with obesity, and to evaluate the impact of obesity on narcoleptic children clinically. Methods Forty cases first diagnosed as narcolepsy were recruited in the study who to see doctors at the Department of Neurology, Children's Hospital of Capital Institute of Pediatrics, from July 2012 to January 2015.According to diagnostic criteria for obesity by the body mass index(BMI)growth curve for the Chinese children and adolescents, they were divided into the obese group and the nonobese group.The general clinical data of 2 groups were analyzed, and the related metabolic indexes and the whole night polysomnography(PSG) of 2 groups were studied. Results In this group, male versus female 3:1, obesity was found in 21 cases(52.5%) and nonobesity was found in 19 cases(47.5%) from the samples.The mean BMI of all patients was(21.55±3.11) kg/m2.The average BMI of the obese group was(23.09±2.46) kg/m2, and BMI of the non-obese group was(19.85±2.89) kg/m2.Obese children were younger at the onset of disease and by the time of diagnosis age [(7.94±2.22)years old, (8.76±2.36) years old] than nonobese children[(10.75±3.10)years old, (12.51±2.88) years old]. The fasting blood glucose and blood lipid in all patients were normal, and there was no significant difference between 2 groups.The total sleep time, sleep efficiency and the ratio of rapid eye movement(REM) phase of the obese group[(397.45±53.76) min, (68.70±8.90)%, (18.37±4.39)%]were significantly lower than those of the non-obese group [(449.95±86.49) min, (76.58±13.60)%, (22.19±6.34)%]. According to the sleep structure, the percentage of stageⅠnon rapid eye movement(NREM) sleep in the obese group[(20.90±6.38)%] was more than that in non-obese group[(16.26±4.22)%]. There was no difference between the percentage of stage ⅡNREM sleep in the obese group[(42.59±5.52)%]and the non-obese group[(38.54±8.74)%]. Stage Ⅲ+ Ⅳ(slow wave sleep) NREM sleep ratio in the obese group[(18.14±6.97)%] was significantly lower than that in the non-obese group[(22.60±5.69)%]. Conclusions Obesity is one of the most common comorbids in narcolepsy, which affects more than 50% of narcoleptic children, mostly younger at disease onset.The narcolepsy children with obesity has total sleep time decreased, sleep efficiency reduced and sleep structure disorder is more obvious.To improve the realization of obesity in narcolepsy children and early treatment is the key to the success of the therapy. Key words: Narcolepsy; Obesity; Child

An Antibiotic for Sleepiness

Excessive daytime sleepiness can occur even with adequate sleep and without an obvious etiology such as depression or narcolepsy. Other than modafinil,

Narcolepsy, Along with an Update

Narcolepsy, Along with an Update

Parkinson's disease and narcolepsy-like symptoms

ObjectiveVarious 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. MethodsAltogether, 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. ResultsThe 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. ConclusionsNarcolepsy-like symptoms may be present in patients with PD. Symptoms of RBD were associated with symptoms of narcolepsy including symptoms of cataplexy.

Moebius syndrome and narcolepsy

Moebius syndrome is a rare neurological disease that has a frequent association with parasomnia. We report on a patient with Moebius syndrome and the clinical presentation of a narcolepsy cataplexy syndrome. With the hypoplasia of the brainstem in the cranial magnetic resonance imaging, we were able to show the morphological correlate of Moebius syndrome. Comorbidity was detected by cognitive tests, polysomnography and detection of hypocretin in the cerebrospinal fluid. Despite normal sleep onset latency and only one episode of sleep onset rapid eye movement (REM) in the multiple sleep latency test, where expressiveness is significantly reduced in cases of paralysis of horizontal eye movement, the diagnosis of parasomnia with narcolepsy cataplexy symptoms could be made. The hypocretin level of 132 pg/ml measured in the cerebro spinal fluid is compatible with this diagnosis and shows the relevance of a detailed diagnostic of parasomnia in patients with Moebius syndrome.

Sleepiness and Performance Is Disproportionate in Patients with Non-Organic Hypersomnia in Comparison to Patients with Narcolepsy and Mild to Moderate Obstructive Sleep Apnoea

Background/Aims: Clinical differentiation between organic hypersomnia and non-organic hypersomnia (NOH) is challenging. We aimed to determine the diagnostic value of sleepiness and performance tests in patients with excessive daytime sleepiness (EDS) of organic and non-organic origin. Methods: We conducted a retrospective comparison of the multiple sleep latency test (MSLT), pupillography, and the Steer Clear performance test in three patient groups complaining of EDS: 19 patients with NOH, 23 patients with narcolepsy (NAR), and 46 patients with mild to moderate obstructive sleep apnoea syndrome (OSAS). Results: As required by the inclusion criteria, all patients had Epworth Sleepiness Scale (ESS) scores >10. The mean sleep latency in the MSLT indicated mild objective sleepiness in NOH (8.1 ± 4.0 min) and OSAS (7.2 ± 4.1 min), but more severe sleepiness in NAR (2.5 ± 2.0 min). The difference between NAR and the other two groups was significant; the difference between NOH and OSAS was not. In the Steer Clear performance test, NOH patients performed worst (error rate = 10.4%) followed by NAR (8.0%) and OSAS patients (5.9%; p = 0.008). The difference between OSAS and the other two groups was significant, but not between NOH and NAR. The pupillary unrest index was found to be highest in NAR (11.5) followed by NOH (9.2) and OSAS (7.4; n.s.). Conclusion: A high error rate in the Steer Clear performance test along with mild sleepiness in an objective sleepiness test (MSLT) in a patient with subjective sleepiness (ESS) is suggestive of NOH. This disproportionately high error rate in NOH may be caused by factors unrelated to sleep pressure, such as anergia, reduced attention and motivation affecting performance, but not conventional sleepiness measurements.

Preliminary results on CSF biomarkers for hypothalamic dysfunction in Kleine–Levin syndrome

ObjectiveTo measure CSF biomarkers of hypothalamic dysfunction in patients with typical Kleine–Levin syndrome (KLS) during symptomatic and asymptomatic periods. Patients/methodsTwo patients with typical KLS were admitted during symptomatic and asymptomatic periods to a research Sleep Disorders Center. Cerebrospinalfluid (CSF) hypocretin-1, histamine (HA), and its major metabolite tele-methylhistamine (t-MHA) levels were measured in two KLS patients in and out of episode. ResultsCSF biomarkers of hypothalamic dysfunction measured in two KLS patients in and out of episode revealed low hypocretin levels (within the narcolepsy–cataplexy range) during a hypersomnia episode in the more severe patient, and a 42% decrease (although within normal range) in the second patient. CSF HA and t-MHA measurements in and out of episode revealed a two-fold in-episode decrease in HA in the more severe patient, with no significant change for the second patient, nor for t-MHA levels. ConclusionWe reported reversible changes in CSF hypothalamic biomarkers in a typical patient with KLS that reinforces the hypothesis that in some patients KLS episodes may be caused by recurrent functional alterations of the hypothalamus.

Narcolepsy: environment, genes and treatment.

Narcolepsy: environment, genes and treatment.

Sodium Oxybatefor Narcolepsy with CataplexyâA Cost-Effective Analysis

Objective: To assess the cost-effectiveness of sodium oxybate plus antidepressants and stimulants compared with the current standard treatment for narcolepsy with cataplexy in the UK. Methods: We developed a Markov model to assess the costs and benefits of sodium oxybate plus antidepressants and stimulants or current standard treatment based on their effects on the quality of life of patients. The main outcome was the incremental cost-effectiveness ratio (ICER) in terms of costs per additional qualityadjusted life year (QALY) gained over 5 years of treatment. One-way, multi-way and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties on the findings. Results: The cost-effectiveness of sodium oxybate plus antidepressants and stimulants were very sensitive to the costs of sodium oxybate (price and dose) and differences in utilities between responders and non-responders. With current clinical evidence, it is recognised that measure of improvement in utilities used in the current model may be an underestimation of the reality. Conclusions: Our analysis suggests that, at the current UK list price, sodium oxybate would not represent good value for money for the NHS. This is unfortunate, since it appears that sodium oxybate is likely to benefit some patients in the management of these two conditions which affect about 0.03% of the UK population.

Decreased hypoxic ventilatory chemoresponsiveness and clinical features in patients with narcolepsy cataplexy

To explore the relationship between hypoxic responsiveness of the patients with narcolepsy-cataplexy and their clinical features. A total of 113 patients with narcolepsy-cataplexy (narcolepsy group) at Peking University People's Hospital from June 2007 to May 2008 and 128 gender-age matched volunteers (control group) were recruited. And their status of human leukocyte antigen (HLA)-DQB1*0602 was examined to differentiate hypercapnic and hypoxic responsiveness. Among them, 93 patients with severe hypersomnolence had hypercapnic and hypoxic responsiveness tested before and after the treatment of methylphenidate and another 20 with severe cataplexy did the same before and after the treatment of chlorimiopramine. Compared with the control group, the narcolepsy group had depressed hypoxic responsiveness ((-0.135 ± 0.105) vs (-0.223 ± 0.136) L×min⁻¹ × %SpO₂⁻¹, P < 0.001). After the treatment of methylphenidate, sleepiness improved significantly in all 93 patients, but their low hypoxic responsiveness did not change ((-0.151 ± 0.111) vs (-0.149 ± 0.105) L×min⁻¹× % SpO₂⁻¹, P = 0.780). After the treatment of chlorimiopramine, cataplexy also improved in 20 patients.However their low hypoxic responsiveness had no change ((-0.114 ± 0.054) vs (-0.115 ± 0.065) L×min⁻¹ × %SpO₂⁻¹, P = 0.949). Lower hypoxic responsiveness in narcolepsy group is not related with the clinical features of disease.

Hypocretin and brain β-amyloid peptide interactions in cognitive disorders and narcolepsy.

Objective: To examine relationships between cerebrospinal fluid (CSF) Alzheimer' disease (AD) biomarkers and hypocretin-1 levels in patients with cognitive abnormalities and hypocretin-deficient narcolepsy-cataplexy (NC), estimate diagnostic accuracy, and determine correlations with sleep disturbances.Background: Sleep disturbances are frequent in AD. Interactions between brain β-amyloid (Aβ) aggregation and a wake-related neurotransmitter hypocretin have been reported in a mouse model of AD.Methods: Ninety-one cognitive patients (37 AD, 16 mild cognitive impairment—MCI that converts to AD, 38 other dementias) and 15 elderly patients with NC were recruited. Patients were diagnosed blind to CSF results. CSF Aβ42, total tau, ptau181, and hypocretin-1 were measured. Sleep disturbances were assessed with questionnaires in 32 cognitive patients.Results: Lower CSF Aβ42 but higher tau and P-tau levels were found in AD and MCI compared to other dementias. CSF hypocretin-1 levels were higher in patients with MCI due to AD compared to other dementias, with a similar tendency for patients with advanced AD. CSF hypocretin-1 was significantly and independently associated with AD/MCI due to AD, with an OR of 2.70 after full adjustment, exceeding that for Aβ42. Aβ42 correlated positively with hypocretin-1 levels in advanced stage AD. No association was found between sleep disturbances and CSF biomarkers. No patients with NC achieved pathological cutoffs for Aβ42, with respectively one and four patients with NC above tau and P-tau cutoffs and no correlations between hypocretin-1 and other biomarkers.Conclusions: Our results suggest a pathophysiological relationship between Aβ42 and hypocretin-1 in the AD process, with higher CSF hypocretin-1 levels in early disease stages. Further longitudinal studies are needed to validate these biomarker interactions and to determine the cause-effect relationship and the role of wake/sleep behavior in amyloid plaque regulation.

R-baclofen shows promise as a treament for narcolepsy

R-baclofen shows promise as a treament for narcolepsy

GABAB agonism promotes sleep and reduces cataplexy in murine narcolepsy.

γ-Hydroxybutyrate (GHB) is an approved therapeutic for the excessive sleepiness and sudden loss of muscle tone (cataplexy) characteristic of narcolepsy. The mechanism of action for these therapeutic effects is hypothesized to be GABAB receptor dependent. We evaluated the effects of chronic administration of GHB and the GABAB agonist R-baclofen (R-BAC) on arousal state and cataplexy in two models of narcolepsy: orexin/ataxin-3 (Atax) and orexin/tTA; TetO diphtheria toxin mice (DTA). Mice were implanted for EEG/EMG monitoring and dosed with GHB (150 mg/kg), R-BAC (2.8 mg/kg), or vehicle (VEH) bid for 15 d-a treatment paradigm designed to model the twice nightly GHB dosing regimen used by human narcoleptics. In both models, R-BAC increased NREM sleep time, intensity, and consolidation during the light period; wake bout duration increased and cataplexy decreased during the subsequent dark period. GHB did not increase NREM sleep consolidation or duration, although NREM delta power increased in the first hour after dosing. Cataplexy decreased from baseline in 57 and 86% of mice after GHB and R-BAC, respectively, whereas cataplexy increased in 79% of the mice after VEH. At the doses tested, R-BAC suppressed cataplexy to a greater extent than GHB. These results suggest utility of R-BAC-based therapeutics for narcolepsy.

Positivity analysis of human leukocyte histocompatibility antigen-DQB1*0602 allele in Chinese patients with narcolepsy

To explore the association of narcolepsy with human leukocyte histocompatibility antigen (HLA)-DQB1*0602 allele in Chinese narcoleptic patients and examine its relationship with different phenotypes. A total of 1 223 narcoleptic patients (NC, narcolepsy with typical cataplexy, n = 1 132; NWC, narcolepsy without cataplexy, n = 91) diagnosed at Sleep Center of Peking University People's Hospital from August 1998 to July 2011 were recruited into this retrospective study. According to the onset age, they were divided into early-onset group (onset age ≤ 15 y, n = 1 037) and late-onset group (onset age >15 y, n = 181). All of them underwent a polymerase chain reaction with specific sequence primer (PCR-SSP) HLA-DQB1*0602 typing. And the cerebrospinal fluid levels of hypocretin-1 (hcrt-1) were measured in 156 narcoleptic patients and they were divided into hcrt deficiency group (hcrt-1<138 ng/L, n = 115) and hcrt normal group (hcrt-1 ≥ 138 ng/L, n = 41). And 728 healthy volunteers were selected as control group. The expression positivity of HLA-DQB1*0602 gene was analyzed for each group. There were 1 223 narcoleptic patients including 825 males (67.5%) and 398 females (32.5%) with an average age of (16.6 ± 12.6) years on visiting. There were 728 normal controls including 443 males (60.9%) and 285 females (39.1%) with an average age of (26.6 ± 11.4) years on blood sampling. The positive rate of HLA-DQB1*0602 in narcoleptic, NC and NWC groups was 94.7% (1 158/1 223), 97.0% (1 098/1 132) and 65.9% (60/91) respectively.NC group had a higher rate of HLA-DQB1*0602 positivity (χ² = 155.4, P = 0.000). Both groups were higher than that in control group of 19.5% (142/728). The positive rate of HLA-DQB1*0602 in early-onset group was 95.5% (990/1 037) versus 90.1% (163/181) in late-onset group (χ² = 9.25, P = 0.010). Among those with hcrt-1 measurement, 98.3% (113/115) were HLA-DQB1*0602 positive in hcrt deficiency narcolepsy group versus 25.6% (11/43) in hcrt non-deficiency group (χ² = 94.6, P = 0.001). HLA-DQB1* 0602 is an important marker in this large sample of Chinese patients with narcolepsy.Its frequency is much higher in patients with cataplexy, early-onset age and hcrt-1 deficiency.

Narcolepsy With Cataplexy

Narcolepsy With Cataplexy