Segregation of HLA genes in multicase narcolepsy families.

In the past 15 years, 411 sporadic narcolepsy patients have been diagnosed in the Hephata Klinik, Schwalmstadt, Germany. They were explored for presence or absence of excessive daytime sleepiness and narcolepsy in their relatives. A subset of 39 patients were explored for presence or absence of parasomnias. Six patients had more than one relative affected by narcolepsy-cataplexy. Forty-seven family members were investigated with the Stanford Center for Narcolepsy Sleep Inventory and a standardized parasomnia questionnaire. Twenty-four relatives had nocturnal polysomnographies and Multiple Sleep Latency Tests. HLA class I typing was performed in all sporadic and familial cases, class II and microsatellite typing was performed in all members of multicase families. Based on the Finnish prevalence study by Hublin et al., 1994, the relative risk for first degree relatives to develop narcolepsy-cataplexy was in our sample 16.5, 34.2 for excessive daytime sleepiness and 426.9 for parasomnias. Cataplexy, excessive daytime sleepiness and single narcoleptic symptoms in the multicase families segregate with the DRBI*1501, CARII:200, CARI: 103, DQBI*0602 haplotype. In two families, members with narcolepsy and isolated symptoms have inherited the DRBI*1501/DQBI*0602 haplotype from the nonaffected parent. The observed segregations in these two families may support the view that narcoleptic symptoms are expressed by DRBI*1501/DQBI*0602 carriers, independent of haplotype origin. Parasomnias do not segregate with a specific haplotype. The frequency of parasomnias in narcolepsy is much higher than in the general population. The empirical risk for first degree family members of narcolepsy patients to develop cataplexy seems to be low, whereas it is higher for EDS and highest for parasomnias.

[Sleep deprivation in somnambulism. Effect of arousal, deep sleep and sleep stage changes]. / Schlafentzug bei Somnambulismus. Auswirkung auf Arousals, Tiefschlaf und Schlafstadienwechsel.

Diagnosis of parasomnias in the sleep laboratory is difficult since the nocturnal behavior reported by the patients often does not show up in the laboratory. To test the efficacy of sleep deprivation as a tool to provoke somnambulism we investigated ten patients (three women and seven men, mean age 27 +/- 3.4) with somnambulism. Their standard polysomnographies and videomonitored nocturnal behavior was compared to that of sex- and age-matched controls and to polysomnography and behavior after sleep deprivation. Patients with parasomnias and controls did not show significant differences in sleep parameters with the exception of longer arousal duration in controls, which was nonsignificant. In magnetic resonance tomography, patients with parasomnias did not reveal abnormality of the brain that might explain release of nocturnal behavior. Sleep deprivation led to significantly reduced number of arousals, reduced arousal index, significantly prolonged arousal duration and more stage shifts from all sleep stages (nonsignificant). Complex behavior during sleep increased under sleep deprivation, whereas sleepwalking did not increase. The majority of complex behavior during sleep is triggered by stage shifts and not by arousal in the sense of the arousal definition of the American Sleep Disorder Society. Complex behavior in sleep is stereotypical and nonviolent. Its complexity seems to depend on the duration and intensity of arousals. Sleep deprivation can be recommended as an efficacious method of increasing complex behavior in sleep, which is a preliminary stage of sleepwalking. Concerning the underlying pathology it seems to be important to register the quality and duration of stimuli that trigger arousals instead of focusing the number of arousals alone.

Endocrinological and polysomnographic findings in Kleine-Levin syndrome: no evidence for hypothalamic and circadian dysfunction.

Five subjects--four men, ages 17-28, and one woman, age 30--with Kleine-Levin syndrome were investigated during symptomatic (SP) and asymptomatic (ASP) periods. Investigations comprised medical history, MRI, polysomnography, 24-hour hormone profile of human growth hormone, melatonin, TSH, cortisol and FSH (in the woman only) assessed every 2 hours, actimetry, and sleep logs. Medical history confirmed presence of the three symptoms diagnostic of of typical Kleine-Levin syndrome: hypersomnia, excessive food intake, and psychic alteration. MRIs of the brain were normal in all patients. Symptomatic periods were triggered by unspecific events, such as infection, sleep deprivation, and alcohol. Polysomnography revealed low sleep efficiency during SPs, decreased amount of slow-wave sleep, and high frequency of stage shifts, indicating sleep fragmentation. Mean 24-hour growth hormone levels were reduced during the SPs in only two patients. Their hGH peaks were dissociated from slow-wave sleep during attacks and intervals, often occurring during wake time. Twenty-four-hour melatonin levels were increased during the SPs in all patients, but were lower in two patients during the nocturnal sleep period. Cortisol, TSH and FSH did not reveal important differences between attacks and intervals. Except for hGH, all hormones had normal circadian excretion during symptomatic and asymptomatic periods. Amplitude of nocturnal activity as assessed by actimetry was significantly increased in two patients, whereas amplitude of daytime activity was significantly reduced in three patients. Actimetry and sleep logs demonstrated prolonged sleep phases during SPs. Our investigation could confirm changes of sleep structure described in the literature. The neuroendocrinological findings could not confirm decreased hGH and cortisol and increased TSH levels during SPs, as previously reported in single cases by many authors. Endocrinological findings did not support an underlying circadian disorder in KLS.

Circadian temperature and activity rhythms in unmedicated narcoleptic patients.

Fifteen unmedicated narcoleptic patients with and without sleep-onset REM period (SOREMP) were compared with 16 unmedicated, age-and-sex-matched control subjects with respect to polygraphic, core body temperature and motor activity recordings. Whereas narcoleptic patients with SOREMPs had significantly more quiet wakefulness during sleep, those without SOREMPs had significantly more quiet wakefulness during daytime than the other groups. Compared with that of controls, temperature of both narcoleptic groups showed (a) less rise of temperature curve in the morning, (b) dampening of temperature amplitude, (c) phase advance of acrophase, and (d) advance of temperature minimum after sleep onset. Maximal temperature decline occurred earlier in patients with SOREMPs during naps and sleep than in the other groups. We could confirm parallels between temperature and motor activity with controls and found no change in the oscillator of narcoleptic patients. Advanced temperature minima and first REMPs relative to sleep onset and maximal temperature decline occurring nearer to sleep onset indicate a defect in the temperature-locked triggering of REM in narcoleptic patients with SOREMP and a circadian rhythm disorder.

[Differential diagnosis of seizures in sleep]. / Differentialdiagnose von Anfällen im Schlaf.

Epilepsies and the NREM and REM parasomnias represent the most important sleep-related attacks that can occur in conjunction with sleep apnoea. Most sleep-related attacks arise from certain sleep stages only, which facilitates their identification. Many attacks can only be classified by thorough observation and description, since they lack special electrophysiological correlates. EEG recordings with at least 16 channels and EMGs from several muscles are necessary for differential diagnosis. Video-documentation often reveals relevant additional information confirming the diagnosis.

Effects of vitamin B12 on performance and circadian rhythm in normal subjects.

This preliminary study investigates effects of methyl- and cyanocobalamin on circadian rhythms, well-being, alertness, and concentration in healthy subjects. Six women (mean age 35 years) and 14 men (mean age 37 years) were randomly assigned to treatment for 14 days with 3 mg cyano-(CB12) or methylcobalamin (MB12) after 9 days of pre-treatment observation. Levels in the CB12 group increased rapidly in the first, then slowly in the second treatment week, whereas increase in the MB12 group was linear. Urinary aMT6s excretion was reduced by both forms of vitamin B12 over 24 hours with a significant decrease between 0700-1100 hours, whereas urinary excretion of potassium was significantly increased between 0700-1100 hours. Activity from 2300-0700 hours increased significantly under both forms of vitamin B12. Sleep time was significantly reduced under MB12 intake. In this group the change in the visual analogue scales items "sleep quality," "concentration," and "feeling refreshed" between pretreatment and the first week of treatment showed significant correlations with vitamin B12 plasma levels. Cortisol excretion and temperature were not affected by either medication. We conclude that vitamin B12 exerts a direct influence on melatonin. Only MB12 has a positive psychotropic alerting effect with a distribution of the sleep-wake cycle toward sleep reduction.

Diagnostic use of daytime polysomnography versus nocturnal polysomnography in sleep apnea syndrome.

The usefulness of daytime polysomnography (DPSG) in the diagnosis of sleep apnea syndrome (SAS) is examined. Diagnostic use was investigated by conducting DPSG of two different time periods (Group M, 11.00-14.00 h, and Group A, 15.00-18.00 h). The subjects were 30 patients (28 men and two women; mean age, 54.0 years). Nocturnal polysomnography (NPSG) and DPSG were investigated by comparing indices of sleep, apnea index (AI) and arterial oxygen saturation (SaO2). There was no significant difference among these indices but there was a significant positive correlation between NPSG and DPSG in all variables related to sleep apnea. Moreover, there was no significant difference in the frequency of each type of apnea between NPSG and DPSG in either group. These findings suggest that DPSG is useful not only in diagnosing SAS but in evaluating its severity.

Effects of vitamin B12 on human circadian body temperature rhythm.

To clarify the effect of vitamin B12 on the human circadian clock, five healthy male adults participated in two constant routine procedures, 2 or 3 weeks apart. In one, subjects received intravenous saline injections (placebo trial) and in the other, intravenous injections of methylcobalamin (MB12) (drug trial). Intravenous administration of MB12 increased rectal temperature in the later hours of the daytime during the constant routine. The activity did not change between treatments in any period during the constant routine. During the later hours of the constant routine, alertness assessed with visual analog scale was higher in the drug trial than in the placebo trial. The period in which drug treatment produced greater alertness almost coincided with that in which MB12 elevated rectal temperature. These results may provide evidence of an effect of vitamin B12 on the circadian clock.

[Differential therapeutic aspects in treatment of obstructive sleep apnea syndrome]. / Differentialtherapeutische Aspekte zur Behandlung des obstruktiven Schlafapnoesyndroms.

We report the case of a 43-year-old man who suffered from obstructive sleep apnea with excessive daytime sleepiness and nocturnal sweating. His initial apnea index of 60/h improved under treatment with an Esmarch device. Apneas were totally suppressed by nCPAP application with a pressure of only 4 mb, but the patient rejected nCPAP therapy. After two years with the Esmarch device he reported increasing temporomandibular joint pain and Esmarch therapy had to be stopped. A cephalometric evaluation showed good prognosis for maxillomandibular advancement osteotomy, which was performed and which suppressed the apneas completely over a period of more than one year. Indication, surgical technique, and risks are discussed.

Cephalometric predictors for orthopaedic mandibular advancement in obstructive sleep apnoea.

The cephalometric analysis of two groups: 30 sleep apnoea patients, and 30 age- and sex-matched control patients, established predictors for the orthopaedic mandibular advancement by means of the Esmarch device (ED) in treating obstructive sleep apnoea (OSA). Polysomnographic sleep and ventilation data gathered for each patient with and without mandibular advancement by means of the ED were compared. Cephalometric data and treatment efficacy for each patient were submitted to a regression analysis. Maximal efficacy is predicted by: 1. The combination of an orthognathic to prognathic maxilla (SNA larger than or equal to 83 degrees) with an orthognatic to retrognathic mandible (SNB less than or equal to 77 degrees) 2. An anterior superior displacement of the mandible, with the supramentale situated at a distance from the anterior part of second cervical vertebra (B-HWK 2 longer than or equal to 95.5 mm) and a narrow angle between the skull and the mandibular ramus (SN/B-Go equal to or less than 1.5 degrees) 3. Short oral height (TB-PNS equal to or less than 35.5 mm), with the uvula not extending beyond the tongue base (UT-PNS, equal to or less than 30 mm). 4. A narrow oropharynx (PAS equal to or less than 3.4 mm). The narrower the SNB-angle, the wider the SNA-angle, and the shorter the uvula, the more effective the device.

Striatal dopamine D2 receptors in patients with narcolepsy measured with PET and 11C-raclopride.

We investigated in vivo D2 receptor binding using 11C-raclopride and PET in the striatum of 17 subjects with the narcoleptic syndrome. Putamen and caudate nucleus 11C-raclopride uptake was comparable in the total patient group and controls, and the tracer uptake was similar in the HLA-DR2-positive (n = 12) and HLA-DR2-negative (n = 5) narcoleptic subjects. There was a significant increase in 11C-raclopride uptake in the putamen of narcoleptic subjects older than 31 years (n = 11) when compared with age-matched controls (n = 15). There was no evidence of involvement of the striatal D2 dopaminergic neurotransmitter system in the basic pathophysiology of the narcoleptic syndrome despite an age-related increase in putaminal 11C-raclopride uptake.

Differential effects of extended sleep in narcoleptic patients.

The aim of the present study was to investigate the effects of extended night sleep on subsequent daytime sleep propensity in narcoleptic patients. The possible differentiation between REM and NREM sleepiness was of particular interest. Ten unmedicated narcoleptic inpatients (8 men, 2 women) aged 23-61 years (mean, 47.9 years) participated in this study. Adapting the patients to the hospital schedule (nocturnal sleep period from 22:00 to 6:00 h and ad lib, nap during daytime) for at least 2 weeks, we conducted a baseline PSG from 22:00 to 6:00 h and subsequent 5-trial daytime sleep recordings with naps (lying on the bed for 20 min light-out period) at 9:30, 11:30, 13:30, 15:30 and 17:30 h (the baseline condition: BC). After a 1-5 day interval, we conducted an extended PSG from 22:00 to 10:00 h. Subsequent to the extended PSG, we carried out 5-trial daytime sleep recordings. We adjusted the start time of the first nap trial at least 90 min after waking time and start time in the 5th nap trial before 19:00 h (the extended condition: EC). Mean TST was 417.0 min in the baseline PSG, and 595.2 min in extended PSG. Mean number of daytime naps per subject exhibiting a sleep latency shorter than 10 min was decreased in EC. Mean sleep latency in EC was significantly prolonged in comparison with that in BC. This prolongation of mean sleep latency per subject was positively correlated with S4 duration and % S4 obtained in the morning of the extended PSG (from 6:00 to wake time).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

[Assessment of the degree of disability in narcolepsy]. / Zur Einschätzung des Behinderungsgrades bei Narkolepsie.

This article sums up the scientific results of the past 10 years on narcolepsy reflecting its impact on socio-medical impairment of narcoleptic patients. Extensive epidemiological studies showed that major restrictions for narcolepsy patients are caused by daytime sleepiness and sleep attacks with consecutive cognitive and memory deficits high accident rates, personality, mood and sexual disorders. We suggest the minimum degree of impairment as a rule should be at least 50%, in case of drug-resistant cataplexy or permanent sleep attacks around 80%.

A deletion in the second exon of an HLA-DRB1 allele found in a DR2-negative narcolepsy patient.

In this report, we describe a new allele of the HLA-DRB 1 gene carrying a form of mutation that has not been observed before. It appeared in an HLA-DR2-negative narcolepsy patient who, besides HLA-DR4, revealed a serologic HLA-DR blank segregating with HLA-DQ1. Oligotyping showed that the new allele belongs to the HLA-DR8 group. Restriction analysis and DNA sequencing revealed the deletion of 12 bp as well as the substitution of 9 flanking base pairs between codons 36 and 43. The expression of the mutated gene was demonstrated by the presence of its messenger RNA and a few positive reactions with DR8 sera. Without interrupting the reading frame, the mutation leads to a gene product composed of a modified amino acid sequence. We anticipate that the mutation influences the conformation of the molecule with possible consequences concerning immune response.

[Abnormal daytime drowsiness--attempt at typology]. / Abnorme Tagesschläfrigkeit--Ansätze zu einer Typologie.

Abnormal drowsiness during the day is defined on the basis of three criteria: 1. subjective feeling of increased tiredness, 2. objective observation of attacks of falling asleep, 3. detection of premature falling asleep in the multiple sleep latency test. About 3 to 4% of the population of modern industrial countries complain of this symptom which very quickly leads to inability to work in numerous occupations (driving instructors, lorry drivers, airline pilots). In many cases, the symptoms can be eliminated by effective methods of treatment. Early diagnosis and therapy is hence an important task of physicians. Clinically suitable tools and methods of measurement for appraising the phenomena are at present: 1. the multiple sleep latency test (Richardson et al., 1978), 2. the multiple staying awake test (Mitler et al., 1982), 3. the vigilance test according to Quatember and Maly from the Vienna test system. In neurophysiological terms, an attempt is made to differentiate between: REM drowsiness, non-REM drowsiness, hypofunction of the arousal systems of the reticular formation, and hyperfunction and overstimulation of the arousal systems of the reticular formation (over-aroused tiredness). Approaches to a clinical typology of abnormal drowsiness are available from two points of departure: 1. Forms of permanent somnolence which are not alleviated but intensified by a brief restorative sleep and resemble the 'oversleeping syndrome' of the healthy individual. 2. Attacks of imperative falling asleep in narcoleptic patients. The characteristic of this form of abnormal drowsiness during the day is that in the interval between the attacks of falling asleep patients can take on any healthy person with regard to alertness, reaction capacity and ready wit. After a brief restorative sleep of less than 5 min., they immediately feel fresh, alert and fit again.

Bright white light does not improve narcoleptic symptoms.

Bright white light (500lx) for 4 h/day was applied to seven narcoleptic patients (age 47-65 years, mean 55 years). The effects of the light on the disturbed sleep-wake cycle in narcoleptics were investigated by the measurement of the following parameters: (1) excessive daytime sleepiness and sustained attention (multiple sleep latency test); (2) rest-activity cycles; (3) self-ratings (mood, anxiety, tiredness); (4) urinary cycles of 6-OH melatonin sulphate and cortisol; (5) sleep EEG. Treatment with bright light showed neither objective nor subjective changes in the clinical symptoms of narcolepsy. While similar "dosage" light applications can phase shift human circadian rhythms and improve depression and hypersomnia in winter depression, it is not an appropriate treatment for narcolepsy.

Cellular approach for detecting narcolepsy-specific alterations in DR2 haplotypes.

In an attempt to detect disease-associated genetic variations and/or exogenously induced alterations in DR2 haplotypes of narcolepsy patients, primed lymphocytes (PLs) were generated in nine families against DR2 haplotypes of narcolepsy patients and healthy family members. Twenty-four PL reagents were obtained and restimulated by cells of unrelated narcolepsy patients and DR2/Dw2-positive healthy individuals. The mean restimulation rates triggered by cells of patients or healthy controls, respectively, never differed significantly. In primary MLC as well as PLT combinations of patients and their HLA-identical siblings no significant stimulation was observed in both directions. We conclude that narcolepsy-specific alterations of class II molecules cannot be cellularly detected or do not exist on peripheral lymphocytes.

[ENT medical findings in obstructive sleep apnea syndromes]. / HNO-ärztliche Befunde bei obstruktivem Schlaf-Apnoe-Syndrom.

Correlations between the manifestation of obstructive sleep apnoea syndrome (OSAS) and anatomical or functional changes in the upper respiratory tract remain controversial. The correlation between obstruction of the upper respiratory tract and the degree of sleep apnoea syndrome was investigated in 60 patients with obstructive sleep apnoea (diagnosed by polysomnography) and in 55 healthy controls. After clinical examination, rhinomanometry and determination of the size of the lower jaw and oropharynx, the motility of the pharyngeal walls during Mueller's manoeuvre was evaluated by flexible endoscopy. No significant anatomical or functional differences were observed between OSAS patients and healthy controls. There was no correlation between the degree of OSAS (expressed by the apnoea index) and pharyngeal size. Although no specific statement concerning diagnosis or degree of OSAS can be made on the basis of an otolaryngological examination, OSAS patients should always undergo otolaryngological examination to exclude pharyngeal disease.