Onset Of Narcolepsy Research Articles

A monozygotic twin pair completely discordant for narcolepsy, with sleep deprivation as a possible precipitating factor

Among the 16 monozygotic twin pairs described in the literature, only five pairs were concordant for narcolepsy, suggesting that non-genetic factors may predispose to narcolepsy. We report a completely discordant narcoleptic twin, with an onset of narcolepsy at the late age of 40 years. Monozygocity was confirmed. The onset of narcolepsy was associated with prolonged sleep deprivation and chronic emotional stress. It was noted that excessive daytime sleepiness preceded the onset of cataplexy, when narcolepsy was precipitated by prolonged sleep deprivation and emotional stress. Our case supports the multifactorial model with dominant human leukocyte antigen inheritance in the development of narcolepsy. Our observation implies that avoidance of poor sleep hygiene might prevent the development of narcolepsy, even in predisposed individuals.

The Natural History of Health and Symptoms in Narcolepsy: A to-year Longitudinal Study

This longitudinal study investigated, over a 10-year period, reported changes in people with narcolepsy (a disorder of excessive daytime sleepiness). The issues of the functional impact of symptoms; stimulant medication status; body mass index, and concomitant illnesses were examined. The study also documented, using retrospective report, environmental factors influencing narcolepsy severity, and reported time of worst symptom severity following narcolepsy onset. In 1991, 127 people with diagnosed narcolepsy and cataplexy completed a wide-ranging questionnaire. In 2001, attempts were made to recontact these participants and 67 were traceable. Of these, 47 people, (18 males, 29 females; mean age 61.76 years, age range 31-86 years) returned a revised questionnaire. The reported impact of excessive daytime sleepiness (EDS) on the ability to carry out day-to-day activities showed minor increases in severity over the 10-year period in this older narcolepsy sample, and this could not be attributed to major changes in medication status. It is argued that the underlying severity of EDS does not increase with time, but rather that the interaction of EDS with the ageing process increases its detrimental impact. Improvements in the functional impact of sleep paralysis, hallucinations and automatic behaviour were reported. There was no evidence that any narcolepsy symptom became substantially worse with time for most people with the disorder. The influence of environmental factors on symptoms was inconsistent within the group. The elevated body mass index, stable over time, suggested that excess weight may be a trait often associated with narcolepsy, possibly linked to hypocretin deficiency.

Experts Study Consequences Of Sleep Deprivation

Experts Study Consequences Of Sleep Deprivation

Age at onset of narcolepsy in two large populations of patients in France and Quebec.

Narcolepsy usually starts around adolescence; however, there is great variability in the clinical presentation of narcolepsy. To determine the age at onset in conjunction with severity of narcoleptic symptoms in two large populations of narcoleptic patients with a similar genetic background. Information on age at onset and severity of the condition was obtained in 317 patients with well-defined narcolepsy-cataplexy from Montpellier (France) and in 202 from Montreal (Canada). The mean age at onset was 23.4 years in Montpellier and 24.4 in Montreal. The age at onset was bimodal in two independent patient populations: a first peak occurring at 14.7 years, and a second peak occurring at 35. Age at onset clearly differentiates patients with a positive family history of narcolepsy (early onset) from those without a family history. Other clinical and polygraphic findings may indicate that young age at onset is associated with increased severity of the condition (higher frequency of cataplexy and decreased mean sleep latency on the Multiple Sleep Latency Test). Bimodal distribution of age at onset of narcolepsy was found in two independent patient populations. Our data suggest that age at onset is genetically determined.

Forty winks: molecular basis of sleep disorders

Although adequate sleep is necessary for all mammals, including humans, the pathways that regulate it are still poorly understood. The sleep–wake cycle is regulated both by homeostatic processes, which are dependent on the ‘sleep debt’ experienced by the individual, and by processes that depend on the circadian clock. Now, researchers in the USA have discovered rare single-gene mutations that cause disorders in both types of process.Narcolepsy is the only known neurological disorder that affects the generation and organization of sleep. It affects 0.05–0.1% of Americans, and is characterized by excessive daytime sleepiness, sleep fragmentation and cataplexy (a sudden, involuntary loss of muscle strength often triggered by positive emotions). It has been studied extensively in canine models, where it shows autosomal recessive transmission with full penetrance. In previous studies, Emmanuel Mignot and co-workers (Stanford University, CA, USA) found mutations in affected dogs, but not in controls, in Hcrtr2, a gene mapping to canine chromosome 12 (Ref. 1xThe sleep disorder canine narcolepsy is caused by a mutation in the Hypocretin (Orexin) Receptor 2 gene. Lin, L. et al. Cell. 1999; 98: 365–375Abstract | Full Text | Full Text PDF | PubMed | Scopus (1696)See all References1). This gene encodes a G-protein-coupled receptor (GPCR) with affinity for two neurotransmitters known as hypocretins (or orexins). Almost simultaneously, symptoms of narcolepsy were reported in transgenic mice lacking hypocretin peptides2xNarcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Chemelli, R.M. et al. Cell. 1999; 98: 365–376Abstract | Full Text | Full Text PDF | PubMed | Scopus (1960)See all References2. Now, Mignot's group has identified a mutation in preprohypocretin (the precursor) in a single, severe case of narcolepsy3xA mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Peyron, C. et al. Nat. Med. 2000; 6: 991–997Crossref | PubMed | Scopus (1291)See all References3.Most cases of human narcolepsy are sporadic. A close association between predisposition to narcolepsy and the HLA subtype DQB1*0602 has suggested an auto-immune etiology, although this has not been proven. However, rare cases of familial narcolepsy do occur, and approximately one-third of cases in these families are DQB1*0602 negative. Mignot screened 74 Caucasian narcolepsy patients and 118 ethnically matched controls for mutations in preprohypocretin and in the two hypocretin receptors, Hcrtr1 and Hcrtr2. All cases either had a family history of the disease or lacked the DQB1*0602 subtype. Fourteen polymorphisms in these genes had no statistical association. However, one severely affected patient had a functional preprohypocretin mutation. ‘This patient is very unusual,’ explains Mignot. ‘He started showing symptoms at six months, whereas almost all patients develop the disease in adolescence. This early onset is reminiscent of our genetically narcoleptic dogs.’ Moreover, in normal humans, hypocretins can be easily detected in the cerebrospinal fluid (CSF). Mignot's group found undetectable concentrations in the CSF of seven out of nine narcolepsy patients, indicating that hypocretin transmission can also be defective in the human disease4xHypocretin (orexin) deficiency in human narcolepsy. Nishino, S. et al. Lancet. 2000; 355: 39–40Abstract | Full Text | Full Text PDF | PubMed | Scopus (1091)See all References4. Further evidence implicating the hypocretins was provided from expression studies where hypocretin transcripts were detected in the hypothalamus of all controls but were absent in the narcolepsy cases tested1xThe sleep disorder canine narcolepsy is caused by a mutation in the Hypocretin (Orexin) Receptor 2 gene. Lin, L. et al. Cell. 1999; 98: 365–375Abstract | Full Text | Full Text PDF | PubMed | Scopus (1696)See all

A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains

We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.

P454 Four vs five measurements in MSLT

This is the first report describing the efficacy of modafinil therapy for narcolepsy in patients in Taiwan. The purpose of this study was to compare the objective Multiple Sleep Latency Test (MSLT) and the subjective Epworth Sleepiness Scale (ESS) for evaluating the efficacy of modafinil in treating excessive daytime sleepiness in patients with narcolepsy in Taiwan. Ten consecutive patients with narcolepsy-with-cataplexy who were treated with 200 mg/day modafinil for more than 6 months at our sleep center between January 2003 and December 2007 were included in this study. This comparative study was prompted by the requirement of the Bureau of National Health Insurance in Taiwan that modafinil users need to be followed up with MSLTs every 6–12 months. The mean age at onset of narcolepsy onset in these 10 patients was 11.8 ± 3.3 years, and eight (80%) were male. We compared the differences in MSLT and ESS between baseline and follow-up at 6–12 months after starting modafinil therapy using paired t tests. ESS scores (p < 0.001) were considerably more sensitive than MSLT scores (p < 0.05) in documenting efficacy of modafinil and that the improvements in MSLT scores were minimal and remained in the pathologically sleepy range. These findings suggest that the ESS is a more sensitive and clinically meaningful tool to evaluate the efficacy of modafinil in narcolepsy.

Major Histocompatibility Class II Molecules in the CNS: Increased Microglial Expression at the Onset of Narcolepsy in a Canine Model

Human narcolepsy is a neurological disorder known to be closely associated with HLA-DR2 and DQB1*0602. Because most autoimmune diseases are HLA-associated, a similar mechanism has been proposed for narcolepsy. However, neither systemic nor CNS evidence of an autoimmune abnormality has ever been reported. In this study, major histocompatibility (MHC) class I and class II expression was studied in the CNS of human and canine narcoleptics using immunohistochemistry and Northern analysis. Results indicated that canine narcolepsy is associated with a significant increase of MHC class II expression by the microglia. Moreover, the highest values were found between 3 and 8 months of age, strikingly concomitant to the development of narcolepsy in the canine model. In humans, class II expression was not found significantly different between control and narcoleptic subjects. This result could be explained by the old age of the subjects (69.86 +/- 5.31 and 68.36 +/- 4.74 years in narcoleptics and controls, respectively), because class II expression is significantly correlated with age in both humans and dogs. For the first time, this study demonstrated that the expression of MHC class II molecules in the CNS is age-dependent and that a consistent increase of their expression by the microglia might be critically involved in the development of narcolepsy.

Life Events in the Year Preceding the Onset of Narcolepsy

A multifactorial etiology for narcolepsy has been postulated, stressing the importance of environmental factors in the clinical onset of the condition. Our study evaluated the occurrence of stressful life events in the year preceding the onset of narcolepsy. Fifty narcoleptic and 50 control subjects completed a life event questionnaire (the Schedule of Recent Experiences). The proportion of narcoleptic subjects reporting the presence of life events in the year preceding the onset of narcolepsy was significantly greater than the proportion of control subjects reporting life events in the corresponding year. Moreover the weight of life events was increased in narcoleptic subjects in comparison with controls. In conclusion life events seem to be increased in narcoleptic subjects in the year preceding the onset of their condition. However a number of other factors could not be taken into consideration, which limits the full significance of these data.

Motor dyscontrol in sleep of narcoleptic patients (a lifelong development?)

In our retrospective study 27 narcoleptic patients were divided into two groups: Group A comprised 14 patients (10 male, 4 female) with a history of REM behaviour disorder (RBD) and Group B comprised 13 age- and sex-matched patients (10 male, 3 female) without a history of RBD. Polygraphic and videometry data, medical history, medication, blood chemistry, psychological and neuroradiological data of the two groups of patients were compared. The narcoleptic patients with a history of RBD differed from the narcoleptic control group without history of RBD in that they had: (a) a higher frequency of parasomnias in their history; (b) a higher percentage of stage 1 REM (P < 0.01); (c) a lower number of arousals during REM sleep; (d) fewer sleep stage changes. Compared to the heterogenous RBD patient group of Mahowald and Schenck, the REM behaviour of most of our narcoleptic patients was less violent. Thus it can be speculated that the motor disorder in REM sleep might still be in the process of developing towards a full-blown REM sleep behaviour disorder. In a possible lifelong development of a motor disorder starting in NREM sleep, the onset of narcolepsy might represent the turning point for its intrusion into REM sleep.

Juvenile Onset Narcolepsy in an Individual with Turner Syndrome. A Case Report

We describe an 8 year old girl who presented with excessive daytime sleepiness and frequent falling. Following extensive investigations, the diagnosis of both narcolepsy and Turner Syndrome were confirmed. To our knowledge, this is the first report of these two conditions in the same individual. Both conditions are common, but the early expression of narcolepsy is unusual. Although there is a genetic basis for each, the two conditions are not necessarily related since Turner is an X-linked abnormality, while narcolepsy has an autosomal basis. Nonetheless we wonder if the hormonal balance of Turner Syndrome might have some role to play in the early expression of narcolepsy.

Narcolepsy and sudden onset of REM periods after nocturnal awakenings

The objective of this study was to evaluate polysomnographic data, and especially the sudden onset of REM periods that occur after spontaneous awakenings during the night as characteristics of narcolepsy. We evaluated 148 consecutive patients with excessive daytime somnolence, except for those with sleep apnea. After clinical evaluation, all-night polysomnographic recording and multiple sleep latency test, 55 were diagnosed as narcoleptics and 93 were grouped as non-narcoleptics. The mean age of narcoleptics was 42.9 +/- 14.4 years old and the non-narcoleptics were 40.3 +/- 13.5 years old. Polysomnographic variables were compared between both samples using unpaired t test. Non-significant differences were found for: sex; total time in bed; total sleep time; time in stages 3, 4 and REM; number of arousals (less than 30 sec); number of body movements; REM density. The following significant differences were found: number of sleep onset REM periods during the night was higher for narcoleptics (p less than 0.001); total sleep time was lower for narcoleptics (p = 0.02); sleep latency was shorter for narcoleptics (p less than 0.001); REM latency to stage 1 was shorter for narcoleptics (p less than 0.001); time in stage 1 was higher for narcoleptics (p less than 0.001); time in stage 2 was lower for narcoleptics (p less than 0.001); number of full awakenings (greater than 30 sec) was higher for narcoleptics (p less than 0.001); number of awakenings longer than 5 minutes was higher for narcoleptics (p = 0.002). In conclusion, there were marked differences in the sleep architecture between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)