Circadian Rhythm Disorder Overview

Circadian Rhythm Disorder Overview
Medical Author:
Mary E Cataletto, MD
Coauthor:
Gila Hertz, PhD, ABSM
Medical Editor:
Selim R Benbadis, MD
Medical Editor:
Mary !indle, PharmD
Medical Editor:
Ste"hen Berman, MD, PhD
http://www.emedicinehealth.com/sleeplessness_and_circadian_rhythm_disorder/artic
le_em.htm
A "erson#s circadian rhythm is aninternal biolo$ical cloc% that re$ulates a &ariety o' biolo$ical
"rocesses accordin$ to an a""ro(imate )*+hour "eriod, Most o' a "erson#s bodysystems
demonstrate circadian &ariations, -he body systems .ith the most "rominent circadian &ariations
are the slee"+.a%e cycle, the tem"erature re$ulation system, and the endocrine system,
-he mal'unctionin$ o' a "erson#s circadian system, or biolo$ical cloc%, causes circadian rhythm
disorders, -he circadian rhythm disorder related to the slee"+.a%e cycle can be cate$orized into
the 'ollo.in$ ) main $rou"s:
-ransient disorders
o /et la$
o Altered slee" schedule due to .or% hours or social res"onsibilities
o 0llness
Chronic disorders
o Delayed slee"+"hase syndrome 1DSPS2
DSPS is characterized by a "ersistent 1that is, lastin$ lon$er than 3
months2 inability to 'all aslee" and a.a%en at socially acce"tabletimes,
0ndi&iduals .ith DSPS 'all aslee" late 1'or e(am"le, in the early mornin$
hours2 and .a%e u" late 1'or e(am"le, in the late mornin$ hours or in the
early a'ternoon hours2,
4nce aslee", ho.e&er, "ersons .ith DSPS are able to maintain their slee"
and ha&e normal total slee" times, 0n contrast, "ersons .ithout DSPS .ho
are unable toslee" because o' di''iculties initiatin$ and maintainin$ slee"
ha&e a lo.er than normal total slee" time than "ersons .ith DSPS,
o Ad&anced slee"+"hase syndrome 1ASPS2
ASPS is characterized by a "ersistent early e&enin$ slee" onset time
1bet.een 3:55 "m and 6:55 "m2 and an early mornin$ .a%e+u" time
1bet.een 7:55 am and 8:55 am2,
ASPS occurs less 're9uently than DSPS and is most commonly seen in
elderly indi&iduals and in indi&iduals .ho are de"ressed,
o 0rre$ular slee"+.a%e cycle
An irre$ular slee"+.a%e schedule 'eatures multi"le slee" e"isodes .ithout
e&idence o' reco$nizable ultradian 1a series o' shorter biolo$ical rhythms
occurrin$ .ithin a )*+hour "eriod2 or circadian 'eatures o' slee" and
.a%e'ulness,
As in "ersons .ith ASPS and DSPS, total slee" time is normal in "ersons
.ith an irre$ular slee"+.a%e schedule,
Daily slee" lo$s demonstrate irre$ularity not only o' slee"but also o'
daytime acti&ities, includin$ eatin$,
Cause
Most o' the time, a "erson#s biolo$ical cloc%, or circadian rhythm, is in synchronization .ith the
)*+hour day+ni$ht en&ironment, 0n some indi&iduals, ho.e&er, the biolo$ical circadian rhythm o'
slee" and .a%e'ulness is out o' "hase .ith the con&entional or desired slee"+.a%e schedule,
Some reasons 'or this brea%do.n may include the 'ollo.in$:
Sensitivity to zeitgebers("time givers," such as light and other environmental
cues: !his sensitivity may be altered or disrupted, which can be
demonstrated under certain conditions. "ltered or disrupted sensitivity to
zeitgebers is probably the most common cause o# the circadian rhythm
disorder o# the sleep$wa%e cycle.
&isrupted pacema%er #unction: " dys#unction may be present in the internal
coupling mechanisms o# biological pacema%ers, #or e'ample, the coupling o#
the sleep$wa%e cycle with the temperature cycle.
(nvironment: )ight, higher noise levels, and elevated room temperature are
not conducive to good sleep and are important variables to consider in both
shi#t wor%ers and night wor%ers.
!ravel: !he severity o# *et lag is related to the direction o# travel and is more
#re+uently seen in individuals traveling in an eastward direction. !he number
o# time zones crossed also has an e,ect on the severity o# *et lag, with
mostindividuals e'periencing *et lag i# they cross - or more time zones. !he
rate o# ad*ustment is ../ hours per day a#ter a westward 0ight and . hour per
day a#ter an eastward 0ight.
1eurological disease: "lzheimer diseaseis one o# the more common e'amples
o# neurological disease associated with a circadian rhythm disturbance2
however, irregular sleep$wa%e cycles can also be seen in other
neurodegenerative diseases. Sundowning, which is a common phenomenon
in persons with "lzheimer disease, is characterized by sleep disruptions with
awa%enings and con#usion.
Shi#t wor%: 3apid shi#t changes and shi#t changes in the countercloc%wise
direction are most li%ely to cause symptoms o# a circadian rhythm disorder.
)i#estyle and social pressure to stay up late can e'acerbate a circadian
rhythm disorder.
4ani#est
Sym"toms commonly 'ound in "ersons .ith a circadian rhythm disorder related to the slee"+
.a%e cycle can include the 'ollo.in$:
Di''iculty initiatin$ slee"
Di''iculty maintainin$ slee"
:onrestorati&e slee"
Daytime slee"iness
Poor concentration
0m"aired "er'ormance, includin$ a decrease in co$niti&e s%ills
Poor "sychomotor coordination
Headaches
Gastrointestinal distress
Sleeplessness and Circadian Rhythm Disorder
"uthor: 4ary ( Cataletto, 4&2 Chie# (ditor: Selim 3 5enbadis, 4&
http://emedicine.medscape.com/article/..66788$overview
Practice Essentials
Disturbances in circadian rhythm;the a""ro(imately )*+hour cycles that are endo$enously
$enerated by an or$anism;can be cate$orized into ) main $rou"s: transient disorders 1e$, <et la$
or a chan$ed slee" schedule due to .or%, social res"onsibilities, or illness2 and chronic disorders
1e$, delayed slee"+"hase syndrome =DSPS>, ad&anced slee"+"hase syndrome =ASPS>, and
irre$ular slee"+.a%e cycle2, Slee"lessness 1insomnia2 is de'ined as di''iculty initiatin$ or
maintainin$ slee",
Essential update: FDA approves first treatment for non-24 hour sleep-wae
disorder in totally !lind individuals
0n /anuary )5?*, the @DA a""ro&ed the melatonin rece"tor a$onist tasimelteon 1Hetlioz2 as the
'irst treatment 'or non+)*+ hour slee"+.a%e disorder 1Anon+)*B2, a chronic circadian disorder that
a''ects the timin$ o' slee", in indi&iduals .ho are com"letely blind,
=?>
-asimelteon should be
ta%en at the same time e&ery ni$ht be'ore bedtime, .ith limited acti&ities a'ter ta%in$ the dru$,
=?>
A""ro&al .as based on ) studies o' ?5* totally blind "atients .ith non+)* disorder in .hich
tasimelteon treatment si$ni'icantly increased ni$httime slee" and decreased daytime slee"
duration com"ared .ith "lacebo,
=?>
-he most common side e''ects .ith tasimelteon use .ere
headache, ele&ated alanine aminotrans'erase le&els in the blood, dro.siness, u""er res"iratory or
urinary tract in'ection, ni$htmaresCunusual dreams, and disturbed ni$httime slee",
=?>
"i#ns and symptoms
Consider the 'ollo.in$ to determine the nature o' the "atientDs circadian rhythm disorder:
&uration o# symptoms (transient vs chronic
9attern o# the sleep$wa%e cycle: "llows diagnosis within chronic subtypes
Shi#t wor% (rotating morning/evening/night shi#ts vs a consistent shi#t
!otal sleep time (normal vs shortened
9ea% alertness (late evening/night vs early morning vs no pattern
3ecent travel: Symptoms #rom high$altitude 0ight in general (: ;8 h versus
those #rom *et lag (persist #or days2 more li%ely to occur i# <- time zones are
crossed
&aytime sleepiness: Seen in all circadian rhythm disorders, with varying
severity/timing
9sychological assessment: 9sychophysiological insomnia, depressive
disorders, other psychiatric disorders (symptoms may be similar to those o#
circadian rhythm disorders
Cognition (ie, impact o# circadian rhythm disorder on comple' cognitive tas%s
such as selective attention and e'ecutive #unction
9atient attempts at treatment (sleep aids (eg, alcohol, herbal preparations,
nonprescription/over$the$counter drugs
4edication history and timing o# administration
Snoring, with/without witnessed apnea
=ther medical conditions (eg, congestive heart #ailure >C?@A, chronic
obstructive pulmonary disease, chronic pain syndromes, thyroid disease
(nvironmental cues (light intensity, noise level, environmental temperature
and sleep hygiene (e'ercise and/or stimulant inta%e be#ore bedtime
"ny history o# motor vehicle accidents or other accidents due to decreased
alertness and/or e'cessive sleepiness
DSPS is characterized by the 'ollo.in$:
9ersistent inability (BC mo to #all asleep and awa%en at socially accepted
times
"bility to maintain sleep once sleep is achieved
1ormal total sleep times
9ea% alertness in late evening and night
!ypically seen in adolescents, young adults, and night wor%ers
ASPS occurs much less 're9uently than DSPS and has the 'ollo.in$ 'eatures:
9ersistent, early evening sleep onset (between C:DD pm and 7:DD pm
(arly morning wa%e$up time (generally between -:DD am and /:DD am
9ea% alertness in early morning
Esually stable sleep schedule
1ormal total sleep time
4ost #re+uently occurs in elderly patients and in depressed individuals
0rre$ular slee"+.a%e cycles include the 'ollo.in$ characteristics:
('cessive daytime sleepiness and/or insomnia
4ultiple sleep episodes without evidence o# recognizable ultradian (biologic
rhythms with : ;8$h cycle or circadian #eatures o# sleep and wa%e#ulness
1ormal total sleep time
Frregularity o# sleep and o# daytime activities, including eating
3andom 0uctuation o# body temperature
1o consistent pattern o# pea% alertness
@re+uently associated with "lzheimer disease and other neurodegenerative
diseases
Patients .ith slee"lessnessCinsomnia ha&e a lo.er than normal total slee" time due to di''iculties
in initiatin$ or maintainin$ slee",
See Clinical Presentation 'or more detail,
Dia#nosis
-he dia$nosis o' circadian rhythm disorders is "rimarily based on a thorou$h history, 0n cases o'
slee"lessness, it is im"ortant to distin$uish indi&iduals .ith di''iculty initiatin$ slee" 'rom those
.ith di''iculty maintainin$ slee", those .ith si$ni'icant daytime im"airment, and those .ith
nonrestorati&e slee",
-he "hysical e(amination is 'ocused on identi'yin$ ris% 'actors 'or other conditions that may
"reci"itate, e(acerbate, or mimic slee"lessnessCinsomnia 1e$, de"ression, obstructi&e slee" a"nea
=4SA>, neurode$enerati&e disease2, E(amination includes the 'ollo.in$ assessments:
General a,ect or sense o# well$being in those with sleeplessness/insomnia as
a primary sleep complaint
5ody mass inde' (54F: Fncreased ris% #or =S" with higher 54F measurements
Cranio#acial morphology: )arge tonsils, narrow oropharyngeal spaces, and
large nec%s (increased ris% #or =S"
Chest: 5arrel chest (associated with chronic lung disease2 crac%les, murmurs,
and cardiac enlargement (as evidenced by displaced point o# ma'imum
impulse may be C?@
&igital clubbing: "ssociated with chronic lung disease or congenital heart
disease, or it may be #amilial2 #urther medical evaluation may be needed
1eurologic e'amination
Sleep tests
Sleep logs: @or assessing sleeplessness2 identiHes sleep$wa%e cycles in the
patientIs normal environment2 permits a sub*ective assessment o# alertness
over a ;$wee% period
4ultiple Sleep )atency !est (4S)!: @or ob*ective measurement o# sleepiness
(pworth Sleepiness Scale: @or an indication o# sleepiness2 correlated with
sleep apnea
Imaging studies
5rain imaging: @or evaluation o# suspected neurodegenerative disease
"ctigraphy: @or gross measurement o# sleep$wa%e cycles over time
=vernight polysomnography: @or identiHcation o# =S", periodic limb
movements o# sleep, or sleep$state misperception2 #or evaluation o#
narcolepsy when used in con*unction with the 4S)!
See !or%u" 'or more detail,
$ana#ement
-hera"y 'or circadian rhythm disturbances is lar$ely beha&ioral, Ho.e&er, the direction o'
e&aluation and treatment "lans is in'luenced by di''erentiatin$ bet.een transient and chronic
circadian rhythm disorders as .ell as bet.een "rimary and secondary disorders,
DSPS o'ten resol&es in adulthood, ASPS o'ten res"onds .ell to a combination o' beha&ioral and
"harmacolo$ic inter&ention,
-reatment 'or circadian rhythm disturbances includes the 'ollo.in$:
5ehavioral therapy
5right light therapy
Chronotherapy
(nhancing environmental cues
)i#estyle changes
4i'ed modalities
Pharmacotherapy
5enzodiazepines (eg, triazolam, temazepam, estazolam, +uazepam,
0urazepam
1onbenzodiazepine hypnotics (eg, zolpidem, eszopiclone, zaleplon
4elatonin receptor agonists (eg, tasimelteon, ramelteon, melatonin
Surgery
Slee" disturbances associated .ith 4SA syndrome may be treatable .ith sur$ical inter&ention,
See -reatment and Medication 'or more detail,
Background
Disturbances in circadian rhythm;the a""ro(imately )*+hour cycles that are endo$enously
$enerated by an or$anism;can be cate$orized into ) main $rou"s: transient disorders and
chronic disorders, -ransient disorders include <et la$ or a chan$ed slee" schedule due to .or%,
social res"onsibilities, or illness, 1See Etiolo$y, Pro$nosis, and Presentation,2
-he most common chronic disorders are delayed slee"+"hase syndrome 1DSPS2, ad&anced slee"+
"hase syndrome 1ASPS2, and irre$ular slee"+.a%e cycle, Eatzenber$ et al su$$ested $enetic
correlations 1ie, cloc% "olymor"hisms2 to circadian rhythm "atterns,
=)>
-he International
Classification of Sleep Disorders 10CSD+)2 reco$nizes 6 distinct circadian rhythm see" disorders,
Most "hysiolo$ic systems demonstrate circadian &ariations, -he systems .ith the most
"rominent &ariations are the slee"+.a%e cycle, thermore$ulation, and the endocrine system, 1See
Etiolo$y,2
%erminolo#y
0m"ortant terms associated .ith circadian rhythm are de'ined as 'ollo.s:
Circadian rhythm (#rom circa, meaning "about," and diem, meaning JdayK $
"ppro'imately ;8$hour cycles endogenously generated by an organism (eg,
sleep$wa%e cycle
Eltradian rhythm $ 5iologic rhythms shorter than a ;8$hour cycle (eg, sleep
stages
(ntrainment $ Synchronization o# the circadian rhythms with environmental
cues
@ree$running cloc% $ 9ersistence o# circadian rhythms in the absence o#
environmental cues (eg, in patients with impaired ability to entrain or in those
without time cues
Leitgeber (time giver $ SpeciHc environmental variables that provide time
cues (eg, light, #ood$availability cycles2 light is the strongest zeitgeber
Sleeplessness (insomnia $ &iMculty initiating or maintaining sleep
Circadian rhythm disorders $ 4al#unctions o# the circadian timing system or
the biologic cloc%
DSPS is characterized by a "ersistent inability 1F3 mo2 to 'all aslee" and a.a%en at socially
acce"ted times, 4nce aslee", these "atients are able to maintain their slee" and ha&e normal total
slee" times, 0n contrast, "atients .ith insomnia ha&e a lo.er than normal total slee" time due to
di''iculties in initiatin$ or maintainin$ slee", 1See Etiolo$y, Pro$nosis, Presentation, !or%u",
-reatment, and Medication,2
ASPS is characterized by "ersistent, early e&enin$ slee" onset 1bet.een 3:55 "m and 6:55 "m2,
.ith an early mornin$ .a%e+u" time, $enerally bet.een 7:55 am and 8:55 am, ASPS is less
common than DSPSG it most 're9uently occurs in elderly "atients and in indi&iduals .ho are
de"ressed,
An irre$ular slee"+.a%e schedule 'eatures multi"le slee" e"isodes .ithout e&idence o'
reco$nizable ultradian or circadian 'eatures o' slee" and .a%e'ulness, As .ith ASPS and DSPS,
total slee" time is normal, Daily slee" lo$s demonstrate irre$ularity not only o' slee" but also o'
daytime acti&ities, includin$ eatin$,
&hysiolo#y
-he neural basis o' the circadian rhythm, the su"rachiasmatic nuclei 1SC:2, is located in the
anterior &entral hy"othalamus and has been identi'ied as the substrate that $enerates circadian
acti&ity, SC: lesions "roduce loss o' circadian rhythmicity o' the slee"+.a%e cycle, the acti&ity+
rest cycle, s%in tem"erature, and corticosteroid secretion, 1See Etiolo$y,2
4ther "acema%ers that are not located in the SC: are obser&ed, @or instance, core body
tem"erature rhythm "ersists des"ite bilateral ablation o' SC:, @urthermore, 'ree+runnin$ studies
ha&e "ro&ided e&idence 'or multi"le circadian oscillators, Hnder 'ree+runnin$ conditions,
circadian rhythm may s"lit into inde"endent com"onents,
Complications
-he conse9uences o' "oor slee" are .ell established, -hey include irritability, im"aired social
interactions and "sychomotor coordination, "oor daytime "er'ormance, and daytime slee"iness,
-he literature su""orts the relationshi" o' "oor slee" to automobile accidents, hea&y machinery
accidents, and other catastro"hes, 1See Pro$nosis,2
Etiology
Most o' the time, the biolo$ic cloc% or the circadian rhythm is in synchronization .ith the )*+
hour day+ni$ht en&ironment, Ho.e&er, in some indi&iduals, the biolo$ic circadian rhythm o'
slee" and .a%e'ulness is out o' "hase .ith the con&entional or desired slee"+.a%e schedule,
Postulated reasons 'or that brea%do.n are as 'ollo.s,
"ensitivity to 'eit#e!ers
Sensiti&ity to zeit$ebers 1ie, en&ironmental cues2 may be altered or disru"ted, .hich can be
demonstrated under 'ree+runnin$ conditions, Altered or disru"ted sensiti&ity to zeit$ebers is
"robably the most common cause o' circadian rhythm disorder,
Disrupted pacemaer function
A dys'unction may be "resent in the internal cou"lin$ mechanisms o' biolo$ic "acema%ers 1e$,
the cou"lin$ o' the slee"+.a%e cycle .ith the tem"erature cycle2,
Environment
i$ht, hi$her le&els o' noise, and ele&ated room tem"erature are not conduci&e to $ood slee" and
are im"ortant &ariables to consider in shi't and ni$ht .or%ers
%ravel
-he se&erity o' <et la$ is related to the direction o' tra&el 1ie, more 're9uently seen .hen
tra&elin$ in an east.ard direction2 and the number o' time zones crossed, Most "atients
e("erience <et la$ i' they cross 7 or more time zones, -he rate o' ad<ustment is ?,8 hours "er day
a'ter an east.ard 'li$ht and ? hour "er day .hen the 'li$ht is in a .est.ard direction,
4ther 'actors that may a''ect the se&erity o' <et la$ are a$e, the ability to slee" .hile tra&elin$,
the time o' the day at the destination, and e("osure to li$ht, Studies ha&e e&en loo%ed at cabin
"ressure and the sli$ht o(y$en de"ri&ation e("erienced durin$ 'li$hts as contributin$ 'actors to
sym"toms o' <et la$,
(eurolo#ic disease
Alzheimer disease is one o' the more common e(am"les o' neurolo$ic disease associated .ith
circadian rhythm disturbanceG ho.e&er, irre$ular slee"+.a%e cycles also can be seen in other
neurode$enerati&e diseases, -he "henomenon o' sundo.nin$ is best described in Alzheimer
disease and is characterized by slee" disru"tions .ith a.a%enin$s and con'usion,
Circadian rhythm disturbances ha&e been re"orted in children .ith cancer and may be seen
'ollo.in$ in<ury to the hy"othalamus or brainstem in those .ith endocrine dys'unction or
'ollo.in$ cranial irradiation,
=7>
0n children .ith autism s"ectrum disorder, slee" onset and slee" maintenance insomnia ha&e
been described,
=*>
-hey ha&e also been associated .ith abnormal slee"+.a%e rhythms,
"hift wor
Ra"id shi't chan$es and shi't chan$es in the countercloc%.ise direction are most li%ely to cause
sym"toms,
)ifestyle
i'estyle and social "ressure 1to stay u" late2 can e(acerbate a circadian rhythm disorder,
Epidemiology
Occurrence in the *nited "tates
Delayed slee"+"hase syndrome 1DSPS2 is common, A""ro(imately I+?5J o' "atients .ho
com"lain o' insomnia are dia$nosed .ith a circadian rhythm disorder, most o'ten DSPS, -he
"re&alence o' DSPS is "robably hi$her than that, because the total slee" time is ty"ically normal
in "atients .ith DSPS and because "atients .ith DSPS ad<ust their li'estyle to accommodate
their slee" schedule and do not see% medical treatment, 0n adolescence, the "re&alence is
a""ro(imately IJ,
-rue ad&anced slee"+"hase syndrome 1ASPS2 is "robably 9uite rare, Ho.e&er, an a$e+related
"hase ad&ance is common in elderly "atients because they tend to $o to slee" early and $et u"
early,
-he "re&alence o' irre$ular slee"+.a%e schedules has not been established but is said to be 9uite
hi$h, An irre$ular slee"+.a%e schedule is common in "atients .ith Alzheimer disease,
A""ro(imately )5J o' HS .or%ers "er'orm shi't .or%, but not all o' these .or%ers de&elo"
shi't+.or% syndrome, and indi&idual "hase tolerance is obser&ed,
+nternational occurrence
Da$an et al re"orted the characteristics o' 7)) 0sraeli "atients .ith circadian rhythm slee"
disorder and 'ound that most o' these "atients 1K7,8J2 had DSPS, About 65J o' the "atients
.ith DSPS re"orted onset o' the syndrome in early childhood or adolescence,
=8>
A cross+sectional, nation.ide e"idemiolo$ic study in :or.ay established an o&erall "re&alence
o' DSPS o' 5,?IJ .hen strict 0nternational Classi'ication o' Slee" Disorders 10CSD2 criteria
.ere used,
=3>
Race-related demo#raphics
Race has been associated .ith &ariations in incidence o' obstructi&e slee" a"nea 14SA2G
ho.e&er, many &ariables may be associated .ith these di''erences, and 'urther research is
necessary to e&aluate this,
"e,-related demo#raphics
-he se( di''erence in circadian rhythm disorders seems to be a$e related, 0n children and
adolescents, no si$ni'icant "re&alence based on se( is obser&ed, Moreo&er, little to no di''erence
in "re&alence based on se( is obser&ed in "atients a$ed )5+*5 years, 0n "ersons older than *5
years, ho.e&er, .omen are ?,7 times more li%ely than men to re"ort insomnia,
A#e-related demo#raphics
Circadian rhythm cycles under$o chan$es durin$ "uberty, as do other "hysiolo$ic systems, At
this time, increased daytime slee"iness is seen alon$ .ith the de&elo"ment o' slee"+"hase delay,
Early school start times at this critically im"ortant de&elo"mental "hase, cou"led .ith
a'terschool acti&ities and home.or%, are associated .ith slee" de"ri&ation and "hase shi'tin$ in
children and adolescents, -his can lead to sym"toms o' daytime slee"iness, "oor concentration,
and im"aired "er'ormance,
DSPS is the most common circadian rhythm disorder in children and adolescents, ASPS is more
li%ely to a""ear in elderly indi&iduals, Health ris%s associated .ith shi't .or%, such as
$astrointestinal 1G02 and "sychosomatic sym"toms, increase .ith a$e,
0rre$ular slee"+.a%e rhythms can be seen in "atients .ith neurolo$ic im"airment, includin$
those .ith dementia,
Prognosis
Pro$noses in circadian rhythm disorders include the 'ollo.in$:
Net lag $ !his is a transient condition that has a good prognosis
Shi#t wor% $ "brupt changes in schedule and countercloc%wise shi#ts are
associated with daytime sleepiness and impaired per#ormance2 older patients
may not ad*ust well to shi#t wor%
&elayed sleep$phase syndrome (&S9S $ !his is typically seen in adolescents
and young adults2 this sleep pattern o#ten resolves in adulthood
"dvanced sleep$phase syndrome ("S9S $ !his is prominent in the elderly and
o#ten responds well to a combination o# behavioral and pharmacologic
intervention
=ther conditions $ Children with special needs, including attention deHcit
hyperactivity disorder and developmental disabilities, generally respond well
to behavioral intervention
$or!idity and mortality
-he mortality rates associated .ith circadian rhythms are di''icult to assess, Many deaths related
to circadian rhythm disorders are the result o' im"aired "er'ormance secondary to slee"
de"ri&ationG there'ore, many times, the deaths are cate$orized into di''erent headin$s 1e$, motor
&ehicle accidents, hea&y machinery accidents2, Sometimes, deaths are se9uelae o' the use o'
hy"notics, alcohol, or both to treat insomnia,
Shi't .or%ers ha&e been 'ound to ha&e a *5J $reater cardio&ascular disease ris% than nonshi't
.or%ers, -he 're9uency o' G0, "sychosomatic, and "sychiatric sym"toms is also increased in
shi't .or%ers, 0n addition, increased alcohol and dru$ use, as .ell as emotional "roblems, ha&e
been described,
Daytime slee"iness in students .ith DSPS has been correlated .ith ne$ati&e mood and increased
smo%in$ and alcohol consum"tion,
Some o' the 'eatures o' de"ressi&e disorders, such as early mornin$ a.a%enin$ and decreased
ra"id eye mo&ement 1REM2 latency, are su$$esti&e o' ASPS, !hether these chan$es are
secondary to de"ression or actually cause it has not been established,
Patient Education
Education can "lay a critical role in thera"eutic res"onseG ho.e&er, education in slee" hy$iene
.ithout other inter&entions is o'ten insu''icient,
Patients should be ad&ised o' ris%s secondary to slee"iness and ha&e 'ollo.+u"s a'ter treatment to
determine i' ris% 'actors ha&e been satis'actorily addressed,
@or "atient education in'ormation, see the Mental Health Center and the Slee" Disorders Center,
as .ell as 0nsomnia, Primary 0nsomnia, 0nsomnia Medications, Slee" Disorders in !omen, Slee"
Disorders and A$in$, and Slee"lessness and Circadian Rhythm Disorder,
C)F1FC") 93(S(1!"!F=1
History
-he dia$nosis o' circadian rhythm disorders is "rimarily based on a thorou$h history,
Di''erentiation o' transient disorders 'rom chronic disorders and "rimary disorders 'rom
secondary disorders in'luences the direction o' e&aluation and treatment "lans,
As .ith all medical and "sychiatric histories, the nature o' the com"laint is the 'irst order o'
business, 0n cases o' slee"lessness, distin$uishin$ indi&iduals .ith di''iculty initiatin$ slee" 'rom
those .ith di''iculty maintainin$ slee", those .ith si$ni'icant daytime im"airment, and those
.ith nonrestorati&e slee" is im"ortant,
Duration of symptoms
-ransient chan$es can be seen .ith air 'li$hts o' lon$ duration, <et la$, transient stresses 1e$,
illnesses2, and short+term slee" schedule disru"tions 1e$, shi't .or%2, Chronic circadian chan$es
can be seen .ith ad&anced slee"+"hase syndrome 1ASPS2, delayed slee"+"hase syndrome
1DSPS2, and irre$ular slee"+.a%e cycles,
&attern of the sleep-wae cycle
-his is an im"ortant "art o' the history in "atients .ith circadian rhythm disturbances, -he
"attern o' the slee"+.a%e cycle allo.s dia$nosis .ithin the chronic subty"es, DSPS is
characterized by a "ersistent inability 1ie, F3mo2 to 'all aslee" and a.a%en at socially acce"ted
times, 4nce aslee", these "atients are able to maintain their slee" and ha&e normal total slee"
times,
DSPS is most 're9uently identi'ied in adolescents, colle$e students, and ni$ht .or%ers,
Di''erential dia$nosis includes li'estyle "re'erence, inade9uate slee" hy$iene, "rimary insomnia,
<et la$, and "sycho"hysiolo$ic insomnia, -eena$ers .ith DSPS are at increased ris% 'or
beha&ioral "roblems and de"ression,
Advanced sleep-phase syndrome
ASPS is characterized by "ersistent, early e&enin$ slee" onset 1bet.een 3:55 "m and 6:55 "m2,
.ith an early mornin$ .a%e+u" time, $enerally bet.een 7:55 and 8:55 am, -he slee" schedule is
usually stable, ASPS occurs much less 're9uently than DSPS and is seen most commonly in the
elderly and in "ersons .ho are de"ressed, 0t needs to be di''erentiated 'rom e(o$enous
de"ression and 'rom e(cessi&e daytime slee"iness 1EDS2, .hich is associated .ith other slee"
disorders 1e$, obstructi&e slee" a"nea =4SA>2,
+rre#ular sleep-wae cycle
An irre$ular slee"+.a%e schedule 'eatures multi"le slee" e"isodes .ithout e&idence o'
reco$nizable ultradian or circadian 'eatures o' slee" and .a%e'ulness, As .ith APSD and DPSD,
total slee" time is normal, Daily slee" lo$s demonstrate irre$ularity not only o' slee" but also o'
daytime acti&ities, includin$ eatin$, Body tem"erature also randomly 'luctuates, -he "rinci"al
com"laints are e(cessi&e daytime slee"iness andCor insomnia,
"hift worers
@or shi't .or%ers, the need to ad<ust the biolo$ic cloc% is cou"led .ith the social "ressure o'
more noise and disturbance durin$ the day, leadin$ to di''iculties in slee"in$, -his is most
di''icult 'or .or%ers .ho must s.itch their schedule and rotate bet.een mornin$, e&enin$, and
ni$ht shi'ts, @or those .ho consistently .or% the same shi't, only en&ironmental issues a''ect
slee" 9uality once their biolo$ic cloc% ad<usts to the ne. time,
%otal sleep time
0n ASPS and DSPS delays, total slee" time is normal, Shi't .or%ers, e&en those .ho .or% a
consistent ni$ht shi't, tend to ha&e shorter slee" times,
&ea alertness
Patients .ith DSPS ha&e their "ea% alertness in late e&enin$ and ni$ht, .hereas "atients .ith
ASPS ha&e their "ea% alertness in the early mornin$, Patients .ith irre$ular slee"+.a%e cycles
demonstrate no consistent "attern o' alertness,
Recent travel
/et la$ is a 'orm o' transient circadian rhythm disturbance, 0t results 'rom an inability to
synchronize one#s normal rhythm to ra"idly chan$in$ time shi'ts o' en&ironmental cues,
Althou$h many o' the sym"toms ha&e been associated .ith hi$h+altitude 'li$ht in $eneral, the
distin$uishin$ 'actor seems to be the len$th o' sym"toms, Sym"toms related to 'li$ht $enerally
last less than )* hours, .hereas those o' <et la$ may "ersist 'or days, -he duration o' the 'li$ht is
the "rimary determinant o' the intensity and duration o' the <et la$, 0n $eneral, <et la$ is most
li%ely to be e("erienced i' 7 or more time zones are crossed, -he li%elihood o' slee" disturbance
durin$ tra&el across time zones increases .ith a$in$,
=I>
Daytime sleepiness
Daytime slee"iness is seen in all circadian rhythm disorders, althou$h the se&erity may &ary
'rom indi&idual to indi&idual and 'rom day to day, Assess 'or the "resence o' conse9uences o'
daytime slee"iness, .hich include "oor concentration, im"aired "er'ormance 1includin$ a
decrease in co$niti&e s%ills2, and "oor "sychomotor coordination, Headaches may also be
"resent, -he "resence o' early mornin$ headaches should su$$est 'urther in&esti$ation 'or
obstructi&e slee" a"nea 14SA2,
@or children and adolescents, early school hours are associated .ith shorter total slee" time and
increased daytime slee"iness, -his is more "rominent in teena$ers,
&sycholo#ical assessment
Psycho"hysiolo$ical insomnia, de"ressi&e disorders, and other "sychiatric disorders may "resent
.ith sym"tom "ro'iles similar to those o' circadian rhythm disorders, Assess "atients 'or these
disorders,
Co#nition
Assess im"act on com"le( co$niti&e tas%s such as selecti&e attention and e(ecuti&e 'unction as
these .ill im"act on ris%s 'or both .or% and school "er'ormance,
&atient attempts at treatment
Per'orm a care'ul in9uiry concernin$ the "atientDs use o' commonly em"loyed slee" aids,
includin$ alcohol, herbal "re"arations, and o&er+the+counter 14-C2 slee" aids, Residual
slee"iness can be seen .ith some o' these "re"arations, as .ell as .ith "rescri"tion hy"notics
and some o' the aller$y "re"arations, /ohnson et al re"orted that ?7J o' the $eneral "o"ulation
had used alcohol as a short+term slee" aid durin$ the "re&ious year,
=K>
$edication history
4btain a care'ul medication history re$ardin$ the timin$ o' administration o' dru$s, @or
e(am"le, beta+adrener$ic dru$s, ty"ically used in the treatment o' asthma, can delay slee"
because o' their stimulant e''ect, Am"hetamines, ca''eine, selecti&e serotonin reu"ta%e inhibitor
1SSR02 antide"ressants, steroids, nicotine, theo"hylline, and clonidine can also a''ect slee",
"norin#
Chronic loud snorin$ .ith or .ithout .itnessed a"nea should direct the "hysician to e&aluate the
"atient 'or ris% 'actors 'or u""er air.ay resistance syndrome and 4SA,
Other medical pro!lems
-he ) most commonly seen medical diseases that a''ect slee" and daytime 'unction are
con$esti&e heart 'ailure and chronic obstructi&e "ulmonary disease, Chronic "ain syndromes and
thyroid disease also a''ect slee" and daytime 'unction, Hy"erthyroidism is associated .ith slee"
disru"tion, .hereas hy"othyroidism is associated .ith daytime slee"iness and 'ati$ue,
Environmental cues and sleep hy#iene
-his is "articularly im"ortant to assess in shi't .or%ers, -he intensity o' li$ht, le&el o' noise, and
en&ironmental tem"erature can in'luence slee", E(ercise and stimulant inta%e "rior to bedtime
are 're9uent la"ses in $ood slee" hy$iene and can be easily addressed,
@inally, in9uire about any history o' motor &ehicle accidents or other accidents occurrin$ as a
result o' decreased alertnessCe(cessi&e slee"iness,
Physical Examination
-he "hysical e(amination com"lements the history in "atients .ith insomnia, @ocus the "hysical
e(amination on identi'yin$ ris% 'actors 'or other conditions that may "reci"itate, e(acerbate, or
mimic insomnia, -hese may include de"ression, obstructi&e slee" a"nea 14SA2, and
neurode$enerati&e disease, -he e(am can include the 'ollo.in$ e&aluations:
",ect $ "ssess general a,ect and sense o# well$being in patients presenting
with insomnia as a primary sleep complaint
5ody mass inde' $ 9atients with obesity who have increased body mass
indices are at increased ris% #or =S"
Cranio#acial morphology $ !he head and nec% e'amination is important in
assessing ris% #or =S"2 patients with large tonsils, narrow oropharyngeal
spaces, and large nec%s are at ris% #or =S"
Chest $ 5arrel chest (ie, increased anteroposterior diameter is associated
with chronic lung disease2 crac%les, murmurs, and cardiac enlargement
evidenced by displaced point o# ma'imum impulse (94F suggest congestive
heart #ailure
&igital clubbing $ Clubbing may be associated with chronic lung disease or
congenital heart disease, or it may be #amilial2 this Hnding suggests a need
#or #urther medical evaluation
1eurologic e'amination $ "lzheimer disease and other neurodegenerative
diseases #re+uently are associated with irregular sleep$wa%e cycles
&&
/et la$ should be di''erentiated 'rom delayed slee"+"hase syndrome 1DSPS2, DSPS should be
di''erentiated 'rom li'estyle "re'erence, inade9uate slee" hy$iene, "rimary insomnia, and
"sychiatric conditions, 1Psycho"atholo$y has been 'ound in 85J o' "atients .ith DSPS,2
-ransient circadian rhythm disturbances de'ine themsel&es by their timin$, Many "sychiatric
conditions distin$uish themsel&es by short slee" times and disru"ted slee", Re$ardless o' their
bedtime, "atients .ith "sychiatric disorders ha&e slee"+onset insomnia, Co"in$ styles distin$uish
the ni$ht o.l,
Ad&anced slee"+"hase disorders should be di''erentiated 'rom aty"ical de"ression, seasonal
a''ecti&e disorder, and e(cessi&e daytime slee"iness 1EDS2 associated .ith other slee" disorders,
Patients .ith irre$ular slee"+.a%e schedules are distin$uished by the irre$ularity not only o'
their slee" cycle, but also o' their cycles o' eatin$ and other daily acti&ities, -he rhythm o' body
tem"erature also is a''ected, 0rre$ular slee"+.a%e schedules should be di''erentiated 'rom
"sychiatric disorders and 'rom insomnia associated .ith shi't .or%,
Daytime slee"iness in DSPS should be distin$uished 'rom slee"+disordered breathin$,
narcole"sy, and aty"ical de"ression, All o' these conditions o'ten "resent .ith early bedtime,
:octurnal eatin$ disorder may also ha&e a substantial im"act on circadian cycles, .ith 're9uent
a.a%enin$s 'or 'eedin$, Slee" distribution may resemble that o' in'ants, .ith slee" and 'eedin$
distributed o&er a )*+hour "eriod,
0nsomnia is a core 'eature o' "osttraumatic stress disorder and has been re"orted in I5J o'
"atients,
O=3PE9
Approach Considerations
!hen assessin$ slee"lessness, a slee" lo$ is o'ten used, Althou$h not technically a laboratory
test, this diary allo.s identi'ication o' slee"+.a%e cycles in the "atient#s normal en&ironment and
"ermits sub<ecti&e assessment o' alertness o&er a )+.ee% time "eriod, -he Practice Parameters
1)55I2 'rom the American Academy o' Slee" Medicine recommend the use o' slee" lo$s in the
e&aluation o' the 'ollo.in$ slee" disorders
=6>
:
Shi#t$wor% syndrome
Net lag
"dvanced sleep$phase syndrome ("S9S
&elayed sleep$phase syndrome (&S9S
@ree$running disorder
Frregular sleep$wa%e rhythm
@ailure to dia$nose other medical conditions associated .ith increased daytime slee"iness, such
as obstructi&e slee" a"nea 14SA2, may carry si$ni'icant conse9uences in terms o' added
morbidity and mortality, Another "otential treatment "it'all is 'ailure to assess a "atientDs ris% 'or
motor &ehicle accidents,
0m"licit in the dia$nosis o' circadian rhythm disorder is a desire to con'orm to traditionally
acce"ted slee"+.a%e "atterns,
+ma#in# studies
Consider ima$in$ studies i' the "atient is to be e&aluated 'or neurode$enerati&e disease, Also
consider ima$in$ studies in "atients .ith 4SA to determine the etiolo$y o' obstruction,
Acti#raphy
An acti$ra"h is a small motion+sensin$ de&ice .orn on the nondominant .rist, $enerally 'or ?
.ee%, 0t is based on the "remise that .rist motion is decreased durin$ slee", -his allo.s a &ery
$ross measurement o' slee"+.a%e cycles o&er time,
Overni#ht polysomno#raphy
-his study is o' &alue in identi'yin$ the "atient .ith 4SA, "eriodic limb mo&ements o' slee"
1PMS2, or slee"+state mis"erce"tion, 0t also is used in con<unction .ith the Multi"le Slee"
atency -est 1MS-2 to e&aluate "atients .ith narcole"sy, 0t is not routinely used in the
dia$nostic e&aluation o' "atients .ith insomnia or in the dia$nostic e&aluation o' "atients .ith
circadian rhythm disturbances,
Sleep Tests
$ultiple "leep )atency %est
-he MS- allo.s 'or ob<ecti&e measurement o' slee"iness, :ormal adult &alues ran$e 'rom ?5+
)5 minutes, .hereas slee" latencies o' less than 8 minutes indicate abnormal slee"iness, MS- is
indicated .hen sus"icion o' narcole"sy is raised by the clinical history, @ollo.in$ a normal
ni$ht#s slee" documented by o&erni$ht "olysomno$ra"hy, s"eci'ic abnormalities in MS- 1ie, )
or more slee"+onset ra"id eye mo&ements =S4REMs>2 su""ort a dia$nosis o' narcole"sy,
Epworth "leepiness "cale
-he E".orth Slee"iness Scale 1ESS2 is based on a 9uestionnaire that as%s "atients to rate their
res"onses to K situations on a scale o' 5+7, based on .hether the situation .as li%ely to be
associated .ith dozin$ beha&ior, 0t .as desi$ned to $i&e an indication o' slee"iness and has been
correlated .ith slee" a"nea,
$ornin#ness Evenin#ness -uestionnaire
-he e&idence is insu''icient to recommend the routine use o' the Mornin$ness E&enin$ness
Luestionnaire 1MEL2 'or the e&aluation o' circadian rhythm disturbances,
!3("!4(1!
-hera"y 'or circadian rhythm disturbances is lar$ely beha&ioral, i$ht thera"y has been sho.n to
be an e''ecti&e modi'ier o' circadian cycles, Mi(ed modalities may be e''ecti&e in elderly
"atients .ith dementia .ho ha&e irre$ular slee"+.a%e rhythms, A combination o' "lanned slee"
schedulin$, timed li$ht e("osure, and timed melatonin administration can be hel"'ul,
.ri#ht li#ht therapy
Circadian rhythm disturbances res"ond &ery .ell to li$ht thera"y, es"ecially bri$ht li$ht 1F355
lu(2, @or entrainment "ur"oses, bri$ht room li$ht o&er time may be su''icientG ho.e&er, a hi$her
intensity o' li$ht 1F3555 lu( o&er 75+35 min2 is o'ten necessary to accom"lish acute "hase shi'ts,
-he timin$ o' li$ht thera"y is also im"ortant because it a''ects the de$ree and direction o' the
rhythm shi't, @or e(am"le, li$ht thera"y a""lied in the early e&enin$ and ni$httime hours delays
the cycle 1in "atients .ith ad&anced slee"+"hase syndrome =ASPS>2, .hereas thera"y $i&en in
the early mornin$ stimulates mornin$ alertness and an earlier bedtime 1in "atients .ith delayed
slee"+"hase syndrome =DSPS>2,
Chronotherapy
-his beha&ioral treatment consists o' a $radual shi't in slee" time in accordance .ith the "atient#s
tendency, -hus, in DSPS, a "ro$ressi&e delay o' 7 hours "er day is "rescribed, 'ollo.ed by strict
maintenance o' a re$ular bedtime hour once the desired schedule is achie&ed, 0n ASPS,
chronothera"y 'ocuses on ad&ancin$ bedtime by )+7 hours "er ni$ht o&er ? .ee% until a desired
schedule is achie&ed,
Enhancin# environmental cues
-his is an im"ortant "art o' the treatment o' circadian rhythm disorders, Patients are encoura$ed
to %ee" a dar%, 9uiet room durin$ slee" and a .ell+lit room u"on a.a%enin$, Bri$ht li$ht
e("osure in the e&enin$ should be a&oided, and re$ular hours o' eatin$ and other acti&ities
should be en'orced,
&harmacotherapy
-asimelteon 1Hetlioz2 .as a""ro&ed by the HS @ood and Dru$ Administration 1@DA2 in /anuary
)5?* 'or treatment o' nonM)*+hour slee"+.a%e disorder in the totally blind, A""ro&al .as based
on results o' ) trials: the Sa'ety and E''icacy o' -asimelteon 1SE-2 trial, a )3+.ee% study that
included K* "atients, and the Randomized !ithdra.al study o' the Sa'ety and E''icacy o'
-asimelteon 1RESE-2, a ?6+.ee% trial that included )5 "atients, all o' .hom had been
"re&iously screened durin$ the SE- trial and entrained durin$ o"en+label tasimelteon treatment,
Entrainment o' the circadian rhythm, as measured by urinary 3+hydro(ymelatonin sul'ate
1aM-3s2, a main metabolite o' melatonin, .as the "rimary e''icacy end"oint 'or SE-, Scores on
the )*+hour clinical res"onse scale .ere another de'ined end"oint 'or SE-, 4utcomes 'or RESE-
included maintenance o' entrainment 1aM-3s2 and maintenance o' clinical res"onse, Study
results demonstrated that tasimelteon entrains the master cloc% 1both melatonin and cortisol2 and
has clinically meanin$'ul e''ects on the slee"+.a%e cycle in terms o' the timin$ and amount o'
slee", and im"ro&ed measure o' $lobal 'unctionin$,
=?5, ??>
)ifestyle
Patients may res"ond to shi'ts in their acti&e "hases by e(hibitin$ si$ns o' slee" de"ri&ation, @or
e(am"le, teena$ers may ha&e di''iculty %ee"in$ late hours and $ettin$ u" 'or an early mornin$
class, Shi't .or%ers may ha&e di''iculty i' shi'ts are chan$ed too ra"idly be'ore they ha&e had a
chance to ad<ust,
"ur#ical care
Slee" disturbances associated .ith obstructi&e slee" a"nea 14SA2 syndrome may be treatable
.ith sur$ical inter&ention,
Consultations
Consultation .ith the 'ollo.in$ s"ecialists can be use'ul in mana$in$ circadian rhythm
disorders:
Sleep medicine specialist
1eurologist
9sychiatrist
9ulmonologist
Diet
:octurnal eatin$ disorder is an entity distinct 'rom circadian rhythm disorders and is
characterized by an inability to maintain slee" o&er the ni$ht, Slee" is interru"ted and "atients
are unable to return to slee" .ithout eatin$ or drin%in$,
Dietary ad&ice includes the 'ollo.in$:
)imit large meals
"void inta%e o# e'cessive 0uids be#ore bedtime2 this is an element that is
generally emphasized when attempting to improve sleep hygiene
&iscourage obesity
Additional concerns and follow-up
Address associated "sycholo$ical issues, Patients .ith DSPS .ho initially res"ond to
chronothera"y may $radually shi't bac% to their old slee" "attern, 4'ten, chronothera"y must be
re"eated e&ery 'e. months to maintain lon$+lastin$ results,
Em"hasize the im"ortance o' $ood slee" hy$iene and a&oidance o' the use o' alcohol, stimulants
1e$, nicotine, ca''eine2, and strenuous e(ercise be'ore bedtime,
%ransfer
-he o&er.helmin$ ma<ority o' "atients .ith insomnia 1e(ce"t elderly "atients2 are treated as
out"atients,
0n the elderly, in .hom numerous other "hysical, "sychiatric, and "harmacolo$ic concerns can
be "resent, institutional care is o'ten necessary, -he "resence o' si$ni'icant slee" disru"tion is
o'ten a "redictor o' .hich "atients re9uire institutionalization,
Deterrence and prevention
Strate$ies to "re&ent circadian rhythm disorders include the 'ollo.in$:
(ncourage good sleep hygiene
Control o# the sleep environment with regulation o# light/dar% e'posure has
been help#ul to shi#t wor%ers in maintaining sleep
@or patients anticipating *et lag, advise that they change their schedule to the
time o# the new location prior to departure2 this can modi#y the e,ects o# *et
lag
@or shi#t wor%ers, advise shi#ting the schedule in a cloc%wise direction2 this is
o#ten better tolerated
Activity
0n "atients .ith irre$ular slee"+.a%e cycles, beha&ioral modi'ication has been sho.n to be
hel"'ul, -his includes encoura$in$ structured daytime acti&ity, e&en in the "resence o' 'ati$ue,
Attendants in nursin$ homes can hel" elderly "atients to remain a.a%e by in&ol&in$ them in
acti&ities and restrictin$ slee" to con&entional time "eriods, Encoura$e a'ternoon na"s scheduled
daily at a re$ular time, -his hel"s to a&oid multi"le brie' daytime na"s and to consolidate slee"
to the desired time,
Em"hasizin$ a "ro$ram o' re$ular mornin$ e(ercise is a com"onent o' "romotin$ slee" hy$iene,
Ad&ise "atients to a&oid strenuous e(ercise be'ore bedtime,
&3EG
edication Summary
Short+actin$ benzodiaze"ines are o'ten "rescribed in the early treatment o' slee"+onset insomnia,
.hile lon$+actin$ a$ents are o'ten used to treat lon$+standin$ insomnia .ith slee" maintenance,
as .ell as slee"+onset, insomnia,
:onbenzodiaze"ine hy"notics ha&e come into increased use because they do not si$ni'icantly
a''ect slee" architecture and, unli%e benzodiaze"ines, are not associated .ith a rebound
"henomenon,
Melatonin re"ortedly is e''ecti&e a$ainst <et la$, as .ell as in the treatment o' slee"+onset
insomnia in elderly "atients .ho are melatonin de'icient, Melatonin a$onists can be "rescribed
'or insomnia characterized by di''iculty .ith slee" onset,
Ben!odia!epines
Class "ummary
-hese a$ents are recommended in "re'erence to barbiturates because o' their lo. to(icity and
clinical e''icacy, -hey ha&e a ra"id onset o' action, Concerns remain .ith re$ard to rebound
insomnia, residual daytime e''ects, and addicti&e "otential,
Short+actin$ benzodiaze"ines are o'ten chosen in the early treatment o' slee"+onset insomnia and
are used in con<unction .ith beha&ioral thera"y, on$+standin$ insomnia .ith slee"
maintenance, as .ell as slee"+onset, insomnia o'ten re9uires lon$+actin$ a$ents,
Qiew #ull drug in#ormation
%ria'olam /0alcion1

-riazolam is 're9uently chosen as a short+term ad<unct to beha&ioral thera"y, -his short+actin$
a$ent is e''ecti&e in hel"in$ "atients 'all aslee", 0t is not e''ecti&e in "ersons .ith slee"
maintenance "roblems,
@or "atients .ith slee" maintenance insomnia, a benzodiaze"ine .ith an intermediate hal'+li'e
1e$, estazolam =ProSom>2 or a lon$ hal'+li'e 1e$, 9uaze"am2 may be considered,
%ema'epam /Restoril1

-emaze"am#s intermediate rate o' absor"tion and duration o' action ma%e it use'ul 'or treatin$
initial and middle insomnia, Because temaze"am has no acti&e metabolite, co$niti&e im"airment
and $ro$$iness the 'ollo.in$ day are reduced, 0t enhances the inhibitory e''ects o' the GABA
neurotransmitter on neuronal e(citability that results by increased neuronal "ermeability to
chloride ions, -he shi't in chloride ions results in hy"er"olarization and stabilization o' the
neuronal membrane,
Esta'olam

Estazolam is an intermediate+actin$ a$ent .ith a slo. onset o' action and a lon$ duration, 0t is a
$ood a$ent 'or slee"+maintenance insomnia, 0t enhances the inhibitory e''ects o' the GABA
neurotransmitter on neuronal e(citability that results by increased neuronal "ermeability to
chloride ions, -he shi't in chloride ions results in hy"er"olarization and stabilization o' the
neuronal membrane,
-ua'epam /Doral1

Luaze"am is used 'or slee"+maintenance insomnia, 0t enhances the inhibitory e''ects o' the
GABA neurotransmitter on neuronal e(citability that results by increased neuronal "ermeability
to chloride ions, -he shi't in chloride ions results in hy"er"olarization and stabilization o' the
neuronal membrane,
Flura'epam

@luraze"am is 're9uently chosen as a short+term treatment o' insomnia, 0t enhances the inhibitory
e''ects o' the GABA neurotransmitter on neuronal e(citability that results by increased neuronal
"ermeability to chloride ions, -he shi't in chloride ions results in hy"er"olarization and
stabilization o' the neuronal membrane,
"on#en!odia!epine hypnotics
Class "ummary
-hese a$ents are $ainin$ "o"ularity because they do not ha&e a si$ni'icant e''ect on slee"
architecture and are not associated .ith the rebound "henomenon seen .ith benzodiaze"ines,
2olpidem /Am!ien3 Am!ien CR3 Edluar1

Nol"idem is a nonbenzodiaze"ine hy"notic o' the imidazo"yridine class, 0t is ra"idly absorbed,
has an elimination hal'+li'e o' ),8 hours, and is a $ood short+term o"tion 'or "atients .ith slee"+
onset insomnia .ho re9uire "harmacolo$ic su""ort, -he e(tended+release "roduct 1Ambien CR2
consists o' a coated, )+layer tablet and is use'ul 'or insomnia characterized by di''iculties .ith
slee" onset andCor slee" maintenance, -he 'irst layer releases dru$ content immediately to induce
slee"G the second layer $radually releases additional dru$ to "ro&ide continuous slee",
Es'opiclone /)unesta1

Eszo"iclone is a nonbenzodiaze"ine hy"notic "yrrolo"yrazine deri&ati&e o' the cyclo"yrrolone
class, 0ts "recise mechanism o' action is un%no.n, but the dru$ is belie&ed to interact .ith the
$amma+aminobutyric acid 1GABA2 rece"tor at bindin$ domains close to or allosterically cou"led
to benzodiaze"ine rece"tors,
Eszo"iclone is indicated 'or insomnia, to decrease slee" latency and im"ro&e slee" maintenance,
0t has a short hal'+li'e o' 3 hours, Hi$her doses 1ie, ) m$ 'or elderly adults and 7 m$ 'or
nonelderly adults2 are more e''ecti&e 'or slee" maintenance, .hereas lo.er doses 1ie, ? m$ 'or
elderly adults and ) m$ 'or nonelderly adults2 are suitable 'or di''iculty in 'allin$ aslee",
2aleplon /"onata1

Nale"lon is a nonbenzodiaze"ine hy"notic 'rom the "yrazolo"yrimidine class, 0t has a chemical
structure unrelated to benzodiaze"ines, barbiturates, or other hy"notic dru$s but interacts .ith
the GABA+benzodiaze"ine rece"tor com"le(, 0t binds selecti&ely to the ome$a+? rece"tor
situated on the al"ha subunit o' the GABAA rece"tor com"le( in the brain, Nale"lon "otentiates
t+butyl+bicyclo"hos"horothionate 1-BPS2 bindin$ and has "re'erential bindin$ to the ome$a+?
rece"tor o' the GABA rece"tor 'amily,
elatonin Receptor Agonists
Class "ummary
Melatonin rece"tor a$onists 1tasimelteon, ramelteon2 ha&e been a""ro&ed by the @DA,
-asimelteon is indicated 'or nonM)*+hour slee"+.a%e disorder, Ramelteon is indicated 'or
insomnia characterized by di''iculty .ith slee" onset,
Melatonin 1herbalCalternati&e2 has been re"orted to be use'ul in the treatment o' <et la$ and in the
treatment o' slee"+onset insomnia in elderly "atients .ho are melatonin de'icient,
Recommendations re$ardin$ melatonin are based on the e(tensi&e literature re&ie. 'rom the
Cochrane ibrary,
=?)>
Ho.e&er, because o' the "henomenon o' "ublication bias, studies sho.in$ e''icacy are more
li%ely to be a&ailable 'or re&ie. than those that do not sho. e''icacy, @urthermore, "otential
users o' melatonin should be cautioned that &ariations in 9uality, "urity, and 9uantity o' acti&e
in$redient in natural "harmaceuticals ma%e inter"retation o' studies di''icult and raises concerns
about interactions and contaminants,
%asimelteon /0etlio'1

-asimelteon is a melatonin rece"tor a$onist .ith hi$h a''inity 'or M-? and M-) rece"tors in the
su"rachiasmatic nucleus o' the brain, M-? and M-) are thou$ht to synchronize the body#s
melatonin and cortisol circadian rhythms .ith the day+ni$ht cycle in "atients .ith nonM)*+hour
disorder, 0t is indicated 'or nonM)*+hour slee"+.a%e disorder in the totally blind,
Ramelteon /Ro'erem1

Ramelteon is a melatonin rece"tor a$onist .ith hi$h selecti&ity 'or human melatonin M-? and
M-) rece"tors, M-? and M-) are thou$ht to "romote slee" and to be in&ol&ed in the
maintenance o' circadian rhythm and the normal slee"+.a%e cycle,
$elatonin

Melatonin is a&ailable as an o&er+the+counter 14-C2 "re"aration, 0t is used to enhance the natural
slee" "rocess and 'or resettin$ the body#s internal time cloc% .hen an indi&idual is tra&elin$
throu$h di''erent time zones, 0t has also been used 'or the treatment o' circadian rhythm slee"
disorders in blind "eo"le .ith no li$ht "erce"tion,
:o recommended daily allo.ance 1RDA2 o' melatonin has been a""ro&ed by the HS @ood and
Dru$ Administration 1@DA2, nor is @DA+a""ro&ed "rescribin$ in'ormation a&ailable 'or any o'
the doses discussed here, 0ndi&idual "atients may or may not e("erience the re"orted bene'its o'
melatonin,
Physicians and "atients should consider the ris%s and bene'its o' each thera"eutic o"tion, Slo.+
release "roducts are re"orted to be less e''ecti&e, Melatonin is belie&ed to be e''ecti&e in "ersons
crossin$ 8 or more time zones and is less e''ecti&e in indi&iduals tra&elin$ in a .est.ard
direction,
5F5)F=
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hour slee"+.a%e disorder in blind indi&iduals =ne.s release>, /anuary 7?, )5?*, A&ailable
at htt":CC...,'da,$o&C:e.sE&entsC:e.sroomCPressAnnouncementsCucm7K*56),htm,
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1"3C=)(9SR
"uthor: "li 4 5ozorg, 4&2 Chie# (ditor: Selim 3 5enbadis, 4&
http://emedicine.medscape.com/article/..668--$clinicalSshowall
Background
:arcole"sy is characterized by the classic tetrad o' e(cessi&e daytime slee"iness, cata"le(y,
hy"na$o$ic hallucinations, and slee" "aralysis, Ho.e&er, this tetrad is seen only rarely in
children,
:arcole"sy 're9uently is unreco$nized, .ith a ty"ical delay o' ?5 years bet.een onset and
dia$nosis, A""ro(imately 85J o' adults .ith the disorder retros"ecti&ely re"ort sym"toms
be$innin$ in their teena$e years, -his disorder may lead to im"airment o' social and academic
"er'ormance in other.ise intellectually normal children, -he im"lications o' the disease are o'ten
misunderstood by "atients, "arents, teachers, and health care "ro'essionals,
:arcole"sy is treatable, Ho.e&er, a multimodal a""roach is re9uired 'or the most 'a&orable
outcome,
Dia#nostic criteria /D"$-4 and +"CD-21
-he Diagnostic and Statistical Manual of Mental Disorders' (ifth !dition )DSM*+, de'ines
narcole"sy as recurrent e"isodes o' irre"ressible need to slee", la"sin$ into slee", or na""in$
occurrin$ .ithin the same day, -hese must ha&e been occurrin$ at least three times "er .ee%
o&er the "ast 7 months, -here also must be the "resence o' at least one o' the 'ollo.in$:
=I>
(pisodes o# cataple'y occurring at least a #ew times per month
?ypocretin deHciency
3(4 sleep latency T./ minutes, or a mean sleep latency T6 minutes and two
or more sleep$onset 3(4 periods (S=3(49s
:arcole"sy can be cate$orized as mild, moderate or se&ere based on the 're9uency o' cata"le(y,
need 'or na"s, and disturbance o' nocturnal slee", 0n addition, the DSM*+ identi'ies 'i&e subty"es
as 'ollo.s:
=I>
1arcolepsy without cataple'y but with hypocretin deHciency
1arcolepsy with cataple'y but without hypocretin deHciency
"utosomal dominant cerebellar atazia, dea#ness and narcolepsy
"utosomal dominant narcolepsy, obesity, and type ; diabetes
1arcolepsy secondary to another medical condition
-he American Slee" Disorders AssociationDs International Classification of Sleep Disorders'
Second !dition )ICSD*-, dia$nostic criteria 'or narcole"sy .ith cata"le(y are 1?2 EDS daily 'or
more than 7 months and 1)2 a de'inite history o' cata"le(y 1ie, sudden and transient e"isodes o'
loss o' motor tone tri$$ered by emotions2,
=K>
0CSD+) dia$nostic criteria 'or narcole"sy .ithout
cata"le(y are the same as those 'or narcole"sy .ith cata"le(y, but .ithout the "resence o' ty"ical
cata"le(y,
!hene&er "ossible, the dia$nosis o' narcole"sy should be con'irmed by "olysomno$ra"hy 1PSG2
'ollo.ed by a multi"le slee" latency test 1MS-2G the MS- should sho. slee" latency K
minutes or less and ) or more S4REMPs, An alternati&e criterion is a CS@ hy"ocretin le&el o'
??5 "$Cm or lo.er, -he hy"ersomnia must not be better e("lained by another slee", neurolo$ic,
mental, or medical condition or by medicine or substance use,
=K>
Pathophysiology
:arcole"sy is thou$ht to result 'rom $enetic "redis"osition, abnormal neurotransmitter
'unctionin$ and sensiti&ity, and abnormal immune modulation, Current data im"licate certain
human leu%ocyte anti$en 1HA2 subty"es and abnormal hy"ocretin 1ore(in2 neurotransmission,
.hich leads to abnormalities in monoamine and acetylcholine syna"tic transmissions,
"articularly in the "ontine reticular acti&atin$ system,
=6> =?5>
Hnderstandin$ o' the neurochemistry o' narcole"sy be$an .ith research in&ol&in$ narcole"tic
do$s 1e$, s"ecial laboratory+bred Dobermans and abradors2, 0n these animal models, the
disorder is transmitted in an autosomal recessi&e 'ashion .ith 'ull "enetrance and is
characterized mainly by cata"le(y,
=??>
Muscarinic choliner$ic stimulation increases cata"le(y in
these animals, and choliner$ic bloc%ade eliminates the sym"tom, :icotinic a$ents ha&e no e''ect
on the cata"le(y,
Rece"tor subty"es such as the al"ha?+noradrener$ic rece"tor a""ear to mediate cata"le(y,
Prazosin, an al"ha?+anta$onist, .orsens sym"toms in human and canine sub<ects,
-he "ons is not the only neuroanatomic site that is res"onsible 'or mediatin$ cata"le(yG the
mesocorticolimbic do"aminer$ic system also has been im"licated, -his connection .ith the
limbic system in "art e("lains the relationshi" o' cata"le(y to emotion,
-he centrality o' hy"ocretin transmission in the "atho"hysiolo$y o' narcole"sy .as
demonstrated .hen hy"ocretin %noc%out mice dis"layed cata"le(y and slee"iness,
=?), ?7>
@urther
e&idence 'or im"aired hy"ocretin 'unctionin$ in humans .as 'ound .ith the disco&ery o' lo.
le&els o' hy"ocretin in the cerebros"inal 'luid 1CS@2 o' narcole"tic "atients,
=?*>
Subse9uently, abnormal immune modulation .as associated .ith the clinical de&elo"ment o'
narcole"sy in children in Scandina&ia and @inland, A'ter &accination a$ainst the H?:? in'luenza
&irus .ith a &accine usin$ a "otent AS47 ad<u&ant, narcole"sy in @innish children increased K+
to ?)+'old, All a''ected children .ho under.ent HA ty"in$ .ere 'ound to ha&e the HA
DLBR535) allele,
=?8, ?3>
Rapid eye movement sleep
Dys'unction and ina""ro"riate re$ulation o' ra"id eye mo&ement 1REM2 slee" are thou$ht to
e(ist in narcole"sy,
=?I>
:euroanatomic control o' REM slee" a""ears to be localized to the "ontine
reticular acti&atin$ system,
-he brain contains REM+on cells, .hich 'ire selecti&ely durin$ REM slee" "eriods, and REM+o''
cells, 'or .hich the con&erse holds true, Most REM+on cells 'unction throu$h choliner$ic
transmission, .hereas REM+o'' cells are noradrener$ic or serotoner$ic, 0n narcole"sy,
monoamine+de"endent inhibition o' REM+on cells may be de'ecti&e,
Sym"toms can be &ie.ed as REM slee" com"onents intrudin$ into .a%e'ul states, @or e(am"le,
cata"le(y and slee" "aralysis re"resent an intrusion o' REM slee" atonia, .hereas hallucinations
re"resent an intrusion o' dreams,
0ypocretin
-he hy"ocretin system "lays an im"ortant role in the "atho"hysiolo$y o' human narcole"sy,
Patients .ith narcole"sy ha&e been 'ound to ha&e little or no hy"ocretin in their CS@,
=?K>
Postmortem "atholo$ic e(amination o' the brains o' "eo"le .ith narcole"sy .ith cata"le(y ha&e
demonstrated dramatically reduced numbers o' hy"ocretin neurons, Hy"ocretin de'iciency is
theorized to "roduce instability o' slee" and .a%e states, thereby "re&entin$ the "erson 'rom
sustainin$ more continuous slee" or .a%e'ulness,
A lar$e ma<ority o' "atients .ith narcole"sy .ithout cata"le(y ha&e normal CS@ hy"ocretin
le&els, Ho.e&er, a small "atholo$ic study o' the brains o' "atients .ho had narcole"sy .ithout
cata"le(y sho.ed "artial loss o' hy"ocretin neurons in the hy"othalamus,
=?6, )5, )?>
0n&esti$ators ha&e identi'ied lo. le&els o' histamine 1a neurotransmitter that may hel" maintain
.a%e'ulness2 in the CS@ o' "atients .ith hy"ocretin+de'icient narcole"sy,
=))>
o. CS@ histamine
le&els are not limited to hy"ocretin+de'icient narcole"sy, ho.e&erG they are also seen in
narcole"sy "atients .ith normal CS@ hy"ocretin le&els and in "atients .ith idio"athic
hy"ersomnia,
=)), )7>
0t is note.orthy that lo. CS@ histamine le&els ha&e not been 'ound in "atients .ith hy"ersomnia
secondary to obstructi&e slee" a"nea syndrome,
=)7>
-he CS@ histamine le&el may ser&e as a
biomar%er re'lectin$ the de$ree o' hy"ersomnia o' central ori$in,
=)), )7>
C:S nuclei 'or .a%e'ulness and the rele&ant neurotransmitters $enerated in those nuclei include
the 'ollo.in$:
)ocus ceruleus U 1orepinephrine
3aphe nucleus U Serotonin
!ubomammillary nucleus U ?istamine
Qentral tegmental area U &opamine
5asal #orebrain U "cetylcholine
-hese areas also inhibit REM slee",
Hy"ocretin neurons, thou$ht to be autoe(citatory, "ro<ect 'rom the lateral hy"othalamus into
these re$ions and ser&e to maintain .a%e'ulness, A de'iciency o' hy"ocretin neurons may
decrease the threshold 'or transitionin$ bet.een .a%e'ulness and slee" 1so+called slee" state
instability2, -his is a "ro"osed e("lanation 'or the slee"iness and REM intrusion into
.a%e'ulness 'ound in narcole"sy,
=?5>
Destruction o' hy"ocretin+"roducin$ neurons a""ears to be an autoimmune "rocess,
=)*>
A study in
a mouse model 'ound that the serum o' narcole"sy "atients .as reacti&e .ith o&er K3J o'
hy"ocretin neurons 'rom the mouse hy"othalamus,
=)8>
le&els o' a s"eci'ic autoanti$en a$ainst
-ribbles homolo$ ) 1-rib)2 ha&e been 'ound to be hi$her in narcole"sy "atients .ith cata"le(y
than in normal controls or "atients .ith other in'lammatory neurolo$ic disorders, Hi$h -rib)+
s"eci'ic antibody titers correlated .ith more se&ere cata"le(y,
=)8>
-he autoimmune model o' narcole"sy ins"ired trials o' intra&enous 10Q2 immuno$lobulin 10Q0G2
thera"y in narcole"tic "atients .ith lo. le&els o' hy"ocretin+?, 0n these trials, 0Q0G re"ortedly
im"ro&ed cata"le(y and slee"iness in many cases, but the e''ects did not last lon$, 0Q0G did not
normalize CS@ hy"ocretin le&els, e(ce"t in ? "atient,
=)3>
0n ) children $i&en 0Q0G early a'ter
dia$nosis o' narcole"sy, the cata"le(y and slee"iness im"ro&ed, but some com"onents o' the
disease .orsened in ? child,
=)I>
5enetic factors
-he $enetics o' narcole"sy are com"le(, !hereas the concordance is only 78J in monozy$otic
t.ins, the ris% is as hi$h as *5J in 'irst+de$ree relati&es,
=)K>
:arcole"sy .ith cata"le(y can be
"roduced in animal models by disru"tin$ the $ene that encodes the hy"ocretin 1ore(in2 rece"tor
or li$and $ene, thereby disru"tin$ hy"ocretin neurotransmission,
=?)>
-here is a stri%in$ association bet.een narcole"sy and the HA ha"loty"e DLA?R5?:5)+
DLB?R53:5), A study in indi&iduals o' Euro"ean descent 'ound that nearly all o' those .ith a
dia$nosis o' narcole"sy .ith cata"le(y carry the HA ha"loty"e DLA?R5?:5)+DLB?R53:5),
com"ared .ith only )*J o' the $eneral "o"ulation,
=)6>
-hus, carria$e o' this ha"loty"e may be
necessary but not su''icient 'or the de&elo"ment o' narcole"sy,
A study o' $enome+.ide e("ression in narcole"sy "atients and controls sho.ed an inde"endent
e''ect o' allelic dosa$e o' DLB?R53:5) on DLB?R53:5) mR:A le&els and "rotein,
=75>
-his
'indin$ su""orts the sus"icion that the ris% o' narcole"sy is hi$her in DLB?R53:5) homozy$otes
than in heterozy$otes, su$$estin$ that HA is 'unctionally in&ol&ed in the occurrence o'
narcole"sy,
=75>
A $enome+.ide association study "ro"osed a "rotecti&e &ariant 1DLB?R53:572, -his allele may
"rotect a$ainst autoimmune disordersG it is almost ne&er seen in "atients .ith narcole"sy,
=7?>
Genome+.ide association studies in Caucasians, .ith re"lication in 7 ethnic $rou"s, ha&e
re&ealed associations bet.een sin$le+nucleotide "olymor"hisms 1S:Ps2 in the -+cell rece"tor
al"ha locus and narcole"sy,
=7)>
-his association 'urther su""orts the autoimmune basis o'
narcole"sy,
An S:P in the "uriner$ic rece"tor subty"e P)O?? $ene 1P-R.//2 also a""ears to be associated
.ith narcole"sy,
=77>
P)RO?? has been identi'ied as an im"ortant re$ulator o' immune cell
sur&i&alG the disease+associated P-R.// correlates .ith a 7+'old lo.er e("ression o' P)RO?? in
CDKS -+cells and natural %iller cells, as .ell as .ith decreased P)RO??+mediated resistance to
adenosine tri"hos"hateMinduced death in those cells,
A $enome+.ide association study that in&esti$ated )5) candidate $enes in a re"lication study in
))) narcole"tic "atients and 7K5 controls identi'ied 3 $enes that .ere associated .ith
narcole"sy: "(#%C-' SCP-' C#C"#/C' %CR#' PO0!, and (#M1D, -hese $ene associations
.ith narcole"sy .ere 'urther su""orted by $ene e("ression analyses sho.in$ that these same
$enes are also associated .ith essential hy"ersomnia, .hich is similar to narcole"sy,
=7*>
Epidemiology
*nited "tates statistics
-he "re&alence o' narcole"sy in the HS is 5,5)+5,?KJ, .hich is com"arable to that o' multi"le
sclerosis,
=78, 73>
-he 're9uency amon$ 'irst+de$ree relati&es is ?+)J 1?5+*5 times $reater than that
in the $eneral "o"ulation2, -he re"orted "re&alence o' narcole"sy in select "o"ulations is as
'ollo.s:
1orth "merican blac%s, D.D;V
1orthern Cali#ornians, D.D/V
Southern Cali#ornian Caucasians, D.DWV
+nternational statistics
:arcole"sy .ith cata"le(y a''ects 5,5)J o' adults .orld.ide,
=7I>
-he re"orted "re&alence o'
narcole"sy in select "o"ulations is as 'ollo.s:
Fsraeli News and "rabs, D.DD;V
Czech Caucasians, D.D;V
@innish Caucasians, D.D;CV
Enited Pingdom Caucasians, D.D8V
@rench Caucasians, D.D/V
@u*isawa Napanese teenagers, D..CV
Napanese general population, D..6V
Frish general population, D.DD/V
>-6A
"e,- and a#e-related demo#raphics
-he male+to+'emale ratio in narcole"sy is ?,3*:?, -he a$e+o'+onset distribution is bimodal, .ith
the hi$hest "ea% occurrin$ at ?8 years and a less "ronounced "ea% occurrin$ at 73 years,
Ho.e&er, narcole"sy has been re"orted in children as youn$ as ) years,
Prognosis
!ith "ro"er mana$ement and treatment, "atients .ith narcole"sy usually lead meanin$'ul and
"roducti&e "ersonal and "ro'essional li&es, 0' le't untreated, narcole"sy may be "sychosocially
de&astatin$,
=76>
:arcole"tic children may su''er "oor school "er'ormance, social im"airment,
ridicule 'rom "eers, and dys'unction in other acti&ities o' normal childhood de&elo"ment,
A''ected adults o'ten "ercei&e narcole"tic sym"toms as embarrassin$, and social isolation may
result, -hey may encounter inter"ersonal stress in relationshi"s, se(ual dys'unction, and
di''iculty .or%in$ as a conse9uence o' either the disease itsel' or its treatment,
/ob im"airment may result 'rom slee" attac%s, memory "roblems, cata"le(y, inter"ersonal
"roblems, and "ersonality chan$es, -hese sym"toms may lead co.or%ers to "ercei&e
narcole"tics as lazy, inattenti&e, and lac%in$ moti&ation, 0n one study, )*J o' narcole"tic
"atients had to 9uit .or%in$ and ?KJ .ere terminated 'rom their <obs because o' their disease,
Peo"le .ith narcole"sy sometimes are 'alsely sus"ected o' ille$al dru$ use, Patients should
in'orm em"loyers concernin$ their stimulant medications because they may test "ositi&e 'or
am"hetamines on screenin$ "reem"loyment dru$ tests,
Patient Education
Educate "atients, "arents, teachers, and other care "ro&iders concernin$ the sym"toms,
"ro$nosis, and sa'ety "recautions, Ad&ise "atients o' the increased ris% o' slee"+related dri&in$
accidents, Ad&ise "atients .ith narcole"sy about dri&in$ res"onsibilities,
As o' March ?66*, only 3 states in the Hnited States 1Cali'ornia, Maryland, :orth Carolina,
4re$on, -e(as, and Htah2 had $uidelines 'or narcole"tic dri&ers, 0n contrast, most Canadian
"ro&inces ha&e $uidelines, as does the Hnited Ein$dom, but .hether such $uidelines are
e''ecti&e in reducin$ tra''ic+related morbidity is un%no.n,
=*5>
@or "atient education in'ormation, see the Slee" Disorders Center, as .ell as :arcole"sy,
93(S(1!"!F=1
History
-he classic tetrad o' narcole"sy consists o' e(cessi&e daytime slee"iness 1EDS2, cata"le(y,
hy"na$o$ic hallucinations, and slee" "aralysis, Children rarely mani'est all * sym"toms,
=?>
EDS
is the "rimary sym"tom o' narcole"sy and must be "resent 'or at least 7 months to <usti'y the
dia$nosis,
Slee"iness is a normal e("erience that cycles and in&ariably occurs a'ter "rolon$ed .a%e'ulness,
0n healthy "ersons, mild slee"iness is a""arent only durin$ borin$, sedentary situations 1e$,
'allin$ aslee" .hile .atchin$ tele&ision2, 0n "ersons .ith narcole"sy, se&ere EDS leads to
in&oluntary somnolence durin$ acti&ities that normally en$a$e attention, such as dri&in$, eatin$,
or tal%in$, Slee"iness in narcole"sy may be se&ere and constant, .ith "aro(ysms durin$ .hich
"atients may 'all aslee" .ithout .arnin$ 1ie, slee" attac%s2,
Patients .ith narcole"sy tend to ta%e short and re'reshin$ na"s 1ie, ra"id eye mo&ement =REM>+
ty"e na"s2 durin$ the day, -heir daytime na"s may be accom"anied by dreams,
A si$ni'icant number o' narcole"sy "atients ha&e trouble slee"in$ at ni$ht,
=)>
0n addition, "atients
may ha&e nocturnal com"ulsi&e beha&iors, includin$ slee"+related eatin$ disorder and nocturnal
smo%in$,
=7>
4besity is another common 'eature o' narcole"sy, -he combination o' narcole"sy and obesity
may "romote the de&elo"ment o' obstructi&e slee" a"nea,
Cataple,y
Cata"le(y is a brie' and sudden loss o' muscle tone and re"resents REM slee" intrusion durin$
.a%e'ulness, 0' se&ere and $eneralized, it may cause a 'all, More subtle 'orms may cause only
"artial loss o' tone 1e$, head nod and %nee buc%lin$2, Res"iratory and e(traocular mo&ements are
"reser&ed, -he most characteristic 'eature o' cata"le(y is that it usually is tri$$ered by emotions
1es"ecially lau$hter and an$er2,
Cata"le(y is seen in about I5J o' "atients .ith narcole"sy, 0ts "resence in con<unction .ith EDS
stron$ly su$$ests the dia$nosis o' narcole"sy,
"leep distur!ances
Patients .ith narcole"sy may e("erience slee" "aralysis, .hich is the inability to mo&e u"on
a.a%enin$;or, less commonly, u"on 'allin$ aslee" .ith consciousness intact, 0t o'ten is
accom"anied by hallucinations, Res"iratory and e(traocular muscles are s"ared, Slee" "aralysis
occurs less 're9uently .hen "atients slee" in uncom'ortable "ositions, 0t can be relie&ed by
sensory stimuli, such as touchin$ or s"ea%in$ to the "erson,
Slee"+related hallucinations may be either hy"na$o$ic 1ie, occurrin$ at slee" onset2 or
hy"no"om"ic 1ie, occurrin$ at a.a%enin$2, -hese hallucinations are usually &i&id 1dreamli%e2
&isual, auditory, or tactile in nature,
Disru"ted nocturnal slee" is also a common 'eature o' narcole"sy, Conse9uently, because o'
daytime na"s, total slee" time in )* hours is essentially unchan$ed in narcole"tic "atients,
6oun# children
-he classic "icture o' narcole"sy may be some.hat di''erent in youn$ children, Children may
deny EDS because o' embarrassment, 0n some cases, restlessness and motor o&eracti&ity
"redominate, Academic deterioration, inattenti&eness, and emotional lability are common,
At disease onset, children .ith narcole"sy and cata"le(y may dis"lay a .ide ran$e o' motor
disturbances that do not meet the classic de'inition o' cata"le(y, -hese motor disturbances,
.hich may be ne$ati&e 1hy"otonia2 or acti&e 1e$, "erioral mo&ements, dys%inetic+dystonic
mo&ements, or stereoty"ic mo&ements2, may resol&e later in the course o' the disorder,
=*>
0n a study o' 8? "re"ubertal "atients .ith narcole"sy, the initial com"laints, as .ell as the ty"ical
misdia$noses, &aried by a$e,
=*?>
Children youn$er than 8 years "resented .ith une("lained 'alls
and Adro" attac%s,B a$$ressi&e beha&ior, sudden irritability, and abru"t dro""in$ o' ob<ects,
Atonic seizures .ere the most common misdia$nosis in this a$e $rou",
0n children a$ed 8+?5 years, the most common initial com"laint .as inattenti&eness, 'ollo.ed by
re"etiti&e slee"iness and then by di''iculty .ith mornin$ arousal associated .ith a$$ressi&e
beha&ior and abru"t 'alls in school,
=*?>
-hese children o'ten .ere misdia$nosed as ha&in$
attention de'icit hy"eracti&ity disorder 1ADHD2, learnin$ disability, de"ression, or another
neurolo$ic disorder,
0n children a$ed ?5+?) years, "oor academic "er'ormance .as a common com"laint,
=*?>
4ther
"resentin$ sym"toms included ina""ro"riate lo. le&el o' alertness, 'allin$ aslee" in class, and
inability to .a%e u" in the mornin$,
-uestionnaires
Se&eral 9uestionnaires are a&ailable 'or e&aluatin$ slee"iness, 4' these, the most commonly used
is the K+9uestion E".orth Slee"iness Scale, Patients res"ond to each 9uestion .ith a numerical
score ran$in$ 'rom 5 1not at all li%ely to 'all aslee"2 to 7 1&ery li%ely to 'all aslee"2G thus, the
lo.est "ossible total score is 5, and the hi$hest "ossible score is )*, Althou$h there is some
contro&ersy as to "recisely .hat score constitutes abnormal slee"iness, it is $enerally considered
that total scores hi$her than ?5 .arrant in&esti$ation,
Physical Examination
Physical e(amination 'indin$s are normal in "atients .ith narcole"sy, A care'ul neurolo$ic
e(amination should be "er'ormed to e(clude other causes o' the "atientDs condition, includin$ an
underlyin$ structural abnormality, -here are no s"eci'ic "hysical 'indin$s that su$$est
narcole"sy, thou$h obesity may be associated .ith the disorder, Durin$ an e"isode o' cata"le(y,
"atients ty"ically demonstrate atonia o' muscles o' the limbs and nec% and loss o' dee" tendon
re'le(es,
Diagnostic Considerations
0dio"athic hy"ersomnia is similar in "resentation to narcole"sy, but "atients .ith this condition
ha&e no slee"+onset ra"id eye mo&ement 1REM2 "eriod, and na"s are unre'reshin$,
=*)>
0n addition,
idio"athic hy"ersomnia is not associated .ith cata"le(y, 0dio"athic hy"ersomnia can be di''icult
to distin$uish 'rom narcole"sy, thou$h the ad&ent o' the modern slee" laboratory has aided in
dia$nosin$ these challen$in$ cases,
Di''erentiation o' these ) disorders can "ro&ide &aluable insi$ht 'or thera"y, Althou$h
am"hetamines are used 'or treatment o' both idio"athic hy"ersomnia and narcole"sy, the
e(cessi&e daytime slee"iness 1EDS2 in "atients .ith idio"athic hy"ersomnia is o'ten resistant to
stimulant treatments, 0n addition, sodium o(ybate, .hich is &ery costly, is not a""ro&ed 'or use
in idio"athic hy"ersomnia,
0n addition to the conditions listed in the di''erential dia$nosis, other "roblems to be considered
include the 'ollo.in$:
9rader$Oilli syndrome
Pasabach$4erritt syndrome
Syndrome o# autosomal dominant cerebellar ata'ia, dea#ness, and
narcolepsy
>8-A
&elayed sleep$phase syndrome
"utism
&epression
&iencephalic lesions
&rug abuse
FnsuMcient sleep syndrome
Pleine$)evin syndrome
>88A
4edication e,ect
1orrie disease
>8/A
9oor sleep hygiene
9osttraumatic narcolepsy
>8CA
Fncreased intracranial pressure
Conversion disorder, #actitious disorder, and malingering
Di$erential Diagnoses
"bsence Seizures
5enign Childhood (pilepsy
5rainstem Gliomas
Comple' 9artial Seizures
@rontal )obe (pilepsy
9eriodic )imb 4ovement &isorder
3(4 Sleep 5ehavior &isorder
Shuddering "ttac%s
Syncope and 3elated 9aro'ysmal Spells
!ransient Global "mnesia
Slee" studies are an essential "art o' the e&aluation o' "atients .ith "ossible narcole"sy, -he
combination o' an o&erni$ht "olysomno$ram 1PSG2 'ollo.ed by a multi"le slee" latency test
1MS-2 can "ro&ide stron$ly su$$esti&e e&idence o' narcole"sy .hile e(cludin$ other slee"
disorders,
Human leu%ocyte anti$en 1HA2 ty"in$ may "ro&ide collateral data, but it is more use'ul 'or
e(cludin$ the dia$nosis by documentin$ that the "atient does not ha&e either DLB?R535) or
DLA?R535), HA ty"in$ is less &aluable 'or con'irmin$ the dia$nosis, in that HA+DR) and
DL.? are "resent in )5+75J o' the $eneral "o"ulation,
Measurement o' hy"ocretin 1ore(in2 le&els in the cerebros"inal 'luid 1CS@2 may hel" establish
the dia$nosis,
=?*>
CS@ hy"ocretin le&els lo.er than ??5 "$Cm are included in the dia$nostic
criteria 'or narcole"sy in the second edition o' the 0nternational Classi'ication o' Slee" Disorders
10CSD+)2, 4n the other hand, hi$h CS@ hy"ocretin le&els do not e(clude the dia$nosis o'
narcole"sy,
0n most cases, ima$in$ studies are unre&ealin$, A 'e. small studies ha&e im"licated ma$netic
resonance ima$in$ 1MR02 chan$es o' the "ons .ithin the reticular acti&atin$ system, 0ma$in$
studies such as MR0 are use'ul 'or e(cludin$ rare causes o' sym"tomatic narcole"sy, Structural
abnormalities o' the brain stem and dience"halon may "resent as idio"athic narcole"sy, 0n
"atients .ith secondary narcole"sy, MR0 o' the brain may sho. &arious abnormalities that
corres"ond to the underlyin$ cause,
Sleep Studies
An o&erni$ht PSG 'ollo.ed by an MS- can e(clude other causes o' e(cessi&e daytime
slee"iness 1EDS2, es"ecially slee" a"nea, and can "ro&ide in'ormation about EDS by measurin$
slee" latency and slee"+onset ra"id eye mo&ement "eriods 1S4REMPs2, -he o&erni$ht PSG
'indin$s ty"ically are normal in narcole"sy, thou$h they may sho. slee" 'ra$mentation, All
central ner&ous system 1C:S2 stimulants and sedati&e+hy"notics should be discontinued ) .ee%s
be'ore the PSG and MS-,
-he MS- in&ol&es 8 o""ortunities to na" at )+hour inter&als o&er the day, More than )
S4REMPs and a mean slee" latency o' less than K minutes stron$ly su$$est narcole"sy, -hese
'indin$s are not com"letely s"eci'ic and also can be seen in "atients .ith se&ere slee"
de"ri&ation, delayed slee" "hase disorder, or se&ere slee" a"nea, @or these reasons, a PSG o' the
"re&ious ni$ht is necessary 'or inter"retation o' the MS-G MS- cannot be used alone to
con'irm or rule out narcole"sy,
Dia$nosin$ narcole"sy in children "resents numerous di''iculties, 4ne study 'ound that K8J o'
children .ith narcole"sy also su''ered 'rom slee"+disordered breathin$, Serial MS-s may be
re9uired, and usually multi"le con'oundin$ 'actors are in&ol&ed 1e$, increased alertness in the
no&el en&ironment o' the slee" laboratory2, @urthermore, normati&e MS- &alues 'or children
ha&e not been established,
Slee" studies are an essential "art o' the e&aluation o' "atients .ith "ossible narcole"sy, -he
combination o' an o&erni$ht "olysomno$ram 1PSG2 'ollo.ed by a multi"le slee" latency test
1MS-2 can "ro&ide stron$ly su$$esti&e e&idence o' narcole"sy .hile e(cludin$ other slee"
disorders,
Human leu%ocyte anti$en 1HA2 ty"in$ may "ro&ide collateral data, but it is more use'ul 'or
e(cludin$ the dia$nosis by documentin$ that the "atient does not ha&e either DLB?R535) or
DLA?R535), HA ty"in$ is less &aluable 'or con'irmin$ the dia$nosis, in that HA+DR) and
DL.? are "resent in )5+75J o' the $eneral "o"ulation,
Measurement o' hy"ocretin 1ore(in2 le&els in the cerebros"inal 'luid 1CS@2 may hel" establish
the dia$nosis,
=?*>
CS@ hy"ocretin le&els lo.er than ??5 "$Cm are included in the dia$nostic
criteria 'or narcole"sy in the second edition o' the 0nternational Classi'ication o' Slee" Disorders
10CSD+)2, 4n the other hand, hi$h CS@ hy"ocretin le&els do not e(clude the dia$nosis o'
narcole"sy,
0n most cases, ima$in$ studies are unre&ealin$, A 'e. small studies ha&e im"licated ma$netic
resonance ima$in$ 1MR02 chan$es o' the "ons .ithin the reticular acti&atin$ system, 0ma$in$
studies such as MR0 are use'ul 'or e(cludin$ rare causes o' sym"tomatic narcole"sy, Structural
abnormalities o' the brain stem and dience"halon may "resent as idio"athic narcole"sy, 0n
"atients .ith secondary narcole"sy, MR0 o' the brain may sho. &arious abnormalities that
corres"ond to the underlyin$ cause,
Sleep Studies
An o&erni$ht PSG 'ollo.ed by an MS- can e(clude other causes o' e(cessi&e daytime
slee"iness 1EDS2, es"ecially slee" a"nea, and can "ro&ide in'ormation about EDS by measurin$
slee" latency and slee"+onset ra"id eye mo&ement "eriods 1S4REMPs2, -he o&erni$ht PSG
'indin$s ty"ically are normal in narcole"sy, thou$h they may sho. slee" 'ra$mentation, All
central ner&ous system 1C:S2 stimulants and sedati&e+hy"notics should be discontinued ) .ee%s
be'ore the PSG and MS-,
-he MS- in&ol&es 8 o""ortunities to na" at )+hour inter&als o&er the day, More than )
S4REMPs and a mean slee" latency o' less than K minutes stron$ly su$$est narcole"sy, -hese
'indin$s are not com"letely s"eci'ic and also can be seen in "atients .ith se&ere slee"
de"ri&ation, delayed slee" "hase disorder, or se&ere slee" a"nea, @or these reasons, a PSG o' the
"re&ious ni$ht is necessary 'or inter"retation o' the MS-G MS- cannot be used alone to
con'irm or rule out narcole"sy,
Dia$nosin$ narcole"sy in children "resents numerous di''iculties, 4ne study 'ound that K8J o'
children .ith narcole"sy also su''ered 'rom slee"+disordered breathin$, Serial MS-s may be
re9uired, and usually multi"le con'oundin$ 'actors are in&ol&ed 1e$, increased alertness in the
no&el en&ironment o' the slee" laboratory2, @urthermore, normati&e MS- &alues 'or children
ha&e not been established,
edication Summary
-he main 'ocus o' "harmacolo$ic thera"y 'or narcole"sy is sym"tomatic treatment o' e(cessi&e
somnolence and cata"le(y .ith central ner&ous system 1C:S2 stimulants and antide"ressants,
Stimulants im"ro&e .a%e'ulness, and antide"ressants 1e$, clomi"ramine, 'luo(etine, dulo(etine,
and &enla'a(ine2 reduce cata"lectic attac%s,
Stimulants
Class "ummary
Stimulants increase .a%e'ulness, &i$ilance, and "er'ormance, -hey are thou$ht to alter midbrain
do"aminer$ic acti&ity, but the "recise mechanism o' action is un%no.n, 0nter"atient &ariability in
the dosa$e re9uired to alle&iate e(cessi&e daytime slee"iness 1EDS2 is considerable and
un"redictable, 0n some "atients, daytime slee"iness is com"letely relie&ed .ith methyl"henidate
8 m$CdayG in others, hi$her dosa$es are re9uired, 0nitiate treatment at lo. dosa$es, and
indi&idualize thera"y as a""ro"riate,
$ethylphenidate /Ritalin1

Methyl"henidate is a "i"eridine deri&ati&e that is the most commonly "rescribed treatment 'or
narcole"sy, 0ts e''icacy has been demonstrated in randomized, double+blind, dose+res"onse, and
"lacebo+controlled trials,
$odafinil /&rovi#il1

Moda'inil is "harmacolo$ically distinct 'rom other stimulants, 0t does not a""ear to act &ia the
do"aminer$ic system,
Armodafinil /(uvi#il1

R+enantiomer o' moda'inil 1mi(ture o' R+ and S+enantiomers2, Elicits .a%e+"romotin$ actions
similar to sym"athomimetic a$ents, althou$h "harmacolo$ic "ro'ile is not identical to
sym"athomimetic amines, 0n &itro, binds do"amine trans"orter and inhibits do"amine reu"ta%e,
:ot a direct+ or indirect+actin$ do"amine rece"tor a$onist, 0ndicated to im"ro&e .a%e'ulness in
indi&iduals .ith e(cessi&e slee"iness associated .ith narcole"sy, obstructi&e slee" a"nea+
hy"o"nea syndrome 14SAHS2, or shi't+.or% slee" disorder,
C"S Depressants
Class "ummary
Cata"le(y in "atients .ith narcole"sy can be treated .ith the C:S de"ressant sodium o(ybate,
4ther a$ents that are used o''+label 'or cata"le(y are tricyclic antide"ressants 1-CAsG e$,
clomi"ramine, desi"ramine, and imi"ramine2, selecti&e serotonin reu"ta%e inhibitors 1SSR0sG e$,
'luo(etine, "aro(etine, and sertraline2, and serotonin+nore"ine"hrine reu"ta%e inhibitors 1S:R0sG
e$, &enla'a(ine and dulo(etine2, -he stron$est e&idence is 'or clomi"ramine, 'luo(etine, and
sodium o(ybate,
"odium o,y!ate /7yrem1

Sodium o(ybate 1Pyrem2
Sodium o(ybate, also %no.n as $amma hydro(ybutyrate 1GHB2, is a C:S de"ressant used to
treat "atients .ith EDS and cata"le(y, -he onset o' thera"eutic e''ects is o'ten delayed, -he
"recise mechanism by .hich sodium o(ybate "roduces an e''ect on cata"le(y is un%no.n,
Because o' sodium o(ybate#s history o' abuse as a recreational dru$, the @DA a""ro&ed it as a
Schedule 000 Controlled Substance, A limited distribution "ro$ram that includes "hysician
education, "atient education, a "atient and "hysician re$istry, and detailed "atient sur&eillance
has been established, Hnder this "ro$ram, "rescribers and "atients .ill be able to obtain the
"roduct only throu$h the Pyrem Success Pro$ram and only 'rom a sin$le centralized "harmacy
1?+K33+66I+73KK2, Sodium o(ybate is a&ailable as an oral solution 1855 m$Cm2

Circadian Rhythm Disorder Overview

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