Upload
nathaniel-kennedy
View
215
Download
1
Embed Size (px)
Citation preview
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
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)
Electronic Image Safe (Remove for final output)
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)
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
Causes of EDS in PDCauses of EDS in PD
Sleep disturbancesSleep disturbances
MedicationsMedications
PD pathophysiologyPD pathophysiology
Concurrent medical illnessConcurrent medical illness
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
Causes of EDS in PD: Causes of EDS in PD: Other MedicationsOther Medications
BenzodiazepinesBenzodiazepines
HypnoticsHypnotics
Tricyclic antidepressantsTricyclic antidepressants
SSRIsSSRIs
AntipsychoticsAntipsychotics
NarcoticsNarcotics
AntihistaminesAntihistamines
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
Sleep-Promoting MedicationsSleep-Promoting Medications
HypnoticsHypnotics
– Zolpidem, zaleplonZolpidem, zaleplon
– BenzodiazepinesBenzodiazepines AntidepressantsAntidepressants
– AmitryptilineAmitryptiline
– TrazodoneTrazodone Antipsychotics Antipsychotics
– QuetiapineQuetiapine
Electronic Image Safe (Remove for final output)
Use of Stimulants in PDUse of Stimulants in PD
CaffeineCaffeine
MethylphenidateMethylphenidate
AmphetamineAmphetamine
PemolinePemoline
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
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)
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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.
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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*
**
Rammohan KW, et al. J Neurol Neurosurg Psych. 2002;72:179.
Electronic Image Safe (Remove for final output)
Rammohan KW, et al. J Neurol Neurosurg Psych. 2002;72:179.
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
Electronic Image Safe (Remove for final output)
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
Electronic Image Safe (Remove for final output)
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