evaluating and treating the patient with hypersomnia · 2016-06-01 · 1. i do not have any...

© Associated Professional Sleep Societies, LLC 1

Evaluating and treating the patient with hypersomnia

Lynn Marie Trotti, MD, MScAssociate Professor of Neurology

Emory University School of Medicine


Conflict of Interest Disclosures for Speakers1. I do not have any relationships with any entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients, OR

x 2. I have the following relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.

Type of Potential Conflict Details of Potential Conflict

Grant/Research Support Grant funding to my institution (not to me) for RCTs of hypersomnia treatments: Jazz Pharma, Balance Therapeutics

Consultant

Speakers’ Bureaus

Financial support

Other

3. The material presented in this lecture has no relationship with any of these potential conflicts, OR

x 4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture:

1. Philip P, Sleep, 2014, 37(3):483-7

2. Trotti LM, 2015 , Annals Neurology; 78(3):454-65

3.


Other Disclosures

• I intend to discuss off-label use of approved medications


Outline

• Evaluation– Distinguishing clinical features– Role of comorbid psychiatric disease

• Treatment– Current(-ish) practice parameter– RCTs in idiopathic hypersomnia– Open label experience in Kleine-

Levin syndrome– Pregnancy/breastfeeding


ICSD-3

• Central Disorders of Hypersomnolence– Narcolepsy type 1– Narcolepsy type 2– Idiopathic hypersomnia– Kleine-Levin syndrome– Hypersomnolence associated with…– Insufficient sleep syndrome

– Hypersomnia ≠ Hypersomnolence– Hypersomnolence ≠ sleeping too long (necessarily)

International classification of sleep disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine 2014


ICSD-3 Diagnostic CriteriaNarcolepsy Type 1 Narcolepsy Type 2 Idiopathic

HypersomniaEDS Yes Yes Yes

Cataplexy Yes (specific, not necessary)

No No

MSLT mean sleep latency

< 8 min < 8 min < 8 min (or TST > 660 min)

SOREMs (MSLT and nocturnal)

2+ 2+ 0‐1

Hypocretin Low/absent Normal Normal



The terminology is a problem

Narcolepsy Idiopathic Hypersomnia


Narcolepsy with Cataplexy(Type 1)

Idiopathic Hypersomnia

Narcolepsy without Cataplexy(Type 2)

The terminology is a problem


Which clinical features are discriminative?

Narcolepsy Type 1 Narcolepsy Type 2 Idiopathic Hypersomnia

Sleep paralysis 69% 35% 20%

Sleep hallucinations

77% 42% 25%

Narcolepsy tetrad (EDS, cataplexy, paralysis, & hallucinations)

42% (although not all present initially)

Absent Absent

Fragmentednocturnalsleep

Common “Maybecommon*…?

Atypical

Khan Z, Chest, 2015, 148(1):262‐73


Narcolepsy type 1: A disorder of state control

Control Subject

Rogers et al. Sleep. 1994;17:590-597.

PWN sleep little more than controls in a 24 hour period.

Controls

Narcoleptics


Narcolepsy type 1

Idiopathic hypersomnia

Narcolepsy type 1: A disorder of state control


• European Narcolepsy Network

• First 1079 patients

• 13 countries

Khatami R et al, 2016, J Sleep Research, epub ahead of print


What clinical features are discriminative?

Narcolepsy Type 1

Narcolepsy Type 2

Idiopathic Hypersomnia

REM sleep behavior disorder (RBD)

45-61% ? ?

Long nocturnal sleep times

18% Common

Effect and duration of naps

Refreshing, short ? Unrefreshing, long

Sleep drunkenness

Rare Common? Common

Khan Z, Chest, 2015, 148(1):262‐73


Trotti LM, Sleep Medicine Reviews, under review

Publication IH N‐C N+C N unspecifiedAnderson 2007 42/77 (55%) 2/63 (3%)

Bassetti 1997 9/42 (21%)

Bassetti 2003 3/5 (60%) 3/4 (75%) 1/4 (25%)

Kretzschmar 2016 7/8 (88%) 1/35 (3%)

Martinez‐Rodriguez 2007 1/8 (12.5%) 4/11 (36%) 7/32 (22%)

Roth 1980 92/167 (55.1%) 57/360 (15.8%);37.7% monosymptomatic, 11.3% polysymptomatic

Vernet 2009 27/75 (36.5%)

Total with sleep drunkenness

47% 47% 8% 16%

Sleep drunkenness


What is the role of nocturnal SOREM in diagnosis?

• SOREM = sleep onset REM period = REM sleep within 15 min of sleep onset

Narcolepsy Type 1

Narcolepsy Type 2

IdiopathicHypersomnia

Total SOREMs(MSLT and nocturnal)

2+ 2+ 0‐1



Diagnostic utility of nocturnal SOREM

• Comparison 4: hypocretin deficient narcolepsy (n = 118) vs narcolepsy with normal hypocretin (n = 118)

• Optimal cut off 8 min

Andlauer O et al, JAMA Neuro, 2013; 70:891‐902


• Clinic population referred for PSG/MSLT

• N = 3059

• 1.8% had NSOREM (n = 54)– Final diagnosis in 48

• Predictors of NSOREM– Older age– Shorter MSL– Higher ESS– Disturbed sleep (arousal index)– OSA– African-American (4x)

Cairns A et al, Sleep, 2015, 38(10):1575‐81

N‐C N+C H other dx

Diagnostic utility of nocturnal SOREM


Cairns A et al, Sleep, 2015, 38(10):1575‐81


How do symptoms cluster?

• Included variables :– # unwanted naps– Duration unwanted naps– Irresistible unwanted naps– Difficulty waking from

naps– Cataplexy– MSL– SOREMPs

• ICSD-2 diagnoses:– Narcolepsy with cataplexy (n =

23) – Narcolepsy without cataplexy

(n = 22)– IH without long sleep time (n =

25)• IH with LST (ICSD-2 except

MSL < 8 min; n = 26)

Šonka K, Sleep Medicine, 2015; 16(2):225‐31.


Šonka K, Sleep Medicine, 2015; 16(2):225‐31.


OVERLAP BETWEEN HYPERSOMNIA AND

PSYCHIATRIC DISORDERS


Idiopathic HypersomniaHypersomnolence associated

with a psychiatric disorder

• Sleepiness > 3 months• No cataplexy• 0 or 1 SOREM• Either:

– MSL < 8 min– TST > 660 min in 24 hours

• Not insufficient sleep

• Not better explained by a psychiatric disorder (or medical/sleep disorder or drug)

• Sleepiness > 3 months• Concurrent psychiatric

disease

• Not better explained by a sleep disorder (or medical/sleep disorder or drug)

• “it is essential to rule out other common causes of sleepiness such as … IH”



Is the MSLT useful in hypersomnolenceassociated with a psychiatric disorder?

• Wisconsin Sleep Cohort, n = 1287• Repeated measures logistic regression

– Controlled for: age, sex, BMI, smoking, EtOH, caffeine, insomnia, sedative medications, other diseases, SDB

Plante DT et al, JCSM, 2016, 12(4):571‐578

OR 95% CI p‐valueESS > 11 1.56 1.31‐1.86 <0.0001Habitual sleep time > 9 hrs

2.01 1.49‐2.72 <0.0001

MSL < 8 min 0.76 0.63‐0.92 0.004


Can the MSLT differentiate these syndromes?

Plante DT, Sleep Medicine Reviews, 2016, epub ahead of print

Mean Sleep Latency on MSLT


Plante DT, Sleep Medicine Reviews, 2016, epub ahead of print

Less than 8 minutes

Less than 5 minutes


Making matters worse…

in RCTs

Alberti S et al, J Clin Psychopharm, 2015, 35(3):296‐303


Treatment of hypersomnolence


Morgenthaler TI, et al, Sleep 2007; 30(12):1705‐1711


AASM Levels of Recommendation

Standard Generally accepted strategy with a high degree of clinical certainty. Either from level I evidence or “overwhelming” level

II evidence

Guideline Reflects a moderate degree of clinical certainty. Either from level II evidence or a consensus of level III evidence

Option Reflects uncertain clinical use. Implies inconclusive or conflicting evidence or

conflicting expert opinion



Current treatment guidelineNarcolepsy Idiopathic

HypersomniaKleine‐Levin syndrome

Modafinil(armodafinil)

Standard Option Option

Sodium oxybate Standard

Amphetamines Guideline Option Option

Selegiline Option

Lithium Option (n = 5)



Risk of stimulant misuse appears low• 105 patients with narcolepsy (1 or 2) or IH

– -51% NT1– -24% NT2– -25% IH– 11% with prior illicit substance misuse– 54% with comorbid psychiatric disease (88% depression)

• First medications:– -35% modafinil– -55% methylphenidate– -10% amphetamine derivative

• 0/105 with evidence of stimulant misuse– -early refill without explanation– -documented use of higher than prescribed amount

Mantyh WG, JCSM, 2016, epub ahead of print


• Subjects:– NT1 = 243– NT2 = 116– IH = 91– Controls = 710

• Face-to-face structured clinician interview (MINI)

Drug/Dose Number exceeding

Methylphenidate 100 mg

0

Modafinil 800 mg 1 (dose 1600 mg)

Sodium oxybate 9 gm 0

Risk of stimulant misuse appears low

Barateau L et al, Sleep, 2016, 39(3):573‐580


Risk of other abuse/dependence also low*

Barateau L et al, Sleep, 2016, 39(3):573‐580

7.5

1.7

6.9

1.7

22.7

4.4

0

3.7

0.9

8.7

2.2 1.12.3

0

10

15.2

2.7

5.9

1.4

4.2

0

5

10

15

20

25

Heavy EtoH EtOHabuse/dependence

Illicit drug use Drugabuse/dependence

Heavy tobacco

Percentage with substance use/abuse

NT1 NT2 IH Controls

Controls > NT1 = OH

Controls = NT1 = OH

Controls = NT1 = OH Controls =

NT1

NT1 > controls; NT1 > OH

*except tobacco


Current treatment could be better

Drakatos, 2016, J Sleep Research; 25(2):203‐10


Current treatment could be better

Anderson KN, Sleep, 2007, 30(10):1274‐81; table excerpted from Ali M, JCSM, 2009, 5(6):562‐8


Flores NM, 2016, JCSM; 12(3):401‐7

Report of physician‐diagnosed narcolepsy (n = 437) Propensity‐matched population controls (n = 837)

The narcolepsies are associated with poor quality of life and

economic burden


The narcolepsies are associated with poor quality of life and

economic burden

• Report of physician-diagnosed narcolepsy (n = 437)• Propensity-matched population controls (n = 837)

Flores NM, 2016, JCSM; 12(3):401‐7


Quality of Life remains impaired in IH even with treatment

• * = worse than population controls while treated

9%

20%

41%

30%

Treatments

MethylphenidateModafinilPemoline≥2 meds

Ozaki A, Sleep Medicine, 2012, 13:200‐6

**‐**‐*‐


Central disorders of hypersomnolence are safety risks

• 282 hypersomnolent patients– 71 IH– 82 NT2– 129 NT1

• 470 healthy controls

• OR car accident in past 5 years– Untreated CDH: 2.21 (1.30-3.76)– Treated CDH: 2.04 (1.26-3.30)

Pizza F, 2015, PLOS One, 10(6):e0129386


Modafinil improves, but doesn’t normalize, risk

Philip P, Sleep, 2014, 37(3):483‐7


What’s new in hypersomnia treatment since 2007?

• 13 PWN (6 without cataplexy), 14 patients with IH, 14 healthy controls

• Modafinil 200 mg at 0800 and 1400 at 1230 vs placebo (cross-over)

Hypersomnia Patients

Modafinil400 mg

Placebo

Driving TestMWT

Driving TestMWT

End

Placebo

Modafinil400 mg

Driving TestMWT

Driving TestMWT

Philip P, Sleep, 2014, 37(3):483‐7


Modafinil: Effects on Sleep Latency

0

10

20

30

40

50

Control Placebo Modafinil

Minutes M

WT Mean Sleep

Latency

P < 0.01

P < 0.001

P < 0.001

Philip P, Sleep, 2014, 37(3):483‐7


Modafinil in IH (without LST)

Mayer G, J Sleep Res, 2015; 24(1):74‐81


Modafinil in IH (without LST)

Mayer G, J Sleep Res, 2015; 24(1):74‐81

Withdrawal


Is there a role for GABA modulators?

Images courtesy of Amanda Freeman and Andrew Jenkins


• Insomnia, mania, psychosis, non-convulsive status epilepticus, “antibiotomania”

• Directly neurotoxic? Increased cortisol/prostaglandins? Effects on hepatic metabolism of other drugs?


Clarithromycin is a negative allosteric modulator of the

GABA-A receptor

Garcia, 2009 Annual Meeting, American Society of Anesthesiologists


Clarithromycin: A randomized, double blind,

placebo controlled trial

20 subjects

Clarithromycin 500 mg c breakfast

& lunch

Matched Placebo

Matched Placebo

Two weeks

Two weeks

Clarithromycin 500 mg c breakfast

& lunch

One week

Funded by the American Sleep Medicine Foundation


Primary outcome measure: median reaction time

(psychomotor vigilance task)

Baseline Placebo Clarithromycin

P = NS

Trotti LM, 2015 , Annals Neurology; 78(3):454‐65


Secondary outcome measures:

Epworth Sleepiness Scale


P < 0.005

CL < PL = B



Secondary outcome measures:

Functional Outcomes of Sleep


P < 0.005

CL > PL = B



Side effects

80% preferred treatment with clarithromycinTrotti LM, 2015 , Annals Neurology; 78(3):454‐65


Kleine-Levin syndrome: Open label use of lithium

• 71 patients treated with lithium

• 49 patients opted for no treatment

Leu‐Semenescu, 2015, Neurology, 85(19):1655‐62


SE from lithium in KLS patients

Leu‐Semenescu, 2015, Neurology, 85(19):1655‐62


What about pregnancy?Medication

FDA pregnancy category

EMA SPC pregnancy statements

Modafinil/armodafinil C Modafinil should not be used during pregnancy

Sodium oxybate C GHB is not to be recommended during pregnancy

Methylphenidate CMethylphenidate is not recommended for use during pregnancy unless a clinical decision is made that postponing treatment may pose a greater risk to the pregnancy

Dextroamphetamine C Dextroamphetamine is contraindicated during pregnancy. Selegiline C It is preferable to avoid the use of selegiline in pregnancy.

Venlafaxine C Venlafaxine must only be administered to pregnant women if the expected benefits outweigh any possible risk.

Atomoxetine C Atomoxetine should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.

Clomipramine C No information availableFluoxetine C Not recommended during pregnancyProtriptyline C No information available

Modified from Thorpy M et al, Sleep Medicine, 2013, 14(4):367‐76


Medication LactMed*

Modafinil/armodafinil No data

Sodium oxybate 2 infants successfully breastfed; avoid for 4‐5 hours after dose

Methylphenidate

Limited evidence – levels very low and might not have adverse effects; effects on neurodevelopment unknown; large doses could suppress production

Dextroamphetamine

Some evidence – might not have adverse effects; effects on neurodevelopment unknown; large doses could suppress production

VenlafaxineMetabolite found in infant plasma but no proven SE reported; watch for sedation and poor weight gain

Fluoxetine

Average amount in mild higher than other SSRIs. Colic/drowsiness reported but fluoxetine not a reason not to breastfeed; continue if already on fluoxetine for pregnancy, otherwise other SSRI

http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm, accessed 4/29/16

*when used in doses prescribed for medical indications


Sodium oxybate and breastfeeding

Busardo FP, Forensic Science International, 2016, 265:172‐181


Methylphenidate and breastfeeding• Relative infant dose

– Mother’s weight-adjusted dose– Infant’s milk intake– Milk concentration of drug– If < 10% mom’s weight-adjusted dose, generally considered safe

• 6 infants reported with methylphenidate– RID < 1% in all 6– Drug undetectable in some cases:

• Breast milk in 1• Infant serum in 4 of 4

– Breast milk concentration up to 19 ug/L (maternal dose up to 80 mg/day)– No adverse events noted– Development normal at 1 year in one reported case

• Motherrisk “methylphenidate…appears to be compatible with breastfeeding” but long term neuropsych pending

Marchese M, 2015, Can Family Physician, 61(9):765‐6


PUTTING IT ALL TOGETHER: QUALITY

MEASURES FOR NARCOLEPSY PATIENT

CARE


AASM Narcolepsy Quality Measures

Krahn LE, 2015, JCSM, 11(3):335



Krahn LE, 2015, JCSM, 11(3):335

evaluating and treating the patient with hypersomnia · 2016-06-01 · 1. i do not have any...

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