AUTOIMMUNE DISORDERS ANDSLEEP.

Alex Iranzo
Neurology Service
Hospital Clinic de Barcelona
Spainø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWűòǹțǬȅǘ/ƑǗƹǌǏǒƳ ǃǘǌǚƴAlex Iranzo+āǘǄG¤ǗǢǤĨ7`ISMSJyŚƙȄȠǬțǬȄǻȖȆȥƯ ”Autoimmune Disorders andSleepȦō,ĈĆǔĚėȧ”ǘűòǹțǬȅǨISMSJǭǮȏǶǬȄǗ/ƑǈǥǃǔǗǖǤǝǆǌƵƳ ÇǻȖȆȥǓǙƴĚėĆǨSǆƻǥō,ĈĊ¡Ǘǐƺǒƴ®ĢĲ®ƓƂĊ¡ǔmđ ĠCČǨǗűòƺǌǍǀǝǆǌƵǝǉĸŰǔǆǒŉǘċkƇǄǔǗǕǘǢƻǖĚėƓƂĊ¡ƿāǇƻǥƾǘŤŮƿƹǤƴ×Ǘ
ÈĜǣǦǒƺǥ®ĢĲ®ƓƂĊ¡ǘĚėĆǘNŰǨÓbǔǔǠǗƽġǆƺǌǍǀǝǆǌƵĶƺǒ¹ǆƺĚėƓƂĊ¡ưIgLON5ȋțǽȗȇǫƱǗǐƺǒūİǖŤŮƿƹǤǝǆǌƿƴǃǘŪƦǗǐƺǒǙŌēûƾǣ
PSG©şǘûȤċĀ©şǗeǑǁċ¦ŰǝǓǘĭĵēǖ0ǓƴŁűŀƿŌĞĥǘƉƊUǨżƩǓǀǥȐȞǼȡȂȥǷȚȡǓǆǌƵÃǗmđ ĠCČǘĚėĆǘĜşǗǠťǦǒƺǌǍǀǝǆǌƵō,ĈĊ¡ǘĚėĆǙƜŤǖƣdǓǈƿƴÇǻȖȆȥǓǙpkǧƾǤǡǈǁŤŮƺǌǍǀǝǆǌƵƳ ǖƽ/ƑǗƹǌǤƴISMSJfȓȥȗȒȥǸwWǗǒƆŨǔŤŮǨż?ƺǌǆǝǆǌƵÇǹțǬȅų·ǘ5ǘø¸ŞŝȤŷźǨģǇǝǈƵISMSJfȓȥȗȒȥǸwWƲŤŮǓǙǘąŭǨĂƺǝǆǌƵ
ƳƳPSG = polysomnography ınĚėȔȜǴțȎ
ƳƳMSLT = multiple sleep latency testƳIĚėóÁð|RBD = REM sleep behavior disorderƳȞȗĚėřBĆČ
SOREM = sleep onset REM sleepƳ-ėĕǘȞȗĚė

ƲŤŮǓǙǘĂŭǨĽǀ³ƼǒĂƺǝǆǌƵƳƳHypocretinƳȌȔǳȞǿȡƯƳƳƳƳƳƳ→ƳOrexinƳǰȞǲǷȡƳƳREM with increased EMG activityƳ→ƳREM sleep without atonia, RWAƳĩèBǨǧǖƺȞȗĚėø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Autoimmune disorders of the CNS
Are characterized by an abnormal immune mediatedresponse (humoral and/or cellular) against antigens
expressed in the central nervous systemÊĢĲĭǘō,ĈĆȦĊ¡ľȧǔǙȲ
Ê¶ĢĲĭǗđþǈǥ®HǨÒēǔǈǥƴ
Ćǖê ȤİŅ ,ĈIǨûǔǈǥĊ¡ľǓƹǥƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Autoimmune disorders of the CNS
associated with sleep abnormalities• Diseases associated with neuronal antibodies
Paraneoplastic or benign limbic encephalitis
Morvan syndrome
IgLON5 parasomnia• Multiple sclerosisĚėĆǨǀǌǈÊĢĲĭǘō,ĈĊ¡ǗǙƴ®ĢĲ®ƓƂĊ¡ǡmđ ĠCČǖǕƿƹǥƵ
®ĢĲ®ƓƂĊ¡ǗǙƴ'ŋĎ Ȫő ŻĹĭŉöƴ
ȘȝȢǪȡČ"ľƴ®IgLON5®ƓƂȋțǽȗȇǫƿƹǥƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Sleep abnormalities••••

Hypersomnia (narcoleptic-like)
Insomnia
Parasomnia (REM behavior disorder)
Disrupted sleep architectureǃǦǣǘċ¦ǓǞǣǦǥĚėǘĆǔǆǒƴȆȝǵȞȐǷȥ
ƧǘƅėƴėƴȋțǽȗȇǫȦRBDȧƴĚėÐīǘğķ
ǖǕƿƹǥƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Narcolepsy
•
•
•
•
•

Hypersomnia
Cataplexy
MSLT: Sleep onset REM sleep
Low or absent hypocretin in CSF
Posterior hypothalamic impairmentȆȝǵȞȐǷȥǙƅėǡ£Bň>đȦǱǾȐȞǲǷȥȧǖǕǨ ǔǈǥĊ¡ǓƹǥƵMSLTǓSOREMǨŬǟƴƪêÎËǓǙǰȞǲǷȡ
ƿ#ǝǌǙð|¥ÆñǓƹǥȦƽǠǗ£Bň>đǨƻǾǬȐǘgOȧƵƇšƇǘƘƿHaǔǅǦǒƺǥƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

REM sleep behavior disorder••••Dream-enacting behaviors
Nightmares
PSG: REM with increased EMG activity
Brainstem and limbic system impairmentȞȗĚėřBĆČȦRBDȧǙƴȞȗĚėǘo0ǗŎǆǌœƶ
ǆƺřBǨ ǔǈǥĊ¡ǓƹǥƵĆřBƴ¡ŀǙ¢oǨǞǒƺ
ǥǃǔƿmƺƵPSGǓǙƷĩèBǨǧǖƺȞȗĚėȦRWAȧƸǨ
ŬǟǥƵŉǔŻĹĭǘĆƿHaǔĿƼǣǦǒƺǥƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Sleep structues damaged• Mesopontine tegmentum / medulla (RBD)• Hypothalamus (Narcolepsy)• Amygdala (RBD + Narcolepsy)ĚėĆǨǀǌǈō,ĈĊ¡ǘƽǠǖŲċkǔǆǒƴ• ŉǘÔŜŖȪƪċk →ƳRBD• šƇċk
→ƳȆȝǵȞȐǷȥČü
• ŻĹĭǘªÍċk→ƳRBDȨȆȝǵȞȐǷȥČüø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWDisorders associated with neuronalantibodies
q Potassium channel Ab-Limbic encephalitis
q Anti-Ma2 encephalitis
q IgLON5 parasomniaĚėĆǨǀǌǈƽǠǖ®ĢĲ®ƓƂĊ¡ǔǆǒƴ• ®VGKCȦƝx ǱȜǭȗǿșȉȝȧ®ƓƂŻĹĭŉö• ®Ma2®ƓƂŻĹĭŉö• ®IgLON5®ƓƂȋțǽȗȇǫø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Potassium channel Ab-Limbic encephalitis• Reversible autoimmune disorder• Non paraneoplastic• High serum VGKC titers (ILG1 and Caspr2)• Limbic syndrome without brainstem damage• Memory deficit, confusional state, seizures• REM SLEEP BEHAVIOR DISORDER®VGKC®ƓƂŻĹĭŉöǙƴLŽ ǘō,ĈĆǗǢǤāǇǥƞ'ŋĎ ǘŉöǓƹǥƵŘí®VGKC®ƿƫ>ǓÎ3ǅǦǥƵƽǠǖČüǙŧ¨Ƙƴì ƴǒǩƾǩđǖǕǓƹǥ
ƵſǙŻĹĭČüƿ ǓƴŉǘƘǙǧǖƺƵRBDǨO
ǆƻǥƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Iranzo, et al. RBD in VGKC-Limbic Encephalitis. Ann Neurol 2006;59:178-182

®VGKC®ƓƂŻĹĭŉöČǗƽǂǥũ¸Áǘ©şȱ
A: MRI-T2ůĄ)ǗǒŻĹĭǘƫ

MCǨŬǟǥƵŉǗĆǙǖƺƵ

B: PSGǗǒȞȗĚėǗphasicǖĩèB¾ǨŬǟǥȦRWAȧƵ
Iranzo, et al. RBD in VGKC-Limbic Encephalitis. Ann Neurol 2006;59:178-182ø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW®VGKC®ƓƂŻĹĭŉöČǗƽǂǥäďǘ©şȱ
A: MRI-T2ůĄ)ǓǙƴŻĹĭǘ

MkCǙérǆǌƵ

B: PSGǓǙƴȞȗĚėǘĩèBǙ¬9ǅǦƴÙǖȞȗĚėǔǖǏǌƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Iranzo, et al. RBD in VGKC-Limbic Encephalitis. Ann Neurol 2006;59:178-182

®VGKC®ƿƓǈǥō,ĈĊ¡ľ15ČǘĚėĆǨůǛǌȦŻĹĭŉö5QƴȘȝȢǪȡČ"ľ4QƴŀǘŞOċ¦6QȧƵ
ĳÉƴ14ČǗë:ǖĚėĆǨŬǟǌȦėƴoÑřBƴnƒ
ǒǩƾǩćƺƴƅėȧƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Cornelius JR, et al. Arch Neurol 2011;68:733-738

Anti-Ma2 limbic encephalitis• Autoimmune disorder

ŻĹĭ

pŉDÿ

• Serum anti-Ma2 titers• Paraneoplastic(testicular and lung cancer)• Limbic syndrome plus

ŉ

• Limbic syndrome precedes cancer• RBD + narcolepsy-like phenotype®Ma2®ƓƂŻĹĭŉöǙƴĬĐǡŃĐǖǕǗƗǈǥ'ŋĎ ǘŉöǓƹǥƵŻĹĭČüǨ ǔǈǥƿƴpŉČü
ǡŉČüǠOǆƻǥƵŻĹĭČüƿŋĎǘũ¸Ǘ+řǈǥǃǔƿmƺƵRBDǡȆȝǵȞȐǷȥƧǘĚėĆǨāǇǥƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Dalmau J, et al. Brain 2004;127:1831-1844

HYPERSOMNIANO CATAPLEXYPSG OR MSLT NOT DONE
MRI: HYPOTHALAMIC DAMAGE
CSF HYPOCRETIN 58 pg/mL®Ma2®ƓƂŉöČǗǞǣǦǌƅėČüȱ
71Ûă ƴı½ǘ(ėČüǨSǆǒJũƵ
Ţǡ£Bň>đǖǆƵ
PSG/MSLTÆ»řƵMRI-FLAIRǗǒšƇǗƫ MƹǤƵƪêǰȞǲǷȡ58pg/mlǔȦÙ>110pg/mlȧƵǹȂȟǬȅĲK­Ǘǒ(ėČüµZƴšƇǘ MkCŸîƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Rojas-Marcos I, et al. Neuro Oncol 2007;9:75-77

HYPERSOMNIACATAPLEXY
PSG : RBDMSLT: 2 SOREM
MRI: NORMALHYPOCRETIN NOT MEASURED®Ma1/Ma2®ƕÌ çšƭčȱ

ǘªÍĐČǗǞǣǦǌȆȝǵȞȐǷȥȤRBDȤ

55Ûă Ƶƅƨǔƌi?ǓđČǆƴcĕ ĘÿƄBƘƴ(ėƴnƒǘĚė4¸CǔĚėĆřBƴ£Bň>đƴšƿĖ×ƺǓ3þƵPSGǗǒnƒĆřBǔRWAǨƴMSLTǗǒĚėóÁĝĻǔSOREM2/5`ǨŬǟǌƵƤƇMRIǙĆǖǆƵƪêǰȞǲǷȡǙÆÎƵđČ7ȣÄÁ÷ǓªÍĐǔũ¸ƵǹȂȟǬȅǔ,Ĉ¬9=­ǗǒČüƃřƿ%ØƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWSLEEP 2007;30:767-769

HYPERSOMNIANO CATAPLEXY
PSG : RBD + SLEEP EFFICIENCY 48%
MSLT: 4 SOREM
MRI: NO HYPOTHALAMIC DAMAGE
CSF HYPOCRETIN 49 pg/mLRBDǔȆȝǵȞȐǷȥǘŌēûƿǞǣǦǌ®Ma2®ƓƂŉöČ
69Ûă ƵȭȣÄƒǓƌǘƅėȤŧ¨ƘȤȋȥǲȡǽȇǺȗȤĘÿƄBƘƿ3þ
Ƶ£Bň>đȤĚėƭčȤ-ėÁŢȤƫïȤƌi?ǙŬǟǉƵPSGǗǒRWAǔ
ĆřBƴĚėAýȦ48%ȧƹǤƵMSLTǗǒSOREM4/5`ƵMRI-RLAIRǗǒ&ǘŉńl&ȤªÍȤš'ÙƇǗƫ MċkƹǤƴšƇǗċkǖǆƵƪêǰȞǲǷȡ49pg/mlǔƵ®Ma2®ƕ ǍƿŋĎÇ¿ƵRBDǔȆȝǵȞȐǷȥ
ǘûǙǔǠǗȞȗĚėǘĆǗƓƂǆǒƽǤƴ(1)ǃǦǣǙªÍǨǙǇǟǔǈǥċk
ǓSǆƻǥǃǔƴ(2)®Ma2®ƓƂŉöǓ3þǆƻǥǃǔƴƿġXǅǦǌČƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW®Ma2®ƓƂŉöČǘMRIȦČüǔŲċǔǘȧ

Limbic syndromeŻĹĭČüǘŲċȦªÍȧ
Brainstem syndromeŉČüǘŲċ
Anti- Ma2®Ma2®ƕø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWConclusions on sleep disorders
associated with neuronal antibodies
RBD and a narcoleptic-like phenotype may occur
due to direct or indirect damage of either thebrainstem, amygdala or posterior hypothalamus®ĢĲ®ƓƂĊ¡ǗƽǂǥĚėĆǘǝǔǟȱ
RBDǡȆȝǵȞȐǷȥÑǘŌČüƿƴŉȤªÍȤƇšƇǘƺǉǦƾǘĕ²ēǝǌǙƒ²ēǖƘǗǢǏǒ3þǈǥǃǔƿƹǥƵ
ȦƘƇǗǢǤƴRBDǝǌǙȆȝǵȞȐǷȥÑČüǘƺǉǦƾƴƹǥ
ƺǙǊǘºƿ3þǈǥƵƔǘǹțǬȅǗǊǘŮ¿ǘÓbƿĶǁȧø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

POSTERIOR HYPOTHALAMUS
ƇšƇȞȗĚėǨǐǁǤǍǈ
ÊǙŉǓƹǥƵ
ȞȗĚėƴŉǙƇšƇǡªÍǔǘĖ ƂĴǨǆǌůĪǨJǂǒƺǥƵ

Hypocretin ǰȞǲǷȡAMYGDALA ªÍ
Glutamate ǴȝǾȖȡƈ

BRAINSTEMŉƯ

GABA, Glutamate GABA, ǴȝǾȖȡƈ

REM SLEEPø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

POSTERIOR HYPOTHALAMUS
ƇšƇȆȝǵȞȐǷȥǡ
RBDǘđþǗǙƴ
ªÍǘÕņĆȦĆǖè CȧƿƓǈǥƵHypocretin ǰȞǲǷȡAMYGDALA ªÍ
Glutamate ǴȝǾȖȡƈ

BRAINSTEMŉƯ

GABA, Glutamate GABA, ǴȝǾȖȡƈ

REM SLEEPø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Narcolpesy
RBD

POSTERIOR HYPOTHALAMUS
ƇšƇ
Anti potassium-LE®VBKC®ƓƂŻĹĭŉöČǓǙƴHypocretin ǰȞǲǷȡ ªÍċkǗǢǤƳ
RBDƿǞǣǦǌƿƴ
ƇšƇǙÙǓƹǏǌǌǟȆȝǵ
ªÍ ȞȐǷȥČüǙǞǣ
ǦǖƾǏǌƵ

AMYGDALA

Glutamate ǴȝǾȖȡƈLimbic damage
No brainstem damage
No hypothalamic damage
RBD
Normal hypocretin
No narcolpesyø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

BRAINSTEMŉƯ

GABA, Glutamate GABA, ǴȝǾȖȡƈ

REM SLEEP

RBD

Anti Ma2 LE

POSTERIOR HYPOTHALAMUS
ƇšƇ®Ma2®ƓƂŻ
Hypocretin ǰȞǲǷȡ ĹĭŉöČǓǙƴƇšƇċk
ǗǢǤȆȝǵȞȐǷ
ȥČüȦƅėȧƿǞ
ǣǦǌƿƴªÍǙªÍ ÙǓƹǏǌǌǟRB
DǙǞǣǦǖƾǏǌƵ

AMYGDALA

Glutamate ǴȝǾȖȡƈ
Hypothalamic damage
Low hypocretin
No brainstem damage
No limbic damage
No RBD

BRAINSTEMŉƯ

GABA, Glutamate GABA, ǴȝǾȖȡƈ

REM SLEEPø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Narcolepsy

POSTERIOR HYPOTHALAMUS
ƇšƇ

Anti Ma2- LE

8ǘ®Ma2®ƓHypocretin ǰȞǲǷȡ ƂŻĹĭŉöČǓǙƴªÍċkǔŉċkǗǢǤȆȝ
ǵȞȐǷȥČüȦƅėȧ
ǔRBDƿǞǣǦǌƵ

AMYGDALA ªÍ

Glutamate ǴȝǾȖȡƈ

BRAINSTEM
Limbic + brainstem damage
Low hypocretin
RBD
Narcolepsyø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWŉƯ

GABA, Glutamate GABA, ǴȝǾȖȡƈ

REM SLEEP

Narcolepsy
RBD

Sleep disorders associated withneuronal antibodies• REM sleep behavior disorder- Brainstem damage (anti-Ma2 LE)- Amygdalar dysfunction (Potassium channel LE)• Narcolepsy-like phenotype- Posterior hypothalamic damage (Hypersomnia)- Amygdalar dysfunction (Cataplexy)ŽǗHaŰƾǣǞǥǔƴRBDǙŉƘȦ®Ma2®ƓƂŻĹĭŉöȧ
ǡªÍÕņĆȦ®VGKC®ƓƂŉöȧǓƴȆȝǵȞȐǷȥÑČü
ǙƇšƇƘȦ→ƅėȧǡŻĹĭÕņĆȦ→ǱǾȐȞǲǷȥȧǓ
ǞǣǦǥƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

IgLON5 parasomnia

Ʒ®IgLON5®ƿƓǈǥĚėVRƘǨǔǠǖƻ¹ǆƺȊȡȞȗ
ȪȞȗȋțǽȗȇǫȱČľǘŌĲƅƾǣ®HǘP|ȤċĀyē
ÎŦǗƺǌǥĺ¸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®ƓƂȋțǽȗȇǫȧǔǙȲ
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

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-SPECTEEGNORMALEMG
CSF 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%ȧƵ
ø¸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*BǨŬǟǌƵ
Ø .ĚėÁƒǔĚėAýƿǡǡîƵØ -ėÁǘ©şǙƴưĚėßƖǨ78ǆƿǌƺȊȡȞȗĚėƱƴƹǥƺǙ
ƥļǖĆƄBǨǔǠǖƻưÙÐƁǘǖƺstage N2ƱƵÙǖstage
N1ƴN2ǙǜǔǩǕŬǟǖƾǏǌƿƴÙǖstage N3ǙŬǟǌƵȞȗĚ
ėǓǙRBDPÑǘĆ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
Tho
Abd
ø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWȦ<ơȧÙÐƁǘǖƺȊȡȞȗĚė
ÇĊ¡ǘĚėǓÃǠûēǖĆ©şǙƴÃ6ǘ-ėǡžŢƋǘ
1-ėƿưĚėßƖǨ78ǆƿǌƺȊȡȞȗĚėȦundifferentiated NREM
sleepȧƱƴƹǥƺǙưÙÐƁǘǖƺstage N2Ȧpoorly-structured stage
N2ȧƱǓvǝǥǃǔǓƹǏǌƵƺǉǦǘȊȡȞȗĚėǔǠƥļǖĆƄBȤřBǨŬǟǌƵ
ưĚėßƖǨ78ǆƿǌƺȊȡȞȗĚėƱǓǙƴŠ;ǖǷȥǾƣdǘåèBƿì-ǆǌƿƴƤƢƇƍåǡKŞOȤįƎåǨŬǟǖƾǏǌƵȞȗ
ĚėÁǔPÑǘƀĘÿƄBǨŬǟǌƵ
ưÙÐƁǘǖƺstage N2ƱǓǙƴKŞOȦěFȧǡįƎåǘ3þƥƿƺºǓƴƥļǖĩèB¾ǡƄBǨŬǟǌƵǝǦǗȞȗĚėÁǢǤ
Ǡ±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
ŞƚǖđjȦŪǈȤħƻȤæǁȧ
ƄBȱ 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-Ref
Chin

1s

75 µV

EKG
FDS L
FDS R
AT L
AT R
EDB L
EDB R
Nas
Tho
Abd
ø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWȦ<ơȧâȃȝǾèBǔįƎå

ĚėǘDǓǙƴįƎåȦěFȧǨǔǠǖƻâ ȃȝǾèBƿ{|ǆǒ3þǆƴÙǖstage N3ǔ7|ǅǦǌƵǃǘƒƴĆǖđjǡƄBǙǞǣ
ǦǖƾǏǌƵ
IgLON5ȋțǽȗȇǫǙƴÙǖstage N3ƿǞǣǦǥ÷Ǔƴagrypnia
excitataȦ¯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-Ref
Chin

1s

75 µV

EKG
FDS L
FDS R
AT L
AT R
EDB L
EDB R
Nas
Tho
Abd

ø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwWȦ<ơȧȞȗĚėřBĆČȦRBDȧ
ȞȗĚėǙƥļǗƇȤ_łǘôǆƺƄBƿ3þǆƴRBDǔ7¸ǅǦǥü¦ǓƹǏǌƵºƴưÙÐƁǘǖƺȊȡȞȗĚėƱǔàŹǆǒƴ
đjǡŞƚǖƄBƿǞǣǦǥƥǙƾǏǌƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Treatment and outcome
Treatment
All patients had immunotherapy ( IV steroids, cyclophosphamide, IVIg, rituximab)
No striking improvement was seenäďȱƳ.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-~ƴÝǤ5QǙōzǓǘĦùÜ
ƳȦŢƋÁȬQƴ 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

HE

Gallyas 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/AT8

Basis 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/CBDǖǕǔ
ǙĆǖǥ¹sǘǾǭǰȋǿȥǓƹǥǃǔƿġXǅǦǌƵø¸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)

mđ

ĠCČ

l 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 ĠCČǓǙÔǘňƪ
ċkǓRBDǨđČǆƻǥø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

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

Resemblances between
narcolepsy 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Ǩǘǋǁȧ
l ŀǨOǆǌǔǈǥfTƹǤø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

Reversible
MS ATTACK
Secondary narcolepsy
ACUTE EDS, NO CATAPLEXY
in 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Ƈċkér
ƪê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