Narcolepsy. Aspects of the psychiatric phenotype

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(2) NARCOLEPSY aspects of the psychiatric phenotype. Hal A. D roogleever Fortuyn.

(3) Narcolepsy, aspects of the psychiatric phenotype Thesis Radboud U n iv e rs ity Nijmegen, t h e N e th erland s. Cover illu s tr a tio n : Dave McKean, c o p y r ig h t © 1997 DC Comics. ISBN: 978-9 0-90 26 27 2-7. L a y -o u t by In Z ic ht G ra fisch O n t w e r p , A rn h e m , The N e th erland s Prin te d by Ipskamp, Enschede, The N e th erland s. C o p y rig h t © H.A. D ro o g le e v e r F ortuyn , 2011.

(4) NARCOLEPSY aspects of the psychiatric phenotype. Een w etenschappelijke p roeve op h et geb ied van de M ed isch e W etenschappen. Proefschrift. t e r v e rk r ijg in g van de graad van d o c to r aan de Radboud U n iv e rs ite it Nijm egen op gezag van de re c t o r m ag nificus prof. mr. S.C.J.J. K ortm an n volgens b e slu it van h e t college van decanen in het o p e n b a a r te v e rd e d ig e n op w o e n sd a g 31 augustu s 2011 om 15.30 precies. door. Hendrik Arie Droogleever Fortuyn G eb oren op 14 n o v e m b e r 19 44 te A m s te rd a m.

(5) Promotoren Prof. Dr. J.K. Buitelaar Prof. Dr. W.O. Renier. Copromotor Dr. S. Overeem. M anuscriptcom m issie Prof. dr. G .W .A.M . Padberg (v o o rz itte r) Prof. dr. J. B. Prins Prof. dr. R. van de r M a s t (LUMC).

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(8) Contents. Chapter 1 Chapter 2. I n t r o d u c t io n and o u t lin e o f t h e thesis. Narcole psy and p syc h ia try : an evo lv in g asso ciation. 9. 21. D roo gleever Fortuyn et al. Sleep M ed (2 0 11), doi: i 0 . i0 i 6/J.S leep .2 0 i i . 0 i . 0 i3 Chapter 3. Psychotic s y m p to m s in narcolepsy: p h e n o m e n o lo g y and a. 41. co m p a ris o n w i t h schizophrenia. D roogleever Fortuyn et al. Gen Hosp Psychiatry 3 1 (20 09) 1 4 6 - 15 4 Chapter 4. A n x ie ty and m o o d diso rd e rs in narcolepsy. 61. D roogleever Fortuyn et al. Gen Hosp Psychiatry 32 (20 10 ) 4 9 - 5 6 Chapter 5. High p re valenc e o f e a tin g d isord ers in narcolepsy. 79. D roogleever Fortuyn et al. Sleep 3 1;3 ;( 20 0 8) 3 3 5 - 341 Chapter 6. Severe fa tig u e in narcolepsy. 97. D roogleever Fortuyn et al. J Sleep Res (pending m in o r revisions) Chapter 7. S um m a ry. 115. Chapter 8. Discussion & Perspectives. 123. Chapter 9. A p p e n d ix : A d d itio n a l clinical notes. 137. Publications. 147. Abbreviations. 153. Summary in Dutch / Nederlandse samenvatting. 157. Acknowlegdments in Dutch / Dankwoord. 167. Curriculum Vitae in D utch/ Curriculum Vitae (Nederlands). 173.

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(10) u a ro .c u. ■M. Introduction and outline of the thesis.

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(12) INTRODUCTION Narcole psy is a p r im a ir y sleep disorder, cla ssified in t h e c a te g o ry o f hyp erso m nia s o f cen tra l origin (ICSD-2, 2005) [1]. N a rcole psy is cha rac terized by t w o main s y m p to m s : excessive d a y t im e sleepiness (EDS) and cataplexy. However, a ra th e r broad s p e c tru m o f o t h e r s y m p to m s is o f t e n present, in c lu d in g hypnagogic and h y p n o p o m p ic ha llu cin atio ns, sleep paralysis, n o c tu rn a l sleep d is r u p tio n , as well as n o n-sleep s y m p to m s such as o b e s ity [2]. Disease on s e t varies f r o m early c h ild h o o d in to t h e f i f t h decade o f life, w i t h a b im o d a l d i s tr ib u tio n w i t h a large peak a ro u n d 15 years o f age and a small peak a ro u n d 36 years [3]. The e s tim a te d pre valence in th e w e s te r n w o r ld (Europe and U.S.) is 0.02% t o 0.07% [4,5] w h ic h w o u ld a m o u n t t o 3 5 0 0 - 10 .000 p a tie n ts in t h e N e th erland s. In re c e n t years, it was dis covered t h a t na rcolepsy is caused by a d e fic ie n c y in h y p o th a la m ic h y p o c r e tin (orexin) n e u ro tra n sm is sio n , w h ic h is re fle c te d in a d e fie n c y o f th e h y p o c r e tin n e u r o p e p t id e in th e c e re bro s pin al flu id [6].. SEMIOLOGY Excessive Daytim e Sleepiness Excessive d a y t im e sleepiness (EDS) is usu ally t h e f ir s t s y m p t o m t o a p pe ar and o f t e n t h e m o s t disabling. The urge t o fall asleep can be im p e r a tiv e and results in lapses in to sleep at unusual tim e s and occasions d u rin g t h e day. Naps ty p ic a lly have a re fre sh in g e ffe c t, w h ic h is s h o r t lived however. A lth o u g h p a tie n ts can so m e tim e s fall asleep d u r in g a c tiv ities , sleep 'a tta c k s ' are m o s t likely t o occur d u r in g s itu a tio n s such as w a tc h in g TV o r s it t in g in t h e passenger seat o f a car, w h e n activ e p a r tic ip a t io n is n o t re q u ire d . W h e n u n m e d ic a te d t h e need t o sleep is. ¡£ _C. v e ry ha rd t o resist, and m o s tly u n c o n tro lla b le [7]; m o v in g a ro u n d can on som e. ~. occasions w a r d o f f a sleep a tta ck . M a in t a in in g d a y t im e alertne ss is a m a jo r issue. ~. f o r pa tie n ts, ever t h r e a t e n in g t h e ir level o f f u n c tio n in g . Patie nts can even be co m e. £. pre o ccu p ie d w i t h losing c o n t ro l o f t h e ir alertne ss and fa llin g asleep in public.. iz. C D O. ~o Cataplexy. ™. Cataplexy, t h e second c h ie f s y m p t o m o f narcolepsy, is v ir t u a lly p a th o g n o m o n ic. °. f o r th e disease. It is cha racterized by a sudden b ila te ral loss o f muscle to n e. ^ -o. pro v o ke d by s tro n g e m o tio n s , usually o f t h e p o sit iv e v a rie ty : laughter, startle,. 2. pride, e latio n, surpris e and e x c ite m e n t in m e e tin g s o m e o n e [8]. C a ta plexy can be. ~. generalized o r pa rtial, a f f e c t in g t h e neck, m o u th o r limbs selectively. A head drop, facial sagging, slu rred speech, bu ck lin g o f t h e knees are all expressions o f pa rtial cataplexy. C a ta plexy n o t on ly varies highly in d is tr i b u ti o n b u t also in. 11.

(13) fre q u e n cy . The d u ra t io n o f a c a ta p le c tic a tta c k ranges f r o m seconds t o a fe w m in u te s at m ost. D u rin g ca ta p le xy consciousness is m a in ta in e d : p a tie n ts hear and r e m e m b e r all w h a t happens a ro u n d t h e m . A m in o r it y o f p a tie n ts r e p o r ts m u ltis e n s o r y ha llu c in a tio n s d u rin g ca ta p le xy [8].. H ypnagogic hallucinations Hyp nagogic. ha llu c in a tio n s. occu r. at. sleep-. w ake. tra n s itio n s ,. c o m m o n ly. e x p erience d at sleep on se t b u t in c id e n ta lly d u r in g ca ta p le c tic attack s and sleep paralysis as w e ll. They are called h y p n o p o m p ic w h e n o c c u rrin g d u r in g w a k in g up. These h a llu c in a tio n s can be e x t r e m e ly frig h te n i n g and v e ry realistic. They are claim ed n o t t o be un iq u e f o r narcolepsy, o c c u rrin g in o t h e r sleep diso rd e rs and in t h e general p o p u la t io n as w ell [4,9]. This has been a reason f o r some a u th o r s to t riv ia liz e the se s y m p to m s , w h ic h is u n fo u n d e d . Patients are o f t e n r e lu c t a n t to r e p o r t the se ha llu cin a tio n s because o f t h e fe a r o f be in g v ie w e d as m e n ta lly ill [10]. Indeed, hypnagogic h a llu c in a tio n s are s o m e tim e s m is take n f o r psychosis by p sych ia trists [11-14] and can c rea te m is lead in g in te r p r e ta ti o n s in t h e legal sphere [15]. Patie nts r e p o r t an im pressiv e loss o f q u a lit y o f life due t o the se sensory p e rc e p tio n s [10].. Sleep paralysis Sleep paralysis occurs on sleep- w a ke t r a n s itio n s as w e ll: p a tie n ts w ake up but ca n n o t m ove o r speak d u r in g a f e w m in utes . Even lift in g a f in g e r is n o t possible at the se perio ds. External s tim u li such as noises or t h e to u c h o f th e b e d p a r t n e r can so m e tim e s end this state. This f r ig h te n in g exp e rie n c e is o f t e n ac co m pa nie d by hyp nagogic o r h y p n o p o m p ic h a llu c in atio ns , w h ic h can push up th e a n x ie ty t o an even h igh er level.. Disturbed nocturnal sleep The sleep d y s re g u la tio n in na rcoleps y is also a p p a re n t in n o c tu r n a l sleep, w h ic h is o f t e n highly f r a g m e n te d . N o c tu r n a l sleep f r a g m e n t a t io n is a c o m m o n c o m p la in t, and o f t e n v e ry t r o u b le s o m e t o pa tie n ts. The n i g h tt im e sleep d i s ru p tio n is n o t the cause o f t h e d a y t im e sleepiness h o w e v e r: t r e a t in g n o c tu r n a l sleep f r a g m e n t a t io n does n o t a m e lio ra te t h e d a y t im e sleepiness.. O ver 24 ho urs p a tie n ts do n o t sleep m o re th a n h e a lth y c o n tro ls [16].. Autom atic behavior N a rc o le p tic p a tie n ts can s ho w autom atic beh avior: in a d e q u a te behavior, m ost likely d u r in g pe rio ds w i t h a decreased vigilance. A c o m m o n e xa m ple is d u rin g w r itin g , w h e n p a tie n ts n o tice t h a t th e y have w r i t t e n nonsense sentences, or illegible text. These autom atism s are s om etimes mistaken fo r dissociative behaviors..

(14) Obesity Narcole psy p a tie n ts have o f t e n be en r e p o r t e d t o be ob ese [17,18], w i t h an an increased w a is t c irc u m fe re n c e as well, p o in tin g t o a b d o m in a l f a t d e p o s itio n [19]. The in creased BMI can be a m a jo r psychological b u rd e n f o r pa tie n ts, likely to c o n t ri b u t e t o t h e lo w self este em t h a t p a tie n ts may r e p o r t [10,20,21]. The increased BMI was classically a t t r ib u t e d t o a life s ty le o f in a c t iv it y in h e r e n t t o the t e n d e n c y t o fall asleep. However, now a days m e t a b o lic changes, m o s t p ro b a b ly du e t o t h e r e d u c tio n in h y p o c r e tin signaling, are believed t o be responsib le fo r th e increase in b o d y w e ig h t [6,22].. DIAGNOSTIC CLASSIFICATION The diagnosis o f na rcolepsy is based on a c o m b in a t io n o f r e p o r t e d sy m ptom s, f o r m a l sleep recordin gs, and - i n selected cases- m e a s u r e m e n t o f h y p o c re tin in th e. c e re bro spin al. flu id .. The. current. diag n o stic. cla ssific atio n. f o llo w s. the. In te rn a tio n a l Classification o f Sleep Disorders (ICSD-2), e d ite d by t h e A m eric an A cad em y o f Sleep M e d ic in e (AASM), and the se crite ria are listed in Box 1 [1]. The DSM IV has a cla ssific atio n f o r na rcolepsy as w e ll [23]. These criteria are h o w e v e r less th a n s atis fa c to ry, le adin g t o a clear o ve rin clu sio n o f na rcolepsy pa tie n ts. In th e f o r t h c o m in g DSM-V, ne w criteria are pro p o se d t h a t closely f o ll o w th e ICSD-2.. NARCOLEPSY AND PSYCHIATRY N arcolepsy m isdiagnosed as psych iatric disease Narcole psy has been f r e q u e n t l y m isdia gnosed - especially by psych ia trists - as a. ¡£ _C. psych ia tric disorder.. Psychiatrists. have recognized. a p a t te r n. o f b o r d e rlin e. ~. p e rs o n a lity disorder, psychosis, and do w o r s e th a n o t h e r medical specialists in. ~. diagnosing na rc olepsy [24]. This has lead t o adm issio ns o f p a tie n ts t o psych ia tric. C. w a rds w i t h diagnoses o f schizophrenia o r b ip o la r d is o r d e r [11,25]. W h a t did de ceive. psychiatrists?. The. most. con spicuous. p o in t. of. c on fusio n. are. £. iz. th e. hypnagogic h a llu c in atio ns . These h a llu c in a tio n s can o ccu r d u r in g d a y t im e to o ,. ro. d u r in g m o m e n t s t h a t p a tie n ts doze o f f t o sleep. Psychiatrists may in t e r p r e t this. °. as a s y m p t o m o f a psy ch otic disorder. Narcole psy p a tie n ts may s u ffe r f r o m m o o d. ^. swings, w i t h ir r ita te d m o o d o r even o u t b u r s t s o f anger w h e n w a k in g up, w h ic h. 2. may re m in d o f m o o d swings in B o rd e rlin e P ers o na lity Disorder. The d is ta n t. ~. im pressio n t h a t som e p a tie n ts make, and a c e rta in in d if f e re n c e can r e m in d o f o t h e r p e rs o n a lity d isord ers as well. Depression is diagnosed f r e q u e n tly : d is tu rb e d. 13. sleep can be a p o in t o f c on fusio n here, as are loss o f c o n c e n tr a tio n , fatig ue, loss. 1.

(15) BOX 1 Diagnostic criteria for narcolepsy with cataplexy A. The patie nt has a com p la in t o f excessive daytim e sleepiness occurring almost daily fo r at least three months.. B. A d e fin ite history o f cataplexy defined as sudden and transient episodes o f loss o f muscle ton e triggered by emotions, is present.. Note: To be labeled as cataplexy, these episodes must be triggered by strong em o tion s - m ost reliably laughing or jo kin g - and m ust be generally bilateral and b rie f (less than 2 minutes). Consciousness is preserved, at least at the beginning o f the episode. Observed cataplexy w ith transient reversible loss o f deep tendon reflexes is a very strong, but rare, diagnostic finding.. C. The diagnosis o f narcolepsy w ith cataplexy should, w h en ever possible, be con firm ed by no cturnal polysom nogra phy follow e d by an MSLT; the mean sleep latency on MSLT is less than or equal to eight m inutes and t o w or m ore SOREMP's are observed fo llo w in g suffic ie nt nocturnal sleep (m in im um six hours) durin g the night prior to the test. Alternatively, hypocretin 1 levels (less than o r equal to 110 pg/mL or one t hird o f mean no rmal control values.. Note: The presence o f t w o or m ore SOREMP's durin g the MSLT is a very specific fin d in g whereas a sleep latency o f less than eight minutes can be fo u n d in up to 30% o f the no rmal popula tio n. Low CSF hypocretin-1 levels (less than o r equal to 110 pg/mL or one third o f no rm al control values) are fou nd in m ore than 90% o f patients w ith narcolepsy w ith cataplexy and alm ost never in controls or in oth er patients w ith o th e r pathologies.. D. The hypersomnia is not be tte r explained by an othe r sleep disorder, medical or neurological disorder, m edication use o f substance use disorder.. o f lib id o and th e t e n d e n c y t o w i th d r a w . Conversio n d is o rd e r is a n o t h e r pitfall, and this diagnosis has be en made f r e q u e n t l y in t h e h i s to ry o f narcolepsy: sleep, ca ta p le x y w e r e seen as defense mechanism s, s up po s ed ly en ab lin g p a tie n ts to cover up m o re serious fla w s in t h e ir person ality.. The reasons f o r psych iatric m isclassification The in trigu in g qu estio n can be posed w h e t h e r psychiatrists w e re j u s t mistaken in diagnosing psychiatric disorders instead o f narcolepsy, o r th a t narcolepsy patients really do sho w psyc h ia tric signs and sy m ptom s, e ith e r se co n d a ry t o na rcolepsy s y m p to m s o r as a d ir e c t expression o f t h e pa th o p h y sio lo g ic a l process. A lt h o u g h.

(16) th e lite r a t u r e on na rcolepsy is p l e n tifu lly fille d w i t h refere nce s t o psychia tric c o m o r b id it y , da ta as t o pre valenc e o r in cid e nce o f psych ia tric d isord ers or f r e q u e n c y o f s y m p to m s are in conclusive. M o s t da ta com e f r o m case series, w here. psych ia tric s y m p to m s. are o f t e n. m o re. illu s tra tiv e. th a n. in fo rm a tiv e .. F u r th e rm o r e , m o s t da ta com e f r o m s e lf- r e p o r t in s tr u m e n ts such as t h e Beck Depression. I n v e n to r y. (BDI). as o p po sed. to. c o n t ro lle d. studie s w i t h. f o rm a l. d iag nostic in s tru m e n ts .. The psych iatric ph enotype in na rcolepsy is n ot w ell described Currently , t o o f e w studie s have t r ie d t o p e r f o r m a d e ta ile d psy ch ia tric assessment o f na rcolepsy pa tie n ts, and t h e psy ch ia tric p h e n o t y p e o f na rcolepsy is only vaguely describ ed. I sorely missed such ps ych ia tric da ta as a re fere nce, w h e n I f ir s t e n c o u n te r e d a n a rc o le p tic p a tie n t, w h o is de scrib ed in Box 2.. BOX 2 case vignette Patient 1 is a 20-year-old physics student, who received the diagnosis of narcolepsy w ith cataplexy at age 14. Around the tim e he turned 18, hypnagogic hallucinations started to play an im portant role in his daily life. In a hypnagogic 'state' he sensed the presence of invisible beings which he called 'synteufles' that came from another 'dimension'. These 'synteufles' tried to possess him, throwing a yellow powder in his nose to bring him under their influence. They wanted to eat his brains, and kill him. A fte r waking up, the reality of these hallucinatory world still existed. The patient developed the habit to 'wash them off', taking showers that sometimes too k a whole night. In his dreams these beings could take the form of chewing gum. The dreams were threatening him, and he started feeling depressed. He began to eat more. At one point, he was not able to separate the 'dream world ' from daytime reality for several weeks. He developed a way to 'defend' himself against the 'synteufli', fighting them by developing a glass plate in the frontal plane before him, that represented his mind. He always wanted to wipe this plate clean, for which he even created an extra extremity. His neurologist prescribed antipsychotics which did not influence the symptoms. To get back to reality, it helped to start talking to someone or turning on the radio. He became obsessed w ith having fresh drinking water which he needed in his battle with the synteufles. Only tw o years later, he gradually became able to put these experiences into perspective. Afterwards he started doing well in his studies, was able to get his MSc and now has a jo b as an information technology expert.. 15.

(17) AIMS OF THIS THESIS The main goal o f this thesis is t o in vestig ate th e psych ia tric p r o file o f narcolepsy in d e p th . W e s t a r t f r o m a sys tem atic search o f th e o ld e r lite ra tu r e , lo o k in g fo r 'u n e x p u r g a te d '. ps ych ia tric. aspects. in. origin al. de s c rip tio n s. of. narcolepsy.. Subsequently, t h e results o f a d e ta ile d s tu d y are de scrib ed in w h ic h t h e psychia tric s y m p to m s o f a large and w e ll- d e f in e d c o h o r t o f na rcolepsy p a tie n ts is com p a re d to p o p u la tio n con tro ls , m a in ly using a w e ll- v a lid a te d s e m i- s tr u c tu r e d diagnostic in s tr u m e n t, t h e Schedules f o r A ssessm ent in N e u ro p s y c h ia tr y (SCAN) version 2.1 [26-29].. Chapter 2 con tain s a d e ta ile d h isto ric a l analysis o f p r im a r y papers on narcolepsy, w i t h an em phasis on psych ia tric fe a tu re s and in v o lv e m e n t o f psych ia trists w o r k in g f r o m d i f f e r e n t angles. A lth o u g h a ps ych ia tric a p pro ach was ju s tifie d in many instances because o f t h e psychological s u ffe rin g , this all t o o o f t e n lead to stig m a tiz a tio n o f pa tie n ts, ad d in g t o a bad r e p u t a t io n t h a t p a tie n ts alrea dy had. O ver t h e years, a reappraisal o f psych ia tric c o m o r b id it y t o o k place, le adin g t o a ne w synthesis o f 'o rg a n ic ' and 'p s y c h ia tric ' fe a tu re s o f narcolepsy.. Chapter 3 focuses on ps ych otic s y m p to m s in narcolepsy, because o f t h e e n d u rin g discussion in t h e li te r a t u r e on t h e d i f f e r e n t ia l diagnosis o f na rcolepsy and schizophrenia . W e s tu d ie d ps ych otic s y m p to m s in th r e e groups: p a tie n ts w ith narcolepsy, schizop hren ic p a tie n ts and a g ro u p o f m atc he d p o p u la tio n controls . A d e ta ile d analysis o f t h e p a t te r n o f ha llu cin a tio n s o f na rcolepsy p a tie n ts and schizop hren ic p a tie n ts is given, t o e nable a clear d i f f e r e n t ia t i o n b e tw e e n t h e t w o . F u rth e rm o r e , w e describ e t h e actual experiences o f hyp nagogic h a llu c in a tio n s in detail, as r e p o r t e d by t h e na rcolepsy patie nts .. Chapter 4 deals w i t h s y m p to m s o f depre ssio n as w e ll as a n x ie ty in narcolepsy. Depression has received a lo t o f a t t e n t i o n in th e lite r a tu re , w h ich c on tra sts w ith t h e scarcity o f in fo r m a t io n re g ard in g a n x ie ty s y m p to m s . M a n y a u th o rs have suggested. an o v e r re p r e s e n ta t io n. o f m a jo r depressio n,. but few. system atic. diagnostic studies have been pe rfo rm ed . Using the SCAN, sym ptom frequencies on depression and an xiety w e re assessed and com pared w ith controls. A discussion is added on t h e sig nific ance o f the se s y m p to m s ; are t h e y a p r im a r y disease expression, o r se co n d a ry t o th e c h ro n ic s y m p to m s o f narcolepsy.. Chapter 5 describ es t h e results o f a s tu d y in to e a tin g diso rd e rs in narcolepsy, w h ic h was tr ig g e re d by t h e o v e r w e ig h t and o b e s ity w h ic h are n o to rio u s associated fea tu res. A case- c o n tro l s tud y was p e r fo r m e d , c o m p a r in g s y m p to m s o f eating.

(18) d isord ers in p a tie n ts w i t h na rcolepsy versus p o p u la tio n con tro ls. In ad ditio n , s y m p to m s w e r e c o m p a re d t o a sep ara te c o n tro l g r o u p w h ic h was m a tc h e d for BMI as well. In Chapter 6, a clinic ally releva nt, b u t d i f f ic u lt to p ic is stud ie d , na m ely the pre valence o f f a tig u e in narcolepsy, and its d i f f e r e n t ia t i o n f r o m sleepiness. This sub je ct has be en n e glected in t h e lite r a t u r e so far. To this end, a f o r m a l in s tru m e n t t o assess fa tig u e - t h e Checklist Ind iv id ual S tre n g th - was ap plie d in a large c o h o r t o f na rcolepsy pa tie n ts. D e te rm in a n ts f o r t h e presence o f severe f a tig u e w e re assessed, and clinical d iffe re n c e s de scrib ed b e tw e e n na rcolepsy p a tie n ts w ith and w i t h o u t f atig ue.. Chapters 7 and 8 c o n ta in a s u m m a ry o f o u r results and a discussion o f th e ir relevance respectiv ely . W e e la b o ra te on possible n e u ro b io lo g ic a l mechanisms, b u t also on t h e p a tie n t's p e rs p e c tiv e and t r e a t m e n t op tio ns.. 17.

(19) REFERENCES [1]. [2] [3] [4] [5] [6] [7] [8]. [9] [10] [11] [12] [13] [14] [15] [16]. [17] [18]. [19] [20] [21] [22]. American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic and coding manual. 2nd ed. W estchester, Illinois: American Academy of Sleep Medicine, 2005. Billiard M, Bassetti C, Dauvilliers Y et al. EFNS guidelines on management of narcolepsy. Eur J Neurol 2006; 13(10):1035-1048. Dauvilliers Y, Montplaisir J, Molinari N et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001; 57(11):2029-2033. Ohayon MM, Priest RG, Zulley J, Smirne S, Paiva T. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology 2002; 58(12):1826-1833. Silber MH, Krahn LE, Olson EJ. Diagnosing narcolepsy: validity and reliability of new diagnostic criteria. Sleep Med 2002; 3(2):109-113. Nishino S, Ripley B, Overeem S et al. Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001; 50(3):381-388. Bruck D. The impact of narcolepsy on psychological health and role behaviours: negative effects and comparisons with other illness groups. Sleep Med 2001; 2(5):437-446. Overeem S, van Nues SJ, van der Zande WL, Donjacour CE, van MP, Lammers GJ. The clinical features of cataplexy: A questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency. Sleep Med 2010. Ohayon MM, Priest RG, Caulet M, Guillem inault C. Hypnagogic and hypnopompic hallucinations: pathological phenomena? Br J Psychiatry 1996; 169(4):459-467. Goswami M. The influence of clinical symptoms on quality of life in patients with narcolepsy. Neurology 1998; 50(2 Suppl 1):S31-S36. Douglass AB, Hays P, Pazderka F, Russell JM. Florid refractory schizophrenias that turn out to be treatable variants of HLA-associated narcolepsy. J Nerv Ment Dis 1991; 179(1):12-17. Kondziella D, Arlien-Soborg P. Diagnostic and therapeutic challenges in narcolepsy-related psychosis. J Clin Psychiatry 2006; 67(11):1817-1819. Kishi Y, Konishi S, Koizumi S, Kudo Y, Kurosawa H, Kathol RG. Schizophrenia and narcolepsy: a review with a case report. Psychiatry Clin Neurosci 2004; 58(2):117-124. Shapiro B, Spitz H. Problems in the differential diagnosis of narcolepsy versus schizophrenia. Am J Psychiatry 1976; 133(11):1321-1323. Szucs A, Janszky J, Hollo A, Migleczi G, Halasz P. Misleading hallucinations in unrecognized narcolepsy. Acta Psychiatr Scand 2003; 108(4):314-316. Montplaisir J, Billiard M, Takahashi S, Bell IR, Guilleminault C, Dement WC. Twenty-fourhour recording in REM-narcoleptics with special reference to nocturnal sleep disruption. Biol Psychiatry 1978; 13(1):73-89. Honda Y, Doi Y, Ninomiya R, Ninomiya C. Increased frequency of non-insulin-dependent diabetes mellitus among narcoleptic patients. Sleep 1986; 9(1 Pt 2):254-259. Schuld A, Beitinger PA, Dalal M et al. Increased body mass index (BMI) in male narcoleptic patients, but not in HLA-DR2-positive healthy male volunteers. Sleep Med 2002; 3(4):335-339. Kok SW, Overeem S, Visscher TL et al. Hypocretin deficiency in narcoleptic humans is associated with abdominal obesity. Obes Res 2003; 11(9):1147-1154. Broughton WA, Broughton RJ. Psychosocial impact of narcolepsy. Sleep 1994; 17(8 Suppl):S45-S49. Beusterien KM, Rogers AE, Walsleben JA et al. Health-related quality of life effects of modafinil for treatm ent of narcolepsy. Sleep 1999; 22(6):757-765. Poli F, Plazzi G, Di Dalmazi G et al. Body mass index-independent metabolic alterations in narcolepsy with cataplexy. Sleep 2009; 32(11):1491-1497..

(20) [23] American Psychiatric Association. Diagnostical and Statistical Manual of Mental Disorders. Fourth Edition, Text Revision ed. Washington DC: American Psychiatric Association, 2000. [24] Kryger MH, Walid R, Manfreda J. Diagnoses received by narcolepsy patients in the year prior to diagnosis by a sleep specialist. Sleep 2002; 25(1):36-41. [25] Douglass AB. Narcolepsy: differential diagnosis or etiology in some cases of bipolar disorder and schizophrenia? CNS Spectr 2003; 8(2):120-126. [26] Malyszczak K, Rymaszewska J, Hadrys T, Adamowski T, Kiejna A. [Comparison between a SCAN diagnosis and a clinical diagnosis]. Psychiatr Pol 2002; 36(6 Suppl):377-380. [27] Rijnders CA, van den Berg JF, Hodiamont PP et al. Psychometric properties of the schedules for clinical assessment in neuropsychiatry (SCAN-2.1). Soc Psychiatry Psychiatr Epidemiol 2000; 35(8):348-352. [28] Schutzwohl M, Kallert T, Jurjanz L. Using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN 2.1) as a diagnostic interview providing dimensional measures: cross-national findings on the psychometric properties of psychopathology scales. Eur Psychiatry 2007; 22(4):229-238. [29] Wing JK, Babor T, Brugha T et al. SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 1990; 47(6):589-593.. 19.

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(22) u a. ■M ro .c. u. Narcolepsy and psychiatry: an evolving association Based on: H.A. D roo gleever Fortuyn, P.C. M ulders, W.O. Renier, J.K. Buitelaar, S. Overeem. N arcolepsy and psychiatry: an evolving association o f in creasing interest. Sleep M ed (20 11), doi: 10 .1016/j.s le e p .2 0 1 1 .01.013.

(23) ABSTRACT Gélineau o rig in a lly de scrib ed na rcolepsy as a disease w i t h an org an ic cause. H o w e v e r , t h e d is o rd e r had u n d e n ia b le e m o tio n a l trig g e rs and psyc h ia tric -lik e expressions, and soon a ps ych ia tric e t io lo g y o f na rcolepsy be cam e a seriously con s id ered o p tio n . In fact, th e psych ia tric v ie w d o m in a t e d s c ie n tific th in k in g fo r a lo ng t im e , not necessarily t o t h e b e n e fit o f pa tie n ts. W h e n h y p o c r e tin (ore xin ) de fects w e re p ro ven t o be t h e cause o f na rcolepsy Gélineau's origin al disease m od el was sh o w n t o be rig ht. However, t h e psyc h ia tric s y m p to m s o f t h e disease w e r e n o t f o r g o t t e n a f t e rw a r d s , b u t gain ed a d i f f e r e n t sig nificance: as psychia tric expressions o f a brain disease. These s y m p to m s , such as a n x ie ty and eating disorders, can be high ly d e b i lit a t in g and w a r r a n t clinical a t t e n ti o n . Here, we describe t h e role o f psychiatry in th e histo ry o f narcolepsy, showing th e ir evolving association.. 22.

(24) INTRODUCTION Ever since its f ir s t d e s c rip tio n , na rcoleps y has been associated w i t h p s ych ia try in various ways (see Figure 1). W h ile ne uro lo g ic a l exp la n a tio n s f o r narcolepsy p revaile d at firs t, v ariou s a lte r n a tiv e t h e o r ie s soon gain ed f o llo w e r s , suggesting u n d e r ly in g psych ia tric distu rba nces as a cause o f t h e disease (for an ov e rv ie w , see [1]). Psychosom atic m echanis m s w e r e pressed by psych ia trists tr e a tin g na rcolepsy pa tie n ts, f o r e xa m ple suggesting sexual d e v ia tio n s and ps ych op athic p e rs o n a lity s tru c tu r e s as u n d e r ly in g fa c to r s [2,3]. These vie w s persis ted f o r a long t im e , even fa r in to t h e 20 th c e n t u r y [4]. W h e n d e fe c ts in h yp o th a la m ic h y p o c r e tin (orexin) n e u ro tra n s m is s io n w e r e p in p o in te d as t h e p r im a r y c u lp r it at th e en d o f th e 1990s, na rcolepsy was f in a lly esta blished as an org an ic brain disease [5]. Perhaps surprisingly, this paved t h e w a y f o r a t h o ro u g h d e scrip tion. and a p p re c ia tio n o f t h e ps ych ia tric c o m o r b id it y w h ic h a ffe c ts m an y n a rc o le p tic pa tie n ts [6-14]. In this re v ie w w e describe t h e role o f psyc h ia try in t h e h is to r y of na rcolepsy, s h o w in g t h e ev o lvin g associa tion b e t w e e n t h e t w o (Figure 1).. A DISEASE, A SYMPTOM OR A SYNDROME? Narcole psy was de scrib ed and na m ed in th e second h a lf o f th e 19th cen tury , by W es tph al and Gélineau r e s p e ctiv e ly [15-17]. Gélineau called na rcolepsy a 'névrose. rare', a rare f o r m o f neurosis, w h ic h t e r m at t h a t t im e was n o t so lely used f o r. o. psych ia tric b u t also f o r n e uro lo g ic a l d isord ers [16,17]. This im p lic a te d t h a t Gélineau reg ard ed na rc olepsy as a 'm orbus su i g en e ris' ('disease o f its o w n kin d'),. $. and a lth o u g h he did n o t use this t e r m him self, t h e expression has been a t t r ib u t e d. m. t o him ever since. The t e r m 'disease' refers t o a c o n d itio n w i t h a specific cause,. _g. and if possible a u n if o r m t r e a t m e n t . But, a lth o u g h Gélineau suggested t h a t. S. TO. na rcolepsy was a d is o r d e r o f t h e ' p r o t u b e r a n c e a n n u la ire ' (pons) he n e it h e r kne w. ™. th e cause o f th e disease n o r had a t r e a t m e n t .. t. Gélineau's publication did not go un noticed: he received reactions and case rep orts. 2 JZ (J £. fro m m any colleagues f r o m France and abroad. However, many o f these cases w e re. TO. pa tie nts w i t h an un de rlyin g disease w h o m ere ly had narcolepsy-like clinical. >■. sym ptom s. As a result, Gélineau described a 'narcolepsie secon d a ire' du e to various. _ü. causes next to th e original 'm o rb u s sui generis' ('n a rco lep sie essentielle') in his 1881. ^. monograph [18]. In o th e r words, narcolepsy was split up in a prim a ry disease and a. z. O. secondary syn d ro m e du e to hysteria, diabetes, he art disease and so on. Gélineau also proposed to f i t narcolepsy du e t o hysteria in Charcot's classification o f. 23. hysterical stages, even adding a subtype: 'état n a rcolep tiq ue' (Figure 2) [16].. <U a. ■M.

(25) N. ■ P». (TO c n>. O eCzrar era o c cr o 3. fD. fD =5 fD. eO ra Q_. ■a “<tn. Langworthy &. Betz N arcole psy is a •brilliantly se le cte d so u rce o f re lie f.. 'Psychiatric'. < 0)’ £.

(26) Figure 2 Gelineau's proposal to f it narcolepsy secondary to hysteria into Charcot's classification o f hysterical stages. W —1. 1. État narcoleptique ;. a. A. •a co. NATURELLE. S5 O. 2. État léthargique ; 3. Elat cataleptiforme;. 4. Etat comateux ; 5. État somnambulique.. I. B PROVOQUÉE PAR , DES \GENTS DIVERS. I 1. Hypnotisme simple; ^ [simple. j. 2. Léthargie. de mort apparente icompliquée, de contractures; , \de catalepsie ;. The s ub div is io n in to essential and se co n d a ry t y p e s did n o t con vin ce all ho w e ver: th e French n e u ro lo g is t Ballet stated in 1882: 'N arcolepsie n'est pas une affection. définie, encore m oins une m aladie: c'est, nous le répétons, un sym ptôm e qu i a , nous le voulons bien, ces caractères propres, sa physion om ie s p e c ia l' [19] . P a rm e n tie r (1891), a pupil o f Charcot, ad voca te d a s lightly d i f f e r e n t cla ssificatio n, em phasiz in g t h a t t h e 'h ysteric a l p a t ie n t' m ig h t m im ic narcolepsy. He p re fe rre d :. 'La fo rm e n arcoleptique de l'a tta q u e de som m eil hysterique: p seu d o -n a rcolep sie h y ste riq u e' [20]. In France, L h e r m it t e (1910) w r o t e an a rtic le called 'les narcolepsies' in w h ic h he stro n g ly p o s itio n e d na rcolepsy as a sy n d ro m e , w i t h m u l ti p le etio lo gie s, and not as a disease [21]. In c on tra st, t h e idea o f n a rcolepsy as a disease re m a in e d still v e ry m uch alive in G erm an y in t h e same p e rio d [22-25].. The con tro ve rs ie s s u r r o u n d in g t h e q u e s tio n w h e t h e r o r n o t t o con sid er narcolepsy as a p r im a r y disease, w e r e p a r tly f u e lle d by th e fa c t t h a t c a ta p le x y was n o t yet sharply d e fin e d and was no r e q u is ite f o r t h e diagnosis.. 25 <U. ■ H. a.

(27) CATAPLEXY, INCLUDED OR NOT? In 1902, th e G erm an a u t h o r L o e w enfe ld p o in te d t o an im p o r t a n t om issio n in the na rcolepsy lite r a t u r e so fa r [22]. He dis covered t h a t Gélineau de scrib ed 'astasia' as an im p o r t a n t s y m p t o m t h a t could be s eparate d f r o m th e excessive d a y tim e sleepiness in narcolepsy. He stip u la te d t h a t the se t w o s y m p to m s -sleepiness and muscle weakness (' kataleptisch eS ta rre') tr ig g e re d by la ughin g and o t h e r e m o tio n s - w e r e th e c h ie f c o m p la in ts in narcolepsy.. A lth o u g h t h e t e r m 'c a ta p le x y ' was in tr o d u c e d 14 years la te r by H e nneberg, [26] L o e w enfe ld alrea dy em phasized t h a t na rcolepsy was an 'eig en a rtig e Krankheits. zustan d' cha racteriz ed n o t ju s t by sleep episodes b u t also by attac ks o f m o t o r in hib itio n . The discussion 'disease o r syn d ro m e ' was n o w exte nde d t o th e question: 'is cataple xy a requisite crite rio n to make a narcolepsy diagnosis or not? 'M a n y au thors in G erm any and Austria an swered this qu estio n a ffirm a tive , im p ly in g a 'res tric ted d e f in itio n ' w ith exclusion o f hysterical cases and th e like [23-25,27-31]. In France, England and t h e USA m ost physicians de fine d narcolepsy in a much b ro ad er sense: by excessive d a ytim e sleepiness and sleep attacks [21,32-35].. The 's y n d ro m e versus disease' discussion, and th e u n c e r t a i n t y a b o u t diagnostic c rit eria, allo w e d th e em e rg e n ce o f a lte rn a tiv e t h e o r ie s f o r th e u n d e r ly in g cause o f narcolepsy, and psych ia tric e x p la natio ns soon gain ed m uch m o re pro m in e n ce .. INFLUENCE OF THE PSYCHO-ANALYTIC MOVEMENT S ta rtin g a ro u n d 1885, Freud s ta r te d t o s tu d y t h e dynam ics o f unconscious processes and t h e ir changes.. expression. He publis he d. in psychological. his op us 'T r a u m d e u t u n g '. s y m p to m s ('on th e. and. behavio ral. i n te r p r e ta ti o n. of. d re am s ') in 1900, in w h ic h he c o n s tru c te d his o w n m o d e l o f sleep and d r e a m in g [36]. He stated t h a t d u r in g sleep ne uro ns at th e m o t o r en d w e r e blocked and the mental processes w e re directed to th e sensory end. In this regressive process, an in te n s ific a tio n o f in te rn a l p e r c e p tio n t o o k place w h ile t h e ego was shu t o f f f r o m access t o o u t w a r d. m o t o r in n e r v a tio n s (Figure 3). Freud a t t r ib u t e d various. ' fu n c t io n s ' t o sleep. In t h e f ir s t place, sleep p r o v id e d a m eans t o dream: h a llu c in a to r y g r a tific a t io n . Freud hyp othesiz ed t h a t in dream s pe o p le w o u ld f u lf il l wishes -conscio us as w e ll as un conscio us- t h a t had arisen d u rin g d a y tim e b u t w e r e le ft un satis fie d. But second, Freud s tated t h a t sleep attacks could be a defense m ech an is m against sexual o r aggressive impulses, at th e same t im e shield in g t h e m f r o m consciousness and g r a tify in g t h e m d u rin g sleep..

(28) Figure 3 Freud's ^ - model o f the mental 'apparatus' : impulses t o action at the m o t o r end at the right (M) are blocked durin g sleep, and redirected to t h e sen sory en d (left). This leads t o in te n s ific a tio n o f t h e in te rna l p e rc e p tio n : dream s. The preconscio us (Vbw) disguises t h e 'dream material' in o rd er not to distu rb internal perception as well as sleep. In this way, 'hallu cin ato ry wish f u lfillm e n t' is reached durin g th e dream.. Ubw = unconscious, Er = memory.. As psychoanalysis gain ed g ro u n d as a m o d e r n s c ie n tific view, p u b lic a tio n s s ta r te d. -2. t o a p pe ar suggesting a re la tio n b e tw e e n the se unconscio us processes and sleep. S. attacks. One o f t h e f ir s t e x p o n e n ts o f this line o f th in k in g was O b e r n d o r f (1916),. m. a psych oa na ly st f r o m Ne w York, w h o w r o te :. uncontrollable attacks o f drow siness w ere in terp reted as an escape fro m intense. TO. J2. > CD. ™. sham e attendant upon a m asturba tion co n flict in which fa n ta sies o f in cest with. ^. the m other played an im po rta n t role. The drow sy spells at the sam e tim e p rovid ed. j=. a substitute f o r the autoerotic a ctivity' [37]. The firs t psychoanalytically orien te d pu blicatio n on narcolepsy came fro m th e British army psychologist M yers (1920) [38,39]. He reacted on a description o f a. TO. £. ■ca TO >. O. placebo tre a tm e n t o f a narcoleptic patie n t th a t appeared in the Lancet: a piece o f. ^. bone was removed f r o m the skull o f a narcoleptic patie nt and attached t o a necklace. z. fo r him t o wear, tu rn in g o u t to be a cure [40,41]. Outraged ab out this 'indefensible tre a tm e n t', Myers described his ow n 'tr e a t m e n t by explo ratio n ' f o r narcolepsy:. 27. 'Repression and dissociation are at the root o f the disorder and reintegration alone. <U a. ■ H.

(29) can effect a true cure'. W o rs ter-D ro ugh t (1923) a neurologist at the Queen's Square National Hospital in London, cited Myers and advised th e f o llo w in g strategy fo r the tre a tm e n t o f narcolepsy in cases w i th o u t evidence o f organic disease:. 'I believe the m ost satisfactory o f the s h o rte r m ethods o f treatm ent to be (1) a p relim in a ry m o d ified 'psychoanalysis' with a detailed investigation into the h istory o f the onset o f the attacks, and o f the individual, fo llo w e d by (2) reco nstru ction of the origin o f n arcolepsy o r the em otional exp erien ce giving rise to the condition, under lig h t h ypnosis' [33] . V a riatio ns on this th e m e c o n tin u e d t o ap pear in t h e lite r a tu r e . W ille y (1924) describ ed t h e escape m ech an is m t h a t na rcolepsy p ro v id e d as 'tem p ora ry su icid e '. [42]. M is sriegler (1924) p o r tr a y e d na rcolepsy as a w a y o f g r a tify in g m u rd e ro u s and sexual im puls es d u r in g sleep: 'A crim ina l com ponent will p ro b a b ly b e fo u n d to. exist in n a rco lep sy ' [43]. F u rth e rm o r e , he de scrib ed successful t r e a t m e n t o f a p a t ie n t w i t h psychoanalysis.. N o t o n ly sleep attacks, b u t o t h e r s y m p to m s o f na rcolepsy cou ld be exp la in e d as n e u ro tic s y m p to m s as w e ll. C oodle y (1948) suggested f o r e xa m ple t h a t cataple xy m ig h t r e p re s e n t 'self castration, in which the entire bod y - equated with the penis. - goes lim p ' [4 4 ]. Ho wever,. not. all. contem porary. a u th o rs. m e n tio n e d. the. p u b lic a tio n s. on. psychoanalysis in narcolepsy. For exam ple, Adie (1926) in his f a m o u s thesis on na rcolepsy did n o t cite one psychoanalyst. N e ith e r did Redlich, t h e Austria n a u t h o r i t y on narcolepsy, exce pt in his v e ry last pa pe r in w h ic h he stated t h a t he was n o t con vin ced o f e i th e r t h e psychogenic causatio n o f n a rcolepsy o r an essential psychological in flu e n c e on t h e disease: 'Ich selbst h abe mich, (...), von eine Psychogenese d er N arkolepsie o d er auch nur. von e in er w esentlichen psychologischen B eeinflussung d er N arkolepsie nicht überzeugen können, ich kann also auch nichts von e in er P sychotherapie b erich ten .' [25,27-29,45,46].. INFLUENCE OF PAVLOV'S INHIBITION THEORY A second a p pro ach t o psychogenic m ech an is m s in na rc olepsy was based on the w o r k o f Pavlov, one o f t h e g o d fa th e rs o f be ha vio ris m w h o received th e Nobel Prize f o r his w o r k on classic c o n d itio n in g in 1904. La ter on, Pavlov de ve lo p e d his o w n t h e o r y o f sleep: th e in h ib it io n th e o r y , based on e x p e rim e n ts w i t h dogs.

(30) [47,48]. He ob serv e d t h a t dogs w o u ld fall asleep a f t e r w i t h h o ld i n g o f a rew ard th e y w e r e c o n d itio n e d to. He reasoned t h a t sleep was n o th in g b u t in te rnal i n h ib it io n r a d ia tin g o ve r t h e c o rte x and in v o lv in g lo w e r bra in cen ters as well. Brailovsky [49] and Adie [45]. ap plie d this t h e o r y t o narcolepsy, Adie using it to explain b o th sleep attacks and cataple xy:. 'It seem s then as if narcolepsy is an expression o f fa tig u e in individuals with a kind o f nervous activity that fa vo rs the sp rea d o f in h ibition s and allow s excessive em otional responses; furth er, that the local respon se to inhibitions, w herever they arise, is abnorm al, and that the sym ptom s are due to a general alteration of nervous activity ra th er than to abnorm al stim u li which a ffect norm al structures at a distance'. Levin, w h o s ta r te d o u t as a n e u ro lo g is t in t h e m ilita ry , e x te n d e d this tra in o f t h o u g h t and suggested t h a t na rcolepsy was caused by a w ave o f in h ib itio n , ju s t as epilepsy was caused by a w a ve o f e x c ita tio n : 'the na rcolep tic p a tient possesses a. brain in which in h ibition occurs with undue ease'. Levin believed t h a t the d e v e lo p m e n t o f t h e 'm a c h in e age' caused th e 're c e n t increase' in th e in cid e nce of narcolepsy: having t o suppress rea ction s t o stim u li, f o r in sta nce w h e n d r iv in g a car, w o u ld lead t o in h ib it io n and c o n s e q u e n tly t o na rcolepsy s y m p to m s [50]. In his la te r w o r k , he stressed t h e im p o r t a n c e o f g u ilt in ca ta p le xy [51]. For example, h i t t in g an a d u lt in an ger w o u ld n o t lead t o cataplexy, w h ile h i t t in g one's o w n child w o u ld . Levin exp la in e d this by Pavlov's physio lo gical co n c e p t o f tr a in e d in h ib itio n .. o ’ (J. 'The classic exam ple is the angry fa th e r who raises his hand to punish his ch ild and. «. is at that m om ent stricken with w eakness o f the upraised arm. The w eakness m ay. m. spread to o ther lim bs as well. This event m ust b e view ed fro m two standpoints -. JE. the psych ological and the physiological. Psychologically, the fa th e r is torn by a. 5. TO. conflict; his aggressive im pulse tow ard his ch ild m akes him fe e l guilty.. ™. Physiologically, he is the victim o f what Pavlov ca lled co n dition ed inhibition'.. t. Levin publis he d on th e s u b je c t r e p e a te d ly in h ig h -ra n k in g jo u r n a ls such as t h e. 2 JZ u £. A m e rica n Journal o f Psychiatry; his last p u b lic a tio n (1961) fell in t h e same t im e. TO. fra m e as t h e last p u b lic a tio n s o f psychoanalysts on na rcolepsy [52]. However, in. >■. th e 1950s, critic al c o m m e n t s s ta r te d t o appear, f o r e x a m p le f r o m t h e British. O. ne u ro p h y s io lo g is t Pond (1952): 'such term s have a deceptive sim p licity and an. ^. appearance o f explaining everything, but as Pavlov's la ter w ork shows, m ore and. z. m ore ad hoc hypotheses have to be invented to co ver the fa cts. Little is gained fro m his term inology, which does not com pletely b rid g e the gap betw een. 29. psych ology and n e u ro lo g y ' [53].. <D a. ■ M.

(31) A FURTHER BOOST FOR THE PSYCHODYNAMIC APPROACH The p sy ch o a n a lytic v ie w on na rcoleps y was s tro n g ly s t im u la te d by t h e a rtic le in Brain by t h e f a m o u s British n e u ro lo g is t Kin nier W ils o n in 19 28 [34]. W hen analyzing t h e e tio lo g y o f th e n a r c o le p tic syn d ro m e , W ilso n op e n e d t h e d o o r w id e ly t o ps y c h ia try and psychoanalysis. Q u o tin g artic les o f Carlill, Myers, W orster-D rought. and. th e. psych oa na ly st. M issriegler,. he. re m a rke d. about. psy ch o p a th o lo g ic a l causes; in a list o f eigh t causal categories he placed 'th e psy ch o p a th o lo g ic a l. group'. second. after. th e. 't r a u m a t ic g r o u p '. and. be fo re. endocrinology, epilepsy and encephalitis. The consequence o f Wilson's reasoning was t h a t p a tie n ts f o r m e r l y called 'h y s te ric a l' could n o w fu lly be classified as having. narcolepsy.. W ilso n's. v ie w. meant. r e c o g n itio n. and. a. fo r m id a b le. b re a k th ro u g h f o r psych ia trists w i t h ps ych oa na lytic o rie n ta tio n , and t h e paper was f r e q u e n t l y. cited. in t h e. la te r. p s ych o a n a lytic li te r a t u r e. on. narcolepsy.. W in n e c o t (1930), Jones (1935), Sim mel (1942) and Schulte (1942) all re p o r te d t h e ir p sych oa na ly tic al w o r k w i t h n a rc o le p tic patients, p o in tin g t o ' t h r e a te n in g sexual fantasies', 'escape f r o m rea lity', 'r e liv in g t h e de ath o f a f a t h e r in o r d e r to be w i t h him', and 'h o m o s e xu a l in versio n' as causing na rcoleps y [54-57]. The psychodynam ic de scrip tions o f na rcoleptic pa tie n ts alm ost showed c on tem pt, as th e ne xt c it a t io n f r o m L a n g w o r th y and Betz (1944) shows:. 'N arcoleptic and cataplectic reaction: a b rillia n tly selected sou rce o f relief. A non verbal adm ission o f inadequacy, n ot in com p a tible with self- respect. (...) This condition is a p erso n a lity reaction to em otional issues ra th er than an organic disease as has fo rm e rly been assum ed. The sym ptom s o f excessive diurnal sleep, cataplexy, sleep paralysis, som nam bulism , [and] nocturn al h allucinations appea r to b e neuro tic defenses with sym bolic sig n ifica n ce against p rim a ry anxieties associated with d ifficu lties in rea listic adjustm ents in p erso n a l relationships with others. The n arcoleptic syndrom e as a n eurotic rea ction seem s sim ila r in m any respects to the hysterical reaction. They fe e l ca ugh t in a life-pattern to which they are expected to conform , bu t which they deeply re se n t' [58].. THERAPEUTIC CONSEQUENCES OF THE PSYCHODYNAMIC APPROACH T here was 'goo d news' f o r n a rc o le p tic p a tie n ts th o u g h : th e psy ch od y na m ic a p pro ach p ro v id e d a th e r a p e u t ic o p tio n , na m ely psychoanalysis. L a n g w o r th y and Betz. de scrib ed. six. patients,. tw o. of. whom. p ro ved. responsiv e. to. t h e ir. p sych oa na ly tic al a p pro ach w i t h an a m e lio r a t io n o f t h e n a rc o le p tic sy m p to m s..

(32) Figure 4 Illustration f r o m Barker's article on EEG registrations durin g a sodium am ytal in te rv ie w w ith a narcolepsy patie nt [60]. See main te x t f o r details.. The a u th o rs state t h a t psych o a n a lytic p s y c h o th e ra p y p ro v id e d 'a fundam ental. approach to th eir difficulty'. Spiegel and O b e r n d o r f (1944) de scrib ed t h e c o n te n ts o f such a t r e a t m e n t : th e b re a k th r o u g h in th e ra p y was a 'confessional catharsis', encou rage d by t h e th e r a p is t [59]. In t h e ir case, a lo ng s ta n d in g sexual co n flic t sup po sed ly was closely related t o th e p a tie n t's states o f sleepiness and o th e r physical s y m p to m s . A f t e r an unsusp ected e le m e n t o f he r sexual life had been discussed w i t h t h e th e ra p is t, she had f e w e r attac ks o f na rcolepsy and her. 31. n o c tu rn a l insom nia d im in ishe d.. <u. ■ H. a.

(33) Barker (1948), a psych oa na ly st f r o m Ne w York, used re p ea te d in te rv ie w s , free association, and in tra v e n o u s sod iu m a m yta l in t h e search f o r in fo r m a t io n [60]. In an a m b it io n t o 'p ro v e ' t h e psyc h o a n a ly tic ap proach, he re c o rd e d th e EEG of t w o p a tie n ts d u r in g such a sod iu m a m yta l in te r v ie w (Figure 4). In th e o b se rva tio n s sectio n o f his paper, a candid d e s c rip tio n o f t h e session was pro vid ed:. T hree m in u te s a f t e r t h e p a tie n t had been given 0.3 gra m s o f sod iu m a m y ta l, the discussion w h ic h had de alt w i t h early aggressive urges and his m e th o d s of h a nd lin g t h e m , p ro c ee ded as follow s:. (...) did you ever have a fig h t with y ou r fa th e r / No / W hat kind o f a m an was h e ? / He was a g oo d guy / Is he liv in g ? / Yes / A re y ou r parents living together? (...) The p a tie n t did n o t re spond t o th e q u e s tio n b u t t u r n e d his head t o t h e r ig h t and w e n t t o sleep. The in te r v ie w c o n tin u e d a f t e r w a r d s and Barkers fin a l conclusion was:. 'when the discussion was turned to incidents in which his aggressive urges co nflicted with his g u ilt o r fe a r o f punishm ents, the p a tient w ent to sleep instead o f discussing them and the EEG show ed patterns as those o f Fig. 1 B and D [i.e. norm al sleep]'.. THE TRIUMPH: FINAL 'PROOF' OF THE PSYCHOANALYTICAL VIEWS In t h e p o s t-w a r pe rio d , t h e psychoanaly sts reached t h e peak o f t h e ir in flu e n c e on narcolepsy, m uch t o th e ir r i t a t i o n o f m o re biolo gical th in k in g n e u ro lo g ists such as Daniels. In a le t t e r t o K le itm an, dated July 21, 1948, Daniels w r o te : 'I (..) have. been decidedly annoyed by recen t attem pts o f the psychosom aticists to revive the old idea that narcolepsy is sim ply a fo rm o f esca p e' [61]. Ho wever, psychoanalysis had a fin a l w o r d t o say. In 1960, Vogel phrased the analytical vie w s in t h e f o ll o w i n g hypothesis:. 'N orm al subjects dream to prese rve sleep, n arcoleptics sleep to dream. The narcoleptic attack provides h allu cin a tory g ra tifica tion o f fo rb id d en fa ntasies by the sp ecific m echanism o f wish fu lfillm e n t through dream ing. In that case, the p u rpose o f the path olo gical sleep is not only to defend, but also to p rovid e the ego regression n ecessary f o r h allucin a tory wish fu lfillm e n t through d re a m in g ' [62 ]. Based on t h e rec e nt dis cove ry o f REM sleep [63] and t h e f in d in g t h a t dre a m in g. 32. m ostly occurred d u rin g this sleep stage [64], Vogel w e n t on t o test his hypothesis by p e rfo rm in g EEG recordings in a n a rcoleptic pa tie n t in t h e a fte r n o o n in th e sleep lab.

(34) [62]. He observed t h a t his p a tie n t fall asleep on ly on e m in u te a fte r th e s ta rt o f the exp e rim e n ta l procedure. M ore ove r, REM sleep recorded occurred w i th in three m in utes a fte r sleep onset, much fa ste r than normal. Vogel to o k these fin d in gs as p r o o f o f his t h e o r y : 'the purpose o f som e narcoleptic sleep is to obtain through a. dream the hallucinatory gratification o f an unacceptable fantasy'. Paradoxically, Vogel's fin d in g s m arked th e en d o f t h e p sy ch o a n a lytic vie w s on the p a th o p h y s io lo g y. of. narcolepsy.. He. dis covered. Sleep. Onset. REM. Periods. (SOREMPs), w h ic h t u r n e d o u t t o be a d iag nos tic h a llm a rk o f t h e d is o r d e r t h a t is still in clinical use today. The o c c u rre n c e o f SOREMPs also f o r m e d a s u p p o r t fo r th e sleep diss oc ia tio n t h e o r y t h a t was f ir s t suggested by B o n h o e f f e r in 1928 [65] and o b ta in e d n e u r o b io lo g ic a l g r o u n d in 20 01 [66]. N everthele ss, in th o se same 1970s, psych oanalysis f o r th e t r e a t m e n t o f na rc olepsy was still ad vo ca te d in the lite r a t u r e [4].. ALTERNATIVE VIEWS In 19 34 Daniels, n e u ro lo g is t at t h e M a yo clinic, w r o t e his la n d m a rk m o n o g r a p h in w h ich he m e tic u lo u s ly describ ed 146 p a tie n ts w i t h na rcolepsy [67]. As m e n tio n e d earlier, Daniels did n o t believe in a psychogenic origin o f narcolepsy, and he addressed several psych oa na ly tic al vie w s dire ctly. For exam ple, Daniels made clear t h a t even if M issriegler's reasonin g t h a t t h e libid o may fin d expression in. a. th e dream s o f som e na rcoleptic s, this w o u ld n o t at all w a r r a n t general conclu sio ns. -2. on th e etiolo gy o f t h e syn d ro m e . He also f e lt t h a t na rc oleptic s did n o t have an. $. a lte re d pe rso n a lity, de scrib in g p a tie n ts as stable, aside f r o m a ce rta in de gree o f ir rita b ilit y , 'likely to b e m anifested by any drow sy person '. Interestingly, exa ctly these possible p e rs on ali ty changes w e re used as f i t t i n g w i t h. m. _| v e. an organic cause by several authors. T hiele and Bernard (1933) w e r e convin ced t h a t. ™. na rcolepsy was a 'complex', localized in th e brain, and po in te d t o th e sleep c en ter. ^. proposed by von Economo, te n ta tiv e ly in clu din g th e hyp otha la m u s [68,69]. Next to. j=. TO. th e sleep s ym p to m s th e y also described psychological distu rbances t o be present. £. in t h e 'genuine narcolepsy' cases. Terms like 'phlegm atic, slo w ' w e re used, b u t also. 1. 'Pom adigkeit' [indifferent, blasé] and 'D ickfelligkeit' [thick skinned]. Im p o rta n tly ,. >. pe rson ali ty s y m p to m s w e re de scribed to be 'organic' in nature and c om p ara ble t o pe rson ali ty changes in post-encephalitis patie nts. M o s t patie nts w e re tre a te d w i t h. TO. l e. a O. ^. m ed ic a tion (thyroxin in c o m b in a tio n w i t h caffeine o r ephedrine).. N. The Swiss B e n e d e tti (1953) f o llo w e d T hie le and Bernard's line o f reasonin g and. 33. describ ed th e p s y c h o p a th o lo g y o f eigh t n a rcolepsy p a tie n ts [70]. He regarded. <U a. ■ H.

(35) na rcolepsy as a focal brain and e n d o c r in e sy n d ro m e . A f t e r d e scrib in g p e rs o n a lity changes in th e sense o f apathy, lack o f in te re s t, in d iffe r e n c e and m o o d la bility, he linked the se t r a it s t o e n d o c rin e d y s fu n c tio n .. It is s trik in g t h a t Thiele, Bernard and B e n e d e tti, be in g psychia trists, t o t a lly dis regarded all c o n t e m p o r a r y p sy ch oa na ly tic al pu b lic a tio n s , as t h e ir references show. In turn, psychoanalysts neglected the m ore 'organic' studies. This constituted a clear separation b e tw ee n 'organic' o r 'phenom enolo gical ' psychiatrists -at that t im e considered as m ore traditional, and 'psychogenic/ psychoanalytical' thin kin g psychiatrists, as the m odern and rev o lu tiona ry m o ve m e n t at th a t time.. THE NEUROBIOLOGICAL CAUSE OF NARCOLEPSY In 1957, Yoss and Daly publis he d a s tu d y o f 241 p a tie n ts th e y exa m in ed at the M a yo Clinic [71]. Based on these series, t h e f o r m u l a t e d f o rm a l d iag nos tic c riteria, and t h e classic ' t e t r a d ' o f na rcolepsy was bo rn: t h e c o m b in a t io n o f excessive d a y t im e sleepiness, cataplexy, sleep paralysis and hypnagogic hallucin atio ns. A lth o u g h r e c e n t insights show t h a t t h e la t t e r t w o are n o t t r u e 'c o re ' s ym p to m s, Yoss and Daly's crite ria c o n s t it u t e d an im p o r t a n t la nd m ark , n o t o n ly clinically, but also scie ntific a lly: t h e d iag nostic crite ria w e r e pivo ta l f o r t h e s y ste m a tic studies in t h e n e x t decades.. The search f o r th e n e u ro b io lo g ic a l cause o f na rcolepsy was also stim u la te d tre m e n d o u s ly , w h e n in 1973 t h e canin e m o d e l was describ ed [72]. The n a rc o le p tic dogs f o r m e d a p e r fe c t anim al m od el f o r such a c o m p le x disease as narcolepsy, especially because t h e ca ta p le xy p h e n o t y p e was s t rik in g ly sim ila r t o c a ta p le x y in humans. Research was f u r t h e r s t im u la te d w h e n it becam e cle ar t h a t in a fe w breeds, na rcolepsy was t r a n s m i t t e d as a m o n o g e n e tic t r a i t in an autosom a l d o m in a n t fa sh io n [73]. The h u n t f o r t h e na rcolepsy ge ne had begun, co m in g t o an end w h e n it was id e n tifie d in 1999: m u t a t io n s in one o f t h e r e c e p to rs f o r the h y p o th a la m ic n e u r o p e p t id e h y p o c r e tin (also k n o w n as orexin ) w e r e responsib le f o r fa m ilia l na rcolepsy in b o th D o b e rm a n s and Labradors [5].. In an un usually fast string o f discoveries, th e h y p o c r e tin system was also p in p o in te d as th e p r im a r y c u lp r it in h u m an narcolepsy. In ea rly 2 0 0 0 it was shown th a t t h e m a j o r it y o f p a tie n ts w i t h na rcolepsy lack t h e h y p o c re tin p e p tid e s in th e ir cere bro spin al f lu id. [74]. W it h the se discoveries, na rcolepsy was fin a lly and. in d is p u ta b ly sho w n t o be a p r im a r y n e uro lo g ic a l disorder..

(36) The h y p o c r e tin system was fo u n d t o have s tro n g co n n e c tio n s n o t o n ly w ith sle ep -w ake systems in t h e b r a in , b u t also w i t h a range o f o t h e r b ra in regio ns, in clu d in g t h e li m b ic system [75-77]. This n o t io n op e n e d up t h e w a y t o address the psych ia tric p a rt o f na rc olepsy in a fu n d a m e n t a l n e w w ay: as an essential p a rt of th e p h e n o ty p e , and a d ire c t con seq ue nce o f th e u n d e rly in g pa thop h ys io lo g ica l mech anisms.. AN OPEN VIEW TOWARDS PSYCHIATRIC COMORBIDITY In several case studie s in t h e second h a lf o f t h e 20 th c en tury, several psychia tric s y m p to m s w e r e r e p o r t e d t o be p re sen t in na rcolepsy [78-83]. Depressive m oo d was m o s t o f t e n describ ed, n e x t t o p e rs o n a lity and sexual disord ers. In a d d itio n , th e r e la tio n b e tw e e n na rcolepsy and sc hizophrenia was discussed in several papers. O n ly recently, c o n t ro lle d studie s in to th e psych ia tric c o m o r b id it y o f na rcolepsy have be en p e r fo r m e d however. In several c o n t ro lle d studies, a h igh er f re q u e n c y o f depre ssiv e s y m p to m s was describ ed in narcolepsy, using q u e s tio n n a ire s such as t h e Beck Depre ssion Inve ntory. How eve r, th e t w o studie s w h ic h used a f o r m a l diag n o s tic in s tr u m e n t sho w e d t h a t t h e f r e q u e n c y o f m a jo r depre ssio n o r o t h e r a f f e c t iv e d isord ers is not increased [6,11]. A n x ie ty diso rd e rs w e r e re c e n tly sho w n t o be o f im p o rta n c e , w i t h a high level o f a n x ie ty s y m p to m s in m o re tha n h a lf o f t h e pa tie n ts, and an increased pre valence o f social phobia and panic attacks [11]. Daniels alrea dy sho w e d t h a t na rcolepsy p a tie n ts are o f t e n o v e rw e ig h t, and p o p u la tio n studie s have n o w c o n f irm e d this v ie w [67]. It rem a in s un cle ar w h e t h e r this o v e r w e ig h t is r elated t o t h e 'c arbo c raving ' t h a t p a tie n ts o f t e n r e p o r t . Indeed, e a tin g d isord ers s y m p to m s are f r e q u e n t l y pre se n t in na rcolepsy [8,13], alth o u g h a h igh er presence o f f o rm a l e a tin g d is o rd e r diagnoses has been dis p u te d [9].. 35 <u. ■ H. a.

(37) CONCLUSIONS The associa tion b e tw e e n ps y c h ia try and na rcolepsy has sho w n m an y d iff e r e n t faces in th e past (Figure 1). O fte n , th e psych ia tric vie w s on na rcolepsy re fle c te d th e c o n t e m p o r a r y w a y o f medical th in k in g . U n fo r tu n a te ly , som e vie ws w e r e not fa v o ra b le f o r th e p a tie n ts in volv ed. N o w t h a t na rcolepsy is f i r m l y established as brain disorder, t h e t im e has com e t o c a re fu lly describ e and u n d e rs ta n d the s p e c tru m o f psych ia tric c o m o r b id it y in narcolepsy. Given t h a t t h e psychia tric s y m p to m s cle arly a f f e c t q u a lit y o f life in a ne gative way, it is o f p a r a m o u n t im p o r t a n c e t h a t t h e y are addressed in t h e clinical care. In a d d itio n , na rcoleps y is an exce lle n t ' m o d e l' t o stud y t h e large n u m b e r o f d i f f e r e n t f u n c tio n s t h a t the h y p o c re tin system p e r fo r m s in t h e brain, and h o p e fu lly the se insights w ill lead to ne w t r e a t m e n t o p tio n s in t h e f u tu r e .. 36.

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(42) u a ro .c u. ■M. Psychotic symptoms in narcolepsy Phenomenology and a comparison with schizophrenia. H.A. D roo gleever Fortuyn, G.A. Lappenschaar , F.J. N ienhuis, J.W. Furer, P.P. Hodiam ont, C.A. Rijnders, G.J. Lammers, W.O. Renier, J.K. Buitelaar, S. Overeem. Psychotic sym ptom s in narcolepsy: p h enom en ology and a com parison with schizophrenia. G eneral H ospital Psychiatry, 3 1 (20 09 ) 14 6 - 15 4 3.

(43) ABSTRACT Objective: Patie nts w i t h na rcolepsy o f t e n exp e rie n ce pervasive hypnagogic ha llu cin atio ns, s o m e tim e s even le adin g t o co n fu sio n w i t h schizophrenia . We aim ed t o p ro v id e a d e ta ile d q u a lit a t iv e d e s c rip tio n o f hypnagogic h a llu cin atio ns and o t h e r "p s y c h o tic " s y m p to m s in p a tie n ts w i t h na rc olepsy and c o n tra s t these w ith. schizophrenia. p a tie n ts. and. h e a lth y. con tro ls.. pre valence o f f o r m a l ps ych otic diso rd e rs b e tw e e n. We. also c o m p a re d. the. na rcolepsy p a tie n ts and. con tro ls .. Methods: W e used SCAN 2.1 in te rv ie w s t o c o m p a re ps ych otic s y m p to m s b e tw e e n 60 p a tie n ts w i t h narcolepsy, 102 w i t h schizophre nia , and 120 m a tch e d p o p u la tio n con tro ls.. In a d d itio n ,. q u a lit a t iv e. data was c o lle cte d. to. enable a d e tailed. d e s c rip tio n o f hy p nagogic h a llu c in a tio n s in narcolepsy.. Results: T here w e r e clear d iffe re n c e s in t h e p a t te r n o f h a llu c in a to ry experiences in na rc olepsy versus s chizophrenia pa tie n ts. N a rcole ptic s r e p o r t e d m u ltis e n s o ry " h o li s ti c " ha llu cin a tio n s r a t h e r tha n t h e p r e d o m in a n t ly ve rb a l- a u d i t o r y sensory m o d e o f schizophrenia pa tie n ts. O th e r psychotic s y m p to m s such as de lusions w e r e n o t m o r e f r e q u e n t in na rc olepsy c o m p a re d t o p o p u la tio n con tro ls. In a d d itio n , t h e p re valence o f f o r m a l psy ch otic d isord ers was n o t in creased in p a tie n ts. w ith. narcolepsy.. A lm o s t. h a lf o f. na rco le p tics. reported. m o d e r a te. in te r fe r e n c e w i t h f u n c t i o n i n g due t o ha llu cin atio ns, m o s tly du e t o related anxiety.. Conclusions: Hyp nagogic ha llu cin a tio n s in na rcolepsy can be d i ff e r e n t ia te d on a p h e n o m e n o lo g ic a l basis f r o m ha llu cin a tio n s in sc hizophrenia w h ic h is useful in d iff e r e n t ia l d iag nos tic dilem m as.. 42.

(44) INTRODUCTION Narcole psy. is a cen tra l. n e rvou s. system. d is o r d e r w i t h. excessive. d a y tim e. sleepiness, f r a g m e n t e d n i g h tt im e sleep and ca ta p le x y as t h e core s y m p to m s . In a d d itio n , p a tie n ts o f t e n e xp erience hypnagogic h a llu c in atio ns , w h ic h are vivid ha llu c in a tio n s o c c u rr in g w h e n. fa llin g asleep. W h e n. ha llu cin a tio n s o c cu r at. aw akenin g, th e y are called h y p n o p o m p ic O veree m Narcole psy is caused by a d e fic ie n c y in h y p o th a la m ic h y p o c re tin (orexin) sig naling [1]. The h y p o c re tin neurons are exclusively located in th e lateral and p e riforn ic al hypothala mus, but p r o je c t exte nsive ly t h r o u g h th e rest o f th e brain, in clu d in g th e li m b ic system. Intere stingly, rec e nt da ta p o in t t o a possible role o f t h e h y p o c re tin system in psychiatric disorders, such as a d dic tion [2,3] and schizophrenia [4]. These data in tu r n focus (ren ew e d) a t t e n t i o n t o possible psy ch ia tric s y m p to m s in narcolepsy.. Hypnagogic ha llu cin a tio n s in na rcolepsy p a tie n ts can be v e r y pervasive. In isolated cases this has be en r e p o r t e d t o c rea te diag n o stic c on fusio n in physicians n o t f a m ilia r w i t h na rc olepsy [5-8] Narcole psy p a tie n ts have even been mistaken f o r having schizophrenia [9-12] On th e o t h e r hand, hypnagogic ha llu cin a tio n s have been r e p o r t e d t o occur in th e general. p o p u la tio n. as well, w h ic h. may q u e s tio n. t h e ir. patholog ic al. sig nific ance [13,14].. In t h e pre se n t study, w e p ro v id e a d e ta ile d p h e n o m e n o lo g ic a l s tu d y o f "p sy cho tic s y m p t o m s " such as (hypnagogic) h a llu cin atio ns, o t h e r p e rc e p tu a l experiences as w ell as de lu sio ns in p a tie n ts w i t h narcolepsy, using th e Schedules f o r Clinical Assessm ent in N e u r o p s y c h ia tr y (SCAN) [15] The f in d in g s are c o n tra s te d w i t h a c o h o r t o f schizophrenia p a tie n ts and c o m p a re d w i t h a c o n tro l g ro u p o f m atche d p o p u la tio n subjects. F u r th e rm o re , w e assess d iffe re n c e s b e tw e e n t h e prevalence o f DSM /^-d ia g n o s e d psych otic diso rd e rs in na rcolepsy p a tie n ts and p o p u la tio n s con tro ls . Finally, w e p r o v id e a q u a lita tiv e d e s c rip tio n o f t h e c o n t e n t o f hypnagogic ha llu c in a tio n s in narcolepsy.. METHODS We. p e r fo r m e d. a. cross-sectional. study,. c o m p a r in g. ps ych otic. s y m p to m s. (ha llu cin atio n s, o t h e r pe rce p tu a l experiences and delusions) in th r e e groups: 60 p a tie n ts w i t h na rcoleps y-c a ta plexy , 102 p a tie n ts w i t h schizophrenia and 120 p o p u la tio n con tro ls .. 43 <u. ■ H. a.

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