AUTOIMMUNE DISORDERS ANDSLEEP.

Alex Iranzo
Neurology Service
Hospital Clinic de BarcelonaSpainø¸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ƾǣPSG©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ǘȞȗĚėƲŤŮ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®HǨÒēǔǈǥƴĆ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¡ǓƹǥƵMSLTǓSOREMǨŬǟƴƪêÎËǓǙǰȞǲǷȡƿ#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ǗŎǆǌœƶǆƺřBǨ ǔǈǥĊ¡ǓƹǥƵĆřBƴ¡ŀǙ¢oǨǞǒƺǥǃǔƿmƺƵPSGǓǙƷĩèB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 encephalitisq 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ǖǕǓƹǥƵſ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¦6QȧƵĳÉƴ14ČǗë:ǖĚėĆǨŬǟǌȦėƴoÑřBƴnƒǒǩƾǩćƺƴƅėȧƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW

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

Anti-Ma2 limbic encephalitis• Autoimmune disorderŻĹĭpŉDÿ• Serum anti-Ma2 titers• Paraneoplastic(testicular and lung cancer)• Limbic syndrome plusŉ• 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 DAMAGECSF HYPOCRETIN 58 pg/mL®Ma2®ƓƂŉöČǗǞǣǦǌƅėČüȱ
71Ûă ƴı½ǘ(ėČüǨSǆǒJũƵŢǡ£Bň>đǖǆƵPSG/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 çšƭčȱǘªÍĐČ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ƿ3þƵ£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¿ƵRBDǔȆȝǵȞȐǷȥǘûǙǔǠǗȞȗĚėǘĆǗƓƂǆǒƽǤƴ(1)ǃǦǣǙªÍǨǙǇǟǔǈǥċk
ǓSǆƻǥǃǔƴ(2)®Ma2®ƓƂŉöǓ3þǆƻǥǃǔƴƿġXǅǦǌČƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW®Ma2®ƓƂŉöČǘMRIȦČüǔŲċǔǘȧLimbic syndromeŻĹĭČüǘŲċȦªÍȧBrainstem 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ǘǝǔǟȱRBDǡȆȝǵȞȐǷȥÑǘŌČüƿƴŉȤªÍȤƇšƇǘƺǉǦƾǘĕ²ēǝǌǙƒ²ēǖƘǗǢǏǒ3þǈǥǃǔƿƹǥƵȦƘ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ƇȆȝǵȞȐǷȥǡRBDǘđþǗǙƴªÍǘÕņĆȦĆǖè CȧƿƓǈǥƵ

Hypocretin 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ǓƹǏǌǌǟȆȝǵªÍ ȞȐǷȥČüǙǞǣǦǖƾǏǌƵ

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

BRAINSTEMŉƯ

GABA, Glutamate GABA, ǴȝǾȖȡƈREM SLEEPRBD

Anti Ma2 LEPOSTERIOR HYPOTHALAMUS
ƇšƇ®Ma2®ƓƂŻ
Hypocretin ǰȞǲǷȡ ĹĭŉöČǓǙƴƇšƇċkǗǢǤȆȝǵȞȐǷȥČüȦƅėȧƿǞǣǦǌƿƴªÍǙªÍ ÙǓƹǏǌǌǟRB
DǙǞǣǦǖƾǏǌƵ

AMYGDALAGlutamate 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- LE8ǘ®Ma2®Ɠ
Hypocretin ǰȞǲǷȡ ƂŻĹĭŉöČǓǙƴªÍċkǔŉċkǗǢǤȆȝ
ǵȞȐǷȥČüȦƅėȧ
ǔRBDƿǞǣǦǌƵ

AMYGDALA ªÍ

Glutamate ǴȝǾȖȡƈ

BRAINSTEMLimbic + brainstem damage
Low hypocretin
RBDNarcolepsyø¸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®ƓƂŉöȧǓƴȆȝǵȞȐǷȥÑČüǙƇšƇƘȦ→ƅėȧǡŻĹĭÕņĆȦ→ǱǾȐȞǲǷȥȧǓǞǣǦǥƵø¸ŷźȤŞŝģ ISMSJfȓȥȗȒȥǸwW