Long-term follow-up on restless legs syndrome patients treated with opioids.

The medical records of 493 patients with restless legs syndrome (RLS) from three major centers were studied to determine the number and outcome of patients who had been treated with opioids as a monotherapy. At one time or another 113 patients (51 men, 62 women; age range, 37-88 years) had been on opioid therapy either alone (36 patients) or with opioids added secondarily to other medications used to treat RLS (77 patients). Twenty-three of the 36 opioid monotherapy patients had failed dopaminergic and other therapeutic agents prior to the initiation of opioid monotherapy. Twenty of the 36 opioid monotherapy patients continue on monotherapy for an average of 5 years 11 months (range, 1-23 years), despite their knowledge of the availability of other therapies. Of the 16 patients who discontinued opioids as a sole therapy, the medication was discontinued in only one case because of problems related to addiction and tolerance. Polysomnography on seven patients performed after an average of 7 years 1 month of opioid monotherapy (range, 1-15 years) showed a tendency toward an improvement in all leg parameters and associated arousals (decrease in PLMS index, PLMS arousal index, and PLM while awake index) as well as all sleep parameters (increase in stages 3 and 4 and REM sleep, total sleep time, sleep efficiency, and decrease in sleep latency). Two of these seven patients developed sleep apnea and a third patient had worsening of preexisting apnea. Opioids seem to have long-term effectiveness in the treatment of RLS and PLMS, but patients on long-term opioid therapy should be clinically or polysomnographically monitored periodically for the development of sleep apnea.

Full polysomnography in the home.

STUDY OBJECTIVES: To evaluate unattended full polysomnography (PSG) recorded in the home by the DigiTrace Home Sleep System (DHSS) and to assess the ability to acquire, store and analyze polysomnographic data using the DHSS compared to standard paper PSG. DESIGN: Part 1 used a prospective, cross-over design. Part 2 consisted of a prospective concurrent collection of polysomnographic data. SETTING: Sleep Disorders Center in a university medical center. PARTICIPANTS: All adult patients who required standard clinical PSG as part of their clinical evaluation, regardless of suspected diagnosis, except patients requiring video recording for abnormal behaviors. MEASUREMENTS AND RESULTS: The DHSS is a digital recording system with miniature preamplifiers and the capacity to record 18 channels of polysomnographic data, including 4 channels of EEG (C3-A2, C4-A1, C3-O1 and C4-O2), right and left EOG, two channels of chin EMG, ECG naso-oral airflow, respiratory effort (piezo crystal thoracic and abdominal belts and bilateral interacostal EMG), snore microphone, bilateral anterior tibialis EMG, and body-position sensor. In part 1,77 DHSS home recordings were evaluated. No recordings were lost due to equipment failure and each parameter was scorable in greater than 95% of all epochs. Most of the subjective assessments by questionnaire following each study revealed no difference between the two testing situations. However, patients reported more sleep time and a better overall test experience in the lab. Assessments of sleep quality and morning alertness compared to usual were rated higher in the lab. After completing both studies, more patients preferred the lab study (p < .01), mostly because of minor inconveniences and apprehension regarding acquisition of data during the home study. There was no difference in the assessment of which test most accurately represented their sleep. In Part 2, the DHSS recorded concurrently with paper PSG in the laboratory in 16 patients. The results show no significant differences for any parameter and strong positive correlations for all parameters. CONCLUSION: Using the DHSS, unattended full PSG can be performed in the home with reliable and high quality recordings. Full PSG can be extended to a larger patient population, because it is no longer limited by the number of beds, and there is a reduction in cost due to elimination of overnight staff and facility cost.

Treatment modalities for narcolepsy.

Narcolepsy, a lifelong disorder, requires long-term management of symptoms. Interventions may be nonpharmacologic, such as lifestyle changes, and pharmacologic for relief of daytime sleepiness. Pharmacologic treatment of narcolepsy has depended on the use of CNS stimulants to increase wakefulness, vigilance, and performance. The medications considered effective in the treatment of narcolepsy include dextroamphetamine, pemoline, methylphenidate, methamphetamine, and modafinil; only methylphenidate hydrochloride and dextroamphetamine are approved for use in the United States. The currently available stimulants are associated with sympathomimetic side effects, limitations in efficacy, and negative effects on nighttime sleep. This has led to the development of alternative agents. Modafinil, a new wake-promoting agent, has been shown to be effective in reducing daytime sleepiness in patients with narcolepsy. The results of a United States 18-center randomized, placebo-controlled, 9-week trial of modafinil in the treatment of patients with narcolepsy has recently been reported. Patients receiving modafinil demonstrated significant improvement in all subjective and objective measures of sleepiness. Treatment with modafinil 200 mg and 400 mg daily significantly reduced mean scores on the Epworth Sleepiness Scale compared with baseline and placebo (p < 0.001) and significantly increased mean scores on the Maintenance of Wakefulness Test (p < 0.001) and the Multiple Sleep Latency Test (p < 0.001) compared with baseline and placebo. More improvement, as recorded on the Clinical Global Impression of Change scale, was seen in the modafinil group than in the placebo group at all time points (p < 0.001). Modafinil was well tolerated, with headache the only adverse event to occur significantly more often in the active treatment group (p < 0.05). These results suggest that modafinil is an important new therapeutic option for the treatment of narcolepsy.

Thermoregulatory, metabolic and sympathoadrenal responses to repeated brief exposure to cold.

This study examined the metabolic, thermoregulatory and sympathoadrenal response pattern of eight male subjects to repeated bouts of brief cold stress. Water immersion (WI) was used to induce cold stress over a 60 min period on three separate occasions on three successive days. Rectal temperature (T(re)), mean skin temperature (T(sk)) and metabolic rate (VO2) were measured at 10 min intervals throughout WI and for 20 min post-immersion (PI). Blood was drawn and assayed for plasma adrenaline (ADR), noradrenaline (NDR) and cortisol at rest, at the end of immersion and PI. Acute cold stress was induced for each of the three exposures with a reduction in T(re) of approximately 0.63 degrees C (p<0.01) and approximately 1.2 degrees C (p<0.01) at the end of immersion and PI, respectively. T(sk) was reduced for all trials by approximately 6.0 degrees C (p<0.01) at the end of immersion and approximately 3.0 degrees C (p<0.01) at PI. VO2 peaked at 40-50 min of WI to 83%, 58% and 47% above rest for each consecutive trial. Plasma ADR did not show any change (p=0.34) as a consequence of cold stress between trials. Plasma NDR increased at the end of immersion (p<0.01) and remained elevated at PI (p<0.01). Plasma cortisol showed no change for any of the exposure periods. DeltaT(re) was more pronounced for the last exposure and was negatively correlated (r= -0.78, p<0.02) with plasma NDR. The results of this investigation complement previous findings of cold adaptation and suggest a possible adaptive response to repeated brief bouts of cold exposure evidenced by the changing trends in body temperature, metabolic rate and plasma NDR.

The indications for polysomnography and related procedures.

This paper is a review of the literature on the use of polysomnography in the diagnosis of sleep disorders in the adult. It is based on a search of MEDLINE from January 1966 through April 1996. It has been reviewed and approved by the Board of Directors of the American Sleep Disorders Association and provides the background for the accompanying ASDA Standards of Practice Committee's Parameters for the Practice of Sleep Medicine in North America. The diagnostic categories reviewed are: sleep-related breathing disorders; other respiratory disorders; narcolepsy; parasomnias and sleep-related epilepsy; restless legs syndrome and periodic limb movement disorders: insomnia; and circadian rhythm sleep disorders. Where appropriate, previously published practice parameters papers are cited and discussed. The relevant published peer-reviewed literature used as the basis for critical decisions was compiled into accompanying evidence tables and is analyzed in the text. In the section on the assessment of sleep apnea syndrome, options for estimating pretest probability to select high risk patients are also reviewed. Sleep-testing procedures other than standard polysomnography are also addressed (daytime polysomnography, split-night studies, oximetry, limited full respiratory recordings, and less-than-full respiratory recording) and treatment-related follow-up studies are discussed.

Inspiratory fall in systolic pressure in normal and asthmatic subjects.

We used a noninvasive monitor of arterial pressure to determine whether respiratory changes in arterial pressure were closely correlated with airflow obstruction in asthmatic patients during bronchial challenge with methacholine. To validate the noninvasive measurement of respiratory changes in arterial pressure, a preliminary study in 6 subjects with normal cardiovascular and respiratory systems was done during cardiac catheterization for suspected coronary artery disease. There were no significant differences between inspiratory falls in systolic pressure measured noninvasively and those measured from intraaortic pressure. In 11 otherwise healthy asthmatic patients we measured finger arterial pressure, end-expiratory lung volume (FRC), and forced expired volume (FEV1) during baseline and bronchial challenge in the supine posture. Finger arterial pressure was also measured in 11 normal control subjects seated and supine. Normal subjects had an inspiratory fall in systolic pressure (IFSP) of 3.2 mm Hg supine and 5.1 mm Hg seated (p < 0.01). Asthmatic patients when bronchodilated (seated FEV1 = 83 +/- 7% of predicted) had an IFSP of 5.9 mm Hg supine (p < 0.01 compared with supine normal subjects). During bronchial challenge (average fall in FEV1 = 22%), IFSP increased to 16.1 mm Hg (p < 0.001 compared with baseline). In asthmatic subjects, there was a significant correlation between IFSP and FEV1 (mean r = -0.92 +/- 0.05, p < 0.01), and the average change in IFSP/change in FEV1 was -0.38 mm Hg per percentage change in FEV1. During subsequent bronchodilation, IFSP decreased with a similar time course as relaxation of airway smooth muscle, assessed by the breath-to-breath fall in FRC.(ABSTRACT TRUNCATED AT 250 WORDS)

Pediatricians and sleep disorders: training and practice.

OBJECTIVE: A series of studies were conducted to investigate pediatricians' training, knowledge, and practices regarding sleep and sleep disorders in children and adolescents. METHOD AND RESULTS: Study 1, a national survey of 156 pediatric residency programs, found that pediatricians receive a mean of 4.8 hours of instruction on sleep and sleep disorders, although the mode and median hours of instruction is 0 hours. In study 2, 88 pediatricians completing a questionnaire concerning general knowledge about sleep disorders in children and adolescents received a mean score of 71.8% (range, 40% to 93%). Pediatricians appear to know the most about developmental issues and sleep hygiene and the least about specific disorders such as narcolepsy and parasomnias. In the third study, 183 pediatricians were surveyed about their actual beliefs and practices regarding young children's sleep problems. Together, those surveyed reported that approximately 25% of their patients experience some type of sleep problem. Most pediatricians recommend behavioral interventions, although 14.8% of pediatricians report prescribing pharmacological treatments, and 48.9% inform parents that their child is likely to outgrow the problem. CONCLUSIONS: The results of these studies support the need for more education in sleep and sleep disorders in children and adolescents within medical schools, pediatric residency programs, and the practicing pediatric community.

Muscle enzymes in the diagnosis of ovine weaner nutritional myopathy.

The diagnostic performance of plasma tests for muscle enzymes was measured in sheep from flocks affected by clinical and sub-clinical nutritional myopathy. Parallel combinations of tests for creatine kinase (CK), alanine amino transferase (ALT), aspartate amino transferase (AST) and lactate dehydrogenase had higher diagnostic sensitivity than CK alone. The enzymes ALT and AST showed the highest correlation with the degree of muscle damage. A parallel combination of tests for plasma CK and ALT as well as tests for plasma alpha-tocopherol and red cell glutathione peroxidase are recommended for the diagnosis of nutritional myopathy and a decision on the appropriate treatment. The number of false negative results based on a diagnosis from the microscopic examination of single muscles was higher than for the parallel combination of tests. The number of false negatives was highest for the vastus intermedius and lowest for the tensor fascia lata. Diagnosis using a panel of blood tests has the advantages of overcoming problems of inadequate muscle sampling, a larger number of sheep in the flock can be tested and a more rapid diagnosis can be obtained.

Plasma indicators of muscle damage in a model of nutritional myopathy in weaner sheep.

Subclinical nutritional myopathy was induced in 5-month-old sheep by feeding them a diet low in vitamin E and selenium. Subsequently clinical myopathy was induced by dosing with protected polyunsaturated fatty acids. Plasma activities of creatine kinase (CK), pyruvate kinase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and aldolase, enzymes of muscle origin, all remained above their reference ranges in clinically affected sheep, but fluctuated widely. Similar fluctuations occurred in subclinically affected animals, resulting in some activities being within the reference ranges and some above, at different times. Plasma malondialdehyde, an indicator of lipid peroxidation, proved of no diagnostic value. Terminal plasma CK activities were significantly correlated with microscopic damage in the vastus lateralis (VL), but not the vastus intermedius (VI) or the tensor fascia lata (TFL) muscles. AST was the most highly correlated with damage in VI and VL. In two clinically affected sheep successfully treated with an oral dose of alpha-tocopherol acetate all enzymes decreased steadily to within their reference ranges, at rates probably related to their plasma half-lives. These results suggest that measurement of plasma CK activity would be useful in monitoring recovery of treated sheep.

Repetitive nocturnal arterial oxygen desaturation and silent myocardial ischemia in patients presenting for vascular surgery.

OBJECTIVE: To determine whether nocturnal respiratory abnormality (cyclic oxygen desaturation and tachycardia) is associated with nocturnal myocardial ischemia in older individuals with ischemic heart disease. DESIGN: Non-invasive monitoring on a single occasion. SETTING: Tertiary care referral hospital. PATIENTS: Thirty four consecutive older (68.5 +/- 6 yrs) patients referred for elective abdominal or carotid reconstructive vascular surgery. RESULTS: Seven patients (21%) had moderately severe nocturnal respiratory abnormality, defined by more than 50 dips in arterial oxygen saturation and increases in heart rate during the night. Two of these seven had clinical risk factors for ischemic heart disease and had nocturnal myocardial ischemia. Ten patients (29%) developed ischemia at some time during the study, of whom seven hand known ischemic heart disease, hypertension, and/or angina. Those with increased nocturnal ischemia showed very low frequency (1-2 cycles per minute) cyclic heart rate oscillations and repetitive nocturnal episodes of arterial oxygen desaturation, similar to patients with sleep apnea. CONCLUSION: Repetitive nocturnal cyclic arterial desaturation and cyclic increases in heart rate are associated with nocturnal myocardial ischemia in individuals with clinical risk factors for ischemic heart disease. Further investigation in a large patient sample utilizing non-invasive monitoring of saturation, heart rate, and blood pressure may provide definitive evidence regarding causation of some of the nocturnal myocardial ischemia occurring in older individuals with vascular disease.

Plasma and tissue concentrations of alpha-tocopherol during vitamin E depletion in sheep.

To determine the relationship between plasma and tissue alpha-tocopherol concentrations during vitamin E depletion, weaned lambs were placed on a vitamin E-deficient diet for 0, 1, 2, 4, 8 and 12 weeks. alpha-Tocopherol was measured in plasma, erythrocytes, liver, adrenal, adipose tissue, three different skeletal muscles and heart muscle. The alpha-tocopherol concentration in plasma fell at the same rate as the alpha-tocopherol concentration in skeletal muscles, heart muscle, adrenal and adipose tissue. The alpha-tocopherol concentration in liver and erythrocytes fell at a faster rate than that of plasma and all muscle tissues. There were significant correlations between alpha-tocopherol concentration in plasma and alpha-tocopherol concentrations in all the tissues measured. Different skeletal muscles had significantly different concentrations of alpha-tocopherol which may relate to their differing susceptibility to nutritional myopathy. The increase in malondialdehyde in oxidatively-stressed muscle tissue and the correlation with alpha-tocopherol concentration in most muscle tissues indicated that the muscles had reduced antioxidant capacity in vitro as a result of vitamin E depletion. It was concluded that during vitamin E depletion in sheep alpha-tocopherol concentration in plasma was a good index of vitamin E status under the experimental conditions employed.

Avoiding false positive findings in measuring nocturnal penile tumescence.

The measurement and interpretation of nocturnal penile tumescence (NPT) studies depend on appropriate measurement techniques, knowledge of the conditions during which NPT was recorded, and a lack of preconceived notions about the relationship of penile circumference to penile rigidity. This case report illustrates several of the most common problems in the measurement and interpretation of NPT that could result in a false positive finding.

Mitochondrial encephalomyopathy with corticosteroid dependence.

A 12-year-old boy with corticosteroid-responsive mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is described. His mother proved to have an asymptomatic mitochondrial myopathy on examination of a muscle biopsy specimen. Three weeks after the onset of vomiting, headache, ataxia and visual and speech impairment, he presented with a background of somatic growth retardation, deafness and school failure. Examination revealed disorientation, dysphasia, dyspraxia, optic atrophy, hemianopia, hemiparesis and sensory inattention. A cranial computed tomographic scan disclosed a large, low-density area, which was consistent with infarction, in the left posterior hemisphere and marked calcification of the basal ganglia bilaterally. Within two weeks of the commencement of corticosteroid treatment, the neurological dysfunction resolved. Attempts to decrease the dosage of dexamethasone caused an exacerbation of symptoms repeatedly. Two weeks after ceasing corticosteroid therapy, the patient developed a serious neurological relapse and a new, large, low-density area, which resembled an infarction, in the right posterior hemisphere on a computed tomographic scan. The reintroduction of corticosteroid therapy again resulted in the rapid resolution of all symptoms. It became evident that the patient had an exquisitely sensitive corticosteroid dependency, whereby a reduction in the dexamethasone dosage of even 0.25 mg a day caused confusion, headaches and increasing lactic acidaemia. Although it is difficult to assess the impact of various therapies in MELAS because of the episodic natural course of the disease, this remarkable corticosteroid responsiveness also has been noted in four previously reported patients with MELAS syndrome; therefore, it would seem reasonable to suggest that corticosteroid therapy now should be considered as standard treatment for this condition. However, corticosteroid therapy in other forms of mitochondrial disorders still awaits careful evaluation.

Periodic leg movements in sleep following treatment of obstructive sleep apnea with nasal continuous positive airway pressure.

Periodic leg movements in sleep are shown to be a common finding in patients with OSA and may become evident or increase in severity after treatment of the OSA with NCPAP. Periodic leg movements in sleep were measured during baseline polysomnography, a NCPAP treatment trial, and a repeat NCPAP recording in 33 patients treated with NCPAP for OSA. During baseline PSG, nine patients had five or more PLMS per hour of sleep (index), while 14 patients had a PLMSI of 5 or more during the NCPAP trial and the repeat NCPAP recording. Among those patients with a PLMSI of 5 or more during repeat NCPAP studies, the PLMSI showed a significant increase from baseline to initial NCPAP (16.9 +/- 25.3 vs 39.3 +/- 29.4; p less than 0.001) and from baseline to repeat NCPAP (16.9 +/- 25.3 vs 42.9 +/- 39.8; p less than 0.05). The number of PLMS associated with electroencephalographic arousal also increased significantly from baseline to initial NCPAP (4.3 +/- 7.4 vs 9.7 +/- 8.9; p less than 0.05) and from baseline to repeat NCPAP (4.3 +/- 7.4 vs 16.5 +/- 18.6; p less than 0.05). The 14 patients with a PLMSI of 5 or more on the repeat NCPAP had significantly more stage 1 sleep and less REM sleep than 19 patients with a PLMSI of less than 5. Bilateral anterior tibialis EMG must be measured during NCPAP recordings in order to recognize sleep disruption caused by PLMS.

Relationship of autonomic nervous system activity to daytime sleepiness and prior sleep.

Autonomic nervous system (ANS) measures have been used frequently as measures of activation or arousal. However, their relationship to standard measures of alertness--the Multiple Sleep Latency Test (MSLT) and Stanford Sleepiness Scale (SSS)--and to the quantity and quality of prior sleep has not been determined. In this study, the direct pupil light reflex (PLR) was measured with the MSLT and SSS to determine how ANS activity varies with daytime sleepiness and how all three measures were related to prior nocturnal sleep in a group of patients with obstructive sleep apnea. When the effects of age and time of day were partialed out, PLR data suggest that increased sleepiness as measured by MSLT is significantly correlated with increased parasympathetic activity (r = -0.60, p less than 0.01) and not with decreased sympathetic activity (r = -0.24, not significant). These partial correlations were significantly different (p less than 0.05). Increased sleepiness as measured by the SSS was significantly correlated with decreased sympathetic activity (r = -0.46, p less than 0.05) and not with increased parasympathetic activity (r = -0.00, not significant). These partial correlations were significantly different (p less than 0.02). In the group of sleep apnea patients, the PLR suggests that increased number of apneas and hypopneas (sleep fragmentation) was significantly correlated with both decreased sympathetic activity and increased parasympathetic activity. These findings suggest that ANS activity is related to daytime sleepiness and to the quality of prior sleep.

What is normal sleep in the elderly?

Changes in the sleep and daytime alertness of the elderly are common and are secondary to a variety of causes. These changes cannot be attributed solely to the aging process. The role of occult sleep disorders in producing these changes in significant, and severe sleep disruption in the healthy elderly is almost always secondary to a sleep disorder such as sleep apnea. A number of precautions must be kept in mind when interpreting studies of sleep in the elderly.

Sleep disorders.

Advancements in sleep research have led to the development of new standards of what is normal sleep and arousal and new diagnostic tests for the detection of sleep disorders. Millions of adults have frequent or chronic complaints about the quality and quantity of their sleep. Sleep complaints increase with increasing age and are more common in women than in men and in women over 45 than in younger women. Sedative-hypnotic drugs are taken more frequently by women than men, and the incidence of use increases with increasing age. Studies of sleep and sleep disturbances during the perimenopausal period suggest that difficulty falling asleep and frequent nocturnal awakenings result from hormonal changes, vasomotor symptoms, and possibly psychologic factors. Other causes for sleep complaints in menopausal and postmenopausal women are occult sleep disorders, especially periodic leg movements in sleep and sleep apnea syndrome. Sleeping pills are inappropriate for most patients with sleep complaints. If sleep difficulties persist after a trial of good sleep hygiene, further evaluation at a sleep disorders center is indicated.

Problems in the interpretation of nocturnal penile tumescence studies: disruption of sleep by occult sleep disorders.

A review of the sleep of 31 patients 45 years old or older undergoing nocturnal penile tumescence studies showed that 19 had a previously undiagnosed sleep disorder. Of the patients 9 had periodic leg movements in sleep, 9 had sleep apnea and 1 had both disorders. In 10 of these patients the sleep disorders affected nocturnal penile tumescence by disrupting sleep and causing brief periods of detumescence, movement artifacts and delays in the tumescing phase of nocturnal penile tumescence. These disruptions resulted in an apparently abnormal nocturnal penile tumescence that appeared as if the patient had difficulty in achieving or maintaining an erection. The nocturnal penile tumescence disruptions may have reflected only a disruption of the necessary conditions for normal nocturnal penile tumescence to occur, namely adequate sleep and rapid eye movement sleep. The results strongly suggest that failure to measure concurrent sleep parameters and screen for occult sleep disorders could result in the incorrect diagnosis of abnormal nocturnal penile tumescence.

Senile miosis: the possible contribution of disordered sleep and daytime sleepiness.

The contribution of disordered sleep and daytime sleepiness to senile miosis was investigated in 23 participants aged 60 to 80 years and 12 participants aged 21 to 40 years. All participants filled out questionnaires and were interviewed about their health, sleep, and daytime alertness. On this basis the older group was subdivided into a group of 13 participants with sleep disorders or daytime sleepiness and 10 participants without. All participants were studied with a computerized infrared television pupillometry system for 15 s in ambient lighting, 15 s after 5 min dark adaptation and with 5 light flashes. Pupil diameter after dark adaptation was significantly larger in the older group without sleep disorders than in the older group with sleep disorders (5.94 +/- .73 mm vs. 4.49 +/- .62 mm, M +/- SD, p less than .001). Significant partial correlation coefficients controlled for age were found between pupillary diameter and a variety of sleep variables. The data suggest that occult sleep disorders and daytime sleepiness may contribute to senile miosis.