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Biomedical subjects

M M Mitler

Publications and source records attributed to M M Mitler.

At least 37 records · Page 2Linked to original sources
PubMed1995

Lentiviral infection, immune response peptides and sleep.

The aberrant sleep documented in subjects with human immunodeficiency virus (HIV) infection is uniquely important because of the contribution this poor quality sleep makes to the fatigue, disability, and eventual unemployment that befalls these patients. Especially given this importance in clinical care, the research on the prominent sleep changes described in HIV infection remains modest in quantity. The chronic asymptomatic stage of HIV infection is associated with the most intriguing and singular sleep structure changes. Especially robust is the increase in slow wave sleep, particularly in latter portions of the sleep period. This finding is rare in other primary or secondary sleep disorders. The sleep structure alterations are among the most replicable of several pathophysiological sequelae in the brain associated with early HIV infection. It is unlikely that these sleep architecture changes are psychosocial in etiology, and they occur before medical pathology is evident. They are not associated with stress, anxiety, or depression. Evidence is accumulating to support a role for the somnogenic immune peptides tumor necrosis factor (TNF)alpha and interleukin (IL-1 beta) in the sleep changes and fatigue commonly seen in HIV infection. These peptides are elevated in the blood of HIV-infected individuals, and are somnogenic in clinical use and animal models. The peripheral production of these peptides may also have a role in the regulation of normal sleep physiology. The lentivirus family contains both HIV and the feline immunodeficiency virus (FIV). The use of the FIV model of HIV infection may provide a way to further investigate the mechanism of a neurotropic, neurotoxic virus initiating the immune acute phase response and affecting sleep. Neurotropic lentivirus infection is a microbiological probe facilitating neuroimmune investigation.

AIDS Dementia Complex↗
PubMed1995

Early central nervous system response to HIV infection: sleep distortion and cognitive-motor decrements.

OBJECTIVE: To repeat and extend findings suggesting that sleep disturbance, excessive daytime sleepiness, and degraded cognitive-motor abilities may be early markers of central nervous system (CNS) involvement in HIV infection. DESIGN: A controlled, cross-sectional, prospective analysis. SETTING: Clinical research center at a teaching hospital and a military health research center. SUBJECTS: Twenty-three HIV-positive (mean CD4+ count, 387 +/- 162 x 10(6)/l) and 13 seronegative men who were Naval personnel or participants of the University of California, San Diego HIV Neurobehavioral Research Center. MAIN OUTCOME MEASURES: Nocturnal and daytime sleep electroencephalogram, electromyogram, and electrocardiogram. Simple and complex cognitive-motor performance assessed via computerized tasks. RESULTS: Comparison of sleep parameters based on HIV status, length of time infected, zidovudine use, and CD4+ count indicated that CD4+ T cells > 400 x 10(6)/l were associated with a distortion in nocturnal sleep characterized by increased stages 3 and 4 non-rapid eye movement (i.e., slow-wave) sleep in the latter portion of the night and reduced nocturnal awakenings. HIV-positive patients were no sleepier in the daytime than controls. Cognitive-motor performance revealed deficits in both accuracy and efficiency for HIV-positive patients. CONCLUSION: Asymptomatic HIV-positive patients with CD4+ counts > 400 x 10(6)/l demonstrate a statistically significant increase in slow-wave sleep during the latter portion of the night and less arousability. CD4+ lymphocyte count in the early phases of HIV infection appears to differentiate between various levels of HIV disease progression with respect to certain CNS measurements of nocturnal sleep and cognitive-motor performance. Sleep structure distortion remains one of the earliest and most consistently replicable physiological signs of HIV infection. This distortion may provide a link to immune function, disease progression, and cognitive-motor disability in HIV infection.

AIDS Dementia Complex↗
PubMed1994

Weight loss for obstructive sleep apnea: the optimal therapy for obese patients.

Obstructive sleep apnea (OSA) is a common disorder in which upper-airway obstruction during sleep results in cessation of breathing. OSA is associated with increased morbidity and mortality and impaired daytime functioning. Upper-body obesity is a risk factor for OSA, and it is well documented that weight loss has a notable ameliorative impact on the occurrence of OSA. Nasal continuous positive airway pressure (nCPAP) during sleep is the primary treatment for OSA, and is usually effective in relieving upper-airway obstruction. However, compliance with prolonged nCPAP use has been proven problematic. Upper-airway surgeries may be efficacious for the treatment of OSA in carefully selected patients, but often are not successful for obese patients with OSA. The concomitant use of nCPAP and behavioral weight loss therapy in obese patients with OSA may result in enhanced weight loss. In moderately obese patients, modest weight reduction may alleviate the need for long-term nCPAP therapy or upper-airway surgery. Severely obese patients usually require more substantial weight loss and may be candidates for behavioral therapy in combination with gastric surgery. The role of the dietitian in the treatment of OSA cannot be overemphasized and warrants further development and study.

Behavior Therapy↗
PubMed1994

Evaluation of treatment with stimulants in narcolepsy.

This paper briefly reviews sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine and methamphetamine. The literature indicates that 1) methylphenidate, dextroamphetamine, pemoline and methamphetamine objectively improve somnolence as measured by the Multiple Sleep Latency or Maintenance of Wakefulness Tests (MSLT or MWT); 2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence than methylphenidate, dextroamphetamine and methamphetamine; 3) there are dose-dependent improvements in performance that parallel MSLT and MWT data; and 4) at the highest doses of stimulants studied to date, narcoleptics, although improved, still did not function on MSLT or MWT and most performance tests at levels comparable to those of control subjects. Future research designs should address issues of placebo effect, practice effects and the degree to which alertness and performance measures can be pharmacologically brought up to levels comparable to those of normal control subjects.

Adult↗
PubMed1993

The treatment of excessive somnolence with stimulant drugs.

Controlling the symptom of excessive sleepiness is an important responsibility of sleep medicine. Our group has reported that methamphetamine, given in the morning at doses of 40-60 mg, allowed narcoleptics to function throughout the day at normal levels of sleep tendency and psychomotor functioning as measured by multiple sleep latency and performance testing. These findings are important because they are the first to show normalization of function in narcolepsy with pharmacotherapy and because the dose of stimulant utilized was more than twice the maximum recommended by the manufacturer. Because it is possible to essentially eliminate the disabling sleepiness of narcolepsy, at least in the short term, we suggest that the following principles be applied in the therapeutic use of stimulant drugs: 1) Pathological sleepiness warrants aggressive treatment when sustained alertness is necessary for individual or public safety; 2) Stimulant drugs are important in the therapeutic approach to patients with pathological sleepiness; 3) The prime goal, although sometimes unachievable, should be symptom-free daytime functioning. It is important that, during therapy, a period of symptom-free daytime functioning be achieved for a frame of reference for evaluating future treatments; 4) Treatment efficacy should be assessed periodically with objective techniques such as the multiple sleep latency test or the maintenance of wakefulness test; 5) In some cases, stimulant doses may exceed the manufacturer's recommendations. However, the clinician should be guided by the prime goal of therapy, the patient's needs and the patient's ability to tolerate the chosen therapy.

Central Nervous System Stimulants↗
PubMed1993

Daytime sleepiness and cognitive functioning in sleep apnea.

Our earliest findings relating sleepiness to cognitive function revealed that, among patients with the symptom of excessive somnolence, sleep apneics were the most impaired on cognitive tasks. Although the multiple sleep latency test (MSLT) has been the standard diagnostic test for assessing daytime sleepiness, the maintenance of wakefulness test (MWT) has clinical advantages over the MSLT when the assessment of daytime alertness is the primary goal. A number of studies on patients with sleep apnea and narcolepsy indicate that the MWT is more sensitive to treatment-related improvements in sleepiness. However, sleep tendency, as measured by the MSLT, and ability to remain awake, as measured by the MWT, probably represent the same physiological process viewed from different perspectives. Some patients, particularly those who have received suboptimal treatment, will show no treatment-related improvement in daytime sleepiness if they are evaluated only by the MSLT. We believe that the MWT and MSLT measure different aspects of the central problem of abnormal sleep tendency. The MWT may be a useful adjuvant daytime test in clinical situations where it is necessary to quantify degree of impairment or effectiveness of treatment.

Cognition Disorders↗
PubMed1993

Effect of bedtime ethanol on total inspiratory resistance and respiratory drive in normal nonsnoring men.

We have previously reported that bedtime ethanol (2.0 ml/kg of 100 proof vodka) increases upper airway closing pressure in males who habitually snored but were otherwise healthy. We also observed that some of these snorers developed obstructive apneas. To explore this phenomenon in more detail, we measured the inspiratory resistance (RI) and respiratory drive after bedtime ethanol in 10 nonobese men (ages 23 to 33) with no history of snoring. Subjects went to bed wearing a tightly fitting valved mask over the nose and mouth that allowed measurement of inspiratory and expiratory flow, pressure in the mask, and endtidal CO2. We measured RI by calculating the pressure difference between the mouth and a balloon positioned in the midesophagus. Respiratory drive was quantified by the inspiratory occlusion pressure (P0.1), the ventilatory response to hyperoxic hypercapnia (delta VE/delta PETCO2), and the ventilatory response to isocapnic hypoxia (delta VE/delta SaO2). Measurements were made during waking and during stage 2 NREM sleep on two nights: (1) when the subjects drank 1.5 ml/kg of 100 proof vodka in orange juice over a 30-min period 15-45 min before lights out and (2) when the orange juice contained less than 0.1 ml of vodka floating on the top. Eight of the nine men in whom we had technically adequate measurements showed a rise in RI during NREM sleep above the waking level on both control and ethanol nights and the sleeping RI was greater on the ethanol than on the control night.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Treatment of narcolepsy with methamphetamine.

Eight pairs of subjects (each consisting of a narcoleptic and a control matched on the basis of age, sex, educational background and job) were evaluated under the following double-blind, randomized treatment conditions: baseline, placebo, low dose and high dose methamphetamine. Subjects were drug-free for 2 weeks prior to beginning the protocol. Methamphetamine was the only drug taken during the protocol and was given in a single morning dose of 0, 20 or 40-60 mg to narcoleptics and 0, 5 or 10 mg to controls. The protocol was 28 days long, with each of the four treatment conditions lasting 4 days followed by 3 days of washout. Nighttime polysomnography and daytime testing were done during the last 24 hours of each treatment condition. Daytime sleep tendency was assessed with the multiple sleep latency test (MSLT). Daytime performance was assessed with performance tests including a simple, computer-based driving task. Narcoleptics' mean MSLT sleep latency increased from 4.3 minutes on placebo to 9.3 minutes on high dose, compared with an increase from 10.4 to 17.1 minutes for controls. Narcoleptics' error rate on the driving task decreased from 2.53% on placebo to 0.33% on high dose, compared with a decrease from 0.22% to 0.16% for controls. The effects of methamphetamine on nocturnal sleep were generally dose-dependent and affected sleep continuity and rapid eye movement (REM) sleep. Elimination half life was estimated to be between 15.9 and 22.0 hours. Mild side effects emerged in a dose-dependent fashion and most often involved the central nervous system and gastrointestinal tract. We concluded that methamphetamine caused a dose-dependent decrease in daytime sleep tendency and improvement in performance in both narcoleptics and controls. Methamphetamine at doses of 40-60 mg allowed narcoleptics to function at levels comparable to those of unmedicated controls.

Adult↗
PubMed1992

Maintenance of wakefulness test in obstructive sleep apnea syndrome.

The usefulness of a 40-min per trial version of the maintenance of wakefulness test was assessed in 322 patients with obstructive sleep apnea. This test is a variant of the multiple sleep latency test in which patients are asked to remain awake in a quiet darkened room, and then monitored for electroencephalographic sleep onset. The four trials of the test are each stopped after 40 min. The mean sleep latency for all patients was 26.0 +/- 11.8 (SD) min. In a group of 24 patients who underwent treatment with nasal continuous positive airway pressure, the mean sleep latency increased from 18.0 +/- 12.3 to 31.9 +/- 10.4. The strongest nocturnal correlates of the MWT sleep latency were respiratory arousal index (r = -.35), mean oxygen saturation (r = .30), and weight/height ratio (r = -.25). These correlations were comparable to other studies using the MSLT. There were strong intercorrelations among the variables. In the more severe groups, measures of hypoxemia were more strongly correlated with MWT sleep latency. A two-factor analysis of variance using respiratory arousal index and several measures of oxyhemoglobin saturation indicated that both arousals from sleep and degree of hypoxemia contribute interactively to daytime dysfunction in patients with sleep apnea. The MWT appears useful in evaluating disability from daytime sleepiness.

Analysis of Variance↗
PubMed1992

Maintenance of wakefulness test and multiple sleep latency test. Measurement of different abilities in patients with sleep disorders.

The multiple sleep latency test and the maintenance of wakefulness test were administered on the same day to 258 consecutive patients whose clinical presentation required evaluation for excessive sleepiness. While the MSLT is the standard test for assessing excessive daytime sleepiness, the MWT may have some clinical advantage over the MSLT when the assessment of daytime alertness is the primary goal. To explore further the relationship between alertness and sleepiness, we have conducted a thorough analysis of the similarities, differences, and correlations between MWT and MSLT. The results of this study show that the coefficient of correlation between MSLT and MWT (r = 0.41), although statistically significant, accounts for less than 17 percent of the variability between the two tests. Factor analysis suggests that two factors, alertness and sleepiness, account for 91 percent of all variance. Our data demonstrate that patients with diagnosable disorders of excessive somnolence may be discordant on the two tests (eg, having low sleep latency on MSLT but high sleep latency on MWT). Specifically, we found that some patients with abnormally low MSLT scores were able to stay awake when asked to do so on the MWT, and conversely, some patients who failed to stay awake when asked to do so on the MWT were unable to fall asleep quickly on the MSLT. We conclude that the MWT and MSLT measure different abilities and that the MWT may be a useful adjuvant daytime test in many clinical situations.

Adult↗
PubMed1992

Disorders of excessive sleepiness. Treatment improves ability to stay awake but does not reduce sleepiness.

A total of 47 patients with sleep disorder (36 male and 11 female) with a mean age of 47.5 +/- 15 years were evaluated for daytime symptoms with a Multiple Sleep Latency Test (MSLT) and a Maintenance of Wakefulness Test (MWT) given on the same day--once at the time of their diagnostic evaluation and again after one to six months of treatment. The MSLT and MWT data are consistent with the notion that sleep tendency, as measured by the MSLT and ability to remain awake, as measured by the MWT, represent different physiologic processes. Data show a marked treatment-related improvement in ability to stay awake as measured by the MWT and no treatment-related improvement in sleepiness as measured by the MSLT. We conclude that there is a heterogeneous subpopulation of patients with sleep disorders whose symptoms of daytime sleepiness will show no treatment-related improvement in daytime symptoms if they are evaluated only by the MSLT. We suggest that, since ability to stay awake (and not ability to fall asleep) is a requisite for all job-related duties, an objective, physiologically based test such as the MWT should be used to assess the impact of sleep disorders in cases where there is a clinical concern about fitness to drive or work.

Antidepressive Agents, Tricyclic↗
PubMed1991

Relative efficacy of drugs for the treatment of sleepiness in narcolepsy.

A survey was conducted on 10 polysomnographic studies on the pharmacologic treatment of the sleepiness of narcolepsy. Three studies employed the MSLT and 7 employed the MWT as their polygraphic measure of sleep tendency. Statistically and clinically significant therapeutic changes were apparent for pemoline, modafinil, dextroamphetamine and methylphenidate. Codeine, ritanserin and protriptyline did show statistically significant effects. The common feature among the drugs that did produce clinically significant improvements seems to be facilitatory action on central catecholaminergic transmission. Within this group of drugs, only methylphenidate and dextroamphetamine brought MWT sleep latencies to approximately 70% of normal levels.

Adult↗
PubMed1990

Narcolepsy.

Narcolepsy is a neurological condition with a prevalence of up to 1 per 1,000 that is characterized by irresistible bouts of sleep. Associated features include the pathological manifestations of rapid-eye-movement (REM) sleep: cataplexy, sleep paralysis, hypnagogic hallucinations, and abnormal sleep-onset REM periods and disturbed nocturnal sleep. The condition is strongly associated with the HLA-DR2 and DQw1 phenotype. The phenomenology of narcolepsy is discussed, and diagnostic procedures are reviewed. Treatment modalities involving central nervous system stimulants for somnolence and tricyclic drugs for REM-sleep abnormalities are discussed. Sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine, protriptyline, and viloxazine are presented. Data suggest that: (1) methylphenidate and dextroamphetamine objectively improve somnolence; (2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence but may improve certain aspects of performance; and (3) protriptyline and viloxazine are effective anticataplectic agents that produce little improvement in somnolence.

Adult↗
PubMed1988

HLA-DR2 association with excessive somnolence in narcolepsy does not generalize to sleep apnea and is not accompanied by systemic autoimmune abnormalities.

Recent reports that nearly all patients with narcolepsy have the HLA-DR2 phenotype suggest that autoimmunity may underly the etiology or pathogenesis of this disorder. Of 11 narcoleptic patients in the present study, 9 were HLA-DR2, confirming the strong association with this class II antigen but indicating that this is not an obligatory phenotype. In contrast only 3/10 patients with sleep apnea were HLA-DR2, suggesting that this form of excessive somnolence has a different etiopathogenesis. Significant levels of rheumatoid factor, antinuclear antibodies or autoantibodies to native DNA, denatured DNA, histones, Sjogren's syndrome B antigen, or Smith antigen were undetectable in sera from narcoleptic patients. Antibodies to rodent brain, primate brain stem, and neurocytotoxic antibodies were also not found. These results along with the absence of laboratory signs and clinical features of a systemic inflammatory process indicate that if narcolepsy is an autoimmune disease, the underlying lesion or pathologic condition may be confined to the central nervous system.

Adult↗
PubMed1988

Bedtime ethanol increases resistance of upper airways and produces sleep apneas in asymptomatic snorers.

Nasal continuous positive airway pressure (nasal CPAP) and polysomnography were used to analyze the time course of the effect of bedtime ethanol on resistance of upper airways and on the number of respiratory pauses during sleep. On one night, six asymptomatic nonalcoholic male snorers drank 2 ml/kg of 100 proof vodka mixed in orange juice (ethanol dose, 0.79 gm/kg, giving a peak blood alcohol level of 71.8 +/- 33.3 mg/dl). On a second night they received a placebo (1-2 drops of vodka floated on top of the orange juice). We measured (a) the minimum nasal (CPAP) required to eliminate snoring, (b) the number of hypopneas and apneas during each hour of sleep and (c) the arterial oxygen saturation (SaO2) by ear oximetry. On the alcohol night there was a significant increase in the CPAP pressure required to eliminate snoring (placebo 4.8 +/- 1.7 cm H2O, alcohol 6.2 +/- 1.5 cm H2O). The number of respiratory events per hour of sleep (apnea index) was 7.5 +/- 2.1 for ethanol nights versus 3.8 +/- 2.7 for placebo nights (p less than 0.0125). An apnea index of greater than 5 is generally considered abnormal. There was no significant difference in the number of desaturation events (declines of 4% or more in the SaO2) or in the mean SaO2, but the minimum SaO2 was significantly lower on the ethanol night (placebo 89.8% +/- 1.6, alcohol 86.8% +/- 2.7, p less than 0.05). The effect of this dose of alcohol on airway resistance was most pronounced during the first 2 hr after ingestion.

Adult↗