Multiple Sleep Latency Test (MSLT) and Maintenance of Wakefulness Test (MWT)

Number: 0330

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses multiple sleep latency test (MSLT) and maintenance of wakefulness test (MWT).

1. Medical Necessity

   1. Aetna considers the multiple sleep latency test (MSLT) and maintenance of wakefulness test (MWT) medically necessary for either of the following 2 indications:

      1. For evaluation of symptoms of narcolepsy, to confirm the diagnosis; or
      2. For evaluation of persons with suspected idiopathic hypersomnia to help differentiate idiopathic hypersomnia from narcolepsy.

   2. Repeat MSLT and MWT tests are considered not medically necessary, unless:

      1. The initial test was invalid or uninterpretable; or
      2. The initial test is affected by extraneous circumstances or when study conditions were not present during initial testing; or
      3. The patient is suspected to have narcolepsy but earlier MSLT or MWT evaluation did not provide polygraphic confirmation.

2. Experimental, Investigational, or Unproven

   1. The following tests and procedures are considered experimental, investigational, or unproven:

      1. Home MSLT because home MSLT has not been proven to be equivalent to formal MSLT performed in a sleep laboratory;
      2. Single nap studies because a full MSLT or MWT is required for accurate diagnosis of narcolepsy.

   2. MSLT and MWT are considered experimental, investigational, or unproven for all other indications because its effectiveness for indications other than the ones listed in Section I have not been established, including the following (not an all-inclusive list):

      1. Attention-deficit/hyperactivity disorder
      2. Chronic fatigue syndrome
      3. Circadian rhythm disorders
      4. Evaluation of common, uncomplicated or non-injurious parasomnias, such as typical disorders of arousal, bruxism, enuresis, nightmares or sleep talking
      5. Evaluation of the effectiveness of modafinil therapy in narcolepsy
      6. Insomnia
      7. Neurologic disorders other than narcolepsy (e.g., dementia (including Alzheimer's disease and dementia with Lewy bodies) and Parkinson's disease)
      8. Obstructive sleep apnea syndrome
      9. Psychiatric hypersomnolence
      10. Restless leg syndrome.

3. Related Policies

   • CPB 0004 - Obstructive Sleep Apnea in Adults
   • CPB 0752 - Obstructive Sleep Apnea in Children

Background

The Multiple Sleep Latency Test (MSLT) and Maintenance of Wakefulness Test (MWT) are specialized, standardized daytime polysomnographic assessments used to evaluate excessive daytime sleepiness and an individual’s ability to stay awake, respectively. The MSLT measures how quickly a patient falls asleep across several nap opportunities and is primarily used to diagnose conditions such as narcolepsy and idiopathic hypersomnia. In contrast, the MWT assesses a patient’s capacity to remain awake in a quiet, non-stimulating environment, often to evaluate treatment effectiveness or safety‑related functional wakefulness. Together, these tests provide complementary, objective data on sleep propensity and wakefulness regulation.

The Multiple Sleep Latency Test (MSLT) is a facility-based study used to measure levels of daytime sleepiness. The results of the study are primarily used to confirm the suspected diagnosis of narcolepsy.

The MSLT involves multiple trials during a day to objectively assess sleep tendency by measuring the number of minutes it takes the patient to fall asleep. During a routine MSLT, an individual is given five nap trials that are separated by two-hour intervals; each trial consists of a twenty-minute session in which the individual attempts to fall asleep. Onset of sleep and rapid eye movement, along with heartbeat and chin movements, are recorded. The test is typically performed on the night following a polysomnography (PSG), where at least six hours of sleep were achieved, in order to rule out other sleep disorders as a cause of excessive daytime sleepiness. The patient may be instructed to lie down in a dark room, with permission or a suggestion given to sleep (MSLT), or to sit up in a dimly lit room and try to stay awake (Maintenance of Wakefulness Test). The MSLT is the better test for demonstrating sleep-onset rapid eye movement (REM) periods, a determination that is important in establishing the diagnosis of narcolepsy. Parameters necessary for sleep staging (including 1 to 4 channels of EEG, EOG, and chin EMG) are recorded. An EEG (electroencephalogram), EOG (electrooculogram), and EMG (electromyogram) are bioelectric, non-invasive methods for measuring brain, eye, and muscle electrical activity, respectively. EEG detects brain disorders like epilepsy, EOG tracks eye movement, and EMG evaluates muscle/nerve function.

The Maintenance of Wakefulness Test (MWT) is a facility-based study used to measure the ability to stay awake and alert. The procedure protocol is similar to that of the MSLT, with the exception that an individual is given four nap trials, each trial consisting of a forty-minute session in which the individual attempts to fall asleep. The test is routinely performed the day after a nocturnal PSG and evaluates the ability to stay awake for a defined period of time. Results may be used to determine the efficacy of therapy for sleep disturbance disorders (such as narcolepsy) or to assess whether the inability to stay awake is a public or personal safety concern.

1. when the initial test is affected by extraneous circumstances or when appropriate study conditions were not present during initial testing,
2. when ambiguous or uninterpretable findings are present,
3. when the patient is suspected to have narcolepsy but earlier MSLT evaluation(s) did not provide polygraphic confirmation.

Huang et al. (2008) noted that the cause and pathogenesis of Kleine-Levin syndrome, a recurrent hypersomnia affecting mainly male adolescents, remain unknown, with only scant information on the sleep characteristics during episodes. These investigators described findings obtained with polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT) and the correlation obtained between clinical and PSG findings from different episodes. A total of 19 patients (17 males) were investigated with PSG and MSLT; 10 had data during both symptomatic episodes and asymptomatic intervals. The analyses considered the day of onset of symptoms and the relationship between this time of onset and the day of recording during the symptomatic period. When PSG was performed early (before the end of the first half of the symptomatic period), an important reduction in slow-wave sleep (SWS) was always present, with a progressive return to normal during the second half (with percentages very similar to those monitored during the asymptomatic period) despite the persistence of clinical symptoms. Rapid eye movement (REM) sleep remained normal in the first half of the episode but decreased in the second half; the differences between the first and second halves of episodes were significant for SWS (p = 0.014) and REM sleep (p = 0.027). The overall mean sleep latency at MSLT was 9.51 ± 4.82 minutes, and 7 of 17 patients had 2 or more sleep-onset REM periods during the symptomatic period. The authors concluded that important changes in sleep occur over time during the symptomatic period, with clear impairment of SWS at symptom onset. However, MSLT is of little help in defining sleep problems, and findings from the MSLT do not correlate with symptom onset.

Yeh and Schenck (2010) compared MSLT and the Epworth Sleepiness Scale (ESS) for evaluating the effectiveness of modafinil in treating excessive daytime sleepiness in patients with narcolepsy. A total of 10 consecutive patients with narcolepsy with cataplexy who were treated with 200 mg/day modafinil for more than 6 months were included in this study. This comparative study was prompted by the requirement of the Bureau of National Health Insurance in Taiwan that modafinil users need to be followed up with MSLTs every 6 to 12 months. The mean age at onset of narcolepsy in these 10 patients was 11.8 ± 3.3 years, and 8 (80%) were male. These investigators compared the differences in MSLT and ESS between baseline and follow-up at 6 to 12 months after starting modafinil therapy using paired t-tests. Epworth Sleepiness Scale scores (p < 0.001) were considerably more sensitive than MSLT scores (p < 0.05) in documenting the effectiveness of modafinil, and improvements in MSLT scores were minimal and remained in the pathologically sleepy range. These findings suggested that the ESS is a more sensitive and clinically meaningful tool to evaluate the effectiveness of modafinil in narcolepsy.

Mariman et al. (2013) evaluated undiagnosed and co-morbid disorders in patients referred to a tertiary care center with a presumed diagnosis of chronic fatigue syndrome (CFS). Patients referred for chronic unexplained fatigue entered an integrated diagnostic pathway, including internal medicine assessment, psychodiagnostic screening, physiotherapeutic assessment, and PSG + MSLT. Final diagnosis resulted from a multi-disciplinary team discussion. Fukuda criteria were used for the diagnosis of CFS, DSM-IV-TR criteria for psychiatric disorders, and ICSD-2 criteria for sleep disorders. Out of 377 patients referred, 279 (74.0%) were included in the study (84.9% female; mean age of 38.8 years, SD 10.3). A diagnosis of unequivocal CFS was made in 23.3%. In 21.1%, CFS was associated with a sleep disorder and/or psychiatric disorder, not invalidating the diagnosis of CFS. A predominant sleep disorder was found in 9.7%, 19.0% had a psychiatric disorder, and 20.8% had a combination of both. Only 2.2% were diagnosed with a classical internal disease. In the total sample, a sleep disorder was found in 49.8%, especially obstructive sleep apnea syndrome, followed by psychophysiologic insomnia and periodic limb movement disorder. A psychiatric disorder was diagnosed in 45.2%, mostly mood and anxiety disorders. The authors concluded that a multi-disciplinary approach to presumed CFS yielded unequivocal CFS in only a minority of patients and revealed a broad spectrum of exclusionary or co-morbid conditions within the domains of sleep medicine and psychiatry.

Ferman et al. (2014) stated that excessive daytime sleepiness (EDS) is a commonly reported problem in dementia with Lewy bodies (DLB). These researchers examined the relationship between nighttime sleep continuity and the propensity to fall asleep during the day in clinically probable DLB compared to Alzheimer's disease (AD) dementia. A full-night polysomnography was carried out in 61 participants with DLB and 26 with AD dementia. Among this group, 32 participants with DLB and 18 with AD dementia underwent a daytime MSLT. Neuropathologic examinations of 20 participants with DLB were carried out. Although nighttime sleep efficiency did not differentiate diagnostic groups, the mean MSLT initial sleep latency was significantly shorter in participants with DLB than in those with AD dementia (mean of 6.4 ± 5 minutes versus 11 ± 5 minutes, p < 0.01). In the DLB group, 81% fell asleep within 10 minutes compared to 39% of the AD dementia group (p < 0.01), and 56% in the DLB group fell asleep within 5 minutes compared to 17% in the AD dementia group (p < 0.01). Daytime sleepiness in AD dementia was associated with greater dementia severity, but mean MSLT latency in DLB was not related to dementia severity, sleep efficiency the night before, or to visual hallucinations, fluctuations, parkinsonism, or rapid eye movement sleep behavior disorder. These data suggested that EDS is a unique feature of DLB that does not depend on nighttime sleep fragmentation or the presence of the four cardinal DLB features. Of the 20 DLB participants who underwent autopsy, those with transitional Lewy body disease (brainstem and limbic) did not differ from those with added cortical pathology (diffuse Lewy body disease) in dementia severity, DLB core features, or sleep variables. The authors concluded that daytime sleepiness is more likely to occur in persons with DLB than in those with AD dementia. They stated that daytime sleepiness in DLB may be attributed to disrupted brainstem and limbic sleep-wake physiology, and further work is needed to better understand the underlying mechanisms.

Cochen De Cock and colleagues (2014) stated that excessive daytime sleepiness (EDS) is a frequent complaint in Parkinson's disease (PD); however, the frequency and risk factors for objective sleepiness remain mostly unknown. These researchers investigated both the frequency and determinants of self-reported and objective daytime sleepiness in patients with PD using a wide range of potential predictors. A total of 134 consecutive patients with PD, without selection bias for sleep complaints, underwent a semi-structured clinical interview and a one-night polysomnography followed by an MSLT. Demographic characteristics, medical history, PD course and severity, daytime sleepiness, depressive and insomnia symptoms, treatment intake, pain, restless legs syndrome, REM sleep behavior disorder, and nighttime sleep measures were collected. Self-reported daytime sleepiness was defined by an Epworth Sleepiness Scale (ESS) score above 10. A mean sleep latency on MSLT below 8 minutes defined objective daytime sleepiness. Of the 134 patients with PD, 46.3% had subjective sleepiness, and only 13.4% had objective sleepiness, with a weak negative correlation between ESS and MSLT latency. A high body mass index (BMI) was associated with both ESS and MSLT, a pain complaint with ESS, and a higher apnea/hypopnea index with MSLT. However, no associations were found between both objective and subjective sleepiness and measures of motor disability, disease onset, medication (type and dose), depression, insomnia, restless legs syndrome, REM sleep behavior disorder, and nighttime sleep evaluation. The authors concluded that they found a high frequency of self-reported EDS in PD, a finding which is, however, not confirmed by the gold standard neurophysiological evaluation.

Bjornara et al. (2014) noted that sleep disturbances, such as REM sleep behavior disorder (RBD) and EDS, are more common in patients with PD than in the general population. Apart from that, their relation to PD seems to diverge considerably. These researchers explored the frequency and associated motor and non-motor features of sleep-related symptoms in PD. A total of 107 patients with PD, 65 men and 42 women, were included in a cross-sectional study. Excessive daytime sleepiness was examined by the ESS; probable RBD (pRBD) was diagnosed by the validated RBD screening questionnaire. Further sleep symptoms were explored by the PD sleep scale. Motor and non-motor symptoms were assessed and compared in patients with and without pRBD and EDS, respectively. pRBD was present in 38%, and EDS was present in 29% of the patients. As opposed to EDS, pRBD showed no association with disease duration or severity. Parkinson’s disease patients with pRBD reported more cognitive problems. There was a trend towards more autonomic dysfunction in patients with pRBD. Nocturia and sleep fragmentation were the most frequent general sleep problems reported by the patients. The authors concluded that these findings suggested that EDS is related to disease duration and possibly caused by progressive neurodegeneration. They stated that pRBD seems to be a distinct feature present in only a proportion of PD patients.

Ataide et al. (2014) noted that sleep disorders are major non-motor manifestations of patients with PD, and EDS is one of the most common symptoms. These investigators reviewed current literature concerning major factors that influence EDS in PD patients, using MSLT. A Medline search found 23 studies. The presence of EDS was observed in 12.7% to 47% of patients without complaints of daytime sleepiness and 47% to 66.7% of those with complaints of daytime sleepiness. Despite being recognized by several authors, major factors that influence EDS, such as the severity of motor symptoms, use of dopaminergic medications, and associated sleep disturbances, presented contradictory data. The authors concluded that available data suggested that the variability of the results may be related to the fact that studies were conducted with small sample sizes, not accounting for the neuropathological heterogeneity of the disease. Thus, before carrying out longitudinal studies with significant samples, careful analysis should be done by assigning a specific agent responsible for EDS in PD patients.

Schrempf et al. (2014) noted that sleep disorders in patients with PD are very common and have an immense negative impact on their quality of life. Insomnia, daytime sleepiness with sleep attacks, restless legs syndrome (RLS), and RBD are the most frequent sleep disorders in PD. Neurodegenerative processes within sleep regulatory brain circuitries, anti-parkinsonian medications (e.g., levodopa and dopamine agonists), and concomitant medications (e.g., antidepressants), as well as co-morbidities or other non-motor symptoms (such as depression), were discussed as causative factors. For the diagnosis of sleep disturbances, these researchers recommended regular screening using validated questionnaires such as the Pittsburgh Sleep Quality Index (PSQI) or the Medical Outcomes Study Sleep Scale (MOS). For evaluating daytime sleepiness, these investigators suggested using the ESS, the inappropriate sleep composite score (ISCS), or the Stanford Sleepiness Scale (SSS). All of these questionnaires should be used in combination with a detailed medical history focusing on common sleep disorders and medication. If necessary, patients should be referred to sleep specialists or sleep laboratories for further investigations. Management of sleep disorders in PD patients usually starts with optimization of (dopaminergic) anti-parkinsonian therapy, followed by specific treatment of the sleep disturbances. Aside from these clinical issues of sleep disorders in PD, the concept of RBD as an early sign for emerging neurodegenerative diseases is of pivotal interest for future research on biomarkers and neuroprotective treatment strategies for neurodegenerative diseases, particularly PD.

Multiple Sleep Latency Test for the Diagnosis of Pediatric Narcolepsy Type 1

Pizza and colleagues (2019) attempted to validate polysomnographic markers (sleep latency and sleep-onset REM periods [SOREMPs] at the Multiple Sleep Latency Test [MSLT] and nocturnal polysomnography [PSG]) for pediatric narcolepsy type 1 (NT1) against CSF hypocretin-1 (hcrt-1) deficiency and the presence of cataplexy, as no criteria are currently validated in children. Clinical, neurophysiologic, and, when available, biological data (HLA-DQB1*06:02 positivity, CSF hcrt-1 levels) of 357 consecutive children below 18 years of age evaluated for suspected narcolepsy were collected. Best MSLT cutoffs were obtained by receiver operating characteristic (ROC) curve analysis by contrasting among patients with available CSF hcrt-1 assays (n = 228) with versus without CSF hcrt-1 deficiency, and further validated in patients without available CSF hcrt-1 against cataplexy (n = 129). Patients with CSF hcrt-1 deficiency were best recognized using a mean MSLT sleep latency of less than or equal to 8.2 minutes (area under the ROC curve of 0.985), or by at least 2 SOREMPs at the MSLT (area under the ROC curve of 0.975), or the combined PSG + MSLT (area under the ROC curve of 0.977). Although the specificity and sensitivity of the reference MSLT sleep latency of less than or equal to 8 minutes and greater than or equal to 2 SOREMPs (nocturnal SOREMP included) were 100% and 94.87%, respectively, the combination of MSLT sleep latency and SOREMP counts did not improve diagnostic accuracy. Age or sex also did not significantly influence these results in this pediatric cohort. The authors concluded that at least 2 SOREMPs or a mean sleep latency of less than or equal to 8.2 minutes at the MSLT were valid and reliable markers for pediatric NT1 diagnosis, a result contrasting with adult NT1 criteria. This study provided Class III evidence that for children with suspected narcolepsy, polysomnographic and MSLT markers accurately identified those with narcolepsy type 1.

Attention-Deficit/Hyperactivity Disorder

Prihodova et al. (2010) evaluated sleep macrostructure, sleep disorder incidence, and daytime sleepiness in children affected by attention-deficit/hyperactivity disorder (ADHD) compared with controls. A total of 31 patients (26 boys, 5 girls; mean age of 9.3 ± 1.7 years, range of 6 to 12) with ADHD diagnosed according to DSM-IV criteria, without co-morbid psychiatric or other disorders, and who had never been pharmacologically treated for ADHD, were included in this study. The controls were 26 age- and sex-matched children (22 boys, 4 girls; mean age of 9.2 ± 1.5 years, range of 6 to 12). Nocturnal polysomnography was performed for 2 nights, followed by the MSLT. No differences between the two groups were found when comparing both nights in the basic sleep macrostructure parameters or in the time (duration) of sleep onset. A first-night effect on sleep variables was apparent in the ADHD group. The occurrence of sleep disorders (sleep-disordered breathing [SDB], periodic limb movements in sleep [PLMS], parasomnias) did not show any significant differences between the investigated groups. A statistically significant difference (p = 0.015) was found in the trend of the periodic limb movement index (PLMI) between the two nights (a decrease of PLMI in the ADHD group and an increase of PLMI in the control group during the second night). While the mean sleep latency in the MSLT was comparable in both groups, children with ADHD showed significant inter-test differences (between tests 1 and 2, 1 and 4, 1 and 5; p < 0.01). The authors concluded that after the inclusion of an adaptation night and exclusion of psychiatric co-morbidities, PSG showed no changes in basic sleep parameters or sleep timing, or in the frequency of sleep disorders (SDB, PLMS) in children with ADHD compared with controls, thus not supporting the hypothesis that specific changes in sleep macrostructure and sleep disturbances are connected with ADHD. A first-night effect on sleep variables was apparent only in the ADHD group. The authors concluded that although they found no proof of increased daytime sleepiness in children with ADHD compared to controls, they did find significant vigilance variability during MSLT in the ADHD group, possibly a sign of dysregulated arousal.

Sobanski and colleagues (2016) evaluated sleep latency (SL) during the MSLT and subjective daytime sleepiness in adult ADHD and controls. Subjective daytime sleepiness was assessed by the ESS in 27 unmedicated adults with ADHD and in 182 controls; 13 ADHD patients and 26 controls underwent MSLT after one night of PSG. The mean MSLT sleep latency was 10.6 ± 4.8 minutes in ADHD and 12.2 ± 4.2 minutes in controls (not significant). The mean ESS score was 9.3 ± 4.9 points in ADHD and 6.9 ± 3.4 points in controls (p < 0.005); MSLT sleep latency and ESS scores correlated inversely by trend (r = -0.45, p < 0.1) but not with ADHD symptoms or ADHD subtype. The authors concluded that adults with ADHD did not differ from controls in mean MSLT sleep latency but experienced increased subjective daytime sleepiness. Patients with higher subjective daytime tiredness fell asleep faster during MSLT.

Home Multiple Sleep Latency Test

In a randomized, cross-over, single-blinded study, Beiske and colleagues (2017) compared mean sleep latencies and the number of sleep-onset rapid eye movement periods (SOREMPs) between modified MSLTs performed in an unattended home setting and in a hospital laboratory setting. A total of 34 subjects referred for MSLT due to suspected hypersomnia or narcolepsy were included. Participants were randomized to perform the modified MSLT in the unattended home or in the hospital first. Scores in the two settings were compared using the Wilcoxon signed-rank test or the exact McNemar test. Agreement between home and hospital categorized mean sleep latency and the number of SOREMPs was assessed using simple kappa (κ) and proportion agreement. Agreement between home and hospital mean sleep latency was assessed using a Bland-Altman plot and an intra-class correlation coefficient. There was no difference between home and hospital assessment of mean sleep latency (p = 0.86); however, two or more SOREMPs were found more frequently on modified MSLTs performed at home compared with those at the hospital (7 and 2, respectively; p = 0.025). Agreement was moderate for categorized sleep latency (κ = 0.53) and fair for categorized SOREMPs (κ = 0.39) in the two settings. Analysis of mean sleep latency using the intra-class correlation coefficient showed very good agreement between the two settings. The authors concluded that group mean sleep latency for home modified MSLTs appeared to be reliable compared with that for the attended sleep laboratory setting. The higher rate of SOREMPs in the unattended home suggested that napping in a familiar environment facilitated the transition into REM sleep. Moreover, they stated that further studies are needed to evaluate the normal limits, sensitivity, and specificity for SOREMPs at home before the clinical utility of home-based napping can be determined.

Psychiatric Hypersomnolence

Nofzinger et al. (1991) characterized objectively the hypersomnia frequently seen in the depressed phase of bipolar affective disorder. On the basis of previous work in sleep and affective disorders, it has been hypothesized that the hypersomnia is related to greater REM sleep. This hypothesis was tested by using a Multiple Sleep Latency Test (MSLT) to compare bipolar affective disorder with narcolepsy, a well-defined primary sleep disorder associated with known REM sleep dysfunction. A total of 25 bipolar depressed patients were selected based on complaints of hypersomnia. They underwent 2 nights of polysomnography (PSG) followed by an MSLT. Data on their nocturnal sleep and daytime naps were compared with similar data on 23 non-depressed narcoleptic patients referred for sleep evaluation. Despite their complaints of hypersomnia, no abnormalities were noted for the bipolar group in the results from the MSLT. Contrary to the working hypothesis, REM sleep was notably absent during daytime naps in the depressed patients, in marked contrast to the findings for the narcoleptic group. The authors concluded that the complaint of sleepiness in the hypersomnic bipolar depressed patient appeared to be related to the lack of interest, withdrawal, decreased energy, or psychomotor retardation inherent in the anergic depressed condition, rather than an increase in true sleep propensity or REM sleep propensity.

Plante (2016) noted that hypersomnolence plays a sizeable role in the course and morbidity of psychiatric disorders. Current sleep medicine nosology relies on the MSLT to segregate hypersomnolence associated with psychiatric disorders from other central nervous system causes. However, the evidence base regarding sleep propensity in psychiatric hypersomnolence, as measured by the MSLT, has not been systematically evaluated, which is vital to clarify the utility and validity of current nosological schema. In this review, the use of sleep propensity assessed by the MSLT in patients with psychiatric hypersomnolence was systematically evaluated, using both qualitative and quantitative assessments. Findings demonstrated high heterogeneity and potential for bias among studies, with a pooled estimate of sleep propensity among patients with psychiatric hypersomnolence similar to normative values. Additionally, approximately 25% of patients with psychiatric hypersomnolence demonstrated a mean sleep latency below 8 minutes, the current cut-point to define pathologic sleepiness. The authors concluded that these data underscored the limitations of the MSLT in segregating psychiatric hypersomnolence from other central nervous system hypersomnias. They stated that further research is needed to evaluate novel measures and biomarkers of excessive sleepiness to advance clinical practice, as well as dimensional approaches to the classification of hypersomnolence disorders.

References