Transcript Diagnosis of PD - Projects In Knowledge

Awake and Involved II:
Addressing Excessive Daytime
Sleepiness and Fatigue in
Neurologic Disorders
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Excessive Daytime Sleepiness
vs Fatigue
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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: evidencebased management strategies for fatigue in multiple sclerosis. Washington, DC: Paralyzed Veterans of
America, 1998.
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Consequences of EDS and Fatigue
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Interferes with social interactions
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Impairs work performance
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Causes loss of independence
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Results in depression
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Influences tolerance to medications
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Increases risk of accidents
(motor vehicle, industrial, home)
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Clinical Evaluation of EDS
and Fatigue
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Detailed sleep/wake history
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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)
Situation
Chance of dozing (0–3)
Sitting and reading
0
1
2
3
Watching television
0
1
2
3
Sitting inactive in a public place—for example, a
theater or meeting
0
1
2
3
As a passenger in a car for an hour without a break
0
1
2
3
Lying down to rest in the afternoon
0
1
2
3
Sitting and talking to someone
0
1
2
3
Sitting quietly after lunch (when you’ve had no
alcohol)
0
1
2
3
In a car, while stopped in traffic
0
1
2
3
Total 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.
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Objective Tests
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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
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Maintenance of Wakefulness Test (MWT)
– Measures patient’s ability to remain awake
– Assesses ability to remain awake when semireclining in a dimly lit room
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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
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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.
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Central Nervous System
Disorders that can Cause
Sleepiness or Fatigue
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Parkinson’s disease
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Intracerebral tumors
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Myotonic dystrophy
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Multiple sclerosis
Cerebrovascular
disease
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Dementia

Head trauma

Amyotrophic lateral
sclerosis

Narcolepsy, restless
legs syndrome
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Sleep/Wake Abnormalities in PD
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It was reported in 1999 that patients with PD
would fall asleep without warning1
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Since then, it has been shown that patients
with PD have a background level of
sleepiness2-6
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Patients with PD have sudden, irresistible
bouts of sleepiness (sleep attacks)4-6
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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
Sleep Parameter
Controls (n = 10)
PD
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
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Since that time, it has become recognized that
patients with PD have a background level of
sleepiness2
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At times, patients with PD may have sudden onset
of irresistible sleepiness (sleep attack)
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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
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Sleep disturbances
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Medications

PD pathophysiology

Concurrent medical illness
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Causes of EDS in PD:
Sleep Disturbances
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PD motor symptoms
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Depression/psychosis
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Dementia
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Nocturia
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Hallucinations/nightmares
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Medications that can disrupt nocturnal
sleep: dopamine agonists,
antidepressants, etc
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Causes of EDS in PD:
Sleep Disturbances (cont’d)
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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
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Benzodiazepines
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Hypnotics
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Tricyclic antidepressants
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SSRIs
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Antipsychotics
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Narcotics
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Antihistamines
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Treating EDS in PD
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Encourage good sleep hygiene
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Treat underlying sleep disorders
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Assess PD medication use
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Withdraw daytime sedative medications
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Consider treating EDS with medications
(eg, modafinil vs stimulants)
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Treat nocturia
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Sleep Hygiene
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Maintain regular and appropriate sleep
and wake times
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Regulate amount of time in bed
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Seek maximum light exposure during the
daytime and minimize light exposure during
the nighttime
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Maximize daytime activities
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Minimize late-day caffeine, nicotine,
alcohol intake
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Reduce length of daytime naps
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Sleep-Promoting Medications
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Hypnotics
– Zolpidem, zaleplon
– Benzodiazepines
Antidepressants
– Amitryptiline
– Trazodone
Antipsychotics
– Quetiapine
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Use of Stimulants in PD
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Caffeine
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Methylphenidate
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Amphetamine
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Pemoline
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Modafinil
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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
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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
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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: Results
Hogl et al, 2002
Baseline
Week 2
ESS Scale
20
16
12
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.
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Modafinil in PD: Methodology
Adler et al, 2003
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Single-site, randomized, double-blind, placebocontrolled, 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.
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Modafinil in PD: Results
Adler et al, 2003
Baseline
Week 3
ESS Scale
20
16
12
8
4
0
Modafinil
(N = 10)
Placebo
(N = 10)
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ESS improved by 3.4 for modafinil vs worsening by 1.0 for placebo (P = .039)
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35% reported improvement with modafinil vs 5% on placebo and 10% on both
Adler CH, et al. Mov Disord. 2003;18:287.
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Modafinil in PD
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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.
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EDS and PD: Conclusions

EDS is common in PD and may be underrecognized
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Patients should be routinely questioned about EDS
and sleep
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Common causes of EDS include sleep disorders and
dopaminergic medications
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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)
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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.
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EDS in DM1
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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
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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.
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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 Dystrophy
Summary
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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
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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 Secondary
MS Fatigue
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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
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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
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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
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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 MS
Study Design
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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)
Mean (± SEM) MFIS
Subscale Score
25
20
Psychosocial (2Q)
*
21.6
19.0
18.3
15
20.4
20.2
*
18.6
18.0
16.1
10
5
4.1
*
3.3
3.9
4.0
Modafinil
200 mg
(n = 71)
Modafinil
400 mg
(n = 66)
Placebo
washout
(n = 70)
0
Placebo
run-in
(n = 72)
*P .001 vs placebo run-in
Rammohan KW, et al. J Neurol Neurosurg Psych. 2002;72:179.
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Safety Profile
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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
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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 secondline therapy
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Overall Summary
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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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