IgLON5 parasomnia

Ʒ®IgLON5®ƿƓǈǥĚėVRƘǨǔǠǖƻ¹ǆƺȊȡȞȗȪȞȗȋțǽȗȇǫȱČľǘŌĲƅƾǣ®HǘP|ȤċĀyēÎŦǗƺǌǥĺ¸ēĞĥƸø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

IgLON5 parasomnia
q A novel sleep disorder involving both nREM and REM sleep
q Obstructive sleep apnea / vocal cord palsy
q Other neurological symptoms (dysphagia, chorea, dysautonomia)
q Antibodies against a neuronal surface antigen (IgLON5)
q Neuronal loss and tau protein deposits in brainstem and hypothalamus

IgLON5ȋțǽȗȇǫȦ®IgLON5®ƓƂȋțǽȗȇǫȧǔǙȲp ȞȗȪȊȡȞȗĚėºǘĆǨǔǠǖƻ¹ǆƺĚėƓƂĊ¡p Ɛh øVRȪjƭčǨSǈǥp Ǌǘǜƾ]ƘƴŐŵƄBƴōĢĲČüǨSǈǥp ĢĲİŅśƟǘ®HȦIgLON5ȧǗǈǥ®ƿƓǈǥp ċĀyēǗŉȤšƇǘĢĲİŅňŔǔǾǭŗĒŕĤǨŬǟǥø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Clinical features (n = 8 patients)ø¸ŷźȤŞŝģISMSJfȓȥȗȒȥǸwW

Five women and three men.
Median age at disease onset: 59 years [range 52–76]
All 8 had abnormal sleep movements and behaviors with obstructive sleep apnea
IgLON5ȋțǽȗȇǫǘŌēûȦn=8ȧȱ u ȮȨă ȭƴđČƮǘq#59ÛȦ52-76Ûȧ.ǓĚėǘĆƄBȤřBǔƐh øVRǨŬǟǌ§ Ĳƅľǔ ĲƅľǗp8

Two clinical presentations
Chronic: n = 6

Subacute: n = 2

Median disease duration: 5 years

Disease duration: 2 and 6 months

Presenting and major symptom:• Sleep disorder: 4• Gait instability / falls: 2
Associated symptoms:• Bulbar symptoms: 6• Dysautonomia: 6• Chorea: 4• Central hypoventilation: 2• Cognitive impairment: 1

Presenting and major symptom:• Gait instability / falls: 2
Associated symptoms:• Sleep disorder: 2• Bulbar symptoms: 2• Central hypoventilation: 2§

ĲƅľȦn=6ȧ

• Ĳƅ¶ǘq#5
• ǖČüȱƯĚėĆ4ƴÚřƘ/Àŷ!2• ƓƂČüȱƯÿƭč6ƴōĢĲČü6ƴŐŵƄB4ƴƳƳƳƳƳƳƳƳƳÊ ³á2ƴŬĜ1ĲƅľȦn=2ȧ

• .ĲƅǙN2ȣÄǔ6ȣÄ• ǖČüȱƯÚřƘ/Àŷ!2• ƓƂČüȱƯĚėĆ2ƴÿƭč2ƴÊ³á2

Clinical features of the sleep disorderØ Patients reported restless sleep and diurnal fatigue
Ø No reported insomnia or abnormal circadian patternØ Bed partners reported abnormal movements and dream-enacting behaviors
Ø Patients did not recall nightmaresØ Bed partners noticed an abnormal respiratory noise in sleep
Ø Bed partners witnessed apneic events

IgLON5ȋțǽȗȇǫǗǞǣǦǌĚėĆǘûȱØ ¡ŀǙĚėǘŔǎęǀǘǖǅǡ½ǘĉ@¥ǨōŢǆǒƺǌØ ėǡÏ½ȜǺȗĆǘōŢǙǖƾǏǌØ ȑȀȅȋȥȄȆȥǙĚėǘĆƄBǡoÑřBǨĔ´ǆǒƺǌØ ¡ŀōŶǗǙ¢oǨǞǌŧ¨ǙǖƾǏǌØ ȑȀȅȋȥȄȆȥǙĚėǘĆǖVRƠǗáǑƺǒƺǌØ ȑȀȅȋȥȄȆȥǙøVRǬȑȡȄǨĔ´ǆǒƺǌø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Ancillary studies
Brain MRIǘÎËǓǙĆǨŬǟǉ

DAT-SPECTEEGNORMALEMGCSF analysis• ŉMRI• ȅȋȖȡȄțȡǹȔȥǾȥǷȡǿ• ŉå• ĩƝb• ƪêȦǰȞǲǷȡȤ¼Ĝǘ®ȧ(hypocretin levels and known antibodies)

HLA typing (in 4 of 4 patients): DQB1*0501 and DRB1*1001 alleles(1.5% in the Spanish population)HLAȦȌȄĒŘÿ®HȧÎËǨ}»ǆǌ¡ŀ4Q.WǓDQB*10501ǔ
DRB1*1001ƿƕ ǓƹǏǌȦƺǉǦǠǹȒǬȡǓǘƕ ýǙ1.5%ȧƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWVideo-polysomnography
Ø Normal occipital alpha rhythm during wakefulness
Ø Total sleep time and sleep efficiency were slightly reduced
Ø NREM and REM sleep are characterized by abnormal sleep
architecture plus abnormal motor activation
Ø Obstructive sleep apnea and mild stridorȍȃǰPÁŧƏPSGȱØ ŢƋÁǙÙǖƤƇ*BǨŬǟǌƵØ .ĚėÁƒǔĚėAýƿǡǡîƵØ -ėÁǘ©şǙƴưĚėßƖǨ78ǆƿǌƺȊȡȞȗĚėƱƴƹǥƺǙƥļǖĆƄBǨǔǠǖƻưÙÐƁǘǖƺstage N2ƱƵÙǖstage
N1ƴN2ǙǜǔǩǕŬǟǖƾǏǌƿƴÙǖstage N3ǙŬǟǌƵȞȗĚėǓǙRBDPÑǘĆƄBǨŬǟǌƵØ ƐhøVRǗƓƂǆǌŸƺ[ƬǨŬǟǌƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWPoorly structured Non REM sleep
EOG-A1
EOG-A2
F3-Ref
F4-Ref
C3-Ref
C4-Ref
O1-Ref1s

75 µV

O2-Ref
Chin
EKG
FDS L
FDS R
AT L
AT R
EDB L
EDB R
Nas
ThoAbdø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWȦ<ơȧÙÐƁǘǖƺȊȡȞȗĚėÇĊ¡ǘĚėǓÃǠûēǖĆ©şǙƴÃ6ǘ-ėǡžŢƋǘ
1-ėƿưĚėßƖǨ78ǆƿǌƺȊȡȞȗĚėȦundifferentiated NREM
sleepȧƱƴƹǥƺǙưÙÐƁǘǖƺstage N2Ȧpoorly-structured stageN2ȧƱǓvǝǥǃǔǓƹǏǌƵƺǉǦǘȊȡȞȗĚėǔǠƥļǖĆƄBȤřBǨŬǟǌƵưĚėßƖǨ78ǆƿǌƺȊȡȞȗĚėƱǓǙƴŠ;ǖǷȥǾƣdǘåèBƿì-ǆǌƿƴƤƢƇƍåǡKŞOȤįƎåǨŬǟǖƾǏǌƵȞȗĚėÁǔPÑǘƀĘÿƄBǨŬǟǌƵưÙÐƁǘǖƺstage N2ƱǓǙƴKŞOȦěFȧǡįƎåǘ3þƥƿƺºǓƴƥļǖĩèB¾ǡƄBǨŬǟǌƵǝǦǗȞȗĚėÁǢǤǠ±ǖƀĘÿƄBǨŬǟǌƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWPoorly structured N2 sleep
Vocalizations: Simple (e.g, whispering, groaning) or complex (e.g, talking, laughing, crying)
Movements: Simple (e.g, limb raising, punching), or finalistic (e.g, eating, manipulation of objects)ȦȍȃǰţȧÙÐƁǘǖƺstage N2
đjȱ EĮǖđjȦ^ǁƴYǥȧ
ŞƚǖđjȦŪǈȤħƻȤæǁȧƄBȱ EĮǖBǀȦŊǨ°ǈǥƴÞǥȧ
OĔēǖBǀȦƨǛǥƴúǨ\ĂǗ«ƻȧø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Diffuse delta activity mixed with sleep spindles
EOG-A1
EOG-A2
F3-Ref
F4-Ref
C3-Ref
C4-Ref
O1-Ref
O2-RefChin

1s75 µV

EKG
FDS L
FDS RAT L
AT R
EDB L
EDB R
NasThoAbdø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWȦ<ơȧâȃȝǾèBǔįƎåĚėǘDǓǙƴįƎåȦěFȧǨǔǠǖƻâ ȃȝǾèBƿ{|ǆǒ3þǆƴÙǖstage N3ǔ7|ǅǦǌƵǃǘƒƴĆǖđjǡƄBǙǞǣ
ǦǖƾǏǌƵ
IgLON5ȋțǽȗȇǫǙƴÙǖstage N3ƿǞǣǦǥ÷ǓƴagrypniaexcitataȦ¯Ķēǖŏt ėü¦ȧǡstatus dissociatusȦ¯ĶēǖŤƛü¦ȧǖǕǘĚėƓƂċ¦ǔǙĆǖǥƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

REM sleep behavior disorder
EOG-A1
EOG-A2
F3-Ref
F4-Ref
C3-Ref
C4-Ref
O1-Ref
O2-RefChin

1s75 µV

EKG
FDS L
FDS R
AT L
AT R
EDB L
EDB R
NasThoAbdø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWȦ<ơȧȞȗĚėřBĆČȦRBDȧȞȗĚėǙƥļǗƇȤ_łǘôǆƺƄBƿ3þǆƴRBDǔ7¸ǅǦǥü¦ǓƹǏǌƵºƴưÙÐƁǘǖƺȊȡȞȗĚėƱǔàŹǆǒƴđjǡŞƚǖƄBƿǞǣǦǥƥǙƾǏǌƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Treatment and outcomeTreatment
All patients had immunotherapy ( IV steroids, cyclophosphamide, IVIg, rituximab)
No striking improvement was seenäďȱ
Ƴ.ǒǘ¡ŀǗ,ĈyēäďƿřǧǦǌƿȦǹȂȟǬȅȤǷǳȟȎǯǹȎ
ƳǪȖȅȤ,ĈǴȟȏȜȡȤȜȁǲǷȕȏȧƴÅ¤ǖµZǙǞǣǦǖƾǏǌ

OutcomeDeath: 6 patients

5 at home suddenly

2 during wakefulness
2 during sleep
1 Unknown

1 in the ICUȱƳȰQȯQƿÜƵƻǎȫQǙICU-~ƴÝǤ5QǙōzǓǘĦùÜƳȦŢƋÁȬQƴ ȬQƴūȫQȧƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

New neuropathologic findings
In 2 patients- Slow progression (59 yrs male, duration 6 yrs)
- Subacute progression (76 yrs female, duration 6 months)

Neuronal loss and tau deposits seen only in neurons• Anterior and posterior Hypothalamus

HEGallyas silver stain

Gallyas silver stain• Tegmentum of the brainstem- Laterodorsal tegmental area
- Periaqueductal gray matter- Pedunculopontine nucleus- Magnocellular nucleus- Nucleus ambiguus

Tau/AT8

Tau/AT8

Tau/AT8Basis Pontis

No other abnormal protein deposits (e.g beta-amyloid or alpha-synuclein)
No inflammatory infiltratesø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWȦ<ơȧ¹ŠǘĢĲċĀ©şȬǓĢĲċĀ©şǨÎŦȦ§ĲƅľȤĲƅľǘN1ȧƵȬǔǠšƇǔŉŜŖȦńl&ŜŖƴõĒŴƴŇÔÌƴpİŅ
ÌƴćÌȧǓĢĲİŅňŔǔǾǭŗĒǘãęǨŬǟǌƵ
ǾǭŗĒ2ƙǙĢĲİŅ0ǘǞǗpretangle/neuropil threadǘǓāǇǒƽǤƴǴȜǫİŅ0ǓǘãęǙŬǟǖƾǏǌƵ
ǜƾβǫȖȟǬȅǡαǷȈǳȞǬȡǘãęƴöČ

kCǙŬǟǖƾǏǌƵ

Ƴ↓Ƴ↓Ƴ↓
ǃǦǣǘĢĲċĀyēûǢǤƴIgLON5ȋțǽȗȇǫǙPSP/CBDǖǕǔǙĆǖǥ¹sǘǾǭǰȋǿȥǓƹǥǃǔƿġXǅǦǌƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWIgLON5 parasomnia
q A novel sleep disorder involving both nREM and REM sleep
q Obstructive sleep apnea / vocal cord palsy
q Other neurological symptoms (dysphagia, chorea, dysautonomia)
q Antibodies against a neuronal surface antigen (IgLON5)
q Neuronal loss and tau protein deposits in brainstem and hypothalamus

IgLON5ȋțǽȗȇǫȦ®IgLON5®ƓƂȋțǽȗȇǫȧǘǝǔǟ
p ȞȗȪȊȡȞȗĚėºǘĆǨǔǠǖƻ¹ǆƺĚėƓƂĊ¡p Ɛh øVRȪjƭčǨSǈǥ
p Ǌǘǜƾ]ƘƴŐŵƄBƴōĢĲČüǨSǈǥ
p ĢĲİŅśƟǘ®HȦIgLON5ȧǗǈǥ®ƿƓǈǥp ċĀyēǗŉȤšƇǘĢĲİŅňŔǔǾǭŗĒŕĤǨŬǟǥø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Multiple sclerosis• Inflammatory autoimmune demyelinating disease of CNS(relapsing-remitting / chronic progressive)• Multiple symtoms and signs (motor, sensitive, visual, etc)
• Sleep symptoms
RBD
Narcoleptic phenotype
Insomnia!!!!!!!! (anxiety, depression, fatigue)mđĠCČl ÊĢĲǘöČ Ȥō,Ĉ Ȥňƪ Ċ¡Ȧ1đŤȪ§ ƃřȧl ċƇǗǢǤmǖČüǨSǈǥȦƄBČüƴ ¥ŢČüƴšŢČü
ǖǕȧl ĚėƓƂČüȦRBDȩȆȝǵȞȐǷȥÑČüƴ{ȤƻǐȤ$¥ǨǔǠǖƻėȧø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

RBD in MS is related topontine demyelinating plaques
Plazzi G, et al.
Remitting REM sleep behavior
disorder as the initial sign ofmultiple sclerosis.
Sleep Med 2002;3:437-439
Tippmann-Peikert M, et al.
REM sleep behavior disorder
initiated by acute brainstem
multiple sclerosis.
Neurology 2006;66:1277-1279

mđ ĠCČǓǙÔǘňƪċkǓRBDǨđČǆƻǥø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

RBD in MS is related topontine demyelinating plaquesmđ ĠCČǓǙÔǘňƪċkǓRBDǨđČǆƻǥø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Resemblances betweennarcolepsy and multiple sclerosis• Autoimmune basis is suspected• Associated with HLA DR2• Affect young people• Hypersomnia is common (not cataplexy)• A few reported cases having both conditionsȆȝǵȞȐǷȥǔmđ

ĠCČǘƧ÷ȱl ńÂċ¦ǔǆǒō,ĈǘƓƿćǧǦǥ
l HLA-DR2ƿƓƂǆǒƺǥLņ ƿƹǥl ŒǗmƺl ƅėČüǨSǈǥȦ£Bň>đǨǘǋǁȧl ŀǨOǆǌǔǈǥfTƹǤø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Reversible
MS ATTACKSecondary narcolepsy
ACUTE EDS, NO CATAPLEXYin multiple sclerosis MSLT: SL 3/5 SOREMP
MRI: HYPOTHALAMIC DAMAGE
CSF HYPOCRETIN UNDETECTABLE
STEROIDSEDS RESOLUTIONNORMAL MSLTNORMAL MRICSF HYPOCRETIN 211 pg/mLšƇċkǗǢǤƅėČüǨSǆǌmđl đČĕȱĠCČȱôǖ½(ė3þƴ£Bň>đȦ−ȧƴMSLTǗǒSOREM3/5`MRIǗǒšƇċk3þƴƪêǰȞǲǷȡÎ3¥l ǹȂȟǬȅȱ ½(ėérƴMSLTǗǒSOREMǖǆƴMRIǗǒšƇċkérƪêǰȞǲǷȡƯ211pg/mlȦÙȧø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWƪêǰȞǲǷȡ#1đÁŤÁ

In MS patients without EDS
and no lesions in the
hypothalamus, CSF
hypocretin is normal bothduring the attack andremission½ǘƅǘėáǨSǅǉƴšƇċkǨÖǁmđ ĠCČ¡ŀǓǙƴƪêǰȞǲǷȡ#Ǚ1đÁǠŤÁǠÙǓƹǏǌƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWConclusions of REM sleep disorders in MS• Secondary RBD occurs in MS patients with demyelinatingplaques in the pontine tegmentum• Secondary narcolepsy occurs in patients with demyelinatingplaques in the hypothalamusmđĠCČǓāǇƻǥȞȗĚėƓƂČüǘǝǔǟȱl ÔŜŖǘňƪċkǓl šƇǘňƪċkǓ×ēǗRBDƿāǇǥǃǔƿƹǥ×ēǗȆȝǵȞȐǷȥČüƿāǇǥǃǔƿƹǥø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW