awake and involved ii: addressing excessive daytime sleepiness and fatigue in neurologic disorders

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Awake and Involved II:Awake and Involved II:

Addressing Excessive Daytime Addressing Excessive Daytime Sleepiness and Fatigue in Sleepiness and Fatigue in

Neurologic DisordersNeurologic Disorders


Excessive Daytime SleepinessExcessive Daytime Sleepinessvs Fatiguevs Fatigue

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

Fatigue:Fatigue: a subjective lack of physical and/or a subjective lack of physical and/or mental energy that is perceived by the mental energy that is perceived by the individual or caregiver to interfere with usual individual or caregiver to interfere with usual and desired activitiesand desired activities11

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 FatigueConsequences of EDS and Fatigue

Interferes with social interactionsInterferes with social interactions

Impairs work performanceImpairs work performance

Causes loss of independence Causes loss of independence

Results in depression Results in depression

Influences tolerance to medicationsInfluences tolerance to medications

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


Clinical Evaluation of EDS Clinical Evaluation of EDS and Fatigueand Fatigue

Detailed sleep/wake historyDetailed sleep/wake history

Use subjective questionnairesUse subjective questionnaires

– Epworth Sleepiness Scale (ESS)Epworth Sleepiness Scale (ESS)

– Stanford Sleepiness Scale (SSS)Stanford Sleepiness Scale (SSS)

– Sleep diariesSleep diaries

Consider referral to sleep specialistConsider referral to sleep specialist

– PolysomnographyPolysomnography

– Multiple Sleep Latency Test (MSLT) Multiple Sleep Latency Test (MSLT)

– Maintenance of Wakefulness Test (MWT)Maintenance of Wakefulness Test (MWT)


Epworth Sleepiness Scale (ESS)Epworth Sleepiness Scale (ESS)Epworth Sleepiness Scale (ESS)Epworth Sleepiness Scale (ESS)SituationSituation Chance of dozing (0–3)Chance of dozing (0–3)

Sitting and readingSitting and reading 00 11 22 33

Watching televisionWatching television 00 11 22 33

Sitting inactive in a public place—for example, a Sitting inactive in a public place—for example, a theater or meetingtheater or meeting

00 11 22 33

As a passenger in a car for an hour without a breakAs a passenger in a car for an hour without a break 00 11 22 33

Lying down to rest in the afternoonLying down to rest in the afternoon 00 11 22 33

Sitting and talking to someoneSitting and talking to someone 00 11 22 33

Sitting quietly after lunch (when you’ve had no Sitting quietly after lunch (when you’ve had no alcohol)alcohol)

00 11 22 33

In a car, while stopped in trafficIn a car, while stopped in traffic 00 11 22 33

Total ScoreTotal Score

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.


Objective TestsObjective Tests Multiple Sleep Latency Test (MSLT)Multiple Sleep Latency Test (MSLT)

– Measures patient’s Measures patient’s tendency to fall asleeptendency to fall asleep

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

Maintenance of Wakefulness Test (MWT)Maintenance of Wakefulness Test (MWT) – Measures patient’s Measures patient’s ability to remain awakeability to remain awake

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

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


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

Measures of FatigueMeasures of Fatigue

Self-reportedSelf-reported11

– Fatigue Severity Scale (FSS)Fatigue Severity Scale (FSS)22

– Fatigue Impact Scale (FIS)Fatigue Impact Scale (FIS) Modified Fatigue Impact Scale (MFIS)Modified Fatigue Impact Scale (MFIS)

– Visual Analog Scale for Fatigue (VAS-F)Visual Analog Scale for Fatigue (VAS-F) Performance-basedPerformance-based11

– Measure changes in motor or cognitive Measure changes in motor or cognitive functioningfunctioning


Central Nervous System Central Nervous System Disorders that can Cause Disorders that can Cause

Sleepiness or FatigueSleepiness or Fatigue Parkinson’s diseaseParkinson’s disease Myotonic dystrophyMyotonic dystrophy Multiple sclerosisMultiple sclerosis DementiaDementia Amyotrophic lateral Amyotrophic lateral

sclerosissclerosis

Intracerebral tumorsIntracerebral tumors Cerebrovascular Cerebrovascular

diseasedisease Head traumaHead trauma Narcolepsy, restless Narcolepsy, restless

legs syndromelegs syndrome


Sleep/Wake Abnormalities in PDSleep/Wake Abnormalities in PD

It was reported in 1999 that patients with PD It was reported in 1999 that patients with PD would fall asleep without warningwould fall asleep without warning11

Since then, it has been shown that patients Since then, it has been shown that patients with PD have a background level of with PD have a background level of sleepinesssleepiness2-6

Patients with PD have sudden, irresistible Patients with PD have sudden, irresistible bouts of sleepiness (sleep attacks)bouts of sleepiness (sleep attacks)4-64-6

EDS is more frequent in PD patients than EDS is more frequent in PD patients than healthy controlshealthy controls44

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.


Sleep and Parkinson’s DiseaseSleep and Parkinson’s Disease11

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

*Significantly different from control at P < .05

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*

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

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


Sleep AttacksSleep Attacks

In 1999, it was reported that patients with PD In 1999, it was reported that patients with PD would fall asleep suddenly and without warningwould fall asleep suddenly and without warning11

Since that time, it has become recognized that Since that time, it has become recognized that patients with PD have a background level of patients with PD have a background level of sleepinesssleepiness22

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

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

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


Causes of EDS in PDCauses of EDS in PD

Sleep disturbancesSleep disturbances

MedicationsMedications

PD pathophysiologyPD pathophysiology

Concurrent medical illnessConcurrent medical illness


Causes of EDS in PD:Causes of EDS in PD:Sleep DisturbancesSleep Disturbances

PD motor symptomsPD motor symptoms Depression/psychosisDepression/psychosis DementiaDementia NocturiaNocturia Hallucinations/nightmaresHallucinations/nightmares Medications that can disrupt nocturnal Medications that can disrupt nocturnal

sleep: dopamine agonists, sleep: dopamine agonists, antidepressants, etcantidepressants, etc


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

InsomniaInsomnia Circadian disruptionCircadian disruption Sleep apneaSleep apnea RLS/PLMDRLS/PLMD REM sleep behavior disorderREM sleep behavior disorder Disrupted nocturnal sleepDisrupted nocturnal sleep


Causes of EDS in PD: Causes of EDS in PD: Other MedicationsOther Medications

BenzodiazepinesBenzodiazepines

HypnoticsHypnotics

Tricyclic antidepressantsTricyclic antidepressants

SSRIsSSRIs

AntipsychoticsAntipsychotics

NarcoticsNarcotics

AntihistaminesAntihistamines


Treating EDS in PDTreating EDS in PD

Encourage good sleep hygieneEncourage good sleep hygiene

Treat underlying sleep disordersTreat underlying sleep disorders

Assess PD medication useAssess PD medication use

Withdraw daytime sedative medicationsWithdraw daytime sedative medications

Consider treating EDS with medicationsConsider treating EDS with medications

(eg, modafinil vs stimulants)(eg, modafinil vs stimulants)

Treat nocturiaTreat nocturia


Sleep HygieneSleep Hygiene Maintain regular and appropriate sleep Maintain regular and appropriate sleep

and wake timesand wake times

Regulate amount of time in bedRegulate amount of time in bed

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

Maximize daytime activitiesMaximize daytime activities

Minimize late-day caffeine, nicotine, Minimize late-day caffeine, nicotine, alcohol intakealcohol intake

Reduce length of daytime napsReduce length of daytime naps


Sleep-Promoting MedicationsSleep-Promoting Medications

HypnoticsHypnotics

– Zolpidem, zaleplonZolpidem, zaleplon

– BenzodiazepinesBenzodiazepines AntidepressantsAntidepressants

– AmitryptilineAmitryptiline

– TrazodoneTrazodone Antipsychotics Antipsychotics

– QuetiapineQuetiapine


Use of Stimulants in PDUse of Stimulants in PD

CaffeineCaffeine

MethylphenidateMethylphenidate

AmphetamineAmphetamine

PemolinePemoline


ModafinilModafinil Novel wake-promoting agentNovel wake-promoting agent

– Chemically and pharmacologically distinct from the Chemically and pharmacologically distinct from the psychostimulantspsychostimulants11

– Does not promote wakefulness via a dopaminergic Does not promote wakefulness via a dopaminergic mechanismmechanism11

– Acts selectively in areas of the brain believed to Acts selectively in areas of the brain believed to regulate physiologic sleep and wake statesregulate physiologic sleep and wake states22

Proven effective and well tolerated as a first-line Proven effective and well tolerated as a first-line therapy for EDS in narcolepsy patientstherapy for EDS in narcolepsy patients33

Peak plasma concentration: 2–4 h, TPeak plasma concentration: 2–4 h, Tmaxmax delayed delayed

(~1 h) by food(~1 h) by food11

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.


Modafinil in PD: Methodology Modafinil in PD: Methodology Hogl et al, 2002Hogl et al, 2002

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

N = 15 (3 noncompleters), 75% maleN = 15 (3 noncompleters), 75% male ESS ESS 10. No difference between groups 10. No difference between groups

at baseline (placebo: 11.8 ± 3.8; at baseline (placebo: 11.8 ± 3.8; modafinil: 13.2 ± 2.2)modafinil: 13.2 ± 2.2)

2-wk treatment/2-wk washout with 2-wk treatment/2-wk washout with modafinil 100 mg/d x 7 d and 200 mg/d x modafinil 100 mg/d x 7 d and 200 mg/d x 7 d, or matched placebo tablets7 d, or matched placebo tablets

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


Modafinil in PD: ResultsModafinil in PD: Results Hogl et al, 2002Hogl et al, 2002

0

4

8

12

16

20

Modafinil Placebo

Baseline Week 2

ESS improved by 3.42 for modafinil compared with 0.83 for ESS improved by 3.42 for modafinil compared with 0.83 for placebo (placebo (P P = .039). No changes in the MWT, sleep logs, or = .039). No changes in the MWT, sleep logs, or depression scores.depression scores.Hogl B, et al. Sleep. 2002.25:905.

ES

S S

cale


Modafinil in PD: MethodologyModafinil in PD: Methodology Adler et al, 2003Adler et al, 2003

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

N = 21 (1 noncompleter), 70% maleN = 21 (1 noncompleter), 70% male ESS ESS 1010 3-wk treatment/1-wk washout with modafinil 3-wk treatment/1-wk washout with modafinil

200 mg/d vs placebo200 mg/d vs placebo There was a washout effect following first treatment There was a washout effect following first treatment

period for ESS so compared group 1 with group 2, period for ESS so compared group 1 with group 2, n = 10 per groupn = 10 per group

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


0

4

8

12

16

20

Modafinil(N = 10)

Placebo(N = 10)

Baseline Week 3

Modafinil in PD: ResultsModafinil in PD: ResultsAdler et al, 2003Adler et al, 2003

ESS improved by 3.4 for modafinil vs worsening by 1.0 for placebo (ESS improved by 3.4 for modafinil vs worsening by 1.0 for placebo (P P = .039)= .039) 35% reported improvement with modafinil vs 5% on placebo and 10% on both35% reported improvement with modafinil vs 5% on placebo and 10% on both

ES

S S

cale

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


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

Modafinil in PDModafinil in PD

Adler et al, 2003Adler et al, 200311 (N = 21) (N = 21)

– No significant effect on parkinsonismNo significant effect on parkinsonism

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

– No changes in vital signs, EKG, labsNo changes in vital signs, EKG, labs Hogl et al, 2002Hogl et al, 200222 (N = 15) (N = 15)

– Effect on parkinsonism not reportedEffect on parkinsonism not reported

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


EDS and PD: ConclusionsEDS and PD: Conclusions

EDS is common in PD and may be underrecognizedEDS is common in PD and may be underrecognized Patients should be routinely questioned about EDS Patients should be routinely questioned about EDS

and sleepand sleep Common causes of EDS include sleep disorders and Common causes of EDS include sleep disorders and

dopaminergic medicationsdopaminergic medications Evaluation must include a detailed sleep and Evaluation must include a detailed sleep and

medication history and may include a sleep studymedication history and may include a sleep study Interventions include good sleep hygiene, treating Interventions include good sleep hygiene, treating

underlying sleep disorders, adjusting medications, underlying sleep disorders, adjusting medications, and the use of modafinil or other medications that and the use of modafinil or other medications that increase wakefulnessincrease wakefulness


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

Myotonic Dystrophy (DM1)Myotonic Dystrophy (DM1) Commonest form of adult muscular dystrophy (incidence 1:8000)Commonest form of adult muscular dystrophy (incidence 1:8000) FeaturesFeatures

– Progressive myotonia and muscle weaknessProgressive myotonia and muscle weakness

– Endocrine dysfunctionEndocrine dysfunction

– CataractsCataracts

– Cardiac conduction defectsCardiac conduction defects

– HypersomnolenceHypersomnolence

– ApathyApathy

– Cognitive impairmentsCognitive impairments Autosomal dominant inheritanceAutosomal dominant inheritance Associated with abnormal expansion of CTG repeat in region of Associated with abnormal expansion of CTG repeat in region of

protein kinase gene on chromosome 16protein kinase gene on chromosome 16


EDS in DM1EDS in DM1

1/3 of patients with DM1 have sleep disorders1/3 of patients with DM1 have sleep disorders11 Hypersomnolence is one of most frequently Hypersomnolence is one of most frequently

reported symptoms in DM1reported symptoms in DM1

– Seen in 31%–77% of DM1 patientsSeen in 31%–77% of DM1 patients2,32,3

Weak correlation with degree of muscular Weak correlation with degree of muscular impairmentimpairment4,54,5

EDS not correlated with age, gender, body EDS not correlated with age, gender, body mass index, age at onset, duration of illness, mass index, age at onset, duration of illness, CTG repeat, apathyCTG repeat, apathy44

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.


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.

Pathogenesis of EDS in DM1Pathogenesis of EDS in DM1

Pathogenesis unclearPathogenesis unclear

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

– May be due to dysfunction of central sleep May be due to dysfunction of central sleep regulationregulation11

Dysfunction of hypothalamic hypocretin systemDysfunction of hypothalamic hypocretin system

– Hypocretin-1 levels found significantly lower in Hypocretin-1 levels found significantly lower in patients vs controlspatients vs controls22

Sleep apnea not more common in sleepy than Sleep apnea not more common in sleepy than nonsleepy patients with DM1nonsleepy patients with DM133


Effect of Modafinil on MWT Scores Effect of Modafinil on MWT Scores in DM1 Patients with ESS in DM1 Patients with ESS 1010

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

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

0

10

20

30

40

Placebo Modafinil

MWT Score


EDS in Myotonic DystrophyEDS in Myotonic DystrophySummarySummary

EDS is one of most frequently reported EDS is one of most frequently reported symptoms in patients with DM1symptoms in patients with DM1

Sleepiness may be attributed to dysfunction Sleepiness may be attributed to dysfunction of hypothalamic hypocretin systemof hypothalamic hypocretin system

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

Modafinil has been shown to reduce EDS in Modafinil has been shown to reduce EDS in DM1 patientsDM1 patients


Fatigue in MSFatigue in MS

Reported by 75%–97% of patients Reported by 75%–97% of patients with MSwith MS1-51-5

66% of 309 patients with MS 66% of 309 patients with MS experienced fatigue dailyexperienced fatigue daily33

Most patients with MS say fatigue is Most patients with MS say fatigue is their worst or one of their worst their worst or one of their worst symptomssymptoms22

Underrecognized and underdiagnosedUnderrecognized 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.


Multiple Sclerosis Council for Clinical Practice Guidelines, 1998.

Primary Primary and Secondaryand SecondaryMS FatigueMS Fatigue

SecondarySecondary

– Typically resulting from mobility and/or Typically resulting from mobility and/or respiratory problemsrespiratory problems

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

– Associated with more advanced disabilityAssociated with more advanced disability PrimaryPrimary

– Real entity of MSReal entity of MS

– DDiaiagnosis by exclusiongnosis by exclusion


Krupp LB.CNS Drugs. 2003;225.

Fatigue in MS: Fatigue in MS: Patient Management GuidelinesPatient Management Guidelines Management of secondary causesManagement of secondary causes

– Correct factors that cause or exacerbate fatigue Correct factors that cause or exacerbate fatigue

– Evaluate with laboratory screen of blood testsEvaluate with laboratory screen of blood tests Once secondary causes addressed, proceed to treat Once secondary causes addressed, proceed to treat

primary MS Fatigueprimary MS Fatigue

– Nonpharmacologic Nonpharmacologic

– PharmacologicPharmacologic Secondary MS fatigueSecondary MS fatigue

– Determine if other MS symptoms contributing to Determine if other MS symptoms contributing to fatigue symptomsfatigue symptoms


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

Nonpharmacologic Treatment of Nonpharmacologic Treatment of Fatigue in MSFatigue in MS

Best evaluated by Occupational TherapyBest evaluated by Occupational Therapy Good sleep hygieneGood sleep hygiene Education and supportEducation and support Energy conservation techniquesEnergy conservation techniques

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

Avoid factors that exacerbate MS like Avoid factors that exacerbate MS like heat or humidityheat or humidity

Behavioral techniquesBehavioral techniques


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.

Pharmacologic Treatment for Fatigue in MSPharmacologic Treatment for Fatigue in MS No drug currently approved by FDA for treatment of MS fatigueNo drug currently approved by FDA for treatment of MS fatigue Methodologic problems found with all studiesMethodologic problems found with all studies

– Different outcome measures, small numbers, different patient populationsDifferent outcome measures, small numbers, different patient populations Medications usedMedications used

– AmantadineAmantadine In 3 double-blind, placebo-controlled studies, MS fatigue showed some In 3 double-blind, placebo-controlled studies, MS fatigue showed some

improvement with amantadineimprovement with amantadine1-3 1-3

Suggested dose: 100 mg BIDSuggested dose: 100 mg BID

– PemolinePemoline May be effective therapy for people who do not respond to amantadine,May be effective therapy for people who do not respond to amantadine,44

black box warning for hepatotoxicity, requires frequent liver function black box warning for hepatotoxicity, requires frequent liver function monitoringmonitoring

– Fampridine (4-aminopyridine)Fampridine (4-aminopyridine) Significant effect only in patients with high serum levels Significant effect only in patients with high serum levels

(>30 ng/mL)(>30 ng/mL)5,65,6


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

Modafinil in MSModafinil in MSStudy DesignStudy Design

2-site, single-blind, 9-wk, forced-titration study2-site, single-blind, 9-wk, forced-titration study N = 72, age 18–65 yrN = 72, age 18–65 yr FSS >4; ESS <10FSS >4; ESS <10 All patients receivedAll patients received

– Placebo 2 wkPlacebo 2 wk

– Modafinil 200 mg/d 2 wkModafinil 200 mg/d 2 wk

– Modafinil 400 mg/d 2 wkModafinil 400 mg/d 2 wk

– Placebo final 3 wkPlacebo final 3 wk Modafinil 200 mg and 400 mg compared with placebo Modafinil 200 mg and 400 mg compared with placebo

run inrun in


The Effect of Modafinil on the The Effect of Modafinil on the MFIS SubscalesMFIS Subscales

Mea

n (

± S

EM

) M

FIS

S

ub

scal

e S

core

Physical (9Q) Cognitive (10Q)

Psychosocial (2Q)

*P .001 vs placebo run-in

0

5

10

15

20

25

Placeborun-in

(n = 72)

Modafinil200 mg(n = 71)

Modafinil 400 mg(n = 66)

Placebo washout(n = 70)

21.6

4.0

20.418.6

18.0

20.2

16.1

19.0 18.3

4.13.3 3.9*

**




Safety ProfileSafety Profile

Modafinil was well toleratedModafinil was well tolerated Adverse events were mild to moderateAdverse events were mild to moderate Most commonly reported adverse events: Most commonly reported adverse events:

headache, nausea, anxiety, astheniaheadache, nausea, anxiety, asthenia No serious adverse events reported; no No serious adverse events reported; no

worsening of underlying diseaseworsening of underlying disease Discontinuation due to an adverse event (6%)Discontinuation due to an adverse event (6%)

– Headache, dry mouth, anxietyHeadache, dry mouth, anxiety


Conclusions: Fatigue and MSConclusions: Fatigue and MS Fatigue is a common and disabling problem in MSFatigue is a common and disabling problem in MS Fatigue can be a primary symptom of MSFatigue can be a primary symptom of MS Mechanism unknown; possibly related to Mechanism unknown; possibly related to

demyelination of intracortical pathwaysdemyelination of intracortical pathways Optimal management should include minimizing Optimal management should include minimizing

factors that exacerbate fatigue, such as heat, stress, factors that exacerbate fatigue, such as heat, stress, or poor sleepor poor sleep

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

– Amantadine may be considered second-line Amantadine may be considered second-line therapytherapy


Overall SummaryOverall Summary

EDS and fatigue are common symptoms of EDS and fatigue are common symptoms of many neurologic diseasesmany neurologic diseases

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

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

awake and involved ii: addressing excessive daytime sleepiness and fatigue in neurologic disorders

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