Sleep Med Rev. 2012 Jan 30;
Berridge CW, Schmeichel BE, España RA

The locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. State-dependent neuronal discharge activity of locus coeruleus noradrenergic neurons has long-suggested a role of this system in the induction of an alert waking state. Work over the past two decades provides unambiguous evidence that the locus coeruleus, and likely other noradrenergic nuclei, exert potent wake-promoting actions via an activation of noradrenergic β- and α(1)-receptors located within multiple subcortical structures, including the general regions of the medial septal area, the medial preoptic area and, most recently, the lateral hypothalamus. Conversely, global blockade of β- and α(1)-receptors or suppression of norepinephrine release results in profound sedation. The wake-promoting action of central noradrenergic neurotransmission has clinical implications for treatment of sleep/arousal disorders, such as insomnia and narcolepsy, and clinical conditions associated with excessive arousal, such as post-traumatic stress disorder.

Sleep. 2012; 35(2): 231-6
Beitinger PA, Fulda S, Dalal MA, Wehrle R, Keckeis M, Wetter TC, Han F, Pollmächer T, Schuld A

Obesity is a common feature of narcolepsy. In addition, an increased occurrence of non-insulin dependent diabetes has been reported. So far, it is not known whether glucose metabolism in narcolepsy is disturbed due to, or independently of obesity.Case-control study.Sleep medicine clinic at a research institute.We studied 17 patients with narcolepsy/cataplexy compared to 17 healthy controls matched for age, sex, and body mass index (BMI).A 75-g oral glucose tolerance test was performed.Glucose tolerance was determined by computing plasma glucose curve following oral glucose challenge for 240 minutes; insulin sensitivity and insulin secretion by homeostasis model assessment and minimal model analysis.Standard outcome measures and indices of the oral glucose tolerance test did not differ between the patient group and the group of control subjects.In this study, no clinically relevant pathologic findings in the glucose metabolism of narcoleptic patients compared to weight matched controls were found. Thus, narcolepsy is unlikely to be a risk factor per se for impaired glucose tolerance or diabetes. CITATION: Beitinger PA; Fulda S; Dalal MA; Wehrle R; Keckeis M; Wetter TC; Han F; Pollmächer T; Schuld A. Glucose tolerance in patients with narcolepsy. SLEEP 2012;35(2):231-236.

Eur J Intern Med. 2012 Mar; 23(2): 110-7
Morrison I, Riha RL

Excessive daytime sleepiness is a common presentation to physicians both in general practice and hospital settings. In this review, we provide an update on the latest theories on the pathogenesis of the condition, and discuss the approach to investigation of the sleepy patient, with particular reference to narcolepsy. Recommended therapy is reviewed for both narcolepsy and cataplexy, to provide physicians with an important reference on the investigation and management of these troubling conditions.

J Sleep Res. 2012 Jan 28;
Lecendreux M, Bruni O, Franco P, Gringras P, Konofal E, Nevsimalova S, Paiva T, Partinen M, Peeters E, Peraita-Adrados R, Plazzi G, Poli F

Sleep Med. 2012 Jan 24;
David A, Constantino F, Santos JM, Paiva T

OBJECTIVE: To evaluate the perception of health-related quality of life (HRQoL) in Portuguese patients with narcolepsy, and to compare the results to normative data. METHODS: Fifty-one narcoleptic adults (26M, 25F), aged between 18 and 80years (mean=43.35, SD=15.32), were included in the final analysis of a multicentric cross-sectional study. The Medical Outcome Study - 36 Item Short-Form Survey (SF-36) was used to assess quality of life, and the Beck Depression Inventory (BDI) was used for self-assessment of depression. RESULTS: Several HRQoL domains were significantly lower than National surveys, except physical function and bodily pain (p between 0.000 and 0.006). SF-36 presented the lowest score in vitality (39.93). Deterioration was significantly higher in role physical (p=0.006), vitality (p=0.011), and mental health (p=0.008) in women, and in physical function (p=0.003) and bodily pain (p=0.045) in elderly subjects. Those with higher literacy had better physical function (p=0.046). CONCLUSION: HRQoL is significantly deteriorated in narcoleptics, affecting all dimensions (except physical function and bodily pain) when compared with the general Portuguese population. The results are consistent with studies of narcolepsy in other countries in demonstrating the profound impact of this disorder on quality of life.

Sleep Med. 2012 Jan 24;
Watson NF, Ton TG, Koepsell TD, Longstreth WT

BACKGROUND: Birth order may play a role in autoimmune diseases and early childhood infections, both factors implicated in the etiology of narcolepsy. We investigated the association between birth order and narcolepsy risk in a population-based case-control study in which all study subjects were HLA-DQB1*0602 positive. METHODS: Subjects were 18-50years old, residents of King County, Washington, and positive for HLA-DQB1*0602. Birth order was obtained from administered interviews. We used logistic regression to generate odds ratios adjusted for income and African American race. RESULTS: Analyses included 67 cases (mean age 34.3 [SD=9.1], 70.2% female) and 95 controls (mean age 35.1 [SD=8.8], 58.1% female). Associations for birth order were as follows: first born (cases 38.8% vs. controls 50.2%, OR=1.0; reference), second born (cases 29.9% vs. controls 32.9%, OR=1.6; 95% CI 0.7, 3.7), and third born or higher (cases 31.3% vs. controls 16.8%, OR=2.5; 95% CI 1.0, 6.0). A linear trend was significant (p<0.05). Sibling number, sibling gender, having children, and number of children did not differ significantly between narcolepsy cases and controls. CONCLUSIONS: Narcolepsy risk was significantly associated with higher birth order in this population-based study of genetically susceptible individuals. This finding supports an environmental influence on narcolepsy risk through an autoimmune mechanism, early childhood infections, or both.

Ann Lab Med. 2012 Jan; 32(1): 57-65
Woo HI, Joo EY, Hong SB, Lee KW, Kang ES

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.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).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.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.

Nihon Shinkei Seishin Yakurigaku Zasshi. 2011 Nov; 31(5-6): 223-9
Sakurai T

Orexin A and orexin B (also known as hypocretin 1 and hypocretin 2) are hypothalamic neuropeptides that we discovered thirteen years ago. Initially, these peptides were recognized as regulators of feeding behavior. Subsequently, several studies suggested that orexin deficiency causes narcolepsy in humans and other mammalian species, highlighting roles of this hypothalamic neuropeptide in the regulation of sleep and wakefulness. Studies of efferent and afferent systems of orexin-producing neurons have shown that the orexin neuronal system has close interactions with systems that regulate emotion, energy homeostasis, reward, and arousal. These observations suggest that orexin neurons are involved in sensing the body's external and internal environments, and regulate vigilance states accordingly.

Learn Mem. 2012; 19(2): 67-72
Abraham AD, Cunningham CL, Lattal KM

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show that MPH, administered before or immediately following extinction of contextual fear, will enhance extinction retention in C57BL/6 mice. Animals that received MPH (2.5-10 mg/kg) before an extinction session showed decreased freezing response during extinction, and the effect of the 10 mg/kg dose on freezing persisted to the next day. When MPH (2.5-40 mg/kg) was administered immediately following an extinction session, mice that received MPH showed dose-dependent decreases in freezing during subsequent tests. MPH administered immediately after a 3-min extinction session or 4 h following the first extinction session did not cause significant differences in freezing. Together, these findings demonstrate that MPH can enhance extinction of fear and that this effect is sensitive to dose, time of injection, and duration of the extinction session. Because MPH is widely used in clinical treatments, these experiments suggest that the drug could be used in combination with behavioral therapies for patients with fear disorders.

Rev Neurol Dis. 2011; 8(3-4): e97-e106
Koziorynska EI, Rodriguez AJ

Narcolepsy is a neurologic disorder characterized by excessive daytime sleepiness and manifestations of disrupted rapid eye movement sleep stage. The pathologic hallmark is loss of hypocretin neurons in the hypothalamus likely triggered by environmental factors in a susceptible individual. Patients with narcolepsy, in addition to excessive daytime sleepiness, can present with cataplexy, sleep paralysis, sleep fragmentation, and hypnagogic/hypnopompic hallucinations. Approximately 60% to 90% of patients with narcolepsy have cataplexy, characterized by sudden loss of muscle tone. Only 15% of patients manifest all of these symptoms together. Narcolepsy can be misdiagnosed as a psychiatric disorder or even epilepsy. An appropriate clinical history, polysomnogram, Multiple Sleep Latency Test, and, at times, cerebrospinal fluid hypocretin levels are necessary for diagnosis. The treatment of narcolepsy is aimed toward the different symptoms that the patient manifests. Excessive daytime sleepiness is treated with amphetamine-like or non-amphetamine-like stimulants. Cataplexy is treated with sodium oxybate, tricyclic antidepressants, or selective serotonin and norepinephrine reuptake inhibitors. Sleep paralysis, hallucinations, and fragmented sleep may be treated with benzodiazepine hypnotics or sodium oxybate. Patients with narcolepsy should avoid sleep deprivation, sleep at regular hours, and, if possible, schedule routine napping.

Clinics (Sao Paulo). 2012; 67(1): 77-8
Mendes MF, Valladares Neto Dde C, Azevedo RA, Caramelli P

Tijdschr Psychiatr. 2012; 54(1): 81-7

Summary background Up till now little is known about psychiatric disorders in relation to the use of psychotropics drugs on the Dutch Antilles, with the exception of Curaçao. aim To map the quantity and type of psychotropics prescribed for Bonairians in 2009. method We performed a retrospective data analysis of the antipsychotics dispensed by the pharmacies on Bonaire in 2009. Our analysis focused on the benzodiazepines and related compounds, antipsychotics, lithium, antidepressants and adhd- and narcolepsy-medication. With regard to antipsychotics and antidepressants, we also investigated ‘the age distribution of the persons to whom the psychotropics were dispensed’. In addition, we mapped the frequency with which the drugs were dispensed: once only, infrequently, regularly. results At least one psychotropic drug was delivered to 18.37% of (N=2365) Bonairians in 2009. Benzodiazepines and related compounds in particular were the most commonly dispensed drugs. conclusion One in five Bonairians received at least one prescription for psychotropicdrugs in 2009.