How, When and Why to Do MSLT

in 2021Madeleine Grigg-Damberger MD

Professor of Neurology

University of New Mexico

ACNS 2021 Annual Meeting Sleep Course

Wednesday, February 10, 2021

2:00 to 2:30 PM

I Have No Conflicts of Interest to Report Relevant to This Talk

Centr

al H

ypers

om

nia

s

Narcolepsy Type 1 (NT1)

Narcolepsy Type 2 (NT2)

Idiopathic hypersomnia (IH)

Kleine-Levin syndrome (KLS)

Symptomatic narcolepsies Excessive daytime sleepiness (EDS) in people

referred to sleep centers is most often due

medical/psychiatric disorders, insufficient sleep

and/or substances.

Only 0.5-5% of people

referred to sleep centers

have hypersomnia

without easy identifiable

cause.

Multiple Sleep Latency Test (MSLT)

• Most widely accepted objective polygraphic test to confirm:

a) Pathologic daytime sleepiness;

b) Inappropriate early appearance of REM sleep after sleep onset.

• Measures of physiological tendency to fall asleep in absence of alerting factors;

• Considered a valid, reliable, objective measure of excessive

daytime sleepiness (EDS).

REFs: 1) Sleep 1986;9:519-524. 2) Sleep 1982;5:S67-S72; 3) Practice parameters for clinical use of MSLT and MWT. SLEEP 2005;28(1):113-21.

.

MSLT Requires Proper Patient Selection, Planning and Preparation to Be Reliable

1) Sleep Medicine Consult before test scheduled:

2) Best to confirm sleep history and sleep/wake

schedule (1 to 2-weeks sleep diary and actigraphy)

→ F/U visit to review before order “MSLT testing”.

3) Standardize sleep/wake schedule > 7 hours bed

each night and document by actigraphy and sleep

log;

4) Wean off wake-promoting or REM suppressing

drugs > 15 days (or > 5 half-lives of drug and its

longer acting metabolite) Recent study showed 7 days of

actigraphy sufficient vs. 28 days to

confirm NT1.

MSLT Protocol1) Level 1 PSG night before (to identify sleep disorders

causing/contributing to EDS and confirm slept > 360 min:

• Review PSG morning of study, consider cancelling MSLT if patient slept < 6 h

on PSG; sleep log + actigraphy shows insufficient sleep (<7 h) or

moderate/severe OSA on PSG.

2) Schedule MSLT patient’s customary wake times (challenging for shift

workers):

3) 4-5 20-min nap opportunities at 2 h intervals beginning 1.5 to 3 h

after awakening from the overnight PSG;

4) 5 naps unless 2 SOREMPs first 4 naps.

5) Urine drug screen morning of MSLT.

Important to Standardize the MSLT Naps

1) Sleep rooms dark, quiet; room temperature adjusted for patient’s

comfort; no caffeine or bright light exposure day of test;

2) 30 min before each nap stop tobacco; 15 min before stop

stimulating activities;

3) Light breakfast 1 h before MSLT start; light lunch after second

(noon) trial;

4) Technologist gives same instructions before each nap: “Please lie

quietly, assume a comfortable position, and try to fall asleep”.

Scoring MSLT

1) Each nap opportunity scored in 30-second epochs from LIGHTS OUT to LIGHTS

ON.

30-seconds

High chin EMG tone

Saccades

Desynchronized EEG of eyes open

Scoring MSLT

2) Sleep onset in a nap: first 30-second epoch of any stage of sleep (N1, N2, N3, R); if patient

falls asleep run for 15 minutes (30 epochs) to see if early onset of REM sleep observed.

REM sleep normally appears 70-110 minutes after sleep onset.

Scoring MSLT

3. If sleep occurs, record 15 min see if REM sleep appears early (SOREMP).

Rapid eye movements

EEG = low voltage mixed frequency Can sometimes see RWA

Scoring MSLT

4) REM latency in a nap = Time in minutes from first epoch of sleep to

first epoch of REM sleep

LVMF

REMs

Chin EMG - Atonia

Scoring MSLT

5) Stop nap after 20 min (40 epochs) if no sleep occurs. If no sleep observed in

nap, score latency for that nap as 20 min.

Reporting and Interpreting Multiple Sleep Latency Test

Data Calculated and Tallied for MSLT

1) For each nap opportunity:✓Start and stop times (min)

✓Sleep latency (min)

✓REM latency (min)

✓Percent REM sleep in nap

2) Number of naps;

3) Number of SOREMPs

4) Mean sleep latency (MSL).

• Sleep Latency: (Sleep Onset Epoch –

Lights Out Epoch) divided by 2

• REM Latency: (REM onset Epoch – Sleep

Onset Epoch) divided by 2;

• Mean Sleep Latency (MSL): Sum of sleep

latency each nap (min)/number of naps.

EXAMPLE: Lights Out Epoch 12, Sleep onset

Epoch 13 (N1); REM onset Epoch 14

Sleep latency = 13-12/2 =0.5 min; REM

latency = 0.5 min after sleep onset).

Fundamental MSLT Results Which Support Narcolepsy Diagnosis

• Mean sleep latency (MSL) usually 2-3 min in patients with NT1.

MSL <8 min in 4 or 5 naps

• More often 3-5 SOREMPs in patients with NT1.

SOREMPs > 2 naps

0

2

4

6

8

10

12

14

Nap 1 Nap 2 Nap 3 Nap 4 Nap 5

Mean Sleep Latency

Control

Narcolepsy

Richardson GS et al. Electroencephalogr Clin Neurophysiol 1978;45:621–7.

MSLT Findings in Narcolepsy Types 1 & 2, Idiopathic Hypersomnia and Insufficient Sleep

• REFs: 1) Drakatos P et al. Sleep stage sequence of SOREMPs in hypersomnia. J Neurol Neurosurg Psychiatry 2013;84:223-7;

Sleep disorder N Mean sleep

latency (MSL)

Naps with

SOREMP

SOREMP

after N1

Narcolepsy type 1 25 2.6 ± 1.6 63% 75%

Narcolepsy type 2 41 4.0 ± 2.1 60% 52%

Idiopathic

hypersomnia

21 5.4 ± 1.8 1% 0%

Insufficient sleep

syndrome

20 7.6 ± 3.9 7% 0%

• Diagnosing idiopathic hypersomnia may require 48 h of extended

sleep monitoring or 7-days of wrist actigraphy.

Other Findings on MSLT Which Increase Sensitivity the Patient Has Narcolepsy

1) 3-5 SOREMPs on MSLT

2) N1-REM SOREMPs on MLST and PSG;

3) Mean REM sleep percent in naps >40-50% of total sleep time (TST);

4) REM sleep without atonia and RBD behaviors on MSLT

• If 4 SOREMPs on MSLT test-reliability was 0.97

(3 naps 0.85, 2 naps 0.65)

Findings on Overnight PSG in Narcolepsy

• SOREMP REM latency < 15 min; • Red flag for narcolepsy; 33-55% of Narcolepsy Type 1 and 2;

• High specificity (95-99%), but low sensitivity (7%); Positive Predictive

Value 89%.

• Marked fragmentation of nocturnal sleep, decreased sleep efficiency,

increased wake and arousals; REM sleep instability; N1-REM transitions.

• PLMS in NREM and REM sleep, RWA, RBD behavior events

REFs: 1) Leschiziner G. Practical Neurology 2014;5:323-31’ 2) Andlauer O JAMA Neurol 2013;70(7):891-902; 3) Cairns A

Sleep 2015;38(10):1575-81; 4) Reiter J Sleep 2015;38 (5): 859-65

Validity and Reliability of MSLT

Validity of MSLT Lessened By

• Deviations from standard protocol (room noisy

or too hot);

• Medications affect sleep and/or REM latencies;

• Patient slept < 360 min overnight PSG;

• Severity of sleep disorder(s) or sleep

fragmentation on PSG;

• Insufficient time after discontinuing drugs

which affect results;

• Drugs on urine toxic screen.

MSLT Interpretation Pitfalls

Test-Retest Reliability of MSLT

•Studies have found the MSLT test-retest reliability is good for narcolepsy type 1 (NT1), poor for NT2 or Idiopathic hypersomnia (IH):• One large study found both MSLTs were positive for

narcolepsy in 78% N1, but only 18% NT2 and 7% controls.

• NT1 10-14 times more likely have 2nd positive MSLT vs. NT2.

False Negative MSLT in Patients with NT1 and False Positive MSLT in Controls

MSLT False-Negative

▪ 7-16% NT1 patients due to

environmental factors, anxiety,

older (or younger) age;

medications that interfere with

sleep.

MSLT False-Positive

▪ 16% of controls had MSL < 5

min;

▪ False-positive MSL <5 min

in 10-25% in patients with sleep

deprivation, sleep apnea,

adolescents with early school

times, drug effects.

1-2 SOREMPs on MSLT Common in General Adult Population

• Study 1: Population-based

sample of 539 adults: 4% > 2

SOREMPs:1

• 2.5% met narcolepsy criteria (MSL

< 8 min + > 2 SOREMPs).

• Majority false positive MSLT due

to shift work, insufficient sleep,

sleep apnea, or medications.

• Study 2: 556 community dwelling

adults:2

• 13% M and 6% F > 2 SOREMPs;

• 4% M and 0.4% F met narcolepsy

criteria (MSL < 8 min + > 2 SOREMPs

+ ESS >10).

• Particularly common shift workers.

REFs: 1) Singh M et al. Prevalence of SOREMPs in population –based sample Brain 2006;29:890-5; 2) Mignot E et al. Correlates

of SOREMPS in community adults. Brain 2006;129:1609-23.

Positive Urine Toxic Screen in MSLT

• 33% of 186 consecutive patients who underwent MSLT:1

• Most often opioids, cannabis or amphetamines;

• 16% patients MSL < 8 min tested positive;

• 52% of 23 NT2; 20% 53 IH patients.2

• 16% of 69 MSLT/MWT patients:

• Amphetamines, THC, opiates or BZPs; none reported self-use

before discovery);3

• 10% of 383 pediatric patients; 43% had MSL < 8 min and

>2 SOREMPs.4

REFs: 1) Kosky CA. JCSM 2016;12(11):1499-1505; 2) Anniss AM JCMS 2016;12(12:1633-40;

3) Drodzomenyo S. JCMS 2015;11(2):93-9; 4) Katz ES. JCSM 2014;10(8):897-901.

Drugs That Decrease REM Sleep Can Cause REM Sleep Rebound When Discontinued

▪ TCAs, MOAIs, SSRIs; Venlafaxine; Lithium;

▪Amphetamine, methylphenidate, cocaine;

▪ Barbiturates; Clonidine; Clomipramine;

▪ Scopolamine; alcohol; trazodone; CBD/THC.

Drugs Half-Life

(hours)

Fluoxetine 48-72

Mirtazapine 20-40

Citalopram 35

Sertraline 26

Paroxetine 21

Venlafaxine 3-7

Amitriptyline 9-46

Longest half life: fluoxetine (2-

4 d) and its active metabolite

norfluoxetine (7-15 d) ➔

5-week washout period.

Cannabis Need 4-Weeks Abstinence

• THC detectable in urine 3-10 days; heavy users positive 1-3 months after ceasing cannabis use.2

• Cannabis withdrawal associated with SOREMPs and REM rebound; need 4 weeks of abstinence to return to baseline.

▪ CBD/THC withdrawal can cause

SOREMPs and REM rebound, need 4-

6 weeks of abstinence if chronic use

to return to baseline.

Moeller KE et al. Mayo Clin Proc 2008;Jan 83(1):66-76

Recognizing Cataplexy in Video-PSG Recording

Clinical Characteristics of Cataplexy

• Sudden partial or complete muscle paralysis with preserved consciousness

awake triggered by strong, generally positive, emotions;

• Weakness usually begins face and neck, sometimes spreads to limbs; full

cataplexy slump to ground unable move/speak for seconds to 1-2 minutes.

• Sustained loss of muscle tone alternates with brief enhanced EMG activity

→ flapping up and down motion of body segments;

• These reported by patient as voluntary trying to fight repetitive postural

losses. Patient conscious entire episode.

Huang B et al. Fluctuation of primary motor cortex excitability during cataplexy in narcolepsy J

Clin and Transl Neurology 2018 doi: 10.1002/acn3.670

Proposed Cataplexy Event Staging Based on Behavioral and EMG Features

Behaviors cease

Stops moving or laughing

Fixed /glazed eyes

Drooping eyelids

Stiff facial expression

EMG shows no obvious or slight alterations of muscle tension

CA1 Triggering

Start twitching

Shaking and raising head

Flapping up and down of body

Postural instability

EMG: paroxysmal enhanced EMG activity against background of muscle atonia

CA2 Resisting

Loss of muscle tone gradually extends from neck, shoulder, trunk or knees ending with partial/global paralysis

EMG silent with occasional eye movement bursts

CA3 AtonicPostural tone recovers graduallyand normal motor control restored.

CA4 Recovering

Huang B et al. Fluctuation of primary motor cortex excitability during cataplexy in narcolepsy J Clin

and Transl Neurology 2018 doi: 10.1002/acn3.670

Clinical Features of Cataplexy and Pseudocataplexy

Clinical Feature Cataplexy Pseudocataplexy

Emotional trigger Most often mirth or laughter More often negative emotions

Muscle weakness

pattern

Focal or global weakness More often global weakness

Duration <1 minute, 15% >2 minutes. Long duration, minutes to even

hours

LOC Fully conscious and alert Fully conscious and alert

Comorbid symptoms Narcolepsy, sleep paralysis, hypnic

hallucinations

Depression

MSLT Short MSL with > 2 SOREMPs Normal

Neurological signs DTRs depressed during attack Normal DTRs during attack

Treatment Respond to antidepressants and sodium

oxybate

Respond to antidepressants

Cataplexy Mimics-1

Cataplexy Mimic Clinical Features

Pseudocataplexy Transient functional motor weakness; negative emotions more often trigger; last

min to h; usually generalized, depression common, respond to

antidepressants.2-4

Hyperekplexia Exaggerated startle to acoustic, tactile or visual stimuli ➔ facial grimace,

shoulder abduction, flexion neck, trunk, elbows and knees, and fall. 53,54

Gelastic syncope LOC during hearty laughter; vasodepressore syncope variant; cardiac tilt-table

abnormalities may be found. 55

Long QT

syndrome type 2

Strong emotions, sudden loud noises, abrupt arousals from sleep/rest trigger;

QTc >500 ms; EKG torsades de pointes type and ventricular fibrillation. 56-59

Cataplexy Mimics-2Cataplexy Mimic Clinical Features

KCNA1 episodic

ataxia/myokymia syndrome

Rubbery or wobbly legs and slurred speech attacks during exercise, emotional stress or illness;

examination shows head tremor, bilateral dysmetria upper and lower limbs, voice tremor,

difficulty extending legs and standing.

Coffin-Lowry syndrome Sudden drop attacks triggered by loud noises, visual threat or unexpected touch; male,

intellectual disability; responsive to sodium oxybate.60-62

Hyperkalemic periodic

paralysis

Episodic limb weakness affecting eyes and trunk with preserved consciousness; begin before

breakfast, last 15-60 minutes; emotional stress can trigger. 63,64

Epilepsy Rare case reports: gelastic-atonic;65 focal seizures with asymmetric loss of tone causing fall;66

cluster of myoclonic jerks causing fall in juvenile myoclonic epilepsy;66 ictal syncope in

temporal lobe epilepsy.67 Ictal activity on EEG.

Myotonic dystrophy type 1 Bilateral facial weakness and ptosis which fluctuates across the day accompanied by central

hypersomnia. Not triggered by emotions.

Prazosin (an a1-adrenergic blocker) precipitates cataplexy, whereas clonidine, an a2-adrenergic agonist,

decreases cataplectic attacks.23,24 Norepinephrine acts to suppress cataplexy.25

Recommended Bedtime Reading on Diagnosis of Central Disorders of Hypersomnolence, Cataplexy and Cataplexy Mimics

REFs: 1) Lammers GJ et al. Sleep Med Rev 2020; 2) Pillen S et al.Curr Treat Options 2017;19:23; 3) Reading P. PractNeurol. 2019 Feb;19(1):21-27.

Take-away Messages

• Patients undergoing MSLT to characterize and confirm central hypersomnia

need proper preparation to reduce false-positive, false-negative, and

confounding results.

• Positive urine toxic screen common in adolescents/adults MSLT

• Cannabis has significant effects on sleep, SOREMPs, and daytime sleepiness.

• Discontinue cocaine and cannabis for at least 4 weeks before MSLT.

• Functional pseudocataplexy often lasts minutes to hours, triggered by

negative emotions and associated with depression.

• Diagnosing idiopathic hypersomnia may require 48 h of extended sleep

monitoring or 7-days of wrist actigraphy.

Thanks For Your Attention

Appendix

When to Consider CSF Hypocretin-1 Levels

to Confirm Narcolepsy Type 1

1) Possible cataplexy, fragmented

insufficient sleep or sleep apnea make

MSLT difficult to interpret;

2) Cannot follow MSLT instructions

(mental age <5 or 6 y);

3) Early onset cases with negative MSLT;

4) Cannot stop psychotropics;

5) False negative MSLT, have cataplexy,

still suspect NT1;

6) Complex cases, difficult to perform

MSLT;

7) Treatment failures (have cataplexy

taking high doses of CNS stimulants

without positive response);

8) Cannot afford MSLT with PSG.

• HLA DQB1*0602 DQB1*0602-positive in 98%

of patient with NT1;

• If HLA DQB1*0602 is negative, CSF hypocretin-

1 level likely to be NORMAL

• Estimated only 1 in 500 HLA DQB1*0602-

negative will have a CSF hypocretin-1 level <

110 pg/ml; don’t do LP in them.

CSF Hypocretin/Orexin Levels Can Be Transiently Low in Some

• Transient low hypocretin-1 levels reported:

• Coma;

• Head trauma;

• Hypothalamic injury;

• Guillain-Barre syndrome

• KLS during sleepy period.

Dauvilliers Y et al. SLEEP 2012;35(10):1359-66

CSF Hypocretin-1 Levels AvailableSince April 2019 as Mayo Clinic Send Out• Patient Preparation: Patient should not have recently received

radioisotopes, either therapeutically or diagnostically, or recently been exposed to animal antigens due to potential assay interference.

• Collect: CSF 1.5 ml (adult); 0.5 ml (pediatric) in plain sterile vial with no additives (minimum volume 0.5 ml).

• Collection Instructions: • Obtain aliquot from second collection vial (preferred, not required).

• Hemolyzed specimens give false-positive results. Specimens should be centrifuged to remove any red cells prior to shipping.

• Specimen Stability: CSF Frozen120 days.

REFs: 1) Bourgin P CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurol 2008 Jul;7(7):649-

62; 2) Mignot E: Arch Neurol 2002:59;1553-62; 3) Dauvilliers Y Lancet 2007;369:4999-5112; 4) Ripley B. Neurology

2001; Dec 26;57(12):2253-8.

MSLT Criteria for NT1, NT2 and IH

MSLT Findings NT1, NT2, IH, ISS, PLMD

• REFs: 1) Drakatos P et al. Sleep stage sequence of SOREMPs in hypersomnia. J Neurol Neurosurg Psychiatry 2013;84:223-7;

• SOREMPs commonly follow N1 sleep in narcolepsy;

• Whereas REM sleep most often follows N2 or N3 in other disorders.

Sleep disorder N Age MSL Naps with

SOREMP

SOREMP after

N1

Narcolepsy type 1 25 31 ± 11 2.6 ± 1.6 63% 75%

Narcolepsy type 2 41 34 ± 9 4.0 ± 2.1 60% 52%

Idiopathic hypersomnia 21 34 ± 11 5.4 ± 1.8 1% 0%

Insufficient sleep

syndrome

20 44 ± 12 7.6 ± 3.9 7% 0%

Periodic limb movement

disorder

20 51 ± 18 10.2 ± 4.9 5% 0%

Findings on MSLT Which Increase Specificity for Diagnosis of Narcolepsy Type 1

2017 study analyzed MSLT findings in 56 NT1, 83 with Parkinson disease, 89 sleep disordered

breathing and and 23 with insufficient sleep syndrome. REF: Murer T et al. Sleep 2017;40(12).

MSLT Finding Sensitivity Specificity PPV

Mean REM latency <5 min 49% 95% 96%

Mean REM Sleep Time > 40% of MSLT

naps

60% 100% 100%

Mean REM latency <5 min +

REM% Sleep Time in MSLT > 50%

50% 99% 99%

Stage R before N2 + REM sleep % >

50% of MSLT naps

53% 96% 97%

Presence of Definite Cataplexy Coupled with EDS Sufficient to Diagnose NT1

Video-PSG of Episode of Partial Cataplexy

Dauvilliers, Y. et al. (2014) Cataplexy—clinical aspects, pathophysiology and

management strategy Nat. Rev. Neurol. doi:10.1038/nrneurol.2014.97

• Sustained loss of

muscle tone

alternates with brief

enhanced EMG

activity → flapping

up and down motion

of body segments;

• These reported by

patient as voluntary

trying to fight

repetitive postural

losses.

• Patient conscious

entire episode.

Dauvilliers, Y. et al. (2014) Cataplexy—clinical aspects, pathophysiology and management strategy

Nat. Rev. Neurol. doi:10.1038/nrneurol.2014.97

• EEG low

voltage alpha

and theta

• Heart rate

slows during

brief

suppressions

of EMG

activity

ICSD-3 Definitions of Narcolepsy

• Narcolepsy type 1 (NT1, narcolepsy with cataplexy):• Excessive daytime sleepiness

(EDS) for at least 3 months; and

• At least one of the following:• Cataplexy and a positive MSLT;

• Low CSF hypocretin-1 (< 110 pg/ml or < 1/3 of normal);

• Narcolepsy type 2 (NT2, narcolepsy without cataplexy):• EDS for at least 3 months;

• Positive MSLT;

• Positive MSLT:• A mean sleep latency (MSL ) < 8

minutes and > 2 sleep onset REM periods (SOREMPs);

• SOREMP = early appearance of REM sleep < 15 min after sleep onset

• A SOREMP on the preceding nocturnal polysomnogram (PSG) may replace one of the SOREMPs on MSLT.

Other Clinical Features of Narcolepsy• Disrupted nocturnal sleep:

• 30-95% of patients with narcolepsy;

• Frequent awakenings, shifts to N1 from W or W to deeper sleep stage;

• Vivid dreams/nightmares:• 83% of patients with narcolepsy (vs. 15% of controls) report confusing

dreams with reality;

• REM Sleep without atonia (RWA) and REM behavior disorder (RBD):3-5

• RBD: 45-61% of patients with narcolepsy vs. 1.6% general population;

• RWA on PSG 36-43% of patients with narcolepsy;

• Periodic limb movements (PLMs):6

• PLM >5/h in 25%; >15/h in 10% of patients with narcolepsy.

REFs: 1) Roth T et al. JCSM 2013; 2) Warmsley E et al. Sleep 2014; 3) Cipoli C Sleep Med 2011; 4)

Franceschini C et al. Sleep Med 2011; 5) Dauvillers Y et al. Sleep Med 2013; 6) Sasai-Sakuma et al. PLOS

One 2015.

Machine Learning Shows Mean REM Latency on MSLT Also Predictive for NT1

• 2018 study applied machine learning (ML) to data from European

Narcolepsy Network (EU-NN):

1) Cataplexy the most influential predictor for NT1;

2) Median PSG sleep efficiency significantly different between NT1 and NT2

with poorer sleep efficiency in NT1: NT1 sleep efficiency 86% [80-91%]

vs. NT2 94% [90-96%])

3) Odds ratio 18.8 of positive HLA DQB1*0602 in NT1 vs. NT2

4) Median REM sleep latency on MSLT shorter in NT1 vs. NT2 (4.8 vs. 8 min);

5) Mean PSG REM sleep latency shorter in NT1 vs. NT2 (14 vs. 59 min).

6) Hypnic hallucinations increased OR for NT1 by 2.4 times.

Narcolepsy Type 1: State Control Disorder

• Patients with

narcolepsy have

only a little more

sleep than controls

Compare Hypnograms NT1 vs. IH