Frequency of narcolepsy symptoms and other sleep disorders in narcoleptic patients and their first-degree relatives.

Narcolepsy is a rare neurological sleep disorder affecting around 0.05% of the general population. Genetic factors are known to have an important role in narcolepsy. However, because of its very low prevalence, it is difficult to have groups of comparison between first-degree relatives and general population subjects in order to identify a specific spectrum of disorders in these families. Consequently, from 157 Italian patients with narcolepsy, 263 first-degree relatives were recruited, two refused to participate. These family members were compared with a matched group of 1071 subjects selected from a sample of 3970 subjects representative of the general population of Italy (46 million inhabitants). Finally, 68 spouses of narcoleptic patients were used to assess for possible role of environmental factors. All subjects were interviewed by telephone using the Sleep-EVAL system. Nineteen cases of narcolepsy were discovered among the first-degree relatives of 17 probands (10.8%). Compared with the general population subjects, the relative risk of narcolepsy among female first-degree relatives was of 54.4 and of 105.1 among male first-degree relatives. First-degree relatives were also at higher risk for idiopatic hypersomnia (OR: 23.0), obstructive sleep apnea syndrome (OR: 6.8), adjustment sleep disorder (OR: 4.0), insufficient sleep syndrome (OR: 7.0), circadian rhythm disorders (OR: 2.5), REM behavior disorder (OR: 4.4), and sleep talking (OR: 2.0). The vulnerability to sleep disorders is very high in first-degree relatives and the link with different expressivity and severity of hypersomnia can be confirmed.

Prevalence of narcolepsy symptomatology and diagnosis in the European general population.

OBJECTIVE: To determine the prevalence of narcolepsy in the general population of five European countries (target population 205,890,882 inhabitants). METHODS: Overall, 18,980 randomly selected subjects were interviewed (participation rate 80.4%). These subjects were representative of the general population of the UK, Germany, Italy, Portugal, and Spain. They were interviewed by telephone using the Sleep-EVAL expert system, which provided narcolepsy diagnosis according to the International Classification of Sleep Disorders (ICSD). RESULTS: Excessive daytime sleepiness was reported by 15% of the sample, with a higher prevalence in the UK and Germany. Napping two times or more in the same day was reported by 1.6% of the sample, with a significantly higher rate in Germany. Cataplexy (episodes of loss of muscle function related to a strong emotion), a cardinal symptom of narcolepsy, was found in 1.6% of the sample. An ICSD narcolepsy diagnosis was found in 0.047% of the sample: The narcolepsy was severe for 0.026% of the sample and moderate in 0.021%. CONCLUSION: This is the first epidemiologic study that estimates the prevalence of narcolepsy in the general population of these five European countries. The disorder affects 47 individuals/100,000 inhabitants.

How age and daytime activities are related to insomnia in the general population: consequences for older people.

OBJECTIVES: To determine the role of activity status and social life satisfaction on the report of insomnia symptoms and sleeping habits. DESIGN: Cross-sectional telephone survey using the Sleep-EVAL knowledge base system. SETTING: Representative samples of three general populations (United Kingdom, Germany, and Italy). PARTICIPANTS: 13,057 subjects age 15 and older: 4,972 in the United Kingdom, 4,115 in Germany, and 3,970 in Italy. These subjects were representative of 160 million inhabitants. MEASUREMENTS: Clinical questionnaire on insomnia and investigation of associated pathologies (psychiatric and neurological disorders). RESULTS: Insomnia symptoms were reported by more than one-third of the population age 65 and older. Multivariate models showed that age was not a predictive factor of insomnia symptoms when controlling for activity status and social life satisfaction. The level of activity and social interactions had no influence on napping, but age was found to have a significant positive effect on napping. CONCLUSIONS: These results indicate that the aging process per se is not responsible for the increase of insomnia often reported in older people. Instead, inactivity, dissatisfaction with social life, and the presence of organic diseases and mental disorders were the best predictors of insomnia, age being insignificant. Healthy older people (i.e., without organic or mental pathologies) have a prevalence of insomnia symptoms similar to that observed in younger people. Moreover, being active and satisfied with social life are protective factors against insomnia at any age.

Heart rate changes during sleep in response to experimental thermal (nociceptive) stimulations in healthy subjects.

OBJECTIVE: During wakefulness, nociceptive thermal stimulation can trigger a rapid and transient rise in heart rate (HR). During sleep, HR variations are different across sleep stages; HR is more variable in stage 2 and in REM than in stages 3 and 4. The aim of this study was to assess the HR response to experimental thermal stimulation during different sleep stages. METHODS: Eight young subjects free of sleep and pain problems, underwent a night of polysomnographic recording during which experimental thermal stimulations were applied. During all sleep stages (St), a series of cold, warm/control and heat pain stimulations were applied over the shoulder skin by means of a water-driven system. Variation of HR interval was measured for 6 s before and for 6 s during the thermal stimulation. RESULTS: In comparison to control warm stimulation, experimental nociceptive thermal stimulation induced a significant rise in HR during sleep; HR increased by 7% in St 2, 5.4% in St 3&4, and by 4.3% in REM sleep. CONCLUSION: The brief increase in cardiac activity with experimental nociceptive stimulation suggests that during sleep, the autonomic-cardiac nervous system remains reactive to external sensory inputs and is part of the physiological response to preserve body safety and sleep integrity in the face of potentially harmful stimulation.

Prevalence and patterns of problematic sleep among older adolescents.

OBJECTIVE: Despite many constraints on time schedules among teenagers, epidemiological data on sleep complaints in adolescence remain limited and are nonexistent for sleep disorders. This study provides additional data on sleep habits and DSM-IV sleep disorders in late adolescence. METHOD: A representative sample of 1,125 adolescents aged 15 to 18 years was interviewed by telephone using the Sleep-EVAL system. These adolescents came from 4 European countries: France, Great Britain, Germany, and Italy. Information was collected about sociodemographic characteristics, sleep/wake schedule, sleep habits, and sleep disorders and was compared with information from 2,169 young adults (19-24 years of age). RESULTS: Compared with young adults, adolescents presented with a distinct sleep/wake schedule: they went to sleep earlier, they woke up later, and they slept longer than young adults did. On weekends and days off, they also slept more than young adults did. However, the prevalence rates of sleep symptoms and sleep disorders were comparable in both groups. Approximately 25% reported insomnia symptoms and approximately 4% had a DSM-IV insomnia disorder. Fewer than 0.5% had a circadian rhythm disorder. CONCLUSIONS: Prevalence of insomnia disorders is lower in the adolescent population than in middle-aged or elderly adults. However, a rate of 4% in this young population is important given their young age and the consequences for daytime functioning.

Is sleep-disordered breathing an independent risk factor for hypertension in the general population (13,057 subjects)?

UNLABELLED: OBJECTIVES Sleep-disordered breathing has been hypothesized to have a close relationship with hypertension but previous studies have reported mixed results. This is an important health issue that requires further clarification because of the potential impact on the prevention and control of hypertension. METHODS: The relationship between hypertension and three forms of sleep-disordered breathing (chronic snoring, breathing pauses and obstructive sleep apnea syndrome (OSAS)) was assessed using representative samples of the non-institutionalized population of the UK, Germany and Italy (159 million inhabitants). The samples were comprised of 13,057 individuals aged 15-100 years who were interviewed about their sleeping habits and their sleep symptoms over the telephone using the Sleep-EVAL system. RESULTS: OSAS was found in 1.9% (95% CI: 1.2% to 2.3%) of the UK sample, 1.8% (95% CI: 1.4% to 2.2%) of the German sample and 1.1% (95% CI: 0.8% to 1.4%) of the Italian sample. OSAS was an independent risk factor (odds ratio (OR): 9.7) for hypertension after controlling for possible confounding effects of age, gender, obesity, smoking, alcohol consumption, life stress, and, heart and renal disease. CONCLUSIONS: Results from three of the most populated countries in Western Europe indicate that OSAS is an independent risk factor for hypertension. Snoring and breathing pauses during sleep appeared to be non-significant predictive factors.

The place of confusional arousals in sleep and mental disorders: findings in a general population sample of 13,057 subjects.

Confusional arousals, or sleep drunkenness, occur upon awakening and remain unstudied in the general population. We selected a representative sample from the United Kingdom, Germany, and Italy (N = 13,057) and conducted telephone interviews. Confusional arousals were reported by 2.9% of the sample: 1% (95% confidence interval: .8 to 1.2%) of the sample also presented with memory deficits (53.9%), disorientation in time and/or space (71%), or slow mentation and speech (54.4%), and 1.9% (1.7% to 2.1%) reported confusional arousals without associated features. Younger subjects (< 35 years) and shift or night workers were at higher risk of reporting confusional arousals. These arousals were strongly associated with the presence of a mental disorder with odds ratios ranging from 2.4 to 13.5. Bipolar and anxiety disorders were the most frequently associated mental disorders. Furthermore, subjects with Obstructive Sleep Apnea Syndrome (OSAS), hypnagogic or hypnopompic hallucinations, violent or injurious behaviors, insomnia, and hypersomnia are more likely to suffer from confusional arousals. Confusional arousals appears to occur quite frequently in the general population, affecting mostly younger subjects regardless of their gender. Physicians should be aware of the frequent associations between confusional arousals, mental disorders, and OSAS. Furthermore, the high occurrence of confusional arousals in shift or night workers may increase the likelihood of inappropriate response by employees sleeping at work.

The macrostructure and microstructure of sleep in patients with autosomal dominant nocturnal frontal lobe epilepsy.

The electroclinical features of autosomal dominant nocturnal frontal lobe epilepsy have been recently described. Although some patients reported a poor quality of sleep, daytime tiredness, and sleepiness, their sleep macrostructure appeared to be indistinguishable from those of the control group. The aim of this study was to evaluate the macro- and microstructure of sleep in a sample of autosomal dominant nocturnal frontal lobe epilepsy patients, diagnosed by videopolysomnography. The authors selected 16 patients, 8 with daytime complaints (morning tiredness and/or excessive sleepiness) (group 1) and 8 without those complaints (group 2). The classical macrostructure of sleep and the microstructure, according to the cyclic alternating pattern (CAP) scoring rules, were compared with another group of 8 healthy controls. In group 1 the motor attacks during sleep took place more frequently during CAP and were significantly related to phase A of the CAP cycle in comparison to group 2 (P = 0.04). Group 2 had a sleep microstructure similar to the controls, whereas group 1 showed higher CAP/nonrapid eye movement sleep (CAP rate) and a higher number of CAP cycles with respect to controls (P = 0.012 and P = 0.001) and to group 2 (P = 0.05 and P = 0.04). The analysis of sleep microstructure showed an increase in sleep instability in patients with autosomal dominant nocturnal frontal lobe epilepsy and daytime sleep complaints and indicated the relationship between sleep fragmentation, nocturnal motor seizures, and daytime symptoms.

Sleep arousal response to experimental thermal stimulation during sleep in human subjects free of pain and sleep problems.

Although the interaction between sleep and pain is generating considerable interest (NIH Technology Assessment Panel, 1996), it is still unknown if chronic pain is the cause or effect of poor sleep. To further this understanding, subjects free of pain and sleep problems need to be studied in order to assess their response to pain during sleep, defined as a behavioral and a physiological state in which sensory processing is altered. (For example, while auditory perception remains active, other sensory inputs are facilitated, attenuated, or suppressed (Velluti, 199746 degrees C) was statistically greater in the lighter sleep stage 2 (48.3%) than in the deeper stages 3&4 (27.9%). A nocifensive behavioral-motor response was associated with only 2.5% of the 351 heat pain stimuli. Two other markers of sleep quality-sleep stage shift and awakening-were not influenced by the thermal stimuli. None of the subjects demonstrated any burns in the morning following the thermal stimulations applied during sleep. We conclude that the processing of nociceptive inputs is attenuated across sleep stages.

The impact of cyclic alternating pattern on heart rate variability during sleep in healthy young adults.

OBJECTIVE: Cyclic alternating pattern (CAP) consists of arousal-related phasic events while the complementary condition, non-CAP (NCAP), is characterized by a rhythmic background activity, reflecting a condition of stable arousal, during non-REM sleep. The arousal swings that accompany the appearance of CAP on the EEG are associated with transient variations of muscle tone and autonomic activities, including heart rate (HR). The aim of our study was to evaluate HR variability in relation to CAP during non-REM sleep in healthy adults. METHODS: Ten healthy subjects (mean age = 28.1 years) underwent 8 h polysomnography. HR variations were measured by power spectrum analysis. The ECG signals were segmented in correspondence of the different sleep stages and different CAP conditions. RESULTS: A significant difference between CAP and NCAP conditions was found in low frequency (LF) component (increased in CAP) and high frequency (HF) component (decreased in CAP). LF/HF ratio was increased in CAP. CONCLUSION: Physiological fluctuations of the EEG arousal level influence cardiac autonomic activity in normal subjects. The studies on nocturnal variation in sympathetic and vagal tone should take in account the microstructural sleep changes, other than the conventional polysomnographic parameters.

Snoring & sleep apnea: a population study in Italian women.

The aim of this cross-sectional study was to evaluate the prevalence of sleep-disordered breathing by means of a validated portable instrument (MESAM IV) and to investigate the relationship between snoring and sleep apnea in a sample of Italian middle-aged female population. We randomly chose 750 subjects aged 40 to 65 years and 365 agreed to participate to the study. In this group, 19.7% of subjects were every-night snorers according to the questionnaire; when recorded, 54.2% snored for more than 10% of the night, and 7.1% for more than 50% of the night. Sleep apnea was also common: 10.7% of subjects had a respiratory disturbances per hour (RDI) between 5 and 9, 7.7% an RDI between 10 and 19, and 2.2% had an RDI > or =20. Snoring percentage and RDI were significantly correlated. However, 50% of subjects who snored for more than half the night had no evidence of sleep apnea. Snoring amount >50% resulted influenced by body mass index, while RDI>10 was influenced by neck diameter. We concluded that in middle-aged women, both snoring and sleep apnea are very common. A high percentage of snoring is not essential for the occurrence of sleep apnea, nor it necessarily indicates the presence of sleep apnea.

Prevalence and pathologic associations of sleep paralysis in the general population.

BACKGROUND: Previous epidemiologic data on sleep paralysis (SP) came from small specific samples. The true prevalence and associated factors of SP in the general population remain unknown. METHOD: A representative sample of the noninstitutionalized general population of Germany and Italy age > or =15 years (n = 8,085) was surveyed by telephone using the Sleep-EVAL questionnaire and the Sleep Questionnaire of Alertness and Wakefulness. RESULTS: Overall, 6.2% (5.7 to 6.7%) of the sample (n = 494) had experienced at least one SP episode in their lifetime. At the time of the interview, severe SP (at least one episode per week) occurred in 0.8% of the sample, moderate SP (at least one episode per month) in 1.4%, and mild SP (less than one episode per month) in 4.0%. Significant predictive variables of SP were anxiolytic medication, automatic behavior, bipolar disorders, physical disease, hypnopompic hallucinations, nonrestorative sleep, and nocturnal leg cramps. CONCLUSIONS: SP is less common in the general population than was previously reported. This study indicates that the disorder is often associated with a mental disorder. Users of anxiolytic medication were nearly five times as likely to report SP, even after we controlled for possible effects of mental and sleep disorders.

Craniofacial modifications in children with habitual snoring and obstructive sleep apnoea: a case-control study.

Habitual snoring and obstructive sleep apnoea in children, which are frequently associated with adenotonsillar hypertrophy, may begin early in life and in relation with orocraniofacial features. The aim of this study was to detect the presence of early bone craniofacial modifications in young children with a long history of habitual snoring. Twenty-six habitually snoring children (mean age 4.6 yrs) were studied by nocturnal portable recording or diurnal polysomnography, cephalometry and orthodontic evaluation. A comparison of cephalometric findings was made between the studied group and 26 age-matched children (mean age 5.1 yrs) with no history of snoring or respiratory problems during sleep. The cephalometric analyses showed a significant increase in craniomandibular intermaxillar, lower and upper goniac angles with a retroposition and posterior rotation of the mandible (high angle face) and a reduction in the rhinopharynx space caused by higher thickness of adenoids in habitually snoring children compared with controls. Cross-bites and labial incompetence as well as daytime symptoms and familiarity for habitual snoring were found in most of the studied group of snorers compared with controls. The results indicate that upper airway obstruction during sleep is associated with mild but significant cephalometric and craniofacial modifications in children complaining of habitual snoring. Whether this skeletal conformation is genetically determined or influenced by the early onset of habitual snoring remains to be assessed.

Central nervous system superficial siderosis, headache, and epilepsy.

Almost 95 cases of superficial siderosis of the central nervous system have been reported in the literature. These patients showed a clinical syndrome characterized by ataxia, deafness, pyramidal system involvement, and mental deterioration with xanthochromic cerebrospinal fluid and neuroradiological findings of hemosiderin deposits. About 30% of the patients had headache as an accompanying symptom. In the present case report, we describe a 33-year-old man with the typical clinical features of superficial siderosis, who complained, since aged 8, of a severe recurrent frontal headache often associated with loss of consciousness occurring after at least 2 hours of pain. The MRI and CSF findings were consistent with subarachnoid bleeding. In our patient, headache due to meningeal irritation by subarachnoid blood induced seizures as a probable reflex of extreme pain. Carbamazepine and nimodipine prophylaxis dramatically reduced the frequency of headaches and seizures.

Myocardial ischemia during sleep.

The role of sleep in the pathogenesis of coronary ischaemic events such as myocardial infarction, transient myocardial ischaemia, or cardiac sudden death, is unclear. This review will analyse the available data on the subject according to: (i) the autonomic and cardiovascular changes during sleep that may potentially favour myocardial ischaemia; (ii) the evidence of a circadian distribution of coronary events; and (iii) the factors possibly involved in the pathogenesis of nocturnal angina. Available data suggest that myocardial ischaemia may occur by different mechanisms in non-rapid eye movement (NREM) (decreased coronary perfusion pressure) and rapid eye movement (REM) sleep (increased myocardial oxygen demand). Coronary events show a major peak of occurrence between 6.00 a.m. and noon; however, the myocardial ischaemic threshold, defined as the heart rate value at which myocardial ischaemia develops, may be lower at night than during the daytime, suggesting an unexpectedly higher susceptibility to myocardial ischaemia during sleep than during wakefulness. These data warrant further study on the pathophysiology of coronary circulation during sleep. Finally, some evidence is available that sleep disordered breathing may precipitate nocturnal angina especially in REM sleep, through decreased arterial oxygen content secondary to hypoventilation or true apnoeas. More data are needed to better understand the effects of sleep on the coronary circulation, and to improve the therapeutic approach of nocturnal angina.

Impairment of memory and plasma flunitrazepam levels.

Flunitrazepam was administered to volunteers in three different oral doses. The effects on psychomotor sedation, attention, working memory and explicit memory were then assessed at various intervals after dosing and compared with levels of the drug in the plasma. Three groups of 12 healthy males with similar levels of education were given placebo or flunitrazepam (1, 2 or 4 mg) in a double-blind, random-sequence study. Volunteers completed a battery of tests at night, 3.5 h after taking the drug and in the morning, 10 h afterward. Blood samples were collected for drug analysis before and after the nocturnal tests and before morning tests. At night, only the highest dose of flunitrazepam (4 mg) induced significant changes in psychomotor sedation, attention, working memory, and prose immediate recall. Doses of 2 and 4 mg flunitrazepam significantly reduced the mean scores of explicit memory (morning tests). Z-scores, calculated from differences between flunitrazepam and placebo, revealed that 2 mg flunitrazepam impaired memory but not alertness or attention. Linear regression analysis of the relationship between plasma levels of flunitrazepam and its effects (Z-scores) indicated that there was a significant positive correlation between peak levels of flunitrazepam at night and impairment of night attention and explicit memory, i.e. delayed recall of prose (r = 0.59, P < 0.01) and trigrams (r = 0.55, P < 0.01). However, memory and attention Z-scores as a function of plasma levels fitted with nonlinear regression analysis to the Emax model had higher correlation coefficients. To produce an effect equal to 50% of the maximum effect for memory impairment, concentrations (EC50) were 6.1 and 6.4 ng/ml for prose and trigrams delayed recall; but for attention they were much higher, at 13.2 ng/ml. The overall results indicate that higher concentrations were needed to impair attention than were required to impair memory.

The neurophysiological evaluation of nocturnal frontal lobe epilepsy.

The most reliable technique for the diagnosis of nocturnal frontal lobe epilepsy (NFLE) is nocturnal video-polysomnography, which is an expensive procedure and unavailable in many Departments of Neurology and Epileptology around the world. The aim of the present study was to evaluate the role of routine video-EEG and video-EEG after sleep deprivation, during the daytime, in the diagnosis of NFLE. We studied 23 patients complaining of repeated nocturnal motor attacks using a 3-level neurophysiological evaluation, including video-EEG when awake (level 1), video-EEG after sleep deprivation, during the daytime (level 2) and nocturnal video-polysomnography (level 3). All the patients had a normal video-EEG when awake. The video-EEG after sleep deprivation (level 2) allowed a diagnosis of NFLE in 52.2% of the patients, while the nocturnal video-polysomnography (level 3) allowed this diagnosis in 87.0% of the same sample. In the patients complaining of repeated nocturnal motor attacks, a video-EEG after sleep deprivation performed during the daytime, could be useful for diagnosis in about one half of cases. This methodology is routinely performed in many Departments of Neurology and Epileptology, and is much less binding and expensive than nocturnal video-polysomnography and so it could be important economically for the health service.

Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.

A number of clinical and aetiological studies have been performed, during the last 30 years, on patients with abnormal nocturnal motor and behavioural phenomena. The aetiological conclusions of these studies were often conflicting, suggesting either an epileptic or a non-epileptic origin. Among the clinical characteristics of these patients, the familial clustering was one thoroughly accepted. A nocturnal familial form of frontal lobe epilepsy (autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE), often misdiagnosed as parasomnia, has been recently described in some families. In one large Australian kindred, a missense mutation in the second transmembrane domain of the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) gene, located on chromosome 20 q13.2-13.3, has been reported to be associated with nocturnal frontal lobe epilepsy. We performed an extensive clinical and video-polysomnographic study in 40 patients complaining of repeated abnormal nocturnal motor and/or behavioural phenomena, from 30 unrelated Italian families. Thirty-eight patients had an electroclinical picture strongly suggesting the diagnosis of ADNFLE. They had a wide clinical spectrum, ranging from nocturnal enuresis to sleep-related violent behaviour, thus including all the main features of the so-called 'typical' parasomnias. The video-polysomnographic recording confirmed the wide spectrum of abnormal manifestations, including sudden awakenings with dystonic/ dyskinetic movements (in 42.1% of patients), complex behaviours (13.2%) and sleep-related violent behaviour (5.3%). The EEG findings showed ictal epileptiform abnormalities predominantly over frontal areas in 31.6% of patients. In another 47.4% of patients the EEG showed ictal rhythmic slow activity over anterior areas. Only 18.4% of the patients had already received a correct diagnosis of epilepsy. In 73.3% of the patients treated with anti-epileptic drugs the seizures were readily controlled. Pedigree analysis on 28 of the families was consistent with autosomal dominant transmission with reduced penetrance (81%). DNAs from 20 representative affected individuals were sequenced in order to check for the presence of the missense mutation in the CHRNA4 gene found in the Australian kindred affected by ADNFLE. Nucleotide sequence analysis did not reveal the presence of this mutation, but it did confirm the presence of two other base substitutions, not leading to amino acid changes. These two intragenic polymorphisms, together with a closely linked restriction fragment length polymorphism at the D20S20 locus, have been used for linkage analysis of ADNFLE to the terminal region of the long arm of chromosome 20 in five compliant families. The results allowed us to exclude linkage of ADNFLE to this chromosomal region in these families, thus confirming the locus heterogeneity of the disorder. Large and full video-polysomnographical studies are of the utmost importance in order to clarify the real prevalence of both nocturnal frontal lobe epilepsy and parasomnias, and to provide a correct therapy.