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Volume 12 No. 12
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Accepted Papers





Scientific Investigations

Importance of Urinary Drug Screening in the Multiple Sleep Latency Test and Maintenance of Wakefulness Test

Angela M. Anniss, PhD1; Alan Young, MBBS, PhD1,2; Denise M. O'Driscoll, PhD1,2
1Department of Respiratory and Sleep Medicine, Eastern Health, Victoria, Australia; 2Eastern Health Clinical School, Monash University, Victoria, Australia

ABSTRACT

Study Objectives:

Multiple sleep latency testing (MSLT) and the maintenance of wakefulness test (MWT) are gold-standard objective tests of daytime sleepiness and alertness; however, there is marked variability in their interpretation and practice. This study aimed to determine the incidence of positive drug screens and their influence on MSLT, MWT, and polysomnographic variables.

Methods:

All patients attending Eastern Health Sleep Laboratory for MSLT or MWT over a 21-mo period were included in the study. Urinary drug screening for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opiates was performed following overnight polysomnography (PSG). Demographics and PSG variables were compared.

Results:

Of 69 studies, MSLT (43) and MWT (26), 16% of patients had positive urinary drug screening (7 MSLT; 4 MWT). Drugs detected included amphetamines, cannabinoids, opiates, and benzodiazepines. No patient self-reported use of these medications prior to testing. No demographic, MSLT or MWT PSG data or overnight PSG data showed any statistical differences between positive and negative drug screen groups. Of seven MSLT patients testing positive for drug use, one met criteria for the diagnosis of narcolepsy and five for idiopathic hypersomnia. On MWT, three of the four drug-positive patients had a history of a motor vehicle accident and two patients were occupational drivers.

Conclusions:

These findings indicate drug use is present in patients attending for daytime testing of objective sleepiness and wakefulness. These data support routine urinary drug screening in all patients undergoing MSLT or MWT studies to ensure accurate interpretation in the context of illicit and prescription drug use.

Citation:

Anniss AM, Young A, O'Driscoll DM. Importance of urinary drug screening in the multiple sleep latency test and maintenance of wakefulness test. J Clin Sleep Med 2016;12(12):1633–1640.


INTRODUCTION

Excessive daytime sleepiness (EDS) is defined as the inability to stay awake during the major waking episodes of the day.1 It is common in many patients attending sleep clinics.2 EDS increases the risk of car and occupational accidents, potentially endangering the individual and the safety of others.35 It can also affect an individual's ability to maintain employment and result in social problems such as depression, low self-esteem, and social isolation.6,7

The multiple sleep latency test (MSLT) and the maintenance of wakefulness test (MWT) are validated procedures increasingly used to objectively assess EDS based on the measurement of sleep latency.1,8 The MSLT provides an objective measurement of an individual's susceptibility to fall asleep during daytime hours and is used to help diagnose suspected narcolepsy or idiopathic hypersomnia. In contrast, the MWT offers an objective assessment of an individual's ability to stay awake in a quiet, nonstimulating environment. It is commonly used for patients where EDS comprises a safety issue, such as for occupational drivers. The MWT can also demonstrate an improvement in EDS in patients following pharmacological or continuous positive airway pressure treatment.1,9

BRIEF SUMMARY

Current Knowledge/Study Rationale: There is marked variability among sleep centers in the interpretation and practice of MSLT and MWT procedures, which are increasingly used to objectively test daytime sleepiness and alertness. This study aimed to further investigate the necessity of routine urinary drug screening in adult patients performing MSLT or MWT studies, by determining the incidence of positive drug screens and their influence on MSLT, MWT, and polysomnographic variables.

Study Impact: The high incidence of positive drug screenings found in our MSLT and MWT studies strongly support routine urinary drug testing. Routine urinary drug screening provides vital information for the clinician, that may not be disclosed in questionnaires or patient clinical history and may assist with accurate interpretation of results leading to correct diagnosis and patient management.

To ensure accurate interpretation of results leading to correct diagnosis, it is vital that MSLT and MWT studies are performed using well-controlled, standardized procedures. The American Academy of Sleep Medicine (AASM) have established guidelines for the clinical use of MSLT and MWT practices.1 However, there is marked variability in the interpretation and practice of these guidelines among different sleep centers. Currently, urinary drug screening for MSLT and MWT studies is recommended as optional under AASM standards.1 A recent assessment of adult sleep laboratories in Europe showed that only 17% performed routine urinary drug screening practices when performing MSLT studies.10 Few reports have investigated whether routine urinary drug screening plays an important role in ensuring accurate interpretation of MSLT and MWT findings or whether this practice is simply a misuse of resources if there are no specific patient concerns.

Conflicting evaluation of routine urinary drug screening in paediatric patients undergoing MSLT procedures has recently been published in two papers. Katz et al.11 showed no incidence of positive testing for drugs of abuse among paediatric MSLT patients over a 15-y period, indicating that routine urinary drug screening was unnecessary in their population of patients. In contrast, Dzodzomenyo et al.12 found 10% of their pediatric patients tested positive for drugs of abuse and strongly supported the use of routine urinary drug screening in interpreting MSLT findings in patients age 13 y or older.12 To our knowledge, there are no published reports from adult clinical populations.

To further investigate the necessity of routine urinary drug screening in patients undergoing MSLT or MWT procedures, the aim of this study was to determine the incidence of positive drug screens in adult patients performing MSLT or MWT studies. In addition, the influence of drugs detected on patient demographics, MSLT, MWT and overnight PSG variables was also examined.

METHODS

The Eastern Health Human Research Ethics Committee granted ethical approval for this project. All consecutive referrals of adult patients attending the Eastern Health Sleep Services for PSG and subsequent MSLT or MWT from January 2014 until September 2015 were included in the study.

Polysomnography

All participants underwent routine overnight PSG using a commercially available PSG system (Compumedics, Abbotsford, Australia). Electroencephalograms (EEGs), electrooculograms (EOGs), chin electromyogram (EMG), electrocardiogram (ECG), left and right leg EMG and body position were recorded. Oxygen saturation (SpO2) was measured by pulse oximetry, thoracic and abdominal breathing movements recorded via uncalibrated respiratory inductance plethysmography, and airflow was recorded via nasal pressure and oronasal thermo-couple. Prior to PSG, height and weight were recorded, and body mass index calculated. The Epworth Sleepiness Scale (ESS) was recorded. Patients filled in a standardized questionnaire regarding smoking status and past medical history and were asked to list all medications.

Sleep and arousals were scored from the EEG, EOG, and chin EMG channels in 30-sec epochs according to standard criteria. Obstructive apneas and mixed apneas and hypopneas were defined according to 2007 AASM standard criteria (hypopneas scored using the alternative criteria).13

MSLT and MWT Studies

MSLT and MWT studies were performed using standard AASM practice procedures.1 All studies were performed 1.5–3 h following overnight PSG to assess night time sleep quality and quantity. Caffeine was prohibited on the day of testing and where applicable, smoking was ceased 30 min prior to nap or trial opportunities.

The MSLT consisted of four to five daytime nap opportunities performed at two hourly intervals. Sleep rooms were dark, quiet and at a comfortable temperature during testing and the patient was instructed to try to fall asleep after biocalibrations were performed. Sleep latency was determined from lights out to the first epoch of any stage of sleep from quantifying EEG, EOG, and EMG recordings. If sleep onset occurred, the test continued for a further 15 min to determine if rapid eye movement (REM) onset was observed. If sleep did not occur, the test was terminated at 20 min.

The MWT procedure consisted of four trials performed at 2-h intervals with the patient seated in a quiet, low-lit room. Biocalibrations were performed and the patient was instructed to remain still and stay awake for as long as possible. Sleep onset was determined as the first epoch of any stage of sleep from quantifying EEG, EOG, and EMG recordings. The test continued until three consecutive epochs of N1 sleep or one epoch of any other stage of sleep was observed, or was ceased after 40 min if no sleep occurred.

Urine Drug Screen

A urine sample was collected with patient consent for drug screening at first morning void following the overnight PSG prior to the commencement MSLT or MWT procedures. Qualitative urinary drug screening for the presence of amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opiates was performed by immunoassay (Roche Cobas c502 analyzer, Basel, Switzerland). Cutoff levels conformed to Australian Standards (AS/NZS 4308-2008). Urine creatinine concentration levels validated that urine samples were free from dilution or substitution.

Statistical Analysis

All sleep studies demographics and PSG variables were compared between groups using unpaired t-tests. Data are presented as mean ± standard deviation. Differences in sex were analyzed with χ2 analysis. In all cases significance was determined at p < 0.05. Analysis was performed using Sigmaplot Version 12.3 statistical software (Systat Software Inc, Germany).

RESULTS

Group Data

A total of 69 studies were performed on 65 patients (41 MSLT and 24 MWT) during the period examined; 2 MSLT and 2 MWT patients repeated testing. Of the 69 studies performed, 11 patients or 16% (7 MSLT and 4 MWT patients) had positive urinary drug screening. No patient refused urine drug testing and all samples met correct urine creatinine concentration levels. None of the patients who tested positive self-reported medications on admission questionnaires or had a clinical history that would have indicated a positive drug screen result.

MSLT Patients

Demographic Data

MSLT patient demographic and PSG data are shown in Table 1 and Table 2. Patients were grouped according to a positive or negative urine drug screen result. Patient referral for MSLT was for ongoing severe EDS despite being free from, or treated for, obstructive sleep apnea. EDS was judged clinically based on patient complaints of chronic daytime tiredness and fatigue for a period greater than 3 mo, often in conjunction with a raised ESS score greater than 10. Eight MSLT patients were referred for vivid dreams, hypnagogic hallucinations, sleep paralysis and/or symptoms of cataplexy, in addition to EDS. Predominant MSLT patient comorbidities included depression and anxiety and hypertension, with a high proportion of MSLT patients reportedly taking antidepressant and/or antihypertensive comedications. Other MSLT patient comorbidities included type 2 diabetes, asthma, reflux, and fibromyalgia. The two patients reporting fibromyalgia were not currently on any opiate medications and urine drug screen results were negative.

Multiple sleep latency test group demographics and comedication data.

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Table 1

Multiple sleep latency test group demographics and comedication data.

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Overnight and multiple sleep latency test polysomnography data.

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Table 2

Overnight and multiple sleep latency test polysomnography data.

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Demographic data did not show any significant difference between the positive and negative urine drug screen groups, although there was a trend for a younger mean age in the positive screened group with six of the seven patients aged between 20–34 y. Three of the seven positive screened patients were male and mean ESS score was 13 ± 5, indicating subjective daytime sleepiness.

Overnight PSG Data and MSLT Results

Overnight PSG data and MSLT PSG results are shown in Table 2. Interestingly, no overnight PSG or MSLT data showed any statistically significant differences between positive and negative urine drug screen groups.

MSLT Positive Urine Drug Screen Patient Group

Individual MSLT data of patients with a positive urine drug screen are shown in Table 3. The classes of drugs that were detected in the positive group of MSLT patients included amphetamines, benzodiazepines, cannabinoids, and opiates. No single class of drug was detected predominantly with two patients testing positive for cannabinoids, two for opiates, one for amphetamines, one for benzodiazepines, and one for both amphetamines and benzodiazepines. One patient testing positive for amphetamines met AASM criteria for diagnosis of narcolepsy with a mean sleep latency less than 8 min and at least two sleep onset REM periods (SOREMPs).1 Another four patients with positive urinary drug screens met AASM criteria for diagnosis of idiopathic hypersomnia with a mean sleep latency less than 8 min but with less than two SOREMPs.1 An additional patient had a mean sleep latency of 8.6 min at the limit of inclusion criteria. Thus, of the seven MSLT patients testing positive for drug use, six met criteria for narcolepsy or idiopathic hypersomnia if drug screening had not taken place.

Individual multiple sleep latency test results for patients with a positive urine drug screen grouped by drug detected.

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Table 3

Individual multiple sleep latency test results for patients with a positive urine drug screen grouped by drug detected.

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No patient who tested positive for drug use had a medical history indicating this prior to testing. Review of sleep physician clinical notes following testing of MSLT patients showed two patients who had a positive urinary drug screen failed to attend follow-up appointments despite repeated booking. Almost all of the patients who did attend follow-up appointments admitted to taking the drug detected in the MSLT study. One patient denied intentionally taking the drug detected but admitted passive inhalation (cannabis) was a possibility. Other patients stated that the drug use was recreational and that they did not think the drugs would still be detectable. The patient who met the AASM criteria for narcolepsy who also tested positive for amphetamines admitted using illicit amphetamines to treat severe EDS. The patient was advised to cease taking the illicit drugs and referred for retesting, but declined any further follow-up. Of the patients who were then referred for a repeat MSLT study (n = 2), both presented a negative urinary screen on their repeat study. Interestingly, no significant change in mean sleep latency was revealed when MSLT studies were repeated; however, the number of REM episodes observed in one patient decreased following a repeat MSLT study (Table 3).

MWT Patients

Demographic Data

MWT patient demographic and PSG data are shown in Table 4 and Table 5, with patients grouped according to a positive or negative urine drug screen. MWT patients were typically referred for assessment of wakefulness for driver safety. Thirteen patients were occupational drivers and the MWT was used to evaluate fitness to drive for employment purposes. Seven MWT patients, some occupational drivers, were reported to have had a recent motor vehicle accident due to sleepiness and ability to stay awake was evaluated for safety concerns. Similarly, six patients not wanting to pursue treatment for severe OSA were required to undertake an MWT to evaluate their ability to stay awake for driver safety.

Maintenance of wakefulness test group demographics and comedication data.

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Table 4

Maintenance of wakefulness test group demographics and comedication data.

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Overnight and maintenance of wakefulness test polysomnography data.

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Table 5

Overnight and maintenance of wakefulness test polysomnography data.

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MWT patients were generally male and older than the MSLT patients. Similar to MSLT patients, MWT patient comorbidities predominantly included depression, anxiety, and hypertension. Eight MWT patients reported taking antihypertensive medications and seven patients reported taking antidepressant medication on admission questionnaires prior to the overnight PSG study. Other MWT patient comorbidities included type 2 diabetes, asthma, reflux, and high cholesterol level.

Overnight PSG Data and MWT Results

Overnight PSG data and MWT PSG results are shown in Table 5. As with MSLT patients, there were no statistically significant differences in overnight PSG data or MWT results between positive and negative urine drug screen groups.

MWT Positive Urine Drug Screen Patients

All MWT patients with positive urine screens were male, varying in age from 21 to 65 y. ESS scores among the positive screened group also varied widely from 4 to 14. The classes of drugs that were detected in the drug screen–positive group of MWT patients included amphetamines, benzodiazepines, and cannabinoids. Using the 40-min MWT protocol, the sleep latency of drug positive patients was variable. One patient had a mean sleep latency of 40 min showing a clear ability to maintain wakefulness despite testing positive for benzodiazepines in urinary screening. Two patients with urine screens positive for cannabinoids had mean sleep latencies of 26.5 and 28.8 min, which passes AASM normal range criteria of more than 8 min.1 The remaining patient with a urine screen positive for amphetamines had an abnormal MWT mean sleep latency of 5.3 min. Interestingly, three of the four MWT patients with positive urine screens had a history of a recent motor vehicle accident, whereas only 18% of the group with negative drug screens had a motor vehicle accident history. In addition, two of the four patients with a positive urine screen were also occupational drivers.

DISCUSSION

This study, for the first time, reports the frequency and classification of positive urine drug screens from adult patients attending for MSLT and MWT in a sleep laboratory based within a tertiary referral hospital. The MSLT and MWT provide objective measures of daytime sleepiness and wakefulness based on the measurement of sleep latency. The MSLT is performed to diagnose narcolepsy and idiopathic hypersomnia, and the MWT is used to assess driving safety and the ability to maintain wakefulness. To ensure accurate interpretation of results leading to a correct diagnosis, it is vital that these tests are performed using well-controlled, consistent procedures. Protocols outlined in AASM practice parameters enable patients to be compared under validated standard conditions. Currently, AASM guidelines recommend drug screening as optional1 and routine practice of this procedure is variable among sleep centers.10 Importantly, our study showed that 16% of patients attending MSLT or MWT studies over a 21-mo period had positive urinary drug screening. None of these patients self-reported use of these medications in pretest admission questionnaires or had a clinical history that would have suggested a positive drug screen result. All drugs detected could potentially affect daytime sleepiness and interpretation of the MSLT and MWT results. Therefore, we contend that urinary drug screening provides vital clinical information that may assist with test interpretation and subsequent patient diagnosis.

Similar to our findings in adult patients, a recent retrospective study by Dzodzomenyo et al.12 found 10% of MSLT pediatric patients also tested positive for drugs of abuse in urinary screening analysis. In contrast to these results, Katz et al.11 found no incidence of usage of drugs of abuse in pediatric MSLT patients. Differences between findings may be due to the performance of these studies within a single sleep center where patient populations may vary. In addition, in our study and that of Dzodzomenyo et al.,12 urine samples were collected in the morning immediately following overnight PSG whereas in the study by Katz et al.,11 urine drug testing was routinely performed at 13:00 when samples may be more dilute. The threshold for positive drug detection was also not defined in the study by Katz et al.11

Positive drugs detected in our patients undergoing MSLT and MWT studies included amphetamines, cannabinoids, opiates, and benzodiazepines. These drugs are available by prescription for therapeutic use, but they may also be illegally sourced and can significantly affect sleep parameters such as sleep efficiency and sleep latency which are vital to MSLT and MWT outcome.1417 Amphetamines are potent stimulators of the sympathetic nervous system,15 increasing wakefulness and sleep latency,18,19 and are prescribed for treatment of narcolepsy.20 They are known to decrease sleep efficiency and REM episodes.14,18 In contrast, amphetamine withdrawal can cause complete exhaustion, decreasing sleep latency and increasing total sleep time and REM rebound.18,21,22 Patients testing positive for amphetamines in our MSLT and MWT studies had abnormally reduced mean sleep latencies that may have been influenced by amphetamine withdrawal. In addition, multiple SOREMPs observed in the MSLT patient testing positive for amphetamines may have also been a consequence of amphetamine withdrawal inducing REM rebound, although it is acknowledged that results from a single patient in our study does not provide conclusive evidence of this. Findings by Dzodzomenyo et al.12 also showed MSLT SOREMPs were significantly increased in a subgroup of pediatric patients who tested positive for cannabinoids, possibly as a result of REM rebound due to cannabinoid withdrawal.14,23,24 Interestingly, in our results, we also observed an increased number of SOREMPs in an MSLT patient who had a positive urinary screen for cannabinoids compared to the repeat study where the urinary screen was negative, although again this result was only observed in a single patient. Nevertheless, an increased number of SOREMPs as a result of cannabinoid or amphetamine withdrawal may confuse interpretation of results, leading to incorrect diagnosis.

The consequences of prescribing treatment to patients testing positive for drugs of abuse should also be taken into consideration when assessing the importance of routine urinary drug screening. Medications treating narcolepsy and hypersomnia require use of drugs with high side-effect potential.20 Existing medications taken by patients for comorbidities should be carefully considered by the clinician prior to prescription of further pharmacological treatment. Drug screening may reveal unexpected use of recreational or nonprescription drugs to the clinician that also require consideration. This is particularly relevant for occupational drivers or for patients in whom EDS may influence the safety of others. Most MWT patients were referred to assess driving safety. The positive urine drug tests in four patients for both stimulant and sedating medications assisted with interpretation of MWT results and also provided vital clinical information relevant to driver safety. This was particularly important given that most patients testing positive had a history of a recent motor vehicle accident or were occupational drivers. These findings argue for the importance of routine urinary drug testing with MWT.

It is noteworthy that most of the patients who tested positive in the urinary drug screen did attend follow-up appointments with their sleep physician and admitted to taking the drugs detected. We speculate that patients did not report taking these drugs in the admission questionnaire because they did not think the drug would still be detected in their system. It is possible that these patients may have knowingly taken the drugs in order to alter sleepiness in their sleep studies but it is more likely that their drug use was for nonrelated recreational purposes. Patients who have a genuine sleep disorder may also self-medicate with illicit or prescription drugs to reduce EDS as claimed by the MSLT patient testing positive for amphetamines. It is important that the sleep physician be aware of all pharmacological agents that may affect sleep parameters when considering the diagnosis.

Urine drug screening provides a robust, inexpensive measure of recent exposure to prescription or illicit drugs. Cutoff levels for each of the drug classes screened conform to Australian standards at a level that eliminates false-positive results due to inadvertent exposure to the drug.15 Urine creatinine levels provide a measure of urine concentration and indicate if a urine sample has been diluted or substituted for another substance.15,16 Despite extra cost and human resources, the high incidence of positive drug screenings found in our study validate the usefulness of urinary drug screening to ensure the quality of the MSLT or MWT data collected.

Limitations to our study may include the analysis of urinary samples solely by qualitative immunoassay screening. Problems with specificity and cross-reactivity of the immunoassay screening test indicates a very high positive predictive value for cannabinoids (92% to 100%), whereas amphetamines (74%) and opiates (71%) are lower.16,25 Use of illicit amphetamines and methamphetamines may be unable to be distinguished from certain over-the-counter medications such as pseudoephedrine that are structurally similar and may produce a false-positive result. Similarly, a positive test for opioids may detect use of codeine as well as use of illicit opioids. Overall risk of false-positive results due to cross- reactivity depends on the specific immunoassay used and a documented knowledge of the use of prescription and over-the-counter medications. The immunoassay used in our study is documented to have high sensitivity and moderate specificity and used government-set threshold standards. Urine specimens with drug concentrations below the threshold are reported as negative, which is intended to eliminate many false-positive results due to ingestion of small quantities of these chemicals that may be present in over-the-counter medications or inadvertently taken through passive inhalation. In addition, all patients were asked to document use of all medications, including non-prescription drugs, prior to overnight PSG. Those patients with positive drugs screens attending follow-up appointments with their sleep physician were documented to readily admit taking the class of drug detected in their MSLT or MWT study, and additional confirmatory quantitative testing was not warranted. However, the value of quantitative urinary drug analysis in improving the specificity of drug detection is acknowledged.

Another limitation to our study may include the timing of urine sample collection. Samples were collected at first morning void so the patient's urine would be at its most concentrated, increasing the chances of drug detection.15 However, it is possible that drugs may have been consumed during the MSLT or MWT procedure following this morning urine collection. In addition, amphetamines and opioids may be detected in urine for 2 to 3 days after the last use, and cannabinoids and benzodiazepines can stay in the system of chronic users for several weeks since their last intake. Therefore, the effect the drug may have on MSLT or MWT data may vary significantly between patients depending on the period of time since the drug was taken, the dosage and form of the drug ingested, and how often the drug is used (chronic versus occasional user).26,27 Large standard deviations within the sleep parameters of the drug-positive patient population may reflect these variable effects.

CONCLUSIONS

Our study has found that 16% of adult patients attending MSLT or MWT studies have positive urinary drug testing to drugs that affect daytime sleepiness and sleep quality. Testing provides vital information for the clinician as these drugs may contribute to the patient's sleepiness, during usage or withdrawal, or may be used to alleviate sleepiness itself. This is particularly relevant because most MSLT patients testing positive met the criteria for narcolepsy or idiopathic hypersomnia, and the MWT patients testing positive had high rates of motor vehicle accidents or were occupational drivers. These findings strongly support routine urinary drug screening in all adult patients undergoing MSLT or MWT procedures to ensure accurate interpretation of results leading to correct diagnosis and patient management.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.

ABBREVIATIONS

AASM

American Academy of Sleep Medicine

AHI

apnea-hypopnea index

BMI

body mass index

ECG

electrocardiogram

EDS

excessive daytime sleepiness

EEG

electroencephalogram

EMG

electromyogram

EOG

electrooculogram

ESS

Epworth Sleepiness Scale

MSLT

multiple sleep latency testing

MWT

maintenance of wakefulness test

OSA

obstructive sleep apnea

PLM

periodic limb movement

PSG

polysomnography

REM

rapid eye movement

SOREMP

sleep onset REM period

TST

total sleep time

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