News and Publications

Sleep Research Group

M. Mitler, D. Darko, A. Dawson, M. Erman, R. Hayduk

NARCOLEPSY

Narcolepsy is a CNS disorder characterized by disabling dysregulation of sleep and wakefulness. It affects about 200,000 persons in North America. Although inheritance of narcolepsy is not known, the disorder is strongly, but not always, associated, with subtypes of the HLA region of chromosome 6 [HLA-DR15(DRB1*1501) and HLA-DQ6(DQB1*0602)]. The presence of HLA- and non--HLA-associated forms indicates that narcolepsy may actually be at least 2 disorders, each with different etiologies.

Our work has shown 4 important findings: (1) The HLA antigen DQB1*0602 is associated with narcolepsy in only 70% of the patients in the case series, and the narcolepsy associated with this antigen occurs mainly in probands whose first-degree relatives are not affected. (2) The majority of multiplex cases (multiple patients in a single family who meet the clinical criteria for narcolepsy) do not have the associated HLA haplotype. (3) Monozygotic twins show differences with respect to clinical symptoms; one has cataplexy and one does not. (4) Daytime and nighttime sleep studies of first-degree relatives of probands who meet full clinical diagnostic criteria for narcolepsy reveal subtle sleep disturbances.

Our group is in the forefront of the evaluation of modafinil, a novel wake-promoting agent for therapeutic use in narcolepsy. Unlike psychostimulant medications, modafinil does not act by releasing presynaptic stores of dopamine. Animal studies indicate that modafinil does not produce a rebound in sleep after it induces a prolongation of wakefulness.

SLEEP DISTURBANCES IN PATIENTS WITH HIV INFECTION

As part of research to prolong the functional period (free of disability) of patients with HIV infection, we are conducting a series of brief clinical trials designed to pharmacologically control disabling CNS-based performance decrements and fatigue in HIV-infected patients and to test and generate hypotheses about the underlying pathophysiologic changes. This work has general application to CNS inflammation and neurodegeneration; normal aging; and several pathologic CNS states, including Alzheimer's disease, syndromes that occur after stroke, chronic pain syndromes, and multiple sclerosis. On the basis of current hypotheses of the pathophysiology of mild, early "AIDS dementia," we are determining potential therapeutic medications that reduce cognitive deficits and fatigue in early-stage HIV infection and are investigating further the pathophysiologic mechanisms that underlie HIV-associated losses in cognition and memory, fatigue, and sleep disturbances.

We are using objective, quantitative computer-based performance testing; CNS evoked potentials; blood levels of sleep-inducing peptides; sleep disruption as measured by nocturnal polysomnography and quantitative electroencephalographic techniques; and a subjective, standard questionnaire on energy level and mood state. The medication trials are straightforward, early phase 2--type, clinical trials that determine potential therapeutic medications, measure the efficacy of the medications, and detect any toxic effects. The trials are designed to rapidly screen pharmacologic compounds in HIV-infected patients that may be useful in controlling disability due to the cognitive confusion, sleep disruption, and fatigue. Individual subjects participate in this project briefly (3 months), and only effects on signs and symptoms related to HIV-relevant CNS abnormalities are under study.

We first used this parallel-groups, placebo-controlled, single-blind design to evaluate the TNF- mRNA antagonist pentoxifylline (Trental). We determined the potential of this agent to reduce the fatigue and daytime sleepiness, lessen performance decrements, and normalize physiologic aspects that may be associated with these functional disabilities. Changes typically found in early-stage HIV infection include poor sleep quality, altered sleep structure, elevated levels of sleep-inducing peptides, and abnormal evoked brain potentials. We tested the hypothesis that the daytime fatigue and increased slow-wave sleep associated with early-stage HIV infection are mediated by TNF-, a sleep-inducing peptide that is elevated in HIV-infected patients.

The dosage of pentoxifylline was 400--1600 mg/day. The drug was tested against a placebo. We had predicted that pentoxifylline, because of its specificity for TNF- mRNA, would reduce fatigue and drowsiness with few side effects (e.g., insomnia). We found that pentoxifylline did not improve any of the measured indices. Both the pentoxifylline and the placebo groups had a modest increase in blood levels of TNF- during the 3-month study; the pentoxifylline group had a lower rate of increase in TNF- than did the placebo group. We are now using the same 3-month protocol to evaluate doses of 5--20 mg/day of the nonspecific CNS neurostimulant methamphetamine (Desoxyn). Trials of additional medications are planned.

PULMONARY DYNAMICS IN SNORERS

Using calibrated respiratory inductance plethysmography, we have developed a less invasive method to measure minute ventilation, tidal volume, and resistance to flow during sleep. These parameters were not often measured in humans during REM sleep and the deeper stages of non-REM (NREM) sleep because the tightly fitting face mask needed to measure airflow interfered with normal sleep.

We have studied normal young male snorers throughout the night in all stages of sleep. It is known that obstructive sleep apnea tends to be more severe in REM than in NREM sleep, but we found that in nonapneic snorers, inspiratory resistance is lower during REM sleep than it is in NREM sleep. We think that this difference is due to diminished inspiratory effort during REM. This reduction decreases the negative pressure in the upper part of the airway at the onset of inspiration and reduces the tendency of this region of the airway to collapse, even though muscle tone in the area is decreased.

PUBLICATIONS

Darko, D.F., Mitler, M.M. Growth hormone, fatigue, poor sleep, and disability in HIV infection. Sleep 21(Suppl.):169, 1998.

Darko, D.F., Mitler, M.M., Miller, J.C. Growth hormone, fatigue, poor sleep, and disability in HIV infection. Neuroendocrinology 67:317, 1998.

Dawson, A., Poceta, J.S., Mitler, M.M. Effect of sleep stage on inspiratory resistance of male snorers. Sleep 21(Suppl.):158, 1998.

Doghramji, K., Mitler, M., Sangal, R.B., Shapiro, C., Taylor, S., Walsleben, J., Belisle, C., Erman, M.K., Hayduk, R., Hosn, R., O'Malley, E.B., Sangal, J.M., Schutte, S.L., Youakim, J.M. A normative study of the Maintenance of Wakefulness Test (MWT). Electroencephalogr. Clin. Neurophysiol. 103:554, 1997.

Harsh, J.R., Peszka, J., Hartwig, G., Mitler, M. Nighttime sleep and daytime sleepiness in narcolepsy. Sleep 21(Suppl.):198, 1998.

Hayduk, R., Flodman, P., Spence, M.A., Erman, M.K., Mitler, M.M. HLA haplotypes, polysomnography and pedigrees in a case series of patients with narcolepsy. Sleep 20:850, 1997.

Hayduk, R., Sobel, D., Mitler, M.M. Brain MRI and HLA class II studies in narcoleptic patients. Sleep Res. 26:374, 1997.

Kelly, T.I., Mitler, M.M., Bonnet, M.H. Sleep latency measures of caffeine effects during sleep deprivation. Electroencephalogr. Clin. Neurophysiol. 102:397, 1997.

Miller, J.C., Mitler, M.M. Predicting accident times. Ergonomics Design 5:13, 1997.

Mitler, E.A., Mitler, M.M. Een Sleep om van te Dromen: 101 Vragen over slapen en Dromen. Cluydts, R., De Roeck, J. (Trans.). Nederlandstalige bewerking: W.V.S.S, vzw, 1998.

Mitler, M.M., Miller, J.C., Lipsitz, J.J., Walsh, J.K., Wylie, C.D. Polysomnographic assessment of sleep during a week of long-haul truck driving. Sleep Res. 26:679, 1997.

Mitler, M.M., Miller, J.C., Lipsitz, J.J., Walsh, J.K., Wylie, C.D. The sleep of long-haul truck drivers. N. Engl. J. Med. 337:755, 1997.

Mitler, M.M., representing the U.S. Modafinil in Narcolepsy Multicenter Study Group. Modafinil for the treatment of pathological somnolence in patients with narcolepsy. Sleep Res. 26:527, 1997.

Mitler, M.M., Walsleben, J., Sangal, R.B., the U.S. Modafinil in Narcolepsy Multicenter Study Group. MWT sleep latencies for 530 drug-free patients with narcolepsy. Sleep Res.26:436, 1997.

Poceta, J.S., Mitler, M.M. (Eds.). Sleep Disorders: Diagnosis and Treatment. Humana Press, Totowa, NJ, 1998.

Sangal, R.B., Mitler, M.M., Sangal, J.M., the U.S. Modafinil in Narcolepsy Multicenter Study Group. MSLT, MWT and ESS: Indices of sleepiness in 522 drug-free patients with narcolepsy. Sleep Res. 26:492, 1997.

White, J.L., Mitler, M.M. The diagnostic interview and differential diagnosis for complaints of excessive daytime sleepiness. In: Pressman, M.R., Orr, W.C. (Eds.). Understanding Sleep: The Evaluation and Treatment of Sleep Disorders. American Psychological Association, Washington, DC, 1997, p. 161.