Sodium Oxybate for the Treatment of Vigilance Impairment in Narcolepsy

Narcolepsy is a sleep-wake disorder characterized by excessive daytime
sleepiness (EDS, tendency to fall asleep), disturbed night sleep, and rapid eye
movement (REM) sleep-associated symptoms, such as hypnagogic hallucinations,
sleep paralysis and cataplexy [AASM 2005, Bassetti and Aldrich 1996]. Cataplexy
is a sudden bilateral loss of muscle tone provoked by strong emotions. The
presence of EDS is mandatory for the diagnosis of narcolepsy. Impaired
vigilance is an additional largely neglected symptom of narcolepsy that is
directly related to reduced daytime performance and quality of life [Valley et
al. 1981].

The Multiple Sleep Latency Tests (MSLT) and the Maintenance of Wakefulness Test
(MWT) are the most common (however, cumbersome and not very specific)
electrophysiological tests for the diagnosis of narcolepsy. The MSLT entails
the measurement of sleep latency at five different times on one day while
subjects are lying in bed in a quiet, dark room and asked to try to fall
asleep. The MSLT thus assesses sleepiness. The MWT follows a similar schema,
but subjects are requested to try to stay awake instead of trying to fall
asleep. The MWT thus assesses the ability to remain awake. Vigilance
impairment, on the other side, has been under valuated in the assessment of
narcolepsy.

Recent studies suggest specific outcome measures (Sustained Attention to
Response Task, SART; Psychomotor Vigilance Task, PVT) for vigilance assessment
in narcolepsy [Fronczek et al. 2006, Khatami et al. submitted]. The SART and
PVT are both tasks that assess vigilance by recording the subject*s responses
to stimuli that are presented on a computer screen.

Sodium oxybate is a strong hypnotic that is effective in the treatment of EDS,
disturbed night sleep, and cataplexy in narcolepsy [US Xyrem Multicenter Study
Group 2002]. However, treatment effects on vigilance have not been evaluated
thus far. In a recent study, changes in quality of life following the
administration of sodium oxybate were measured with the Functional Outcomes of
Sleep Questionnaire [Weaver 2006]. The nightly administration of sodium oxybate
produced signi*cant dose-related improvements in the Total Functional Outcomes
of Sleep Questionnaire score, as well as in the Activity Level, General
Productivity, Vigilance, and Social Outcomes subscales. Thus, the nocturnal
administration of sodium oxybate in patients with narcolepsy was associated
with statistically signi*cant and clinically relevant improvements in
functional status, an important component of quality of life. Objective tests
to measure vigilance, however, have not been applied.

An actigraph is a wrist-worn device that uses an accelerometer to measure
motion. Sleep/inactivity and activity levels can thus be recorded with the
extra help of sleep logs.

In this protocol, feasibility of measuring vigilance on seven days using
portable versions of the PVT and the SART that can be administered while
subjects are outside the hospital during normal daily, will be assessed in
healthy controls and in narcoleptic patients. To objectively assess the effect
of sodium oxybate, performance on this task battery will be compared before and
after treatment in narcoleptic patients.

Optional Part 1:
In the field of sleep research, the relationship between skin temperature and
sleep has recently received attention. Earlier laboratory studies with
predefined sleep moments, showed a correlation between sleep latency and
minimal changes in skin temperature. Healthy subjects whose distal skin
temperature was relatively high compared to their proximal skin temperature,
fell asleep faster (*warm hands and feet*). The distal-to-proximal gradient
(DPG) is a measure for this thermoregulatory profile. A higher DPG is
associated with a shorter sleep latency.

In a previous study we showed that the thermoregulatory profile of narcoleptic
patients is continuously in a mode that is associated with sleep in healthy
subjects, a *sleepy mode* (Fronczek et al, Sleep 2006). Moreover, specific
manipulations of distal and proximal skin temperature and core body temperature
can influence sleep latency, vigilance and nocturnal sleep (Fronczek et al,
submitted). Measuring skin temperature in relationship to treatment efficacy
may lead to new pathofysiological insights and a new way to measure sleepiness
in narcolepsy.

In this new protocol we will study skin- and core body temperature in a
non-clinical setting without fixed sleep moments. Thermoregulatory profiles and
sleep-depth will be measured in both patients and controls for 24 hours.

Optional Part 2:
The OSLER test utilizes a computerized, non-assisted method for monitoring
wakefulness and detecting sleep onset. The basic setting for the OSLER test is
the same as for the MWT (dark room, patient sitting on the bed). The patient's
dominant hand is placed on a box held in the lap. The index finger is
positioned on a non-recoil proximity sensor, with a sensing distance of 1-2 mm,
transmitting finger contact to a computer. A light emitting diode (LED) is
positioned 4 feet away at eye level in the frontal visual field. The light
flashes regularly for 1 s every 3 s. Both the LED and hand device are connected
to a personal computer located in the adjacent control room, which records the
response data. The specific instructions given to each subject before the Osler
test are to stay in contact with the finger to the button, and to remove the
finger for 1 second when the red light flashes. The OSLER algorithm defines
sleep onset when there is no response to seven consecutive flashes (>=18 s).
Test ends after sleep onset or after 40 min if no sleep occurs.

Core:

1. Quantify vigilance using a portable task battery three times daily during 7
days while subjects are outside the hospital
1.1 Comparing narcoleptic patients to controls
1.2 Comparing narcoleptic patients before and after treatment with
sodium oxybate
2. Quantify activity levels using Actigraphy during 14 days while subjects are
outside the hospital
2.1 Comparing narcoleptic patients to controls
2.2 Comparing narcoleptic patients before and after treatment with
sodium oxybate

Optional Part 1:
1. Quantify distal and proximal skin and core body temperature using iButtons
and a wireless core body temperature pill system while subjects are outside the
hospital
1.1 Comparing narcoleptic patients to controls
1.2 Correlating thermoregulatory profiles to sleep attacks


Optional Part 2:
1. Quantifying OSLER sleep latency in narcoleptic patients versus controls
2. Exploring the effects of treatment with sodium oxybate on OSLER sleep
latency.

Core:
The duration of this project will be 1.5 years. First subjects can be included
in June 2007.

Treatment-naïve patients and healthy subjects will first be asked to wear an
actigraph (appendix D) for 14 days. During this time, subjects are asked to log
bedtimes. After these two weeks, subjects will visit the hospital, where the
MWT (appendix D) will be performed. This will take a full day. On that day,
both the PVT and the SART (see appendix D) will be practised. After this,
subjects will take home a pocket-size PDA (personal digital assistant) computer
that can administer the SART, PVT and the Stanford Sleepiness Scale (Appendix
D). Subjects will take this PDA with them wherever they go during the next
seven days. Daily, the device can only be turned on during 1-hour-intervals
around 10:00 hr, 15:00 hr and 20.00 hr (that is: from 09.30 to 10.30 hr,
a.s.f.). The contents of this 15-minute task battery will be described in
appendix D.

Control subjects will only follow this procedure once. Narcoleptic patients
will follow this procedure before and three months after stable treatment with
the normal therapeutic dose of sodium oxybate (4,5 - 9,0 g / day). All
narcoleptic patients that participate in this study will thus be treated with
sodium oxybate (as was already their treatment plan).

Optional Part 1:
Subjects will wear the following sensors for 24 hours. All sensors will be
attached in the LUMC at 16.00 hrs on day one, and removed on at 16.00 hrs on
day 2:

- Ibuttons
16x6 mm2 large, battery shaped devices that can store temperature information
for 24 hours internally. They will be attached on ten different skin locations:
both hands, both feet, stomach, midtigh, infraclavicularly and both ears.
- Core Body Temperature sensor
Core body temperature will be measured using a wireless temperature pill. This
is a new, patient friendely method for which no rectal probe is needed. The
pill can be used only once en van be swallowed just like any ordinary pill The
device emits a temperature signal that can be received by a small box that test
subjects can wear using a belt.
- Standard Sleep Polysomnography (PSG)
Using electrodes on the head, breast, next to the eyes and on the chin. Sleep
stages will be scored by a skilled lab technician.

Test subjects are requested to go to sleep and wake up at their normal bedtime.
Possible sleep attacks in narcoleptic patient will be logged in a diary.

Optional Part 2:
In addition to the core protocol described above, subjects will have to visit
the hospital for one full extra day after the MWT day. On that day the OSLER
will be performed.

Core:
Participation in this protocol will not harm patients or controls in any way.
Narcoleptic patients who have to stop sodium oxybate can experience a slow
return of their complaints. This will be evaluated and discussed with their
physician. Participant will receive a gift cheque of ¤50 for each PDA test week
(so narcoleptic patients will receive ¤100).

Optional Part 1:
Participation in this protocol will cost 24 hours and two hospital visits, but
will not harm patients or controls in any way. Narcoleptic patients that have
to stop sodium oxybate can experience a slow return of their complaints. This
will be evaluated and discussed with their physician. Participant will receive
a gift cheque of ¤75.

Optional Part 2:
Participation in this optional part of the protocol will not harm patients or
controls in any way. Narcoleptic patients that have to stop sodium oxybate can
experience a slow return of their complaints. This will be evaluated and
discussed with their physician. Participant will receive a extra gift cheque of
¤50.