Neuropharmacology 2006 May 18; (Read article online)

Govindaiah G, Cox CL

Orexins (hypocretins) are peptides of hypothalamic origin that play an important role in maintaining wakefulness. Reduced orexin levels have been associated with an increased incidence of narcolepsy. Considering thalamic nuclei are interconnected with virtually all neocortical regions and the thalamus has been found to produce distinct activities related to different levels of arousal, we have examined the actions of orexins on thalamic neurons using an in vitro thalamic slice preparation. The orexins (orexin-A and orexin-B) produced distinct actions within different intralaminar nuclei. Orexin-B strongly depolarized the majority of centrolateral nucleus (CL) neurons (71%), but depolarized a significantly smaller population of parafascicular nuclei (Pf) neurons (10%). In the mediodorsal thalamic nucleus (MD), orexin-B depolarized 21% of the neurons tested. Overall, orexin-B was found to be more potent than Orexin-A. Orexin-A depolarized a significantly smaller population of CL neurons (23%), but had no effect on Pf neurons. In addition, orexin-A produced a small depolarization in 28% of neurons in the thalamic reticular nucleus (TRN). Both orexin-A and orexin-B had no effect on neurons in the lateral posterior (LP), lateralodorsal (LD), posterior thalamic (Po), ventrobasal (VB) nucleus and lateral geniculate nucleus (LGN). The depolarizing actions of orexins were sufficient to alter the firing mode of these neurons from a burst- to tonic-firing mode. The excitatory actions of orexin-B result from a decrease in the apparent leak potassium current (K(leak)). The orexin-B mediated excitation was also attenuated by bupivacaine suggesting the involvement of K(leak) current. Further, the actions of orexin-B were occluded by the classical neurotransmitter dopamine, indicating the orexins may share similar ionic mechanisms. Thus, the depolarizing actions of orexins may play a key role in altering the firing mode of thalamic neurons associated with different states of consciousness.

Neurology 2006 May 23; 66(10): 1577-9 (Read article online)

Plazzi G, Parmeggiani A, Mignot E, Lin L, Scano MC, Posar A, Bernardi F, Lodi R, Tonon C, Barbiroli B, Montagna P, Cicognani A

In children, narcolepsy may be the symptom of a brain lesion or genetic disease. The authors report two cases with severe narcolepsy-cataplexy emerging in childhood in close temporal association with obesity and precocious puberty.

J Pediatr Endocrinol Metab 2006 Apr; 19 Suppl 1: 423-9 (Read article online)

Müller HL, Müller-Stöver S, Gebhardt U, Kolb R, Sörensen N, Handwerker G

Prognosis in childhood craniopharyngioma survivors hinges upon late effects such as pituitary deficiency and obesity. Observations indicate that reduced physical activity and increased daytime sleepiness might be risk factors for obesity. We analyzed the degree of daytime sleepiness in 115 childhood craniopharyngioma patients (47% obese) using the Epworth Sleepiness Scale (ESS). Thirty-five (30%) displayed increased daytime sleepiness (ESS score > 10) of whom 14 were obese (26% of obese cohort). Polysomnography (PSG) and Multiple Sleep Latency Tests (MSLT) were conducted with 10 obese patients presenting increased daytime sleepiness, with only two craniopharyngioma patients revealing a sleep related breathing disorder. Four patients had repeated episodes of SOREM (sleep onset rapid eye movement), the classic PSG criterion for narcolepsy. Three patients displayed hypersomnia. All but one patient qualified as acutely obese. We speculate that secondary narcolepsy is an exacerbating condition of childhood craniopharyngioma obesity, supported by recent reports on orexin and narcolepsy which suggest hypothalamic failure in idiopathic narcolepsy.

Clin Pediatr (Phila) 2006 May; 45(4): 361-3 (Read article online)

Hayes D

SUMMARY: Narcolepsy is a rare neurologic sleep disorder with morbidity associated with functional impairment and frequent delay in diagnosis. Symptoms typically manifest in adolescence or early adulthood, but diagnosis of narcolepsy has been reported in early childhood. Diagnosis rates are as low as 50% of the total population of patients with narcolepsy and are delayed as much as 10 years after disease onset due to inadequate patient-physician communication and/or misdiagnosis. I present the complexity of diagnosing narcolepsy in early childhood in a patient with cataplexy that started soon after independent ambulation at age 10 months. Clin Pediatr. 2006;45:361-363.

Nature 2006 May 10; (Read article online)

Lu J, Sherman D, Devor M, Saper CB

Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip-flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (gamma-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip-flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions-for example, in narcolepsy.

Chronobiol Int 2006; 23(1): 63-70 (Read article online)

Selbach O, Haas HL

The appropriate time and place for sleep and waking are important factors for survival. Sleep and waking, rest and activity, flight and fight, feeding, and reproduction are all organized in relation to the day and night. A biological clock, the suprachiasmatic nucleus (SCN), synchronized by photic influences and other environmental cues, provides an endogenous timing signal that entrains circadian body rhythms and is complemented by a homeostatic sleep pressure factor. Cholinergic, catecholaminergic, serotonergic, and histaminergic nuclei control wakefulness and mutually interact with the SCN as well as sleep- and wake-promoting neurons in the hypothalamus to form a bistable switch that controlls the timing of behavioral state transitions. Hypocretin neurons integrate circadian-photic and nutritional-metabolic influences and act as a conductor in the aminergic orchestra. Their loss causes narcolepsy, a disease conferring the inability to separate sleep and waking. Their role in appetitive behavior, stress, and memory functions is important to our understanding of addiction and compulsion.

Neurol Sci 2006 May; 27 Suppl 2: s149-52 (Read article online)

Provini F, Vetrugno R, Lugaresi E, Montagna P

Obtructive sleep apnoea syndrome (OSAS) is a common disorder in the general population with an estimated prevalence in an adult population of 2% in women and 4% in men. Although several studies have suggested that headaches, particularly morning headaches, are more common in patients with OSAS than in normal subjects, others have yielded contradictory findings. When the sleep-related breathing disorder was treated with success, the headache generally disappeared, supporting a causal role of the sleep disorder for headache. Several hypotheses have been proposed to explain the relationship between OSAS and the occurrence of headache, particularly on awakening. Night-time fluctuations of oxygen saturation during the night with hypercapnia, vasodilatation, increased intracranial pressure and impaired sleep quality are all considered contributing factors. However the exact mechanisms of headache pathogenesis and the relationship between OSAS, headache and morning headaches in particular remain controversial.

Curr Med Res Opin 2006 Apr; 22(4): 761-74 (Read article online)

Harsh JR, Hayduk R, Rosenberg R, Wesnes KA, Walsh JK, Arora S, Niebler GE, Roth T

OBJECTIVE: This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of modafinil, for the treatment of excessive sleepiness in patients with narcolepsy. RESEARCH DESIGN AND METHODS: This was a multicenter double-blind study with 196 patients (aged 18-65 years) randomized to receive armodafinil 150 mg (n = 65), armodafinil 250 mg (n = 67), or placebo (n = 64) once daily for 12 weeks. MAIN OUTCOME MEASURES: Efficacy was assessed using the Maintenance of Wakefulness Test (MWT) (six 20-min subtests across the day), the Clinical Global Impression of Change (CGI-C), subjective measures of sleepiness (Epworth Sleepiness Scale), patient diaries, and evaluations of cognitive performance (Cognitive Drug Research) and fatigue (Brief Fatigue Inventory). RESULTS: Armodafinil significantly increased MWT mean sleep latency (at 0900-1500) compared with placebo. The mean change from baseline at final visit for armodafinil was an increase of 1.3, 2.6, and 1.9 min in the 150-mg, 250-mg, and combined groups, respectively, compared with a decrease of 1.9 min for placebo (p < 0.01 for all three comparisons). Mean late-day MWT latency (1500-1900) was also significantly improved (difference of armodafinil combined group relative to placebo at final visit: 2.8 min, p = 0.0358). The proportions of patients who showed at least minimal improvement in the CGIC rating from baseline to final visit in the armodafinil 150-mg, 250-mg, and combined groups were 69%, 73%, and 71%, respectively, compared with 33% for placebo (p < 0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (p < 0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness. CONCLUSIONS: Armodafinil significantly improved ability to sustain wakefulness throughout the day in patients with narcolepsy. Armodafinil also significantly improved overall clinical condition, memory, attention, and fatigue when compared with placebo.

Neuro Endocrinol Lett 2006 Apr 29; 27(1-2): (Read article online)

Sonka K, Kemlink D, Pretl M

BACKGROUND: Narcolepsy with cataplexy is a debilitating sleep disease of which some symptoms can be treated with antidepressants. The antidepressant escitalopram is considered the most specific serotonin reuptake inhibitor. PATIENTS AND METHODS: Ten patients (5 men and 5 women, age range 18-77 years) suffering from narcolepsy with cataplexy occurring at least weekly were treated with escitalopram 5 or 10 mg a day for 28-98 days. These patients were barred from taking any drugs influencing cataplexy and also had no other diseases affecting sleep or vigilance. RESULTS: The mean number of cataplexies per week in 8 compliant patients declined significantly from 6.7 (+/-SD=7.2) to 0.3 (+/-0.6), P=0.02 (Sign test). Cataplexy completely disappeared in 6 patients. Subjective daytime sleepiness, power of concentration, quality of night sleep and mood remained unchanged. During the treatment, two patients had ejaculation disturbances. Two patients withdrew from the therapy (one because of ejaculation disturbance, the other for unknown reason). CONCLUSION: Escitalopram proved to have anticataplectic effects in this small-scale open-label study.

Pediatr Neurol 2006 May; 34(5): 337-50 (Read article online)

Gropman AL, Duncan WC, Smith AC

The Smith-Magenis syndrome is a rare, complex multisystemic disorder featuring, mental retardation and multiple congenital anomalies caused by a heterozygous interstitial deletion of chromosome 17p11.2. The phenotype of Smith-Magenis syndrome is characterized by a distinct pattern of features including infantile hypotonia, generalized complacency and lethargy in infancy, minor skeletal (brachycephaly, brachydactyly) and craniofacial features, ocular abnormalities, middle ear and laryngeal abnormalities including hoarse voice, as well as marked early expressive speech and language delays, psychomotor and growth retardation, and a 24-hour sleep disturbance. A striking neurobehavioral pattern of stereotypies, hyperactivity, polyembolokoilamania, onychotillomania, maladaptive and self-injurious and aggressive behavior is observed with increasing age. The diagnosis of Smith-Magenis syndrome is based upon the clinical recognition of a constellation of physical, developmental, and behavioral features in combination with a sleep disorder characterized by inverted circadian rhythm of melatonin secretion. Many of the features of Smith-Magenis syndrome are subtle in infancy and early childhood, and become more recognizable with advancing age. Infants are described as looking "cherubic" with a Down syndrome-like appearance, whereas with age the facial appearance is that of relative prognathism. Early diagnosis requires awareness of the often subtle clinical and neurobehavioral phenotype of the infant period. Speech delay with or without hearing loss is common. Most children are diagnosed in mid-childhood when the features of the disorder are most recognizable and striking. While improvements in cytogenetic analysis help to bring cases to clinical recognition at an earlier age, this review seeks to increase clinical awareness about Smith-Magenis syndrome by presenting the salient features observed at different ages including descriptions of the neurologic and behavioral features. Detailed review of the circadian rhythm disturbance unique to Smith-Magenis syndrome is presented. Suggestions for management of the behavioral and sleep difficulties are discussed in the context of the authors' personal experience in the setting of an ongoing Smith-Magenis syndrome natural history study.

J Clin Psychiatry 2006 Apr; 67(4): 554-66 (Read article online)

Ballon JS, Feifel D

BACKGROUND: Modafinil is a novel wake-promoting agent that has U.S. Food and Drug Administration approval for narcolepsy and shift work sleep disorder and as adjunctive treatment of obstructive sleep apnea/hypopnea syndrome. Modafinil has a novel mechanism and is theorized to work in a localized manner, utilizing hypocretin, histamine, epinephrine, gamma-aminobutyric acid, and glutamate. It is a well-tolerated medication with low propensity for abuse and is frequently used for off-label indications. The objective of this study was to systematically review the available evidence supporting the clinical use of modafinil. DATA SOURCES: The search term modafinil OR Provigil was searched on PubMed. Selected articles were mined for further potential sources of data. Abstracts from major scientific conferences were reviewed. Lastly, the manufacturer of modafinil in the United States was asked to provide all publications, abstracts, and unpublished data regarding studies of modafinil. DATA SYNTHESIS: There have been 33 double-blind, placebo-controlled trials of modafinil. Additionally, numerous smaller studies have been performed, and case reports of modafinil's use abound in the literature. CONCLUSIONS: Modafinil is a promising drug with a large potential for many uses in psychiatry and general medicine. Treating daytime sleepiness is complex, and determining the precise nature of the sleep disorder is vital. Modafinil may be an effective agent in many sleep conditions. To date, the strongest evidence among off-label uses exists for the use of modafinil in attention-deficit disorder, postanesthetic sedation, and cocaine dependence and withdrawal and as an adjunct to antidepressants for depression.

Eur Arch Otorhinolaryngol 2006 May 3; (Read article online)

Yıldırım SV, Durmaz C, Pourbagher MA, Erkan AN

Achondroplasia is the most common skeletal dysplasia in children. Achondroplasic patients have a short cranial face and midface hypoplasia. They often have sleep-related respiratory disturbances that lead to hypoxemia caused by midfacial hypoplasia, a small upper airway, hypotonia of airway muscles, or brain stem compression. It has been well described that obstructive sleep apnea can cause pulmonary hypertension (PH) through the mechanism of chronic hypoxemia. However, severe PH due to obstructive-type sleep disorder is rare in patients with achondroplasia. In this report, we describe a 5-year-old girl with achondroplasia whose severe PH was caused by upper-airway obstruction and was resolved gradually after adenotonsillectomy.

Rev Neurol Dis 2005; 2(4): 203-10 (Read article online)

Culebras A

Summary of presentations given at the Teaching Course at the 19th Annual Meeting of the Associated Professional Sleep Societies, June 18-23, 2005, Denver, CO. Medical professionals gathered in Denver, CO, in June 2005 to explore the current knowledge base of idiopathic narcolepsy and the symptomatic narcolepsies. Dr. Culebras summarizes notable presentations concerning clinical features, role of hypocretin, sleep laboratory assessments, updates of the conditions, and pharmacologic management, ending with future treatment options.

Swiss Med Wkly 2006 Mar 4; 136(9-10): 149-54 (Read article online)

Schwegler K, Klaghofer R, Nirkko AC, Mathis J, Hersberger KE, Bloch KE

BACKGROUND AND OBJECTIVE: Sleep disturbances are prevalent but often overlooked or underestimated. We suspected that sleep disorders might be particularly common among pharmacy customers, and that they could benefit from counselling. Therefore, we described the prevalence and severity of symptoms associated with sleep and wakefulness disorders among Swiss pharmacy customers, and estimated the need for counselling and treatment. METHODS: In 804 Swiss pharmacies (49% of all community pharmacies) clients were invited to complete the Stanford Sleep Disorders Questionnaire (SDQ), and the Epworth Sleepiness Scale (EPW). The SDQ was designed to classify symptoms of sleep and wakefulness into the four most prevalent disorders: sleep apnoea syndrome (SAS), insomnia in psychiatric disorders (PSY), periodic leg movement disorders/restless legs (RLS) and narcolepsy (NAR). Data were entered into an internet-linked database for analysis by an expert system as a basis for immediate counselling by the pharmacist. RESULTS: Of 4901 participants, 3238 (66.1%) were female, and 1663 (33.9%) were male. The mean age (SD) of females and males was 52.4 (18.05), and 55.1 (17.10) years, respectively. The percentages of female and male individuals above cut-off of SDQ subscales were 11.4% and 19.8% for sleep apnoea, 40.9% and 38.7% for psychiatric sleep disorders, 59.3% and 46.8% for restless legs, and 10.4% and 9.4% for narcolepsy respectively. The prevalence of an Epworth Sleepiness Scale score >11 was 16.5% in females, and 23.9% in males. Reliability assessed by Cronbach's alpha was 0.65 to 0.78 for SDQ subscales, and for the Epworth score. CONCLUSIONS: Symptoms of sleep and wakefulness disorders among Swiss pharmacy customers were highly prevalent. The SDQ and the Epworth Sleepiness Scale score had a satisfactory reliability to be useful for identification of pharmacy customers who might benefit from information and counselling while visiting pharmacies. The internet-based system proved to be a helpful tool for the pharmacist when counselling his customers in terms of diagnostic classification and severity of symptoms associated with the sleeping and waking state.

Respir Care Clin N Am 2006 Mar; 12(1): 31-54, viii (Read article online)

Roldan G, Ang RC

Sleep disorders are common and can affect anyone, from every social class and every ethnic background. It is estimated that more than 70 million Americans are afflicted by chronic sleep disorders.Currently about 88 sleep disorders are described by the International Classification of Sleep Disorders as established by The American Academy of Sleep Medicine. This article describes the dyssomnias and parasomnias most commonly seen in the clinical setting of the sleep disorder clinic or laboratory.

Exp Brain Res 2006 Apr 22; (Read article online)

Moller HJ, Devins GM, Shen J, Shapiro CM

The constructs "sleepiness" and "alertness" are often assumed to be reciprocal states of consciousness. This distinction is of increasing concern in relation to psychomotor performance tasks such as driving. We developed two separate subjective scales of alertness to complement existing sleepiness scales. Subjective sleepiness and alertness were compared in four groups of sleep-disordered patients. In a 175-patient cohort [25 narcoleptics and 50 each with sleep apnea, insomnia and periodic leg movement disorder (PLMD)], the Epworth Sleepiness Scale (ESS) was used to measure sleepiness while the Toronto Hospital Alertness Test (THAT) and ZOGIM Alertness Scale (ZOGIM-A) were used to measure alertness. Significant differences existed for sleepiness scores, with narcoleptics scoring highest on the ESS, followed by sleep apnea, with similar ESS scores for insomnia and PLMD. By contrast, alertness scores on both the THAT and ZOGIM-A did not differ significantly between the four groups. Sleepiness scores show a correlation of close to nil to alertness scores for the combined sleep disorder patient cohort, with the exception of insomnia patients, where a modest but significant inverse relationship was noted between sleepiness and alertness. Subjective states of impaired alertness and excessive sleepiness are independent constructs in the evaluation of sleep-disordered patients. The specific primary sleep disorder diagnosis may play a relevant role in mitigating this interrelationship.

Respir Care Clin N Am 2006 Mar; 12(1): 111-9 (Read article online)

Robertson B

The patient who is suffering from a sleep disorder is seeking help for one of the basic necessities of life: a good night's sleep. For all those who have developed a problem in sleeping, whether it is physiologic or psychologic, the sleep medicine profession can be literally a lifesaver.

Peptides 2006 Apr 18; (Read article online)

Fujiki N, Yoshida Y, Zhang S, Sakurai T, Yanagisawa M, Nishino S

Recent studies in human and animal models of narcolepsy have suggested that obesity in narcolepsy may be due to deficiency of hypocretin signaling, and is also under the influence of environmental factors and the genetic background. In the current study, using two hypocretin/orexin deficient narcoleptic mouse models (i.e. preproorexin knockout (KO) and orexin/ataxin-3 transgenic (TG) mice) with cross-sectional assessments, we have further analyzed factors affecting obesity. We found that both KO and TG narcoleptic mice with mixed genetic backgrounds (N4-5, 93.75-96.88% genetic composition of C57BL/6) tended to be heavier than wild type (WT) mice of 100-200 days old. The body weight of heterozygous mice was intermediate between those of KO and WT mice. Obesity was more prominent in females in both KO and TG narcoleptic mice and was associated with higher serum leptin levels, suggesting a partial leptin resistance. Obesity is less prominent in the congenic TG narcoleptic mice, but is still evident in females. Our results confirmed that hypocretin/orexin ligand deficiency is one of the critical factors for the obese tendency in narcolepsy. However, multiple factors are also likely to affect this phenotype, and a sex difference specific alteration of leptin-hypocretin signaling may be involved.

Brain 2006 Apr 5; (Read article online)

Mignot E, Lin L, Finn L, Lopes C, Pluff K, Sundstrom ML, Young T

The diagnosis of narcolepsy without documented cataplexy is based on the observation of two or more sleep-onset REM periods (SOREMPs) during the Multiple Sleep Latency Test (MSLT). We report on the prevalence and correlates of SOREMPs in the community-based Wisconsin Sleep Cohort Study. MSLTs were conducted following nocturnal polysomnography (NPSG) and daily sleep diaries in 289 males and 267 females (age 35-70, 97% Caucasians). Multiple SOREMPs were observed in 13.1% of males and 5.6% of females. An MSLT mean sleep latency /=2 SOREMPs (diagnostic of narcolepsy) was observed in 5.9% (males) and 1.1% (females), all without cataplexy. Because of significant sex interactions, analyses were stratified by sex. Increased prevalence of HLA-DQB1*0602, a marker of narcolepsy, was observed in males but not in females with >/=2 SOREMPs. Males with multiple SOREMPs compared with those with no SOREMPs had shorter rapid eye movement (REM) latency during NPSG, were sleepier on the MSLT and reported increased sleepiness, hypnagogic hallucinations and cataplexy-like symptoms, suggesting a narcolepsy-like phenotype. In males only, the occurrence of SOREMPs increased with shift work and some indirect markers of sleep restriction, such as shorter sleep a day before NPSG. SOREMPs were unrelated to age, body mass index, depression (Zung Scale), anxiety (State-Trait Anxiety Scale) and the number of apnea and hypopnea events per hour of sleep (AHI), but were associated with decreased mean lowest oxygen saturation in males. Finally, we found that both males and females with SOREMPs reported taking more antidepressants, but those were of the types known not to suppress REM sleep. These results suggest a high prevalence of narcolepsy without cataplexy, as defined by the International Classification of Sleep Disorders, and/or a large number of false-positives for the MSLT.

Respir Care Clin N Am 2006 Mar; 12(1): 121-4, ix-x (Read article online)

Robertson B

The accreditation of a sleep program ensures a high quality of care for the patient who has a sleep disorder. With more sleep laboratories becoming available, accreditation may be the best single way for a consumer to determine the adequacy of the facility.The process for accreditation requires the sleep program to develop policies and procedures that meet rigorous national and local standards. By adhering to protocols that have been proven to outline the optimal care for any given disorder associated with sleep, the provider of that care can assure the public that the program will deliver the appropriate treatment for these problems.