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Awake and Involved II: Addressing Excessive Daytime Sleepiness and Fatigue in Neurologic Disorders. Excessive Daytime Sleepiness vs Fatigue. Excessive Daytime Sleepiness (EDS): the inability to remain fully alert or awake during the wakefulness portion of the sleep/wake cycle

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Awake and involved ii addressing excessive daytime sleepiness and fatigue in neurologic disorders l.jpg

Awake and Involved II:

Addressing Excessive Daytime Sleepiness and Fatigue in Neurologic Disorders


Excessive daytime sleepiness vs fatigue l.jpg
Excessive Daytime Sleepinessvs Fatigue

  • Excessive Daytime Sleepiness (EDS): the inability to remain fully alert or awake during the wakefulness portion of the sleep/wake cycle

  • Fatigue: a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities1

1. Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. Washington, DC: Paralyzed Veterans of America, 1998.


Consequences of eds and fatigue l.jpg
Consequences of EDS and Fatigue

  • Interferes with social interactions

  • Impairs work performance

  • Causes loss of independence

  • Results in depression

  • Influences tolerance to medications

  • Increases risk of accidents (motor vehicle, industrial, home)


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Clinical Evaluation of EDS and Fatigue

  • Detailed sleep/wake history

  • Use subjective questionnaires

    • Epworth Sleepiness Scale (ESS)

    • Stanford Sleepiness Scale (SSS)

    • Sleep diaries

  • Consider referral to sleep specialist

    • Polysomnography

    • Multiple Sleep Latency Test (MSLT)

    • Maintenance of Wakefulness Test (MWT)


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Epworth Sleepiness Scale (ESS)

0 = would never doze 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing

Johns MW. Sleep. 1991;14:540.


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Objective Tests

  • Multiple Sleep Latency Test (MSLT)

    • Measures patient’s tendency to fall asleep

    • Assesses patient’s ability to fall asleep when lying down in a dark room without stimuli

  • Maintenance of Wakefulness Test (MWT)

    • Measures patient’s ability to remain awake

    • Assesses ability to remain awake when semi-reclining in a dimly lit room

  • Both are 20-minute tests performed 4 times a day at 2-hour intervals beginning approximately 2 hours after nocturnal polysomnography is completed


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Measures of Fatigue

  • Self-reported1

    • Fatigue Severity Scale (FSS)2

    • Fatigue Impact Scale (FIS)

      • Modified Fatigue Impact Scale (MFIS)

    • Visual Analog Scale for Fatigue (VAS-F)

  • Performance-based1

    • Measure changes in motor or cognitive functioning

1. Krupp LB. CNS Drugs. 2003;225. 2. Krupp LB, LaRocca NG, et al. Arch Neurol. 1989;46:112.


Central nervous system disorders that can cause sleepiness or fatigue l.jpg

Parkinson’s disease

Myotonic dystrophy

Multiple sclerosis

Dementia

Amyotrophic lateral sclerosis

Intracerebral tumors

Cerebrovascular disease

Head trauma

Narcolepsy, restless legs syndrome

Central Nervous System Disorders that can Cause Sleepiness or Fatigue


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Sleep/Wake Abnormalities in PD

  • It was reported in 1999 that patients with PD would fall asleep without warning1

  • Since then, it has been shown that patients with PD have a background level of sleepiness2-6

  • Patients with PD have sudden, irresistible bouts of sleepiness (sleep attacks)4-6

  • EDS is more frequent in PD patients than healthy controls4

1. Frucht S, et al. Neurology. 1999;52:1908.

2. Tandberg E, et al. Mov Disord. 1998;13:895.

3. Lees AJ, et al. Clin Neuropharmacol. 1988;11:512. 4. Tandberg E, et al. Mov Disord. 1999;14:922.

5. Ondo WG, et al. Neurology. 2001;57:1392. 6. Hobson DE, et al. JAMA. 2002;287:455.


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Sleep and Parkinson’s Disease1

PD Sleep Parameter Controls (n = 10) Patients (n = 10)

Time in bed (min) 482.8 ± 3.1 475.1 ± 10.0

Total sleep time (min) 382.2 ± 38.3 307.6 ± 82.21

Sleep efficiency (%) 83.1 ± 7.8 72.1 ± 17.0*

No. of awakenings 13.6 ± 3.8 25.9 ± 10.6*

Wake time (% SPT) 18.3 ± 8.3 34.0 ± 15.1*

No difference between groups in sleep onset latency, REM latency, stage 1 or 2, SWS, or REM.

*Significantly different from control at P < .05

1. Wetter TC, et al. Sleep. 2000;23:361.


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Sleep Attacks

  • In 1999, it was reported that patients with PD would fall asleep suddenly and without warning1

  • Since that time, it has become recognized that patients with PD have a background level of sleepiness2

  • At times, patients with PD may have sudden onset of irresistible sleepiness (sleep attack)

  • EDS doesn’t need to include sleep attacks to be dangerous; some patients with sleep attacks are not aware of their EDS

1. Frucht S, et al. Neurology. 1999;52:1908. 2. Roth T, et al. Sleep Med. 2003;4:275.


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Causes of EDS in PD

  • Sleep disturbances

  • Medications

  • PD pathophysiology

  • Concurrent medical illness


Causes of eds in pd sleep disturbances l.jpg
Causes of EDS in PD:Sleep Disturbances

  • PD motor symptoms

  • Depression/psychosis

  • Dementia

  • Nocturia

  • Hallucinations/nightmares

  • Medications that can disrupt nocturnal sleep: dopamine agonists, antidepressants, etc


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Causes of EDS in PD:Sleep Disturbances (cont’d)

  • Insomnia

  • Circadian disruption

  • Sleep apnea

  • RLS/PLMD

  • REM sleep behavior disorder

  • Disrupted nocturnal sleep


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Causes of EDS in PD: Other Medications

  • Benzodiazepines

  • Hypnotics

  • Tricyclic antidepressants

  • SSRIs

  • Antipsychotics

  • Narcotics

  • Antihistamines


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Treating EDS in PD

  • Encourage good sleep hygiene

  • Treat underlying sleep disorders

  • Assess PD medication use

  • Withdraw daytime sedative medications

  • Consider treating EDS with medications

    (eg, modafinil vs stimulants)

  • Treat nocturia


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Sleep Hygiene

  • Maintain regular and appropriate sleep and wake times

  • Regulate amount of time in bed

  • Seek maximum light exposure during the daytime and minimize light exposure during the nighttime

  • Maximize daytime activities

  • Minimize late-day caffeine, nicotine, alcohol intake

  • Reduce length of daytime naps


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Sleep-Promoting Medications

  • Hypnotics

    • Zolpidem, zaleplon

    • Benzodiazepines

  • Antidepressants

    • Amitryptiline

    • Trazodone

  • Antipsychotics

    • Quetiapine


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Use of Stimulants in PD

  • Caffeine

  • Methylphenidate

  • Amphetamine

  • Pemoline


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Modafinil

  • Novel wake-promoting agent

    • Chemically and pharmacologically distinct from the psychostimulants1

    • Does not promote wakefulness via a dopaminergic mechanism1

    • Acts selectively in areas of the brain believed to regulate physiologic sleep and wake states2

  • Proven effective and well tolerated as a first-line therapy for EDS in narcolepsy patients3

  • Peak plasma concentration: 2–4 h, Tmax delayed (~1 h) by food1

1. PROVIGIL Prescribing Information. 2004. 2. Lin JS, et al. Proc Natl Acad Sci USA. 1996;93:14128. 3. US Modafinil in Narcolepsy Multicenter Study Group. Ann Neurol. 1998;43:88.


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Modafinil in PD: Methodology Hogl et al, 2002

  • Single-site, randomized, double-blind, placebo-controlled, 6-wk, crossover study

  • N = 15 (3 noncompleters), 75% male

  • ESS 10. No difference between groups at baseline (placebo: 11.8 ± 3.8; modafinil: 13.2 ± 2.2)

  • 2-wk treatment/2-wk washout with modafinil 100 mg/d x 7 d and 200 mg/d x 7 d, or matched placebo tablets

Hogl B, et al. Sleep. 2002;25:62.


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Modafinil in PD: ResultsHogl et al, 2002

Baseline

Week 2

20

16

12

ESS Scale

8

4

0

Modafinil

Placebo

ESS improved by 3.42 for modafinil compared with 0.83 for placebo (P = .039). No changes in the MWT, sleep logs, or depression scores.

Hogl B, et al. Sleep. 2002.25:905.


Modafinil in pd methodology adler et al 2003 l.jpg
Modafinil in PD: MethodologyAdler et al, 2003

  • Single-site, randomized, double-blind, placebo-controlled, crossover study

  • N = 21 (1 noncompleter), 70% male

  • ESS 10

  • 3-wk treatment/1-wk washout with modafinil 200 mg/d vs placebo

  • There was a washout effect following first treatment period for ESS so compared group 1 with group 2, n = 10 per group

Adler CH,et al. Mov Disord. 2003;18:287.


Modafinil in pd results adler et al 2003 l.jpg
Modafinil in PD: ResultsAdler et al, 2003

Week 3

Baseline

  • ESS improved by 3.4 for modafinil vs worsening by 1.0 for placebo (P = .039)

  • 35% reported improvement with modafinil vs 5% on placebo and 10% on both

20

16

12

ESS Scale

8

4

0

Modafinil(N = 10)

Placebo(N = 10)

Adler CH, et al. Mov Disord. 2003;18:287.


Modafinil in pd l.jpg
Modafinil in PD

  • Adler et al, 20031 (N = 21)

    • No significant effect on parkinsonism

    • Elevated BP (1), hot flashes (1), insomnia (1)

    • No changes in vital signs, EKG, labs

  • Hogl et al, 20022 (N = 15)

    • Effect on parkinsonism not reported

    • Insomnia (1), constipation (1), dizziness (1), diarrhea (2)

1. Adler CH, et al. Mov Disord. 2003;18:287. 2. Hogl B, et al. Sleep. 2002;25:62.


Eds and pd conclusions l.jpg
EDS and PD: Conclusions

  • EDS is common in PD and may be underrecognized

  • Patients should be routinely questioned about EDS and sleep

  • Common causes of EDS include sleep disorders and dopaminergic medications

  • Evaluation must include a detailed sleep and medication history and may include a sleep study

  • Interventions include good sleep hygiene, treating underlying sleep disorders, adjusting medications, and the use of modafinil or other medications that increase wakefulness


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Myotonic Dystrophy (DM1)

  • Commonest form of adult muscular dystrophy (incidence 1:8000)

  • Features

    • Progressive myotonia and muscle weakness

    • Endocrine dysfunction

    • Cataracts

    • Cardiac conduction defects

    • Hypersomnolence

    • Apathy

    • Cognitive impairments

  • Autosomal dominant inheritance

  • Associated with abnormal expansion of CTG repeat in region of protein kinase gene on chromosome 16

MacDonald JR, et al. Neurology. 2002;59:1876.


Eds in dm1 l.jpg
EDS in DM1

  • 1/3 of patients with DM1 have sleep disorders1

  • Hypersomnolence is one of most frequently reported symptoms in DM1

    • Seen in 31%–77% of DM1 patients2,3

  • Weak correlation with degree of muscular impairment4,5

  • EDS not correlated with age, gender, body mass index, age at onset, duration of illness, CTG repeat, apathy4

1. Parkes JD. Sleep and its Disorders. Philadelphia: WB Saunders, 1985. 2. Netherlands Fatigue Research Group. J Neurol Neurosurg Psych. 2003;74:138. 3. Van der Meche GF, et al. J Neurol Neurosurg Psychiatry. 1994;57:626. 4. Laberge L, et al. J Sleep Res. 2004;13:95. 5. Rubinsztein JS, et al. J Neurol Neurosurg Psych. 1998;64:510.


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Pathogenesis of EDS in DM1

  • Pathogenesis unclear

    • May be caused by hypoxia from weakness of respiratory muscles or obstructive sleep apnea

    • May be due to dysfunction of central sleep regulation1

  • Dysfunction of hypothalamic hypocretin system

    • Hypocretin-1 levels found significantly lower in patients vs controls2

  • Sleep apnea not more common in sleepy than nonsleepy patients with DM13

1. Damian MS, et al. Neurology. 2001;56:794. 2. Martinez-Rodriguez JE, et al. Sleep. 2003;26:287. 3. Van der Meche GF, et al. J Neurol Neurosurg Psychiatry. 1994;57:626.


Effect of modafinil on mwt scores in dm1 patients with ess 10 l.jpg
Effect of Modafinil on MWT Scores in DM1 Patients with ESS 10

*

40

MWT Score

30

20

10

0

Placebo

Modafinil

N = 19, modafinil 200 mg, randomized, crossover, double-blind, placebo-controlled, two 4-week periods separated by 2 week washout; *P < .01

Talbot K, et al Neuromusc Disord. 2003;13:357.


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EDS in Myotonic DystrophySummary

  • EDS is one of most frequently reported symptoms in patients with DM1

  • Sleepiness may be attributed to dysfunction of hypothalamic hypocretin system

  • Methylphenidate may improve EDS but use is limited by side effects or tolerance

  • Modafinil has been shown to reduce EDS in DM1 patients


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Fatigue in MS

  • Reported by 75%–97% of patients with MS1-5

  • 66% of 309 patients with MS experienced fatigue daily3

  • Most patients with MS say fatigue is their worst or one of their worst symptoms2

  • Underrecognized and underdiagnosed

1. Krupp LB. CNS Drugs. 2003;225. 2. Fisk JC, et al. Can J Neurol Sci. 1994;21:9. 3. Freal JE, et al. Arch Phys Med Rehabil. 1984;65:135. 4. Krupp LB, et al. Arch Neurol. 1988;45:435. 5. Bergamaschi R, et al. Funct Neurology. 1997;12:247.


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Primary and SecondaryMS Fatigue

  • Secondary

    • Typically resulting from mobility and/or respiratory problems

    • Other potential causes: medical co-morbidities, medications, depression, stress, sleep disruption, environmental conditions

    • Associated with more advanced disability

  • Primary

    • Real entity of MS

    • Diagnosis by exclusion

Multiple Sclerosis Council for Clinical Practice Guidelines, 1998.


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Fatigue in MS: Patient Management Guidelines

  • Management of secondary causes

    • Correct factors that cause or exacerbate fatigue

    • Evaluate with laboratory screen of blood tests

  • Once secondary causes addressed, proceed to treat primary MS Fatigue

    • Nonpharmacologic

    • Pharmacologic

  • Secondary MS fatigue

    • Determine if other MS symptoms contributing to fatigue symptoms

Krupp LB.CNS Drugs. 2003;225.


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Nonpharmacologic Treatment of Fatigue in MS

  • Best evaluated by Occupational Therapy

  • Good sleep hygiene

  • Education and support

  • Energy conservation techniques

    • Exercise: how much is right? What time is best?

  • Avoid factors that exacerbate MS like heat or humidity

  • Behavioral techniques

Krupp LB. CNS Drugs. 2003;17:225.


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Pharmacologic Treatment for Fatigue in MS

  • No drug currently approved by FDA for treatment of MS fatigue

  • Methodologic problems found with all studies

    • Different outcome measures, small numbers, different patient populations

  • Medications used

    • Amantadine

      • In 3 double-blind, placebo-controlled studies, MS fatigue showed some improvement with amantadine1-3

      • Suggested dose: 100 mg BID

    • Pemoline

      • May be effective therapy for people who do not respond to amantadine,4 black box warning for hepatotoxicity, requires frequent liver function monitoring

    • Fampridine (4-aminopyridine)

      • Significant effect only in patients with high serum levels (>30 ng/mL)5,6

1. Canadian MS Research Group. Can J Neurol Sci. 1987;14:273. 2. Krupp LB, et al. Neurology. 1995;45:1956. 3. Murray TJ. Can J Neurol Sci. 1985;12:251. 4. Multiple Sclerosis Council for Clinical Practice Guidelines, 1998. 5. Polman CH, Bertelsmann FW, et al. Arch Neurol. 51:292. 6. Rossini PM et al. Mult Scler. 2001;7:354.


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Modafinil in MSStudy Design

  • 2-site, single-blind, 9-wk, forced-titration study

  • N = 72, age 18–65 yr

  • FSS >4; ESS <10

  • All patients received

    • Placebo 2 wk

    • Modafinil 200 mg/d 2 wk

    • Modafinil 400 mg/d 2 wk

    • Placebo final 3 wk

  • Modafinil 200 mg and 400 mg compared with placebo run in

Rammohan KW, et al. J Neurol Neurosurg Psych. 2002;72:179.


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The Effect of Modafinil on the MFIS Subscales

Physical (9Q)

Cognitive (10Q)

25

Psychosocial (2Q)

*

21.6

20

20.4

*

20.2

19.0

18.6

18.3

18.0

16.1

15

Mean (± SEM) MFIS

Subscale Score

10

*

5

4.1

4.0

3.9

3.3

0

Modafinil 400 mg

(n = 66)

Placeborun-in

(n = 72)

Modafinil200 mg

(n = 71)

Placebo washout

(n = 70)

*P £ .001 vs placebo run-in

Rammohan KW, et al. J Neurol Neurosurg Psych. 2002;72:179.


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Safety Profile

  • Modafinil was well tolerated

  • Adverse events were mild to moderate

  • Most commonly reported adverse events: headache, nausea, anxiety, asthenia

  • No serious adverse events reported; no worsening of underlying disease

  • Discontinuation due to an adverse event (6%)

    • Headache, dry mouth, anxiety

Rammohan KW, et al. J Neurol Neurosurg Psych. 2002;72:179.


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Conclusions: Fatigue and MS

  • Fatigue is a common and disabling problem in MS

  • Fatigue can be a primary symptom of MS

  • Mechanism unknown; possibly related to demyelination of intracortical pathways

  • Optimal management should include minimizing factors that exacerbate fatigue, such as heat, stress, or poor sleep

  • Modafinil should be considered the first-line treatment for moderate to severe MS fatigue

    • Amantadine may be considered second-line therapy


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Overall Summary

  • EDS and fatigue are common symptoms of many neurologic diseases

  • Clinicians should be aware of these conditions, which may have a significant negative impact on quality of life

  • Innovative therapies are available to provide relief from EDS and fatigue for patients with Parkinson’s disease, myotonic dystrophy, multiple sclerosis, and other neurologic disorders


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