CPAP to Treat Cognitive Dysfunction in MS

Up to 70% of patients with MS suffer from cognitive dysfunction (difficulties with thinking,
information processing, verbal expression, or memory). Cognitive dysfunction is one of the
most disabling symptoms of MS, that can profoundly affect job performance, family
responsibilities, and quality of life. While no treatments have been shown to improve
cognitive dysfunction in MS, many patients have not been evaluated or treated for other
common health problems that could be contributing to their cognitive dysfunction.

Up to 50% of MS patients also suffer from obstructive sleep apnea (OSA). Obstructive sleep
apnea is a common disorder in which the upper airway collapses during sleep, causing poor
sleep quality and decreased oxygen levels in the blood. In patients without MS, OSA is a
well-established cause of poor cognitive performance. Recent studies of non-MS patients also
suggest that cognitive performance may improve with OSA treatment. Yet, despite the high
number of MS patients with OSA, the relationship between OSA and cognitive performance, and
the effects of OSA treatment on cognitive performance in MS, has not received sufficient
study.

The objectives of this study are to determine the effects of obstructive sleep apnea (OSA) on
cognitive function in patients with multiple sclerosis (MS); and to evaluate whether OSA
treatment with positive airway pressure therapy could improve cognitive dysfunction in MS
patients who also have OSA.

Interested participants with MS who screen positive on a commonly used screening tool used to
detect those at high risk for OSA will be invited to participate. Consenting participants
will have a baseline cognitive (memory and thinking) test to assess their cognitive function,
and an overnight sleep study (polysomnogram, or PSG) to determine if they have obstructive
sleep apnea. If the sleep study shows signs of sleep apnea, participants will be assigned
treatment for their sleep apnea with positive airway pressure (PAP) therapy, either
immediately (Group 1), or 3 months after the baseline sleep study (Group 2). Groups will be
assigned at random (like flipping a coin). There is a 2/3 chance that participants will be
assigned to Group 1. PAP therapy is considered standard clinical care for OSA. It involves
wearing an apparatus that includes a hose and a mask (that covers the nose, or nose and
mouth), connected to a small machine that blows air into the airway during sleep. In order to
determine which airway pressure most effectively treats an individual's sleep apnea, and what
type of mask is needed, a separate sleep study known as an overnight "PAP titration study"
will also be performed. This study is similar to a PSG but also involves fitting of various
masks which are then hooked up to the individual and PAP machine to test the effectiveness of
various PAP settings, and to determine which mask is most tolerable for the individual.

Participants will also receive repeat cognitive testing at 3 months to see if the immediate
sleep apnea treatment group (Group 1) shows improvements memory and thinking, as compared to
the standard care treatment group (Group 2), who will not start apnea treatment until after
their repeat cognitive test. Participants will be compensated for their travel and time
throughout the course of the study.

Inclusion Criteria

1. Age of 18-70 years at screening

2. Diagnosis of clinically definite MS

3. Willingness to undergo in-lab baseline polysomnography (PSG) and positive airway
pressure (PAP) titration (if needed)

4. Willingness to undergo 2 separate 90-minute cognitive testing sessions

5. Either one of the following:

Score of >=2 sleep apnea risk factors on the "STOP-Bang" sleep apnea screening
questionnaire. The STOP-Bang questionnaire is a screening tool consisting of eight
items which reflect OSA risk factors. STOP-Bang scores of ≥3 indicate elevated risk
for moderate-severe OSA in the general population, and scores as low as 2 are
frequently seen in MS patients with OSA, based on previous data from the PI).

OR

Have a pre-existing diagnosis of OSA based on a previous overnight sleep study (either
home study or in-lab) but have not yet started using PAP therapy on a compliant basis.
*If OSA was NOT diagnosed by a U-M in-lab sleep study within the past year prior to
screening, subjects must be willing to get new baseline in-lab U-M PSG as part of
study.

6. Willingness to start treatment with PAP if OSA present

Exclusion Criteria

1. Physical, psychiatric or cognitive impairment that prevents informed consent, PSG, PAP
use, or reliable longitudinal follow-up

2. Cardiopulmonary conditions that may increase sleep apnea risk

3. Current treatment, such as PAP, for obstructive or central sleep apnea

4. History of surgical treatment for OSA

5. Nervous system diseases other than MS that may predispose subjects to OSA (such as
Parkinson's disease, amyotrophic lateral sclerosis, or recent stroke)

6. History of concomitant central nervous system disease that could influence cognition,
such as large vessel territory stroke, Alzheimer's disease, Parkinson's disease, or
Lewy body dementia

7. Concomitant systemic autoimmune disease with secondary central nervous system
involvement (including CNS lupus or neurosarcoidosis).

8. Pregnancy

9. Evidence of clinical MS relapse within the last 30 days prior to enrollment

10. Systemic high dose steroid use (1 gram IV methylprednisolone daily for 3-5 days or
equivalent)for an MS relapse within the last 30 days prior to enrollment

11. Unwillingness to initiate PAP therapy if clinically indicated

12. Severe depression at screening per the Patient Health Questionnaire-8 (PHQ-8) (The
PHQ-8 is a brief, self-administered questionnaire that evaluates core symptoms
associated with major depressive disorder. Scores range from 0 to 24 based on the
frequency and severity of depressive symptoms over the previous two weeks.)

13. Anticipated initiation, dosage change, or discontinuation in medications that could,
per the opinion of the investigators, influence cognitive test scores from baseline to
follow-up, including MS disease modifying therapies, hypnotic agents, narcotic-based
medications, benzodiazepines, antispasmodics, or 4-aminopyridine

14. ESS scores >= 16 on baseline visit

15. Subjects with extreme OSA accompanied by signs of cardiopulmonary compromise (RDI>60
respiratory events per hour with severe nocturnal hypoxia or unstable ECG rhythms on
PSG), will be excluded unless they are randomized to immediate PAP arm

16. Any other condition or treatment that in the opinion of the investigator could affect
subject safety or study eligibility