Narcolepsy: Clinical features, co-morbidities & · PDF fileNarcolepsy: Clinical features, co-morbidities & treatment Jeremy Peacock & Ruth M. Benca Department of Psychiatry, University

Narcolepsy is a disabling neurlogical illnessthatusuallybeginsearly in life. Itmanifestsassleepdisturbances andREMsleepphenomena that intrudeinto the lives of affected individuals. There are twosubtypesofthedisorder:narcolepsywithcataplexyandnarcolepsywithoutcataplexy.Thecauseisuncertain,butthereisevidenceofbothgeneticandenvironmentalfactors. The brain peptide hypocretin appears to bedeficient in most cases involving cataplexy. There are several co-morbid conditions linked to narcolepsy,especiallyothersleepdisorders.Thesymptomsoverlapwithmanymedicalandpsychiatricillnesses,whichcanresultinmisdiagnosis.Therefore,carefulhistoryalongwithobjectivesleepdatagatheredinpolysomnographyandmultiplesleeplatencytestingareneededtomakeanaccurate diagnosis. Stimulant medications, modafinil,

Narcolepsy:Clinicalfeatures,co-morbidities&treatment

JeremyPeacock&RuthM.Benca

Department of Psychiatry, University of Wisconsin-Madison, USA

ReceivedNovember24,2008

Narcolepsy is a neurologic illness that typically begins in the second and third decades of life. It is chronic in nature and negatively impacts the quality of life of affected patients. The classic presentation is a tetrad of excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. The exact cause remains unknown, but there is significant evidence that hypocretin deficiency plays an integral role. Some primary conditions that result in secondary narcolepsy include traumatic brain injury, congenital disorders, tumours, and strokes. Some medical and psychiatric disorders share characteristics of narcolepsy, at times leading to diagnostic inaccuracy. Other sleep disorders are commonly co-morbid. Diagnosis relies on patient history and objective data gathered from polysomnography and multiple sleep latency testing. Treatment focuses on symptom relief through medication, education, and behavioural modification. Both classic pharmacological treatments as well as newer options have significant problems, especially because of side effects and abuse potential. Novel modalities are being examined to expand options for treatment.

Key wordsCataplexy-excessivedaytimesleepiness-hypocretin-MSLT-narcolepsy

and sodium oxybate target the excessive daytimesleepinesswhile antidepressants and sodiumoxybateare useful for cataplexy. Therapies that focus onvariousneurotransmittersystems,immunomodulation,andhypocretinreplacementarebeingevaluated.

Epidemiology

The prevalence of narcolepsy varies acrosscountriesandwithdifferentethnicgroups,andsotheexact prevalence is not known. Discrepancies mayrelate in part to disease definitions, study designs, and age groups studied. Prevalence estimates have beenreported to be between 168 and 799 per 100,000 inmoststudies,althoughJapanesestudieshaveindicateda higher prevalence of 1600 per 100,0001,2. None ofthesestudiesusedpolysomnographyintheirdiagnostic

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approach,however,andinsteadreliedonsurveydata.An estimated incidence of 0.74 per 100,000 person-yearsforadiagnosisofnarcolepsywithcataplexyand1.37per100,000person-years forpatientsdiagnosednarcolepsy with and without cataplexy was basedon the incidence rates and prevalence of narcolepsyin Olmsted County, Minnesota between 1960 and1989, as measured by the record linkage system oftheRochesterEpidemiologyProject3.Theprevalenceof narcolepsy without cataplexy is more difficult to ascertain, and thesepatients aremore likely tobeundiagnosed;thissubgroupmayrepresent10to50percentofthenarcolepsypopulation4,5.

Narcolepsy can begin at any age, although themajorityofthepeoplediagnosedwithnarcolepsybegintoshowsymptomsbetweentheagesof10and25yr6.There may be a bimodal distribution with a significant butsmallerpeakoccurringinthefourthdecadeoflife7.Younger populations report that excessive daytimesleepiness (EDS) is the first symptom to appear, whereas older cohorts report that cataplexy is themostcommoninitialsymptom6.Menseemtobemorecommonly affected, with narcolepsy occurring 1.6timesmoreofteninmenthaninwomen1.

Although the specific causes of narcolepsy remain unknown,itappearsthattherearebothenvironmentaland genetic factors contributing to the developmentof this disease. Supporting the evidence for anenvironmental influence is the fact that the disease is not apparent at birth, but instead commonly has itsonset during the second decade of life.Additionally,there are apparent precipitating factors such as headtrauma,infection,andchangesinsleep-wakinghabitsthat have been identified in some cases8. A higherincidenceofnarcolepsyhasbeenseeninpeopleborninthemonthofMarchandalowerincidenceamongthoseborn in September9.While most cases of narcolepsyare sporadic, there are multiple reports of familialnarcolepsy10.First-degree relativeshaveanestimateda 1 to 2 per cent chance of developing narcolepsy10.Although small, it is substantially higher than theprevelanceofnarcolepsyinthegeneralpopulation.

Narcolepsy is associated with the HLA DR2haplotype11. Because of this observation, it hasbeen postulated that narcolepsy may result from anautoimmune process, though this has not been verified11.DNA analysis has revealed that there are severalgenes linked to narcolepsy. Moreover, different genesubtypes carry various levels of frequency, specificity, and relationship to ethnic backgrounds10. However,

thesegenescanalsobefoundinsubjectswhodonotappear to have symptoms of narcolepsy. There hasbeena strongassociationobservedwithHLADQB10602/DRB11501,whichisparticularlyprevalentwhencataplexyispresent11;over90percentofnarcolepticswithcataplexyexpressthismarker,butitisalsoseeninapproximately1/10–1/3ofthegeneralpopulation.ConfoundingthisisthefactthattherearerarepatientswithobviouscataplexywhodonothaveHLADQB10602, thus HLA typing is not useful as a diagnostictool10.

Role of hypocretin

Hypocretin is a peptide derived from thedorsolateral hypothalamus that has been linked tomultiple regulatory functions including sleep/wakecycles,foodintake,andpleasureseekingbehaviour12.

Sleep fragmentation is observed when there is adeficiency of hypocretin. There are currently two known variants, hypocretin 1 and 2, also known asorexin A and B, respectively. Hypocretin functionsthrough two G protein coupled receptors. The cellscontaining hypocretin are linked to monoaminecell groups in the locus ceruleus, raphe nucleus,tuberomammillary nucleus, and ventral tegmentalarea corresponding to norepinephrine, serotonin,histamine, and dopamine respectively. Deficiencies of hypocretin can lead to abnormailities in thefunctionofthesemonoaminesystems,whichinturncanmediatethesymptomsofnarcolespy.Dopaminehas significant wakefulness promoting properties, as does histamine. Abnormalities related to rapid eyemovement (REM) sleep can be produced with thechangestotheadrenergicandserotonergicsystems13.

Animal studies provided some of the earliestevidencethathypocretinplayssomeroleinnarcolepsy14.Certainbreedsofdogs,includingDobermanPinschers,canexpressthenarcolepticphenotypethatistransmittedbyanautosomalrecessivegene.Studyoftheseanimalshasrevealedthepresenceoffragmentedsleep,episodesthought to be similar to cataplexy, and short REMsleep latencies.Genetic analysis led to thediscoveryofadysfunctionalreceptorintheneuropeptidesystem,specifically hypocretin 2 receptor. Studies in mice revealed a model in which mutations found in thepreprohypocretin promoter produce the narcolepsyphenotype14. Hypocretin 2 receptor knockout micealsodisplayepisodessimilartocataplexy15. Animalswithout the hypocretin 1 receptor are not observedto have cataplexy-like behaviours, but do showfragmentationoftheirsleep.

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With animal studies yielding evidence of alink between narcolepsy and abnormalities in thehypocretinsystem,attentionhasturnedtohypocretininhumannarcolepsy16.HumanpathologystudieshaverevealedreductionsofHcrt1,Hcrt2,andpreproHcrtmRNA. However, only one report so far has foundmutations in the Hcrt gene itself16. The resultantlow level of hypocretin despite normal Hcrt geneslendssomeweight to theideathatnarcolepsyis theresultofanautoimmuneprocess.Alsoinsupportofthisideaisthatnarcolepsyhasatypicalonsetinthesecond and third decades of life, which is commoninmanyotherautoimmunedisorders.Onereporthasidentified monozygotic twins who were concordant for narcolepsywithcataplexybutfoundtohavenormalcerebral spinal fluid concentrations of hypocretin-1 andnomutationsinthehypocretingeneorhypocretinreceptor gene, suggesting that dysfunction of thehypocretin system may not be the only pathway tonarcolepsy17.

Inhumannarcolepsy,theroleofhypocretinsystemabnormality appears to be variable16. Many studieshavefoundhypocretintobeabsentorreducedinthecerebrospinal fluid of narcoleptics; over 90 per cent of patients show significant reductions in hypocretin levels when there is clear cataplexy and HLApositivity12,18.However,thisassociationisnotasclearwhencataplexyisabsent,withonlyapproximately20-40 per cent of non-cataplectic patients showing lowhypocretinlevels.ThelackoflowCSFhypocretinmayrepresentanentirelydifferententitywithpathologyinanothersystemversusalesssevereformofthedisease.Additionally,thismayrepresentsecondarynarcolepsyresultingduetofromtumours,traumaticbraininjury,and encephalomyelitis19. Alterations in hypocretinhave not been seen in other sleep disorders such assleep apnoea, insomnia, and restless leg syndrome11.Ontheotherhand,therearemanyotherdisorderswithsymptomsofdaytime sleepinessor fatigue that havebeenassociatedwithlowCSFhypocretinlevelssuchas encephalitis, multiple sclerosis, genetic disorders,tumours,andGuillian-Barresyndrome12.

Clinical features

The classic tetrad of symptoms for narcolepsyincludesexcessivedaytimesleepiness(EDS),cataplexy,sleepparalysis,andhypnagogichallucinations8.Notallsymptomsarepresentinallpatientsandthesemayvaryandinfrequencyandintensityovertime6,20.Also,thesesymptomscanbe found inotherdisorders, includingotherdistinctsleepdisorders21.

Excessivedaytimesleepinessincludesspontaneous,recurring urges to sleep and a general sense ofbackgroundsleepinessthatispresentmuchofthetime;this is the most commonly occurring feature of thetetrad22.Theseepisodesvaryinlengthfromsecondstooveranhour.Patientswithnarcolepsymayexperiencemultipleepisodesofoverwhelmingsleepinessperday.The sleep attacks can occur at inappropriate timessuch as driving, when engaged in conversation, andother times the patient is active and participating insome task.Thisurge to sleep tends tobeheightenedby more monotonous activity or in low stimulationsurroundings. Narcoleptics often report that taking anap or succumbing to these sleep attacks help them,as they often feel refreshed upon waking, althoughusuallyonlyforashortperiod.Patientswithnarcolepsygenerallydonotspendagreaterportionoftheirtimeasleepcomparedtopeoplewhodonothavenarcolepsydespite these recurring daytime sleep spells becausetheir nocturnal sleep is oftenhighly fragmented; thisresultsinalossoftotalsleeptimeatnightsothattheaddeddaytimenappingresults ina“normal”amountoftotalsleepacrosstheday23.Thebackgroundlevelofsleepiness can also have significant impact on daytime functioning,impairingconcentration,workandschoolperformance,andgeneralqualityoflife24,25.

Itisimportanttoclarifythatthenarcolepticpatientissleepyandnotjustfatigued,althoughbothsymptomsare often reported. Clinicians and patients often usethese terms interchangeably, although these do notnecessarilydescribethesameentity.Fatiguereferstolackingenergyorfeelinglistless,asopposedtohavingatruetendencytofallasleepinappropriately.Fatigueisassociatedwithmanymedicalandpsychiatricillnesses.Individuals who suffer from fatigue do not usuallyexhibit abnormal results on multiple sleep latencytesting24.

Cataplexyisasuddendecreaseinorlossofmuscletone. It usually occurs bilaterally and is often inresponsetoemotionssuchashumour,anger,surprise,andtremendousjoy22,23.Theseattackstypicallyaffectcertain muscle groups but may be more generalized, resulting in the patient collapsing. Patients withnarcolepsy are often aware of these attacks and takeactionsuchasproppingthemselvesuporsittingdownwhenastheyperceivetheattackcomingon.Theremaybetwitchingofthefacialmusclesorlimbswhichcanleadtoamisdiagnosisofepilepsy22.Inmilderversions,patientsmaydescribeageneralsenseofweaknessbutstillmaintaincontrol.Speechmaybeslurredorbroken

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as a result of muscle inhibition. Patients may alsocomplainofsimplyfeelingclumsyorunco-ordinated,particularly at times involving strong emotions. It ispossible for cataplexy to emerge without the eventbeing triggered by an emotion or stress, but this ismore unusual. Typically, cataleptic episodes arebrief, lastingafewsecondstoafewminutes.Inrarecircumstances,thesecanpersistforhours,resultinginstatuscataplecticus.

In normal sleep, NREM sleep always occurs first and then alternates with REM sleep. Because of theearly onset REM periods and dissociation of certaincomponentsofREMsleep,apatientmayexperienceotheraspectsofREMsleepduringwakefulness20,22,23.InnormalREMsleep,thebodylosesmuscletone,anddreaming occurs. Sleep paralysis occurs as a patientwithnarcolepsyiseitherfallingasleeporawakening.Thiscanbeafrighteningexperiencebecausethepatientisunabletomovelimbs,opentheeyes,orspeak.Theseepisodesaregenerallybriefandpatientsareawareoftheir state. Often, hallucinations coincide with sleepparalysis.

Patients with narcolepsy may experiencehallucinations at sleep onset (hypnagogic) and uponawakening(hypnopompic)20,22,23.Likenormaldreams,thesephenomenatendtobevisual innaturebutmayalso be auditory. Characteristically, these includesimpleforms,objects,animals,andpeople.Patientswillsometimesrespondtotheirhallucinations,particularlyif theybelievethatanintruderispresentorthat theyareinsomeformofdanger.Patientsalsoreportothertypesofdream-likephenomenawhichmight includelevitationoroutofbodyexperiences.

In addition to the classic tetrad, patients alsodescribe significant problems with insomnia, repeated awakenings, and complaints related to their level oftirednesssuchasblurryvision,diploplia,andtroublewithconcentrationandmemory22,23,26.Thereareoftenautomaticbehavioursthatoccuratthetimeofincreasingsleepiness22.Theseautomaticbehavioursaregenerallyrelatedtoroutineactivitiesthatrequirelittleattentionbut may involve significant errors or risk, such as driving.Narcolepsyisoftenco-morbidwithothersleepdisorderssuchasREMsleepbehaviourdisorder,sleepapnoea, and periodic limb movement disorder24,27.The symptoms of narcolepsy and secondary effectsofthedisordercanhavemajornegativeeffectsonallaspectsoflifeincludingthepatient'seducation,workperformance, ability to drive safely, relationships,mood,andoverallwellbeing.

Ofthefoursymptomsintheclassictetrad,excessivedaytimesleepinessistheonemostconsistentlyreportedbypatientswithnarcolepsy28.Evaluatingthiscomplaintis problematic, however, because it is observed innumerous other disorders related to sleep and manygeneral medical and psychiatric disorders. Severalprimarysleepdisordershavedaytimesleepinessasasymptom, including sleep deprivation, delayed sleepphase disorder, advanced sleep phase disorder, sleepdisordered breathing, periodic limb movements,idiopathichypersomnia,andkleine-Levinsyndrome.

Excessive daytime sleepiness is routinely linkedto psychiatric disorders as well24,28. Epidemiologicstudies have revealed significant co-morbidity of hypersomnia and psychiatric disorders. Dysthymia,atypical depression, seasonal affective disorder, andbipolar disorder are commonly associated with sleepdysregulationandcomplaintsofhypersomnia.Severalanxietydisordersmayalso impact thepatient's sleepandshouldbeevaluatedandaddressed29,30.

Causes of narcolepsy

The exact cause of primary human narcolepsyremainsunknown,althoughlossofhypocretinappearstoplayaroleinmostcaseswithcataplexy12,18.Therearealsootherneurologicalinsultsthatappeartohavenarcolepsy symptoms as a consequence19. Just as inprimary narcolepsy, these entities may or may notinclude cataplexy as a symptom. Measurement ofCSF hypocretin levels may reveal a broad range ofvariations in the low,normal,and intermediaterangeas well8. Lesions of the hypothalamus and nearbystructures can produce narcolepsy-like symptoms.Multiplesclerosis,tumours,andstrokeshaveallbeenassociatedwithnarcolepsyaswell.Moreglobalinsultssuch as traumatic brain injury, encephalomyelitis,and congenital disorders such as Neimann-Pick typeC disease, myotonic dystrophy, and Prader-Willisyndrome are also associated with narcolepsy8. Itis unknown if the changes inhypocretin levels are aconsequence of the primary insult or a coincidentalfinding. Additionally, these changes can be transient, asthelowlevelsfoundinmanytraumaticbraininjurypatientsmayreturntonormalaftersixmonths12.

Diagnostic considerations

The International Classification of Sleep Disorders consists of two classifications of narcolepsy: with or without cataplexy21. The tetrad of EDS, cataplexy,sleepparalysis, andhallucinations is thehallmark ofnarcolepsy, though not all of the symptoms need be


present(TableI).Also,someofthesymptomsmaybepresent in isolationeven if apatienthasexperiencedthe whole tetrad. For example, cataplexy may beseen without necessarily having a sleep attack, andsleepattacksdonotnecessarilyincludeanepisodeofcataplexy. Because excessive daytime sleepiness isthemostcommonfeatureinpatientswithnarcolepsy,having methods to determine levels of sleepinessaccuratelyisimportant.Severalscalesexisttomeasuresleepiness, including theEpworthSleepinessScale31.Acommonproblemwithsubjectivescales,however,istheirinconsistentreliabilitytocorrelatewithobjectivedata.

Themultiplesleeplatencytest(MSLT)iscurrentlytheacceptedstandardtoobtainobjectiveinformationregarding sleep drive and excessive sleepiness. Itconsists of five scheduled naps, each 20 min in length, thatarescheduledevery2hacrosstheday.Ideally,thesleepingconditionsaresetsothatthepatientsarebestabletofallasleep.Thisrequiresappropriatetemperature,limitedstimulation,andmakingthenapascomfortableas possiblegiven theobvious limitationsof being inthelabandattachedtorecordingequipment.Followingeachnapopportunity,thepatientistostayawakeuntilthe next scheduled nap. During the test, physiologicdataaregatheredsuchasthetimeittakestofallasleepandthepresenceorabsenceofREMsleep.REMsleepthat occurs within the first 15 min of sleep, an event termed sleep onset REM (SOREM), rarely occursin normal individuals, but is common in narcolepsy.MSLTresultsmayvarywiththeageofthepatient32.Thecurrentcriteriarequirefallingasleepinlessthaneightminutesonaverageacross thenapsandhavingtwoSOREMsor theoccuranceofREMsleepwithinthe 20 min naps21. There is some evidence that thiscriteria are not specific to narcolepsy. Having multiple SOREMsontheMSLThasbeenassociatedwithotherdisorderswithEDSsuchassleepapnoea, shiftworksleepdisorder,andperiodiclimbmovementdisorder33.

kleine-Levin syndrome, Prader-Willi, obsessive-compulsivedisorder,andParkinson'sdiseasehavealsobeen linked to SOREMs33. Multiple SOREMs haverarely been seen in patients who were thought to beotherwisenormal.

On the night prior to an MSLT, the patient istypicallybroughtintothesleeplaboratoryinordertoperform the nocturnal polysomnogram. The patientis monitored all night to gather data on breathing,movement,timeinbed,timeasleep,andheartrate.Thepatient also will have electroencephalogram (EEG)recorded throughout the night to monitor when thepatientfallsasleepandwakesup,aswellastoprovideinformationregardingwhatstagesofsleepareattainedandthelengthofthosestages.WhiletheEEGmontageis limited, it has the potential to identify seizure activity. Patients may have audio and video monitoring torevealsnoring,sleeptalking,andrevealmovementsorcomplexbehavioursthatthepatientmaybeperformingwhileasleep.Thepolysomnogramitselfmayrevealtheaetiologyofaperson'sexcessivedaytimesleepinessorothersleeppathologies.Narcolepsycanbeco-morbidwith other sleep disorders such as REM behaviourdisorder, apnoea, and sleep related movementdisorders.Conversely,thesleepstudyproceduremaycauseapersontohaveabnormalsleepbecauseofthedisruptionofsleepinginanewenvironmentandwiththe recording electrodes, thus potentially influencing the next day's MSLT, particularly if the patient hadsignificant difficulty falling asleep or staying asleep in the laboratory. To minimize the effects of possible sleep deprivation,theAmericanAcademyofSleepMedicinerecommends that the patient have at least six hoursof recorded sleep on the night prior to the MSLT34.This could still be insufficient for a given individual, however,andideallyapatientshouldsleepad libitumforat least severaldaysprior tobeingstudied in thelaboratory.

At its most basic level, an MSLT measuressleepiness. It does not determine what causes theobservedsleepiness.Becauseofthis,aconditionthatwould promote one's ability to take multiple napsduring the daytime could significantly interfere with the validity of using MSLT to diagnose narcolepsy.Further complicating the issue is that many of thesymptoms of narcolepsy, with the exception ofcataplexy, can be produced with sufficient sleep deprivation35,36. Co-morbid medical and psychiatricconditionscouldcontributetoanincreasedtendencytofallasleepduringtheday.Numerousmedications

Table I . PrimaryandsecondaryaetiologiesHypocretin deficiencyHypothalamiclesionStrokeTumourPrader-WillisyndromeTraumaticbraininjuryNeimann–PickdiseasetypeCMyotonicdystrophyEncephalomyelitis


canalsointerferewiththevalidityofthetest.AsdataaregatheredregardingREMsleep,medications thateithersuppressorpromoteREMsleepcanaffecttestresults.Assuch,medicationsthatcanalteralertness,sleep cycle, and other physiologic data that wouldbe recorded during the test should be reduced oreliminatedforatleastseveralweekspriortothetest,ifpossible.

A significant confounder for the MSLT is insufficient sleep time since many people are chronically sleepdeprived35. Therefore, a complaint of EDS requirestakingdetailedhistoryandgatheringdataonaperson'ssleep35. To further assist in making the diagnosis,patientsmaybeasked tokeepa sleepdiary inordertoverifytheirsleephabits,timeinbed,andattempttolearnhowmuchtimeisspentsleepingeachday.Thereissomeevidencethatsuchlogsmaybeunreliableincomparison to actigraphy, which consists of wearinga motion sensitive device that records when there ismotionandusesthelackofmovementasasurrogatefortimeasleep.

There arenogenetic tests currently available forclinicalusetomakeapositivediagnosisofnarcolepsy.Genetic testing may correlate best to narcolepsywhenthereisalreadyclearcataplexy8,12.Additionally,the genes identified so far are specific to various ethnic backgrounds, further limiting their utility10,37.There are also no blood tests available to confirm a diagnosis.Analysis of CSF is useful in patients whoalsohavetypicalcataplexy.Atypicalcataplexy,whichinvolvesacataplecticeventthatisnotinitiatedbyanemotional event such as laughter, is only associatedwith hypocretin deficiency in 20 per cent of cases8.In evaluating patients for narcolepsy with cataplexy,almost all cases with deficient hypocretin are also positiveforHLADQB18,11,18.Itisimportanttokeepinmindthatnarcolepsydoesnotexcludeotherdiagnosesfrom being co-morbid, and conversely, narcolepsysymptomsmaybesecondarytosomeotherconditionssuch as traumatic brain injury, infection, tumour, orcerebrovascular accident8. Multiple sclerosis (MS) isparticularly problematic because the common HLADQB1 haplotype can be seen in MS, and plaques inthehypothalamuscouldpotentiallyleadtosecondarynarcolepsy. It is reasonable to expect these chanceplaques to be the cause of sleep related symptoms,because MS patients positive for HLA DQB1, butlacking plaques in the hypothalamus, do not showchangesinhypocretinanddonotexhibitthetetradofnarcolepsysymptoms.

Differential diagnosis

Narcolepsysharesmanysymptomswithpsychiatricillnesses, which can sometimes lead to it beingdiagnosed as a psychiatric illness. According to theFourtheditionoftheDiagnosticandStatisticManualIV with text revision (DSM-IV-TR), nearly everypsychiatric illness requires some level of functionalimpairment30. Patients with narcolepsy can exhibitsignificant problems in work, school, relationships, andtheirqualityoflife,andthesetypesofimpairmentsmaybringthemtopsychiatricattention19,25.Commonpsychiatricillnessessuchasmajordepressivedisorder(MDD),bipolardisorder,andpsychoticdisordershavesymptomoverlapwithnarcolepsy23.Patientswithmooddisorders often have insomnia and/or hypersomnia38.PatientswithMDDorwhoareinthedepressedphaseofbipolardisordermayexperienceEDSinadditiontotheirfatigue39.Mooddisorderpatientsingeneralcanshowpolysomnographic findings of reduced REM latency when not taking REM suppressing antidepressants38.However, these generally do not result in SOREMperiods as seen in narcolepsy. Mood disorders canbe associated with psychosis, and hypnagogic/hypnopompic hallucinations may be interpreted aspsychoticsymptoms40.Patientswithpsychiatricillnessand thosewithnarcolepsycanexpress some levelofimpairment incognitiveperformance30,41. Inchildren,narcolepsymaypresentwithjustEDS42.Consequently,thebehaviours observed as a result of the sleepinessmay mimic that seen in children with attention deficit/hyperactivity disorder43. To further confound thediagnosis,bothoftenrespondtotreatmentwithstimulantmedicationsandthereisevidenceof improvementinpaediatric patients with attention deficit hyperactivity disorder (ADHD) who take modafinil44.Malingeringisanotherpossibility,aspatientsmaybeseekingmedicalleave,disability,orseekingstimulants.Narcolepsycanalsobemisdiagnosedasaconversiondisorder.

Schizophrenia and narcolepsy also share some features that can lead to misdiagnosis and thusinappropriate treatments24. Both tend to start inadolescence and young adulthood. Patients withschizophrenia can have alterations in the sleep cycle and complain of insomnia. Some schizophrenics may have reducedREMsleeplatencies.Hallucinationsarefoundinboth,thoughacarefulhistoryanddetailedassessmentofthesecanhelpdistinguishthetwoentities.Auditoryhallucinationsareexperiencedbybothgroups,thoughmuch more commonly in patients with schizophrenia. Conversely, visual hallucinations are reported by


patientswithnarcolepsyinratesashighas83percentwhile seen by patients with schizophrenia only 29 per cent of the time40. Further, patients with narcolepsyusuallyreporttheirhallucinationstobeassociatedwithsleep and those with schizophrenia do not generally link thesephenomenon to their sleep.Asopposed tothe case of narcolepsy misdiagnosed as ADHD, thetreatments of schizophrenia and narcolepsy do not often overlap.Infact,providingstimulantstoapatientwithschizophrenia may worsen their psychotic symptoms. Conversely, many antipsychotic medications mayworsen EDS because of their sedative side effects.Dependingontheneurotransmittersaffectedbyagivenagent,therecanbemyriadeffectsonsleeparchitecturethat may be inadvertently beneficial. For example, REMsleepsuppressionmayhelpwithcataplexyandthe hypnagogic hallucinations. Thus, the clinicianandpatientmaybeledastraybytheresolutionofthepsychoticsymptoms.

Severalneurologicdisordersshouldbeconsideredwhenmakingthediagnosisofnarcolepsy.Epilepsyisacommonlyoccurringconditionthatmaybegivenastheinitialdiagnosis45.Thecataplexyandsleepattacksmay appear to an observer to be a seizure. Parkinson's disease and Alzheimer's disease both exhibit significant alterations in sleep and prominent EDS46,47. There isalsoanoverlapinParkinson'sdiseaseandnarcolepsybecause of their shared association with REM sleepbehaviour disorder46. The presence of hallucinationsmay confuse patients and clinicians. Treatmentstrategiesfortheseneurologicdisordersmayoverlap,particularly with dopamine agonist medications,though such agents can also cause sleep attacks andworsensymptomsofParkinson'sdisease.

Treatment of Narcolepsy

As a definitive cause of narcolepsy has yet to be identified, treatment strategies must focus on relief of symptoms.WithEDSbeingthemostprevalentandthemost problematic issue for narcoleptics, most of thetreatments target this particular symptom8. Stimulantmedications have been the mainstay of therapy formanydecades4,13.Thesemedicationsprimarilyactbyincreasingmonoaminergicactivity.Thosemedicationsthat influence dopamine and norepinephrine have been themosteffectiveformanagingEDS,butdonottypicallyprovide reflief from cataplexy, though some patients do find that amphetamines can reduce this symptom as well.Thusamphetaminesandmethylphenidate,intheirvarious formulations, have been the most commonly

utilized pharmacotherapy. Both of these mediations are available in immediate release and longer actingformulations.Adderall isgivenindosesof10-60mgper day, with 60 mg being the maximum total dailydose.Methylphenidatecomesinnumerousbrandsanddosage formulations.The usual dosages are between10and60mgperday,thoughthiswilldependontheactualbrandandformulationchosen4,13.

Thesemedicationscanhaveprofoundsideeffects,andcanbeaddictive48,49.Becauseofthenoradrenergiceffects,amphetaminescancausehypertension.Patientswithhighbloodpressure,cardiacdisease,symptomatichyperthyroidism, and arteriosclerosis should useamphetamines with caution49. Both methylphenidateand amphetamines have been linked to significant substanceabuse,inpartthoughttobemediatedbytheirrolewithincreasingdopaminelevels.Insomepatients,stimulants canalsoproduceor exacerbate co-morbidpsychiatriccomplicationssuchasanxiety,mania,andeven psychosis. Because narcoleptic patients oftenhave insomnia, the time of day when stimulants aretaken must be monitored, so as not to produce evenmore sleep disturbance. Loss of appetite, sometimeswith weight loss, and motor tics are associated withstimulants.

Modafinil is approved by the United States Food and Drug Administration for the treatment ofexcessivesleepinessrelatedtonarcolepsy,obstructivesleep apnoea/hypopnoea syndrome, and shift worksleepdisorder50. Itsmechanismof action is not fullyunderstood, but it is believed to work through thedopaminergic, adrenergic, and histaminergic systemsinthehypothalamus13,51.Thisdifferenceledtoitbeingtermed a wakefulness promoting agent rather than astimulant. While it appears useful for the treatmentof EDS, it also seems to be beneficial for cataplexy13.The therapeutic range is 100 to 400 mg each day50.Dosing itmultiple timesperdaycan reduce residualEDScomparedtoasingledailydose52.Onedrawback,though, is compliance with the second daily dose,which may then hinder the true effectiveness ofthis medication. The most common side effects areheadache,drymouth,insomnia,nausea,andanxiety50,52.Some people also experience cardiovascular effectsincluding tachycardia, palpitations, or chest pain.There can be serious dermatologic reactions andhypersensitivityincludingStevens-Johnsonsyndromeand toxic epidermal necrolysis. Neurocognitivecomplaints include difficulty in concentrating, depression,andparesthesias.Whilenocausative link


hasbeenestablished,theliteraturerevealscasereportsof patients taking modafinil and experiencing suicidal ideation50,53. There are also reports linking modafinil to visual hallucinations in mania50. Modafinil is currentlynotscheduledasotherstimulantmedications.ComparedtoothermedicationsusefulforEDS,itdoesnotappeartohavethesamelevelofabusepotential.

Multiple studies have been conducted in whichmodafinil is compared to traditional stimulant medication,withmixed results4. In studies involvinga placebo, modafinil and stimulants were both superior intermsofreducingEDS.However,subjectsalreadyfamiliarwiththeeffectivenessofamphetaminesattimesrequested to be switched back to these medications,as they did not believe they were adequately treatedwith modafinil alone because of a subjective sense of sleepiness4.Additionally,somereported that theydidnothaveastrongsenseofcontrolovertheircataplexyandsleepparalysis.Asamphetaminesinteractwiththenorepinephrinesystemtheymayshowsomeadditionalbenefits for these symptoms. Studies that revealed no particular difference between stimulants and modafinil generally used longer washout periods, and subjectsreceived modafinil at its upper dosage limits4. Withtreatment, subjects reported improvements in qualityof life,mood, andahigher levelof satisfactionwithmodafinil compared to stimulants54(TableII).

Modafinil is not currently approved for treatment inchildren.However, it isprescribedtochildrenandappearstobeeffective55. In a small study of modafinil

in children ages 2-18 yr, it was associated withimprovements in academic performance and furthershowedimprovementinobjectivemeasuresonMSLT55.Thereissomeevidencethatitismosteffectivewhenused in divided doses, with one in the morning andanotherintheafternoon43.Careshouldbetakennottoadminister modafinil in such a way that would impair thechild'ssleep.

Another medication found to be effective forthe treatment of cateplexy and EDS is gamma-hydroxybutyric acid (GHB). It is produced forsale in the US as sodium oxybate, the salt form ofGHB43. Historically, GHB has been utilized for many differentconditionssuchasdepression,insomnia,andalcoholism56.IntheUnitedStates,itiscurrentlyonlyapproved to treatcataplexyandEDSassociatedwithnarcolepsyandistheonlymedicationapprovedbytheUSFDAforcataplexy57.ThepropertiesofGHBcanappear tobeparadoxical56.Becauseof its interactionwiththeGABAsystem,whichisinhibitory,itcanactas a sedative. However, in relative low doses it canstimulatedopaminerelease,andathigherdosesinhibitdopaminerelease,therebyresultinginbothinhibitoryandstimulatingcentralnervoussystemeffects.Italsoappearstopromoteglutamaterelease,furtherenhancingitsstimulatingproperties.

The effectiveness of sodium oxybate has beenestablishedinplacebocontrolledtrials4.Therearealsostudies inwhichsubjectshave takensodiumoxabateafter being on other available treatments for EDS58.In this comparative study of modafinil versus sodium oxybate,bothobjectiveandsubjectivemeasureswereassessed, utilizing the maintenance of wakefulness test and Epworth sleepiness scale, respectively.Findingsfromthestudyrevealedthatbothsubjectiveandobjectiveeffectsofsodiumoxalateweresuperiorcompared to treatment with modafinil58. The samestudy also found that modafinil did not separate from placebo,however.

GHB has been associated with significant abuse, dependence,andwithdrawal59.Streetusershavecalledit“liquidecstasy,”asitcanproduceeuphoriaandhasbeen utilized in the nightclub scene56.Ithasalsobeencalledadate rapedrug,beingassociatedwithsexualassault. It has been utilized by bodybuilders because of its ability to stimulate human growth hormone. ItiscontraindicatedforusewithotherCNSdepressants,and has synergistic effects with alcohol57. AbruptdiscontinuationofGHBcan result in life-threateningwithdrawal60. Because of its shared agonism with

Table II. Treatment - behavioural and pharmacological (forexcessivesleepinessandcataplexy)BehaviouralEnsuregoodsleephygiene(avoidsleepdeprivation)ConsideruseofstrategicnappingPharmacological: For excessive sleepinessMethylphenidateAmphetamineModafinilSelegiline(alsoanti-cataplectic)Pharmacological: For cataplexy Gamma-hydroxybutyricacid/sodiumoxybateProtriptylineDesipramineImipramineClomipramineVenlafaxineDuloxetineSelectiveserotoninreuptakeinhibitors


GABA, baclofen is very useful in the treatment ofGHB withdrawal61. Overdoses of GHB can resultin significant CNS sedation, respiratory depression, bradycardia, and seizures57.

As sodium oxybate, it can have importantcardiovasculareffectssecondarytowaterbalanceinthefaceof heightened sodium levels57.At themaximumrecommendedhumandoseof9g,itcontains1638mgof sodium.As such, patients who have heart failure,hypertension,orrenalimpairmentmayneedadditionalevaluationpriortostartingsodiumoxybate.Itundergoessignificant first pass metabolism in the liver, so patients withhepaticimpairmentshouldbestartedatone-halftheusualdosage.

Common side effects of sodium oxybate includeheadache, nausea, dizziness, nasopharyngitis, somnolence, vomiting, and urinary incontinence20,57.There are also reports of obstructive sleepapnoea worsening while taking sodium oxybate.Somnambulism, or sleep walking, occurred in 4 percentofthesubjectsintheclinicaltrialssubmittedforFDA approval57. However, in patients who had beenexposed to thedrugforup to16yr, the incidenceofsleep walking increased to 32 per cent57. Because ofthedangersinherentinsomnambulism,patientsmustbe cautioned regarding this potentially problematiceffect.

Selegiline is another agent used to reduce EDS4.Selegiline is an irreversible monoamine oxidaseinhibitor (MAOI) with selectivity for MAO-B13.As the dose increases, it can lose the selectivity andblockboththeAandBsubtypes.Ithaswakefulness-promotingpropertiesandcanalsoreducecataplexy,inpartthoughttobearesultofitsREMsleepsuppressingproperties. Selegiline has significant disadvantages though, as it requires a low tyramine diet and hasnumerousinteractionswithothermedications.Patientsshould be counselled regarding the numerous foodsandmedicationsthatarerestrictedwithongoingMAOIuse. Many medications, including antidepressantswhichmayhavebeenusedtocontrolcataplexy,needawashoutperiodpriortoinitiatinganMAOI.

While modafinil and stimulants are the mainstay of treatment for EDS, these are not often effectiveforcataplexy13.Incontrast,sodiumoxybateimprovesnocturnalsleep,relievesEDS,andhasanticataplecticproperties as well. Aside from sodium oxybate,antidepressants (TCAs) used for decades. The exactmechanism for this effect is not fully known, but

it is thought that the suppression of REM sleep isresponsible. Other REM related symptoms (sleepparalysis and hypnagogic hallucinations) areimproved with TCA usage. Routinely used TCAsinclude protriptyline, desipramine, and imipramine.Clomipramine causes the maximum serotonergicblockade, often resulting in substantial REMsuppression. The significant side effects of TCAs such as their cardiovascular effects, especially conductionchanges, may limit their use.Anticholinergic effectssuch as blurred vision, urinary retention, orthostatichypotension, constipation, dry mouth, and dizziness are commonaswell.Sexualsideeffectsoccurfrequently.In addition to the side effects,TCAs have importantwithdrawalcomplication,particularlyfornarcoleptics,inthatpatientsmayexperiencereboundcataplexy.Inrarecircumstances,thecataplexymayprogresstostatuscataplecticus,impairingfunctionforhoursordays.

With the effectiveness of TCAs in treatingcataplexy, it follows that other antidepressants mayprove useful as well13. Selective serotonin reuptakeinhibitors (SSRIs) have been shown to reducecataplexy,buttheliteraturebaseislimited.LikeTCAs,thesecansuppressREMsleep.Otherantidepressantsarealsoreportedtohaveeffectiveness.Venlafaxineandduloxetine, both serotonin- norepinephrine reuptakeinhibitors, have been used successfully62. However,venlafaxineusageislinkedtotoleranceandreturnofthe symptoms47. In a small sample, duloxetine wasnot found toproduce toleranceatoneyearof followup62. The advantage that newer antidepressants holdoverolderTCAsis in their lessersideeffects.Giventheusualageofonsetofnarcolepsy,itisimportanttoconsider the potential moods changes in adolescentsand young adults and the FDA warnings associatedwithantidepressantusageinthispopulation63.Sexualside effects, headaches, gastrointestinal changes, andsleep changes are common with these medications.Venlafaxineisassociatedwithsustainedhypertension.Also,therearenumerouspossibledrug-druginteractionswithmanyoftheantidepressants,particularlytheolderTCAsandMAOIs.

Given the possible immune mediated natureof narcolepsy, plasmapheresis and intravenousimmunoglobulinareinterestingpotentialoptions.Inasmallseries,cataplexywasreducedusingintravenousimmunoglobulins (IVIG)64. In follow up, however,therewasstillaneedfor treatmentofEDS65.Caninenarcolepsyhasrespondedtoimmunosuppresiveagentssuch as steroids, azothiaprine, and methotrexate when


administeredshortlyafterbirthandthedogsraisedina controlled environment66. It appeared effective forcataplexyandconsolidatedsleep.Afewhumancaseshavebeenreported inwhichsteroidshavebeenusedtotreatforotherconditionsandthenpatientsnoticedthat their narcolepsy symptoms also diminished67,68.TiprolisantisaninversehistamineH(3)-receptoragonistthat has been used in a small study of 22 subjects68.Itappears tohavewakefulnesspromotingproperties,affectingthenoradrenergicandhistaminergicsystems.Subjective sleepiness was reduced on the EpworthSleepinessScale(ESS)bynearlysixpointscomparedto one point with placebo. Hypocretin replacementtherapies are also being explored13,20.Administrationof hypocretin has not been efficacious so far because it doesnotcrossthebloodbrainbarrier.

Inadditiontothemedicationoptionsfortreatment,non-pharmacological approaches are important toprovideoptimalcareof thepatientwithnarcolepsy.The powerful sleep drive that results in the sleepattacks can be temporarily abated by taking naps.Nappingforseveralminutestoanhour,though,doesnot generally suit the demands of most schedulesand can seriously interfere with work or school.Nonetheless,napsmaybenecessaryforsomepatientsand arrangements should be made with employersand schools to accommodate a lunchtime nap andanother in the late afternoon. Good sleep hygieneis a powerful component of successful treatment,as sleep consolidation and insomnia are prominentproblemsinnarcolepsy.Patientsshouldbecounselledregarding the nature of the illness. Given the earlyonset and lifelong aspects, career counselling maybe needed as well. Positions that require significant vigilance or concentration for extended periods oftimemaybeunsuitableoptions.Shiftworkjobsandthose with call schedules may also be problematicfor narcoleptics. Driving restrictions are anotherimportant consideration. Because of the reboundcataplexy with discontinuation of medications,medication compliance becomes particularly vitalin order to prevent accidents. Worsening EDS isalso implicated in accidents and steps should betaken to promote wakefulness and reduce drivingwhile sleepy69. In trying to determine what level ofsleepinessistoosleepytodrive,multipleapproacheshave been taken, with conflicting results. In one large study, ESS predicted an increased risk of accidentswhen controlling for driver demographics, drivingdistance, weekly alcohol use, and the per cent of

nighttime driving69. In another study, however, ESSand neuropsychiatric evaluation did not predictaccidentswhencomparedtodrivingsimulations70.

Summary

Narcolepsy is classically a tetrad of symptomsincluding EDS, cataplexy, sleep paralysis, andhypnagogichallucinations.Theexactpathophysiologyis not yet known, but hypocretin deficiency appears to play a significant role, especially in cases with cataplexy. Narcolepsy is associated with several other sleepdisordersaswellasavarietyofmedicalandpsychiatricillnesses.Thesymptomsofnarcolepsycanoverlapwithmanyotherdisorders,attimesleadingtomisdiagnosisand inappropriate treatments. Diagnosis is made bytaking a careful history along with polysomnographyfollowed by an MSLT. While not definitive, having two periodsofSOREMsleepisusuallyacceptedasobjectiveevidence tomake thediagnosis.Stimulantshavebeentheprimary treatmentofEDSandantidepressants areuseful in the REM related aspects such as cataplexy.Attentiontosleephygieneandstrategicuseofdaytimenapsmayalsobehelpful.Newerpharmacologicoptionsare available that may have improved side effect profiles and/or greater efficacy in comparison to older treatments. Novelapproachesarebeingexploredtoprovidebetterresolutionofsymptoms.

References1. LongstrethWT,Jr.,koepsellTD,TonTG,HendricksonAF,

vanBelleG.Theepidemiologyofnarcolepsy.Sleep2007;30:13-26.

2. Tashiro T, kanbayashi T, Iijima S, Hishakawa Y. Anepidemiological study on prevalence of narcolepsy inJapanese.J Sleep Res1992; (Suppl1):228.

3. Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiologyofnarcolepsyinOlmstedCounty,Minnesota:apopulation-basedstudy.Sleep2002;25:197-202.

4. Wise MS, Arand DL, Auger RR, Brooks SN, Watson NF.Treatment of narcolepsy and other hypersomnias of centralorigin.Sleep2007;30:1712-27.

5. Mignot E, Hayduk R, Black J, Grumet FC, GuilleminaultC. HLA DQB1*0602 is associated with cataplexy in 509narcolepticpatients.Sleep 1997;20:1012-20.

6. Ohayon MM, Ferini-Strambi L, Plazzi G, Smirne S, Castronovo V. How age influences the expression of narcolepsy. J Psychosom Res2005;59:399-405.

7. Dauvilliers Y, Montplaisir J, Molinari N, Carlander B, Ondze B, BessetA, et al.Age at onset of narcolepsy in two largepopulations of patients in France and Quebec. Neurology 2001;57:2029-33.

8. Bourgin P, Zeitzer JM, Mignot E. CSF hypocretin-1 assessment insleepandneurologicaldisorders.Lancet Neurol2008;7:649-62.


9. PicchioniD,MignotEJ,HarshJR.Themonth-of-birthpatterninnarcolepsyismoderatedbycataplexyseverityandmaybeindependentofHLA-DQB1*0602.Sleep 2004;27:1471-5.

10. Mignot E. Genetic and familial aspects of narcolepsy.Neurology 1998;50(2Suppl1):S16-22.

11. MignotE,LammersGJ,RipleyB,OkunM,NevsimalovaS,OvereemS,et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and otherhypersomnias.Arch Neurol 2002;59:1553-62.

12. Krahn LE, Pankratz VS, Oliver L, Boeve BF, Silber MH. Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLADQB1*0602status.Sleep 2002;25:733-6.

13. Thorpy M. Therapeutic advances in narcolepsy. Sleep Med 2007;8:427-40.

14. Hungs M, Fan J, Lin L, Lin X, Maki RA, Mignot E.Identification and functional analysis of mutations in the hypocretin(orexin)genesofnarcolepticcanines.Genome Res 2001;11:531-9.

15. WillieJT,ChemelliRM,SintonCM,TokitaS,WilliamsSC,kisanukiY, et al. Distinct narcolepsy syndromes in Orexin Receptor-2andOrexinnullmicemoleculargeneticdissectionof Non-REM and REM sleep regulatory processes. Neuron2003;38:715-30.

16. PeyronC,FaracoJ,RogersW,RipleyB,OvereemS,CharnayY,et al.Amutation inacaseofearlyonsetnarcolepsyanda generalized absence of hypocretin peptides in human narcolepticbrains.Nat Med2000;6:991-7.

17. khatamiR,MaretS,WerthE,Rétey J,SchmidD,MalyF,et al. Monozygotic twins concordant for narcolepsy-cataplexy withoutanydetectableabnormalityinthehypocretin(orexin)pathway.Lancet2004;363:1199-200.

18. HongS,LinL,JeongJ,ShinY,HanJ,LeeJ,et al.Astudyof the diagnostic utility of HLA typing, CSF Hypocretin-1 measurements, and MSLT testing for the diagnosis ofnarcolepsyin163koreanpatientswithunexplainedexcessivedaytimesleepiness.Sleep2006;29:1429-38.

19. Stores G, Montegomery P, Wiggs L. The psychosocialproblemsofchildrenwithnarcolepsyandthosewithexcessivedaytimesleepinessofuncertainorigin.Pediatrics2006;114:198-204.

20. DauvilliersY,ArnulfI,MignotE.Narcolepsywithcataplexy.Lancet2007;369:499-511.

21. American Academy of Sleep Medicine. International classification of sleep disorders: Diagnostic and coding manual,2nded.Westchester,IL:AmericanAcademyofSleepMedicine;2005.

22. NishinoS.Clinicalandneurobiologicalaspectsofnarcolepsy.Sleep Med 2007;8:373-99.

23. National Institute of Neurological Disorders and Stroke.Narcolepsy Fact Sheet. National Institute of NeurologicalDisorders and Stroke 2008. Available at: http://www.ninds.nih.gov/disorders/narcolepsy/detail_narcolepsy.htm,accessedonAugust1,2008.

24. Benca R. Narcolepsy and excessive daytime sleepiness:Diagnosticconsiderations,epidemiology,andcomorbidities. J Clin Psychiatry2007;68(Suppl13):5-8.

25. Ervik S, Abdelnoor M, Heier MS, Ramberg M, Strand G.Health-relatedqualityoflifeinnarcolepsy.Acta Neurol Scand2006;114:198-204.

26. Plazzi G, Serra L, Ferri R. Nocturnal aspects of narcolepsy withcataplexy.Sleep Med Rev2008;12:109-28.

27. NishinoS,kanbayashiT.Symptomaticnarcolepsy,cataplexyandhypersomnia,andtheirimplicationsinthehypothalamichypocretin/orexinsystem.Sleep Med Rev2005;9:269-310.

28. Green PM, Stillman MJ. Narcolepsy. Signs, symptoms,differentialdiagnosis,andmanagement.Arch Fam Med 1998;7:472-8.

29. klugeM,SchüsslerP,DreslerM,YassouridisA,SteigerA.SleeponsetREMperiods inobsessivecompulsivedisorder.Psychiatry Res2007;152:29-35.

30. DiagnosticandStatisticalManualofMentalDisorders,FourthEdition,TextRevision.Arlington,VA:APA;2000.

31. JohnsMW.Anewmethodformeasuringdaytimesleepiness:theEpworthsleepinessscale.Sleep1991;14:540-5.

32. DauvilliersY,GosselinA,Paquet J,Touchon J,BilliardM,MontplaisirJ.EffectofageonMSLTresultsinpatientswithnarcolepsy-cataplexy.Neurology2004;62:46-50.

33. SinghM,DrakeC,RothT.Theprevalenceofmultiplesleep-onsetREMperiodsinapopulation-basedsample.Sleep2006;29:890-895.

34. LittnerMR,kushidaC,WiseM,DavilaD,MorganthalerT,Lee-ChiongT, et al. Practice parameters for clinical use ofmultiplesleeplatencytestandthemaintenancewakefulnesstest.Sleep2005;28:113-21.

35. BlackJ,BrooksS,NishinoS.Conditionsofprimaryexcessivedaytimesleepiness. Neurol Clin2005;23:1025-44.

36. Leibowitz S, Brooks S, Black J. Excessive daytime sleepiness: considerationsforthepsychiatrist.Psychiat Clin N Am2006;29:921-45.

37. MignotE,LinL,RogersW,HondaY,QiuX,LinX,et al.Complex HLA-DR and -DQ interactions confer risk ofnarcolepsy-cataplexyinthreeethnicgroups.Am J Hum Genet2001;68:686-99.

38. Riemann D. Insomnia and comorbid psychiatric disorders.Sleep Med 2007;8(Suppl4):S15-20.

39. Nofzinger EA, Thase ME, Reynolds CF, Himmelhoch JM, MallingerA,HoustP,et al.Hypersomniainbipolardepression:acomparisonwithnarcolepsyusingthemultiplesleeplatencytest.Am J Psychiat 1991;148:1177-81.

40. Dahmen N, kasten M, Mittag k, Müller MJ,. Narcolepticand schizophrenic hallucinations. Implications for differential diagnosisandpathophysiology.Eur J Health Econ.2002;3(Suppl2):S94-8.

41. Ha KS, Yoo HK, Lyoo IK, Jeong DU. Computerized assessment of cognitive impairment in narcoleptic patients.Acta Neurol Scand 2007;116:312-6.

42. Meltzer LJ, Mindell JA. Sleep and sleep disorders in children andadolescents.Psychiat Clin N Am2006;29:1059-76.

43. Peterson PC, Husain AM. Pediatric narcolepsy. Brain Dev2008;30:609-23.

44. Biederman J, Pliszka SR. Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in childrenandadolescents.J Pediatr2008;152:394-9.


45. MacleodS,FerrieC,ZuberiS.Symptomsof narcolepsy inchildrenmisinterpretedasepilepsy.Epileptic Disord2005;7 :13-7.

46. ArnulfI.Excessivedaytimesleepinessinparkinsonism.Sleep Med Rev2005;9:185-200.

47. LeeJH,BliwiseDL,AnsariFP,GoldsteinFC,CellarJS,LahJJ, et al. Daytime sleepiness and functional impairment inAlzheimer disease. Am J Geriatr Psychiatry2007;15:620-6.

48. Auger RR, Goodman SH, Silber MH, Krahn LE, Pankratz VS, SlocumbNL.Risksofhigh-dosestimulantsinthetreatmentofdisordersofexcessivesomnolence:acase-controlstudy.Sleep2005;28:667-72.

49. Shire US Inc., "Prescribing Information" sheet (PDF) forAdderall XR. Available at: http://www.adderallxr.com/,accessedonAugust1,2008.

50. Cephalon“PrescribingInformation”Sheet(PDF)forProvigil.Available at: https://www.provigil.com/hcp/default.aspx,accessedonAugust2,2008.

51. ScammellTE,EstabrookeIV,McCarthyMT,ChemelliRM,Yanagisawa M, Miller MS, et al. Hypothalamic arousalregions are activated during Modafinil-induced wakefulness. J Neurosci2000;20:8620-8.

52. Morganthaler TI, kapur Vk, Brown TM, Swick TJ,AlessiC,Aurora RN, et al. Practice parameters for the treatmentof narcolepsy and other hypersomnias of central origin:AnAmericanAcademy of Sleep Medicine Report. Sleep 2006;29:1415-9.

53. Dunlop BW, Crits-Christoph P, Evans DL, Hirschowitz J, SolvasonHB,Rickelsk,et al. Coadministration of modafinil andaselectiveserotoninreuptakeinhibitorfromtheinitiationof treatment of major depressive disorder with fatigue andsleepiness: a double-blind, placebo-controlled study. J Clin Psychopharmacol2007;27:614-9.

54. Becker PM, Schwartz JR, Feldman NT, Hughes RJ. Effect of Modafinil on fatigue, mood, and health-related quality of lifeinpatientswithnarcolepsy.Psychopharmacol2004;171:133-9.

55. Ivanenko A, Tauman R, Gozal D. Modafinil in the treatment ofexcessivedaytimesleepinessinchildren.Sleep Med2003;4:579-82.

56. Tunnicliff G. Sites of action of gamma-hydroxybutyrate(GHB) - a neuroactive drug with abuse potential. J Toxicol1997;35:581-91.

57. Jazz Pharmaceuticals. Prescribing Information Sheet (PDF) for Xyrem. Available at: http://www.xyrem.com/healthcare-

professionals/prescribing-information.php, accessed onAugust1,2008.

58. BlackJ,HoughtonWC.Sodiumoxybateimprovesexcessivedaytimesleepinessinnarcolepsy.Sleep2006;29:939-46.

59. ElliottS,BurgessV.Thepresenceofgamma-hydroxybutyricacid(GHB)andgamma-butyrolactone(GBL)inalcoholicandnon-alcoholicbeverages.Forensic Sci Int2005;16:289-92.

60. Wojtowicz JM, Yarema MC, Wax PM. Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone: a case report and systematic review. CJEM2008;10:69-75.

61. LeTourneauJL,HaggDS,SmithSM.Baclofenandgamma-hydroxybutyratewithdrawal.Neurocrit Care2008;8:430-3.

62. Izzi F, Placidi F, Marciani MG, Zannino S, Torelli F, Corte F, et al.Effectivetreatmentofnarcolepsy–cataplexywithduloxetine:Areportofthreecases.Sleep Med2009;10:153-4.

63. WyethPharmaceuticals.PrescribingInformationSheet(PDF)forEffexorXR.Availableat:http://www.wyeth.com/content/showlabeling.asp?id=100,accessedonAugust2,2008.

64. Dauvilliers Y, Carlander B, Rivier F, Touchon J, Tafti M.Successful management of cataplexy with intravenousimmunoglobulinsatnarcolepsyonset.Ann Neurol2004;56:905-8.

65. DauvilliersY.Follow-upof fournarcolepsypatients treatedwith intravenous immunoglobulins. Ann Neurol 2006; 60 :153.

66. Boehmer LN, Wu M-F, John J, Siegel JM. Treatment withimmunosuppressive and anti-inflammatory agents delays onset of canine genetic narcolepsy and reduces symptomseverity.Exp Neurol2004;188:292-9.

67. HechtM,LinL,kushidaCA,UmetsuDT,TaheriS,EinenM,et al.Reportofacaseofimmunosuppressionwithprednisonein an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy. Sleep2003;26:809-10.

68. LinJS,DauvilliersY,ArnulfI,BastujiH,AnacletC,ParmentierR, et al.An inverse agonist of the histamine H(3) receptorimproveswakefulnessinnarcolepsy:studiesinorexin-/-miceandpatients.Neurobiol Dis2008;30:74-83.

69. Powell NB, Schechtman kB, Riley RW, Guilleminault C,Chieng RP, Weaver EM. Sleepy driver near-misses maypredictaccidentrisks.Sleep2007;30:331-42.

70. kotterba S, Mueller N, Leidag M, Widdig W, Rasche k,MalinJP, et al.Comparisonofdrivingsimulatorperformanceand neuropsychological testing in narcolepsy. Clin Neurol Neurosurg2004;106:275-9.

Reprint requests:DrJeremyPeacock,DepartmentofPsychiatry,UniversityofWisconsin-Madison,USA e-mail:[email protected],[email protected]


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