Proposal Title: Pupillometric Sleepiness in Treated Sleep Disorders, NIH RO1 NR04959, 5/15/00 – 2/29/04
Principal Investigator: S. L. Merritt, RN, MSN, EdD
1. Abstract
Patients with obstructive sleep apnea and narcolepsy can experience a diminished quality of life, decreased
productivity, and workplace and traffic accidents due to the pathologic excessive daytime sleepiness (EDS)
associated with these disorders. Currently, the extent of EDS is determined by polysomnography and the Multiple
Sleep Latency Test (MSLT), two EEG-based physiologic sleepiness measures that are labor intensive, timeconsuming, expensive and receive limited health insurance coverage. As people become sleepy, their pupils
oscillate widely and decrease in size. In this study, the Pupil Unrest Index (PUI) will be calculated to estimate
sleepiness using desk top pupillometry, an efficient, convenient, non-invasive and easily repeatable technique. The
PUI quantitatively describes the extent of pupillary oscillation during 15 minutes of alertness testing. Quantitative
data comparing the PUI to other physiologic sleepiness measures are not available. The subject cohorts for this
repeated measures, known groups methodologic study will consist of normal controls, and obstructive sleep apnea
and narcolepsy subjects before and after usual treatment. The specific aims are to (1) correlate the PUI with MSLT
sleep latencies among the subject groups; (2) compare the PUI to the MSLT in detecting sleepiness among the
three subject groups; and (3) compare the PUI and the MSLT to other objective and subjective sleepiness measures
between subject groups, and before and after usual treatment among the OSA and narcolepsy subjects. MANOVA
will be used to examine the linear relationship between the PUI and the MSLT among the subject groups, and the
differences in measures of perceived sleepiness, sleep quantity, sleep quality and continuity, mood and functional
status between the subject groups, and pre-posttreatment for subjects with OSA and narcolepsy. The sensitivity and
specificity of the PUI in detecting sleepiness will be estimated using the MSLT results as the “gold standard” for
classifying subjects. MLR will be used to estimate the relationship between the PUI or the MSLT, and other
objective and subjective sleepiness measures. Results will provide evidence about the PUI as a reliable and valid
objective outcome measure of waking tendency among controls, and pre-posttreatment for OSA and narcolepsy
subjects.
1
2. Specific Aims
The specific aims of this project are to: 1) Examine the relationship between the PUI and sleep latencies
obtained in the MSLT among controls as well as untreated and treated OSA and narcoleptic subjects; 2) Compare
the sensitivity and specificity of the PUI to the MSLT in detecting sleepiness among the three subject cohorts; 3)
Compare the PUI and the MSLT of normal controls to that of untreated OSA and narcolepsy subjects, and before
and after usual treatment of OSA and narcolepsy subjects; and 4) Describe the relationship of the PUI and the
MSLT to other objective and subjective sleepiness measures among normal controls, and before and after usual
treatment of OSA and narcolepsy subjects.
3. Background/Significance
This methodological (measurement) study is being conducted to validate the Pupil Unrest Index (PUI), a
pupillometric measure of physiologic sleepiness, as a feasible alternative to the EEG-based Multiple Sleep Latency
Test (MSLT), the current “gold standard” for objectively measuring level of physiologic sleepiness. Nighttime
polysomnography (PSG), conducted in sleep centers the night before the MSLT, is used in conjunction with sleep
center MSLT testing to identify the probable cause of excessive daytime sleepiness (EDS). The necessity of these
highly technical, expensive procedures is being questioned. Increasingly, partial night PSG and overnight PSG in
home settings are being advocated to lower testing costs even though these practices are controversial since their
reproducibility and accuracy have not been established1-2. MSLT daytime sleepiness testing in a sleep center is
being used only at the time of initial diagnosis. Currently, self-report and subjective ratings of level of sleepiness
are used to estimate treatment efficacy for people with obstructive sleep apnea (OSA) and narcolepsy even though
significant residual sleepiness after treatment is a common finding3-4, and estimates of perceived EDS are often
inaccurate5-6. The 1999 AHCPR report, as part of its Evidence-Based Practice Program 1) noted that the costs of
using current strategies to identify all suspected OSA cases would be prohibitive, 2) called for long-term outcome
studies to document findings of treated vs. untreated OSA patients, and 3) stated that monitoring systems must be
validated in the setting in which they would be used2,7.
4. Preliminary Studies
In a program of research conducted in the center since 1994, we have 1) documented that pupillometry
outcomes are repeatable in normal subjects with a consistent sleep/wake/activity pattern; 2) documented that
pupillometry is capable of detecting a midday circadian change in level of alertness in normal subjects; and 3)
provided evidence about the validity of pupillometry as a measure of sleepiness as reflected by an increase in the
amount of theta activity as papillary oscillation increase and pupil size decreases (#3 funded by a R15 by NINR,
NIH). These studies were conducted to provide evidence about aspects of reliability and validity of pupillometry
not available in published literature.
However, the MSLT is considered the gold standard physiologic sleepiness measure and researchers and
clinicians are not likely to accept pupillometry ALT and its associated measures until it is compared to the MSLT.
The initial comparison of pupil changes with EEG was undertaken because it was much less expensive to conduct
and, if positive, would provide evidence for undertaking the more expensive and comprehensive study of
pupillometry concurrent with MSLT that is outlined in this proposal.
5. Research Design and Methods
a. Study design. We are using a cohort, repeated measures known groups methodology for this measurement
study consisting of normal controls with no clinically detectable evidence of a sleep disorder, and obstructive sleep
apnea (OSA) and narcolepsy subjects before and after usual treatment. The narcolepsy and OSA groups represent
the preponderance of people seen in U.S. sleep centers. Pervasive EDS that interferes with their ability to function
in daily life is one of the primary findings in people with these disorders. Data on pupillary changes during
decreasing wakefulness in normal healthy subjects is meager although available evidence suggests that the pupil
changes are identical during decreased wakefulness in normals to those seen during the EDS associated with sleep
disorders8. Furthermore, what studies are available about normals used a variety of procedures and lacked adequate
controls in determining that the subjects were adequately rested and free from a sleep disorder9-10. Therefore, data
on normal controls are needed to address the aims outlined above.
Screening measures to be used include the following:
1. Background Questionnaire (BQ), an instrument consisting of sociodemographic, general medical
history, and OSA and narcolepsy history and treatment items, has been used extensively in prior studies conducted
by the Center for Narcolepsy Research. 2. Sleep Disorders Questionnaire (SDQ) is a standardized, validated
instrument that was initially developed based on the Stanford Sleep Questionnaire. Scale scores for OSA,
narcolepsy, psychiatric sleep disorders and periodic leg movements were found to be highly correlated with PSG
2
findings11-12. 3. Urine drug screen (UDS) testing is commonly used in clinical settings to test for recreational and
other drug use that can affect sleep and wakefulness. 4. Beck Depression Inventory (BDI) is widely used to
assess for the presence of major depressive symptoms13. Since people with mood disorders often experience sleep
disturbances and show abnormalities in PSG findings14-15, potential subjects with high BDI scores will be excluded
from participation.
Objective measures are as follows:
1. Polysomnography (PSG), with a minimum of three systems (EEG, EOG and EMG) and standardized
criteria established by Rechtschaffen and Kales16, is used to record and stage sleep, and diagnose sleep disorders.
With the addition of EKG, oxygen saturation and nasal or oral airflow measurements, information about
respiratory disturbances during sleep is obtained. The PSG measures of particular interest are those associated
with the sleep disordered breathing that occurs in OSA (the apnea/hypopnea index) 1 and measures that denote
fragmented sleep (arousals and awakenings)17.
Diagnostic criteria for the presence of OSA in adults include subjective complaints of EDS or insomnia,
frequent episodes of obstructed breathing during sleep and associated features which may include loud snoring,
AM headaches, and/or dry mouth upon awakening. PSG objectively confirms OSA when 5 or > obstructive apneas
lasting 10 secs or > per hour of sleep are present, and are accompanied by either frequent arousals from sleep,
bradytachycardia or arterial oxygen desaturation18.
Diagnostic criteria for the presence of narcolepsy include subjective complaints of EDS, recurrent
unplanned lapses into sleep almost daily for 3 months and/or sudden muscle weakness or loss of postural tone
associated with intense emotion. Auxiliary complaints may include sleep paralysis, hypnagogic hallucinations,
automatic behavior or disturbed nighttime sleep. Objectively, PSG demonstrates a sleep latency less than 10
minutes and/or REM sleep latency less than 20 minutes with no other sleep disorder that could be the primary
cause of the symptoms. The MSLT (see the next section) demonstrates a mean sleep latency less than 5 minutes
averaged across the 4 nap opportunities and two or more sleep onset REMs. Additionally, no other medical or
mental disorder is present that accounts for the symptoms18.
2. The Multiple Sleep Latency Test (MSLT) measures physiological sleep tendency in the absence of
alerting stimuli18-21. After undergoing an all-night sleep study, the person, wearing comfortable loose street
clothing, lies in bed in a quiet, temperature-controlled, darkened room and is instructed to try to fall asleep during
four to five 20 minute nap opportunities scheduled at 2 hour intervals from 10:00 AM to 6:00 PM. For each nap
opportunity, how long it takes for the individual to fall asleep (sleep latency, the first 3 consecutive epochs of
Stage 1 sleep or the first epoch of any other sleep stage) is measured as well as the presence or absence of a REM
sleep stage if the individual does fall asleep.
3. Pupil oscillation in size and miosis, measured with infrared video pupillometry in the dark during the
soporific conditions of alertness testing, is considered an objective and sensitive measure of central influences on
the sympathetic and parasympathetic branches of the peripheral autonomic nervous system (ANS) that control
pupil movement22-23. Yoss, Moyer & Hollenhurst24-25 developed the Alertness Level Test (ALT) at Mayo Clinic.
This test is conducted with the subject seated quietly in a darkened room and focusing on a red spot of light
projected about 2 meters from the subject; the individual is instructed to try to stay awake while the diameters of
the pupils are measured continuously by infrared video cameras for 15 minutes. Pupillometry ALT studies will be
conducted in the UIH Sleep Center at times that alternate between the MSLT nap opportunities (i.e., 9 AM, 11
AM, 1 PM & 3 PM) using the PST system (AMTech, Weinheim, Germany). Customized software provided with
the system allows the user to calculate the power spectrum of pupil behavior up to .8 Hz as well as the pupil unrest
index (PUI)26, the amount of pupillary oscillation (change is pupil size) that occurs during alertness testing while
the subject is awake. Higher PUI values reflect greater pupillary movement (and ensuing sleepiness) during awake
pupillometry testing.
4. During the Psychomotor Vigilance Task (PVT) subjects push a button as fast as they can with either
the thumb or forefinger of their dominant hand whenever a small LED millisecond clock begins counting up from
000027-28. Pressing the button stops the clock. The PVT is conducted for 10 minutes and the interstimulus interval
for the task varies randomly from 2 to 10 seconds. Reaction time (RT) data are stored on a microchip and
downloaded to a PC for analyses. Performance outcomes include the number of lapses (RT  500 ms), increases in
the duration of responses in the lapse domain, shifts in optimum reaction times, time-on-task decrements and the
median trial RT.
Subjective measures are as follows:
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1. The Visual Analog Scale (VAS) is used by the subject to rate his/her level of alertness on a 10 cm line
with the left or 0 end being “asleep” and the right or 10 end being “as awake as I can be.” This method of
measuring sleepiness has been shown to be correlated with other subjective measures such as the Stanford
Sleepiness Scale29 and will be used immediately prior to and after each pupillometry test. 2. The Epworth
Sleepiness Scale (EES) is a self-report instrument on which respondents rate their chance of falling asleep in 8
common daily situations. Johns30-31 found a significant relationship between EES and sleep latencies on the MSLT
and PSG. Significant differences in scores have been found between nonpatients, and patients with a disorder of
sleepiness, people with different degrees of severity in sleep disorder breathing32 and narcolepsy33. 3. The
Pittsburgh Sleep Quality Index (PSQI)34-35 is a self-rated questionnaire which assesses sleep quality, latency,
duration, efficiency, disturbances, sleep medication and daytime dysfunction over a 1-month time interval. A total
score > 5 on the PSQI has a sensitivity of 89.6% and specificity of 86.5% in distinguishing good and poor sleepers,
and compares favorably with other clinical and PSG measures. The PSQI has been widely used to measure sleep
quality in normal subjects as well as individuals with a variety of sleep disturbances. 4. The Profile of Mood
States (POMS)36 is a 65 item inventory that will be administered to determine if there are differences in mood preposttreatment that could have an effect on the pupillometry and MSLT results. Based on a rating of 65 adjective
descriptors, items are clustered into 6 scales that can affect wakefulness (i.e tension-anxiety, depression-dejection,
anger-hostility, vigor, fatigue-inertia, and confusion-bewilderment). 5. The Functional Outcomes of Sleep
Questionnaire (FOSQ) is a self-report survey instrument designed to assess generally how sleepiness affects a
person’s daily ability to function in the following areas: activity level, vigilance, general productivity, social
relations and intimacy and sexual relationships37. When tested with 134 OSA and 32 normal subjects, factor
analyses with varimax rotation confirmed the validity of the five subscales.
Adherence measures are being used since it is a concern with both sleep disorder subject groups. Many
OSA patients do not use CPAP treatment every night and for the whole night of sleep as recommended 38, but selftitrate their treatment to a level that achieves subjectively defined improvement in their EDS. Eligible OSA
subjects on CPAP treatment will use a ResMed machine that records the hours per night of actual use at the
prescribed pressure. The percentage of sleep time per day at which the subjects used their CPAP machine at the
prescribed pressure over the month following CPAP stabilization will be used to estimate subject adherence.
Rogers found that only 39% of narcoleptics on dextroamphetamine or methylphenidate took the amount of
medication prescribed39. For this study adherence is being monitored using the Medication Event Monitoring
System, Child Resistant cap (MEMS-CR) together with pill counts. The MEMS-CR cap (Aprex, Menlo Park, CA)
fits 30, 40 & 60 dram medication bottles, and contains an electronic chip that records the date and time whenever
the bottle is opened. Adherence will be estimated by determining the proportion of time each subject took the
appropriate medication dose within 2 hours of the prescribed time during the past month or since the last
medication change..
Sleep Disorders Treatment.
For OSA and narcolepsy, the usual methods for instituting and monitoring
treatment at the University of Illinois Medical Center will be followed. Following the initial diagnosis of OSA,
subjects who agree to the recommended treatment return for a CPAP pressure titration study. Those who then
agree to a home trial are seen by a home care agency that checks the equipment and continues the instruction
initiated at the titration trial. Stabilization at a comfortable pressure can take some time with CPAP follow up as
necessary. For narcolepsy patients being seen in the Department of Neurology, narcolepsy treatment compounds
are gradually introduced, titrated and monitored over a 3 month period to a level that promotes the desired level of
symptom control without intolerable side effects.
OSA treatment. Continuous positive airway pressure (CPAP) therapy, which is usually applied nasally
during sleep at a water pressure ranging from 5-20 cm, creates a pneumatic splint by maintaining airway patency
and preventing collapse. CPAP has been shown to be effective in eliminating obstructed breathing and the
associated arousals during sleep as well as blood oxyhemoglobin desaturation and is the usual treatment of first
choice for OSA. Arousals occur when the sleeping person with OSA increases respiratory effort in order to
terminate an apnea event. The more frequent the apneic events, the more often the arousals and sleep disruption
occur. Daytime hypersomnolence is the result of frequent arousals and the subsequent reduction in the proportion
of slow-wave and REM sleep. The maintenance of airway patency prevents this cycle of events and ameliorates the
EDS. Following titration in a sleep center, it can take some time for OSA patients to adjust to nightly CPAP use;
some adjustment in the prescribed CPAP pressure may be needed in order for reach an acceptable comfort level for
the patient. A pattern of use is usually established by the 1 month period following pressure stabilization40.
4
Narcolepsy treatment. Wake promoting medications (stimulants and related compounds) and anticataplectic compounds are usual treatment for controlling symptoms in narcolepsy. Modafinil, methylphenidate
hydrochloride, dextroamphetamine and sodium oxybate will be used to treat symptoms in narcoleptics (Table 1
below). Standards of practice for the treatment of narcolepsy41 cite methylphenidate hydrochloride, modafinil and
dextroamphetamine as effective in improving narcolepsy symptoms. Sodium oxybate was not yet FDA approved at
the time the standards were written but was noted as being promising in the standards document. People who have
been on anti-cataplectic medications and reached the desired control will return to the compound they were on
prior to baseline testing. The goal of therapy is to alleviate sleepiness, cataplexy and the other REM symptoms,
and allow return to the fullest possible normal function without the development of significant side effects.
Table 1. Medication Protocol for Narcoleptics
Compound/
Rec d. Dose Range
Initial Dose
1 month
Modafinil
(100-600 mgs/day)
100 mgs q day for
1 week; then
200 mgs q day
Methylphenidate
(30-100 mgs/day)
5 - 10 mgs q day
3 months
200 mgs in AM;
200 mgs at 1300
hrs
400 mgs in AM; 200 mgs
at 1300 hrs.
20 mgs q day
OD or in divided doses
Up to 40 mgs q day
in divided doses
20 mgs q day
Up to 40 mgs q day
in divided doses
Dextroamphetamine
Sulfate
(15 – 100 mgs/day)
5 – 10 mgs q day
Sodium oxybate
(Xyrem)
(3 gms – 9 gms/day)
4.5 gms q night
2.25 gms at bedtime
(increase or de& 2.25 gms at the
crease by 1.5 gms
midsleep period
per noct. after 2 wks
based on response)
Up to 9 gms q noct
in divided doses
Modafinil will be the first choice of medication because this compound has been shown to promote
wakefulness without causing the side effects associated with stimulants and, therefore, can be more tolerable. The
potential subjects for this compound include newly diagnosed narcoleptics who have never been on stimulants, or
previously diagnosed narcoleptics who are dissatisfied with their response to stimulants and are motivated to try
this compound. For people whose EDS does not respond to modafinil, the next drug of choice will be
methylphenidate. If neither drug is effective in controlling sleepiness, a trial of dextroamphetamine sulfate will
commence. Sodium oxybate will be prescribed for narcoleptics 1) who were on this compound prior to enrollment
and want to continue its use, 2) whose cataplexy and/or EDS was not controlled with the other narcolepsy agents,
or 3) who report significant disturbed nighttime sleep with residual EDS while on other narcolepsy treatment
compounds. The anticipated dosage and scheduling of each medication is listed above in Table 1.
The major variables and related outcome measures that will be analyzed are listed in Table 2.
Table 2. Major Variables and Outcome Measures
Major Variables
Physiologic sleepiness - dependent variables
Pupil oscillation
Daytime sleep propensity
Independent variables:
Perceived sleepiness
Chronic
Measures
Pupillometry alertness test - pupillary unrest index
Multiple Sleep Latency Test - sleep latency in minutes
Epworth Sleepiness Scale score
5
Acute
Sleep Quantity
Duration
Sleep Continuity/Quality
Mood
Functional Status
Performance
Adherence
Visual Analogue Scale score
Polysomnography (PSG) - time asleep, sleep efficiency
Sleep Log (7 days) - mean hrs of sleep/week
PSG - proportion of NREM sleep stages 3 & 4 & proportion of
REM sleep stage, apnea/hypopnea index, arousal index,
number of awakenings
Pittsburgh Sleep Quality Index score - quality, latency, duration,
Profile of Mood States score - tension-anxiety, depressiondejection, anger-hostility, vigor, fatigue-inertia, confusionbewilderment
Functional Outcomes of Sleep Questionnaire score - activity
level, vigilance, general productivity, social outcome,
intimacy/sexual relations
Psychomotor Vigilance Task - number of lapses (RT  500 ms),
increases in the duration of responses in the lapse domain, shifts
in optimum reaction times, time-on-task decrements and the
median trial RT
OSA - percent of sleep time CPAP was used within 2 cm of H20 of
the prescribed pressure; data collected for 30 days following use
at a stable acceptable pressure
Narcolepsy - percent of correct doses taken within 2 hours of
prescribed time for the last month of treatment
b. Laboratory procedures. In addition to the urine drug screen done with all subjects (samples sent to American
Institute of Toxicology, all supplies provided for collection and mailing), controls undergo blood testing (metabolic
chem panel, T4 and CBC with differiential), an urinanalysis (all blood and urine testing is done at the UIC
Pathology Lab), and an EKG (done at the UIH EKG lab). Narcoleptic and OSA subjects with adult onset diabetes
undergo a glycosylated hemoglobin blood test if results from the past 6 months are not available in their medical
record.
c. Statistical Analysis. Data analysis will be performed with SPSS-PC Version 1142. Descriptive statistics will
be used to describe the sociodemographic and medical history of the total sample; Chi square or analysis of
variance (ANOVA) will be used to examine the comparability among groups (control, OSA and narcoleptic) on
selected characteristics, e.g., age, gender, etc. Symptom experiences and perceptions of treatment also will be
compared pre-posttreatment within sleep disorder groups. The method of Maximum Likelihood Estimates will be
used to replace missing values. Internal consistency reliability (Chronbach’s alpha) will be estimated for the
Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), the Profile of Mood States (POMS)
and the Functional Outcomes of Sleep Questionnaire (FOSQ).
Multivariate analysis of variance will be used to examine the relationship between the PUI and the MSLT
among the subject groups (AIM 1)43-44. Follow up ANOVA procedures will be used to compare the PUI and the
MSLT of normal subjects to those of the two sleep disorders groups in both the untreated and treated states (AIM
3). Sensitivity, specificity and receiver operator characteristics 45 of the PUI and the MSLT will be examined
among the controls and untreated OSA and narcolepsy subjects using a cutpoints of < 5 minutes for the MSLT and
2 standard deviations above the mean of the control subjects for the PUI46-47. For the posttreatment analyses, a
cutpoint of < 10 minutes and 1 SD above the control mean will be used (AIM 2). Multiple linear regression will
be used to examine the relationship between the PUI or the MSLT with other objective and subjective measures
among controls, untreated OSA and untreated narcolepsy subjects, and among treated OSA and narcolepsy
subjects (AIM 4)44,48.
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6. Human Subject Considerations
a. Population. We have chosen to study OSA (N=32) and narcolepsy (N=36) subjects before and after usual
treatment. A comparison group of normal controls (N=50) is included. Sleep disorder subjects will be
consecutively selected for participation as they agree to participate and meet the criteria for inclusion until the
number for each gender is reached. Control subjects will be consecutively selected for participation as they agree
to participate and meet the criteria for inclusion by age range and gender until the desired numbers are reached for
each subject category. No particular population based on gender, race or ethnic status is excluded from
participation. Since initial contact is made through return of the subject flyer or by telephone or email contact, we
often are not aware of the ethnic status (and sometimes gender) of subjects until they come for their initial clinic
visit unless they volunteer this information. We expect to enroll more males than females in the OSA group
because the prevalence by gender is estimated to be 4% for males and 2% for females. No prevalence data by
gender are available for narcolepsy.
The age range of the subjects is 20 – 60 years of age. The lower cutpoint of 20 was chosen because
information is not available in the literature about the pupil behavior of children and adolescents during sleepiness
states. The cutpoint of 60 was chosen because OSA in older adults can be more complicated to diagnose due to of a
higher occurrence of apneas and hypopneas in older individuals; for narcolepsy subjects this disorder is rarely
diagnosed above the age of 50. OSA and narcolepsy consecutive volunteers diagnosed with PSG and MSLT who
meet the criteria for selection will be enrolled. Healthy control volunteers without any subjectively or objectively
detectable evidence of a sleep disorder or other chronic disease will be enrolled – 10 subjects per decade balanced
by gender until each of the four age groups is filled.
The inclusion and exclusion criteria by subject group are outlined below.
All subjects
In addition to providing informed consent, the inclusion criteria for all subjects are as follows:
1. Provide consent for release of medical records, and sleep/nap studies when available from the sleep
disorder subjects to the Center for Narcolepsy Research.
2. English-speaking and between 20–60 years of age.
3. Able to complete self-rating scales.
4. Limit caffeine intake to the equivalent of 8 cups of coffee per day.
5. Beck Depression Inventory score < 16.
6. Urine drug screen results as follows:
 Negative for recreational drugs at clinic visit.
 Negative for prescription or over-the-counter compounds that affect sleep or wakefulness
at the time of baseline PSG & MSLT (OSA subjects will taper and then discontinue
medically unnecessary drugs that influence wakefulness or sleep for 14 days in
consultation with the referring health care provider and Dr. Olopade; previously treated
narcoleptics will be off stimulant and antidepressant therapy for the prior 14 days with
tapering and washout period supervised by Dr. Vern).
7. Maintain their usual sleep pattern for the previous 7 days before testing as documented on a Sleep Log.
Exclusion criteria for all subjects are as follows:
1. History of eye disorders or eye surgery that could interfere with pupil motility.
2. Employment in a rotating or straight night shift schedule.
Control (normal) subjects
Additional inclusion criteria for control subjects are as follows:
1. Negative scale scores on the Sleep Disorder Questionnaire (SDQ) – OSA, narcolepsy, restless legs,
psychiatric sleep disorder.
2. Negative on the medical and health history sections of the Background Questionnaire.
3. Body mass index < 30, Epworth Sleepiness Scale score < 10, PUI within one standard deviation of
previous CNR findings for normal subjects (6.7 4 in AM or 8.43.1 in PM), normal labs (urine analysis, blood
chemistry, thyroid-T4, CBC), EKG, and normal History and PE (no clinical evidence of disease).
4. Negative polysomnography (PSG) and Multiple Sleep Latency Test (MSLT) (no findings consistent
with a sleep disorder or excessive daytime sleepiness).
7
Sleep disorder subjects
Inclusion criteria for sleep disorder subjects are as follows:
Both Sleep Disorder groups:
1. Present with a complaint of excessive daytime sleepiness.
2. Elevated scores on either the OSA, OR the narcolepsy scale of the Sleep Disorders Questionnaire.
3. Background Questionnaire (medical and health history findings) consistent with the diagnosis of the
respective sleep disorder.
4. Diagnosed with the respective sleep disorder as follow:
 OSA subject diagnosed via PSG with an Apnea/Hypopnea Index (AHI) of 15 or >
(moderate or severe OSA) and negative findings for another sleep disorder.
 Narcoleptic subject with negative PSG findings and positive MSLT [mean sleep latency <
8 minutes and 2 or more Sleep Onset REM Periods (SOREMPs), or a history of recurrent
lapses into daytime sleep almost daily for 3 months or longer and cataplexy] and negative
findings for another sleep disorder.
5. Absence of any medical or psychiatric disorder that could account for the symptoms.
6. Negative for another chronic disease (e.g., hypertension, chronic obstructive pulmonary disease or
coronary heart disease) that is in obvious organ failure or at an uncompensated stage.
7. If a Type II (non-insulin dependent) diabetic, have an A1C level  9 %, and no evidence of retinopathy
on fundoscopic examination [Type I diabetics are excluded].
Narcoleptic subjects
Additional inclusion criteria for narcoleptic subjects are as follows:
1. If narcoleptic and female, not be pregnant or lactating, or attempting to become pregnant;
2. If a newly diagnosed narcoleptic, not require the use of REM suppressant antidepressant medications
to control cataplexy or the other REM symptoms. (Previously treated narcoleptics who have been stabilized on an
anticataplectic antidepressant medication may continue on this medication following PSG/MSLT baseline testing.)
b. Source of research material.
Volunteer control subjects will be prescreened with a telephone interview to determine that they meet
selected criteria for participation. Following this interview, control subjects who meet the criteria will be mailed
the Consent for Release of Medical Information form to secure permission to obtain copies of their health records.
If these records confirm that the individual does not have a chronic health problem, the Sleep Disorders
Questionnaire-Short Form (SDQ-SF), a Sleep Log and the Beck Depression Inventory (BDI) will be mailed to
potential control subjects with instructions to return completed questionnaires by mail. After providing informed
consent and completing selected laboratory tests (urine analysis and drug screen, blood chemistry, thyroid-T4,
CBC, and an EKG) eligible control subjects will complete the Current Medications form, the Background
Questionnaire (BQ), and the Epworth Sleepiness Scale, will participate in pupillometry testing and will be seen in
the clinic by physician co-investigators for a history and complete physical exam (results will be documented on
the Medial History and Physical Examination forms). Persons will be disqualified if they have 1) a possible sleep
disorder that was identified with the SDQ, 2) a possible mood difficulty identified with the BDI, 3) a chronic
disease identified with the BQ, the Medical History or the Physical Examination 4) obtain inadequate sleep
documented on the Sleep Log, 5) have an elevated papillary unrest index on pupillometry and/or 6) participate in
recreational drug use identified with the urine drug screen. Following a routine history and physical examination,
controls subjects will complete another sleep log for 7 days prior to polysomnography (PSG). After their admission
to the Sleep Center, another urine drug screen is conducted. Pupillometry, the Multiple Sleep Latency Test
(MSLT) and a psychomotor vigilance task are completed the day following the PSG sleep study. The remaining
questionnaires [the Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FSOQ), the
Pittsburgh Sleep Quality Index (PSQI) and the Profile of Mood States (POMS)] will be completed between
pupillometry and the MSLT. The order in which the questionnaires are completed between the pupillometry and
MSLT testing periods are varied.
For OSA and narcolepsy subjects the order and approximate time of measure administration are outlined
below in Table 3. Previously diagnosed sleep disorder subjects are asked to sign a consent for release of their
previous sleep/nap studies and pertinent medical records. Results of the studies are reviewed to insure that the
sleep disorder subjects met the International Classification of Sleep Disorders criteria for the pertinent disorder at
the time of initial diagnosis.
8
Table 3. Schedule of Procedures and Data Collection for OSA and Narcolepsy Subjects
Obstructive Sleep Apnea Subjects
Narcolepsy Subjects
A. Screening
A. Screening
Telephone interview of volunteers
Telephone interview of volunteers
Consent for Release of Medical Records
Consent for Release of Medical Records
Completion of mailed Beck Depression
Completion of mailed BDI
Inventory (BDI)
B. Pre-Baseline testing clinic visit
B. Pre-Baseline testing clinic visit
Informed Consent signed
Informed Consent signed
Current Medications form
Current Medications form
Complete Background Quest. (BQ-SF) and Sleep
Complete BQ and SDQ-SF
Disorders Quest. (SDQ-SF)
Hemoglobin A1C level if adult onset diabetic
Hemoglobin A1C level if adult onset diabetic
History and complete physical exam;
History and complete physical exam;
completion of the Medical History and
completion of the Medical History and
Physical Examination forms
Physical Examination forms
Urine drug screen, Sleep Log
Urine drug screen, Sleep Log
C. Sleep Center (split night study)
PSG with 4-6 hrs of continuous positive airway pressure
titration (CPAP), OSA & CPAP education
D. Sleep Center Baseline Testing
C. Sleep Center Baseline Testing
Urine drug screen
Urine drug screen
Polysomnography (PSG)
PSG
Current Medications form
Current Medications form
24 Hour History questionnaire
24 Hour History questionnaire
Multiple Sleep Latency Test (MSLT)
MSLT
Pupillometry & Sleepiness Visual Analog Scale (VAS)
Pupillometry & VAS
Psychomotor Vigilance Task (PVT)
PVT
Questionnaire assessment (1)
Questionnaire assessment (1)
OSA education
Narcolepsy education
Instruct about Medication Event Monitoring Cap
(MEMS) placement on medication vial and pill
counts documented on Narcolepsy Medication
Account
Patient Medication Diary Card – distribute and
instruct about use
Modafinil, sodium oxybate dispensed; methylphenidate or
dextroamphetamine, and antidepressant prescription
given to subject
E. Sleep Center (if not previously done as above)
D. Telephone follow up (1- 2 wks)
PSG with continuous positive airway pressure
Monitor treatment response, adjust mediation
titration (CPAP), OSA & CPAP education
prescription, reinforce education, Subject Contact
form
E. Posttreatment clinic visit (1 month after treatment
initiation)
(2)
F. CPAP Care
Brief examination, monitor response & education,
CPAP setup with education about machine
pupillometry & VAS, Epworth Sleepiness Scale,
monitor for treatment adherence
collect and redistribute Patient Medication Diary
follow up if necessary
Card, MEMS cap adherence data download and
reissue new cap if necessary; dispense modafinil or
sodium oxybate or new Rx for methylphenidate, or
dextroamphetamine and antidepressant complete
Narcolepsy Medication Accountability form
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G. Telephone follow up (2wks)
Monitor treatment response, reinforce education,
Subject Contact form
F. Sleep Center (3 mos posttreatment)
Beck Depression Inventory, urine drug screen, Sleep
Log, Current Medication form, 24 Hour History,
Posttreatment Background Questionnaire, PSG,
MSLT with concurrent Omni actigraph placement,
pupillometry & VAS, PVT, questionnaire
assessment(1) and adherence data collection (MEMS
cap download, Patient Medication Diary Card,
Narcolepsy Medication Accountability form)
H. Sleep Center (1 month post CPAP use)
G. Posttreatment clinic visit
Beck Depression Inventory, urine drug screen, Sleep
Brief examination, monitor response & education
Log, Current Medication Form, 24 Hour History,
Posttreatment Background Questionnaire, PSG,
MSLT with concurrent Omni actigraph placement,
pupillometry & VAS, PVT, questionnaire
assessment(1) and adherence data collection (download
CPAP utilization data from machine monitor)
I. Posttreatment clinic visit
Brief examination, monitor response & education
(1)
Questionnaires include: Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Profile of
Mood States, Functional Outcomes of Sleep Questionnaire - completed between pupillometry and
MSLT procedures with order varied.
(2)
CPAP set up is being provided by Health Management Inc, an agency with which the UICMC Sleep Center has
contracted for this care.
c. Recruitment of subjects. The University of Illinois Medical Center (UICMC) is a major tertiary facility that is
located in an urban inner-city environment, and serves a largely medically underserved, minority population. The
1990 U.S. census data indicate that the population of the Chicago metropolitan region is 65% white and 35% nonwhite. The Sleep Disorders and Research Center at UIH is located in the UICMC, about a 1-2 block walk from the
Colleges of Nursing and Medicine. OSA and narcolepsy subjects will be recruited from the pool of subjects
referred to the sleep center for diagnosis of these disorders as well as advertisements placed in regional editions of
the local and regional newspapers. The sleep center conducts about 850 sleep studies a year with adults. About 500
are diagnosed with OSA; of these, about 70% are from minority groups and 47 % of the newly diagnosed OSA
patients were female in 1998. Additionally, OSA and narcolepsy subjects are being recruited 1) from the research
subject registry maintained by the Center for Narcolepsy Research (N=~300); 2) through the WWW homepage that
has been maintained by the Center for the past 8 years (we receive about 300 hits per month on our homepage); 3)
from contacts with Narcoleptics and Partners, a support group sponsored and coordinated by the narcolepsy center;
and 4) through networking relationships maintained with sleep centers (N=24) located throughout the Chicago
metropolitan area. Control subjects are being recruited from university employees (N=9500) and students
(N=15000) and relatives and friends of OSA and narcoleptic subjects as well as newspaper advertisements and
announcements on the University of Illinois intranet that encompasses the three campuses.
Potential subjects will be contacted by mailing flyers, by telephone calls received in response to flyer
mailings and advertisements, and by personal contact during clinic visits by the co-investigators. Procedures of the
study will be described, and the project staff will verify (by querying the subject on items in the inclusion and
exclusion criteria) that the potential subject is eligible for the study. For all subject groups, project staff will verify
that the person agrees to sign a consent form for release of their prior clinic and sleep study information to the
CNR. If the subject is willing and a consent form is signed, an appointment for the initial clinic, and day of sleep
center project testing will be made. In all recruitment, the voluntary nature of participation will be emphasized.
Staff involved in this project have worked together in past projects with control, OSA and narcolepsy subjects.
We are familiar with helping subjects experiencing pathologic EDS feel positive about their contribution to
advancing scientific knowledge.
Potential subjects sign and return a consent for release of their prior medical information by mail. They
sign a consent for participation in this study at the time of their clinic (first) visit to UICMC. The form is
10
presented and read with the potential subject at the beginning of the clinic visit by the PI, one of the coInvestigators or the project coordinator. Since people with sleep disorders often have questions about their
treatment in addition to questions about the project, patient education often takes place at this time as well as while
various phases of the project are completed.
d. Potential risks/alternative treatments.
Previously diagnosed narcoleptics who taper and then discontinue their wake promoting and/or anticataplectic medications for the 2 weeks prior to their first series of PSG and MSLT studies will be advised not to
drive, or participate in work or recreational activities during which their safety could be compromised because of
return of narcolepsy symptoms.
Urine drug screen results will be returned to Dr. Sharon Merritt. Drs. Olopade, Lloyd, Vern and the project
coordinator, Mr. Fred Meyer, will be told about the results. The written results will be placed in a locked file
cabinet. Drs. Merritt and Lloyd and the project coordinator have access to a key to the cabinet. While it is highly
unlikely that anyone but the people named above will have access to the drug screen results, a break in secrecy
could occur even with these safety measures. A positive urine drug screen [the presence in the urine of illegal
drugs, or drugs that have not been prescribed by a health care provider] could become known to people other than
those listed above. This loss of secrecy could have unplanned negative effects if people or groups the subject did
not want to know about the results became aware of them. We have been conducting UDS in the center since 1994
and to date have only had 2 subjects who needed to be excluded because of their use of illicit substances.
There are no known serious risks associated with the other testing and sleep disorders treatment that could
occur as a result of participation in this study. For pupillometry, the subject is sitting in the dark in a large
comfortable chair fixating on a light stimulus while the diameter of the pupil is measured 60 times/sec with
infrared sensitive video cameras.
The PSG units are FDA approved and do not involve any electrical hazard; contact with the subject is via small
electrodes.
Control subjects and sleep disorder subjects who are diabetic may experience some temporary discomfort when
their blood is drawn. If abnormal clinical test results are detected, subjects will be informed about the findings and
referred to their primary health care provider, or a resource at the University of Illinois Medical Center if desired.
Completion of some of the testing procedures and questionnaires could cause subjects to become mildly
anxious if they perceive that the findings might indicate some abnormality. Subjects will be encouraged to ask
questions and be counseled about findings at the end of the testing procedures during a debriefing session if
desired.
For OSA, CPAP treatment is the most effective approach and has no known serious risk. Some people may
experience nasal irritation and stuffiness, inconvenience, or a feeling of being closed in when they begin using
CPAP treatment.
Some people with narcolepsy may not reach the desired level for controlling their EDS with the medications
that will be used. Additionally, they may experience side effects, the most common being irritability, headache
and nervousness. At the conclusion of this study, they will be offered the opportunity to try another wake
promoting agent and continue seeing Dr. Vern in clinic visits if desired.
Continuing care with a health care provider is important. OSA and narcolepsy subjects will be advised to
seek continuing care with their primary health care provider upon completion of this study, or may be followed by
the University of Illinois Sleep Center or Neurology for their sleep disorder if desired.
The alternative available to subject is not to participate in this study. A previously undetected health
problem could be found in control subjects. Sleep disorder subjects may benefit from the usual care they receive
for their disorder.
Pupillometry and other sleepiness measurement procedures as well as the questionnaire assessments are not
involved in the subjects’ medical care and are not intended to benefit the personal health of subjects.
e. Procedures for minimizing risk.
Procedures in this research will be conducted by the co-investigators, project staff, and sleep center and
home care staff who have been trained and are experienced in conducting them. Clinical lab tests (blood draw) and
the EKG will be conducted by trained UICMC staff. Pupillometry is a non-invasive video-based method for
recording pupil diameter. There are no known risks of an accident or complication related to this procedure.
Copies of previous medical records and clinical testing results will be returned to the PI. All results with
identifying information (i.e., subject name) will be kept in a locked file cabinet in the Center for Narcolepsy
11
Research. Only the PI and CNR co-investigators will have access to a key to the cabinet. Data needed for analyses
(e.g., sleep and nap study results) will be identified by subject number only.
Narcoleptic subjects who discontinue their medication will be advised not to drive, or participate in work
or recreational activities during which their safety could be compromised because of return of narcolepsy
symptoms.
Potential subjects will be advised that urine drug screening will take place and that, even though results
with identifying information will be kept in a locked cabinet, a breach in security could occur. Urine drug screen
results will not be input into computerized databases. People who believe they will have a positive result may
choose to not participate.
Control and sleep disorders subjects will be informed about abnormal lab test findings and referred for
follow up care to their primary health care provider, or a resource at the University of Illinois Medical Center if
desired.
Since subjects could be concerned about other procedure and questionnaire findings, they will be
encouraged to ask questions and be counseled about findings at the end of the testing procedures during a
debriefing session if desired. Subjects will also be advised that they do not have to complete any questionnaire
items that make them feel anxious, or they feel are unacceptably intrusive. They and/or their usual health care
provider are provided with a copy of their sleep and nap study and lab/EKG findings if they sign a reverse consent
for release of medical information,.
OSA subjects on CPAP will be advised that the initial discomfort associated with its use tends to dissipate
over time. As part of the setup the home care agency routinely provides information about how to deal with the
discomforts, e.g., nasal stuffiness. People with OSA who experience moderate to severe excessive daytime
sleepiness are often willing to put up with these discomforts because their sleepiness and quality of life are
significantly improved as a result of CPAP use.
At the conclusion of this study, people with narcolepsy who are dissatisfied with their medications will be
offered the opportunity to try another wake promoting agent and continue seeing Dr. Vern in clinic visits if desired.
Since continuing care is important, OSA and narcolepsy subjects will be advised to seek ongoing care with
their primary health care provider upon completion of this study, or may be followed by the University of Illinois
Sleep Center or Neurology for their sleep disorder if desired.
Discontinuing medication, and urine drug screening are important because the presence of substances that
affect sleep and wakefulness could invalidate test results.
Health screening testing of normal control subjects is necessary to establish that these participants do not
have an unapparent health problem.
Completion of the Sleep Disorders Questionnaire and the Beck Depression Inventory is necessary to rule out
the presence of a health problem that could cause significant sleepiness (or contribute to the sleepiness experienced
by the sleep disorder subjects). For example, people who are depressed or have a psychiatric disturbance often
experience significant sleep problems that cause excessive sleepiness.
Excessive daytime sleepiness in people with OSA and narcolepsy can be very disabling and threaten their
ability to hold a job, attend school or conduct their other usual activities of daily living. Even when the usual
treatment is annoying and inconvenient, many people with these disorders find that the relief from daytime
sleepiness they experience offsets these side effects.
Pupillometry has the potential for becoming a reliable and efficient technique for measuring sleepiness.
This proposal provides a means for comparing the effectiveness of pupillometry in measuring sleepiness to other
physiologic measures that are invasive, inconvenient and expensive to administer. Findings could confirm
pupillometry as an effective measure of sleepiness that is more convenient and affordable. This technique would
provide an alternative method for objectively measuring sleepiness and become a basis for improving treatment for
people with OSA and narcolepsy.
7. Proposed Study Visit Schedule
This information has been integrated into 6. Human Subjects Considerations, b. Source of research
material (see above).
12
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9. Subject Selection by gender, age and ethnicity/race.
(see Tables on pages 6 & 7 of application form for subjects by gender and ethnicity/race who have
participated to date)
We anticipated collecting data from 64 males and 54 females as outlined below:
OSA subjects: 21 M, 11 F -- less female OSA subjects are likely to be recruited since the U.S. prevalence is
estimated at 4% in M and 2% in F.
Narcolepsy subjects: 18 M, 18 F
Control subjects: 25 M, 25 F. Desired minimum numbers of subjects are as follows: ages 20-29, 5 M and 5 F;
30-39, 5 M and 5 F; 40-49, 5 M and 5 F; 50-60, 5 M and 5 F.
We have had difficulty attracting African American (AA) subjects to this study. In Winter/Spring, 2003,
we placed media ads in the Defender, Indigo, and the Hyde Park Harold in an attempt to attract more AA subjects.
We have also asked AA subjects who have participated to assist us with recruitment. The participation of Hispanic
individuals is also somewhat limited. We do not place any restrictions in this regard and are unaware of the
15
ethnicity/race of volunteers until they come for their clinic visit unless this information is offered unsolicited by
the volunteer.
In terms of controls the subject groups are balanced by age and gender because we will be gathering the
first data (that we are aware of) about normal pupil behavior that are collected under carefully controlled
situations, e.g., time of day is consistent, the prior sleep/wake cycle is carefully documented, subjects are
determined to be alert, etc.
Children below the age of 20 are not included in the control group because of the paucity of information
available in published literature about the pupil behavior of younger individuals in both alert and sleepiness states.
16