ABSTRACT
Hypersomnia is a frequently encountered symptom in clinical practice. The cardinal
manifestation is inappropriate daytime sleepiness, common to all types of hypersomnias.
Hypersomnias of central origin are a rare cause of excessive daytime sleepiness, much
rarer than the hypersomnia related to other pathologies, such as sleep-disordered
breathing. Narcolepsy, with or without cataplexy, remains the most well studied of
the primary hypersomnias. Although recognized more than a century ago, it was not
until the end of the 20th century that major breakthroughs led to a better understanding
of the disease, with hope of more specific therapies. The authors review the major
aspects of this disorder, including the newer treatment modalities. Idiopathic hypersomnia
is also part of the primary hypersomnias. Although difficult to diagnose, certain
peculiarities stand out to help us differentiate it from the more commonly seen narcolepsy.
The recurrent hypersomnias, particularly the Kleine–Levin syndrome, will be discussed.
This rare disorder has been studied more closely in the last few years with abundant
epidemiologic data assembled through literature and worldwide case reviews. Understanding
the primary central hypersomnias warrants a thorough look from the original description,
as well as a peek at the future, while more efficacious diagnostic and therapeutic
interventions are currently being developed.
KEYWORDS
Primary hypersomnia - narcolepsy - cataplexy - idiopathic hypersomnia - Kleine–Levin
syndrome
REFERENCES
- 1
Schenck C H, Bassetti C L, Arnulf I, Mignot E.
English translations of the first clinical reports on narcolepsy and cataplexy by
Westphal and Gélineau in the late 19th century, with commentary.
J Clin Sleep Med.
2007;
3(3)
301-311
- 2
Adie W J.
Idiopathic narcolepsy: a disease sui generis; with remarks on the mechanism of sleep.
Brain.
1926;
49
257-306
- 3
Prinzmetal M, Bloomberg W.
The use of Benzedrine for the treatment of narcolepsy.
JAMA.
1935;
105
2051-2054
- 4
Billiard M, Besset A, Montplaisir J et al..
Modafinil: a double-blind multicentric study.
Sleep.
1994;
17(8, Suppl)
S107-S112
- 5
Akimoto H, Honda Y, Takahashi Y.
Pharmacotherapy in narcolepsy.
Dis Nerv Syst.
1960;
21
704-706
- 6
Broughton R, Mamelak M.
The treatment of narcolepsy-cataplexy with nocturnal gamma-hydroxybutyrate.
Can J Neurol Sci.
1979;
6(1)
1-6
- 7
U.S. Xyrem Multicenter Study Group .
A randomized, double blind, placebo-controlled multicenter trial comparing the effects
of three doses of orally administered sodium oxybate with placebo for the treatment
of narcolepsy.
Sleep.
2002;
25(1)
42-49
- 8
Juji T, Satake M, Honda Y, Doi Y.
HLA antigens in Japanese patients with narcolepsy. All the patients were DR2 positive.
Tissue Antigens.
1984;
24(5)
316-319
- 9
Mignot E, Lin X, Arrigoni J et al..
DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian
and Black Americans.
Sleep.
1994;
17(8, Suppl)
S60-S67
- 10
de Lecea L, Kilduff T S, Peyron C et al..
The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity.
Proc Natl Acad Sci U S A.
1998;
95(1)
322-327
- 11
Nishino S, Ripley B, Overeem S, Lammers G J, Mignot E.
Hypocretin (orexin) deficiency in human narcolepsy.
Lancet.
2000;
355(9197)
39-40
- 12
Peyron C, Faraco J, Rogers W et al..
A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin
peptides in human narcoleptic brains.
Nat Med.
2000;
6(9)
991-997
- 13
Thannickal T C, Moore R Y, Nienhuis R et al..
Reduced number of hypocretin neurons in human narcolepsy.
Neuron.
2000;
27(3)
469-474
- 14
Yoss R E, Daly D D.
Treatment of narcolepsy with ritalin.
Neurology.
1959;
9(3)
171-173
- 15
Vogel G.
Studies in psychophysiology of dreams. III. The dream of narcolepsy.
Arch Gen Psychiatry.
1960;
3
421-428
- 16
Xyrem approved for muscle problems in narcolepsy.
FDA Consum.
2002;
36(5)
7
- 17
Ohayon M M, Priest R G, Zulley J, Smirne S, Paiva T.
Prevalence of narcolepsy symptomatology and diagnosis in the European general population.
Neurology.
2002;
58(12)
1826-1833
- 18
Silber M H, Krahn L E, Olson E J, Pankratz V S.
The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study.
Sleep.
2002;
25(2)
197-202
- 19
Dauvilliers Y, Montplaisir J, Molinari N et al..
Age at onset of narcolepsy in two large populations of patients in France and Quebec.
Neurology.
2001;
57(11)
2029-2033
- 20
Mignot E.
Genetic and familial aspects of narcolepsy.
Neurology.
1998;
50(2, Suppl 1)
S16-S22
- 21 Guilleminault C, Dement WC, Passouant P Narcolepsy. New York; Spectrum Publications
1976
- 22
Dauvilliers Y, Billiard M, Montplaisir J.
Clinical aspects and pathophysiology of narcolepsy.
Clin Neurophysiol.
2003;
114(11)
2000-2017
- 23 Bassetti CL, Billiard M, Mignot E Narcolepsy and Hypersomnia. Lung Biology in Health
and Disease. Vol. 220. New York; Informa Healthcare 2007
- 24
Hishikawa Y, Shimizu T.
Physiology of REM sleep, cataplexy, and sleep paralysis.
Adv Neurol.
1995;
67
245-271
- 25
Takeuchi T, Miyasita A, Inugami M, Sasaki Y, Fukuda K.
Laboratory documented hallucination during sleep-onset REM period in a normal subject.
Percept Mot Skills.
1994;
78(3 Pt 1)
979-985
- 26
Szucs A, Janszky J, Holló A, Migléczi G, Halász P.
Misleading hallucinations in unrecognized narcolepsy.
Acta Psychiatr Scand.
2003;
108(4)
314-316, 316–317
- 27
Plazzi G, Serra L, Ferri R.
Nocturnal aspects of narcolepsy with cataplexy.
Sleep Med Rev.
2008;
12(2)
109-128
- 28
Sturzenegger C, Bassetti C L.
The clinical spectrum of narcolepsy with cataplexy: a reappraisal.
J Sleep Res.
2004;
13(4)
395-406
- 29
Aldrich M S.
Diagnostic aspects of narcolepsy.
Neurology.
1998;
50(2, Suppl 1)
S2-S7
- 30
Dauvilliers Y, Pennestri M H, Petit D, Dang-Vu T, Lavigne G, Montplaisir J.
Periodic leg movements during sleep and wakefulness in narcolepsy.
J Sleep Res.
2007;
16(3)
333-339
- 31
Nightingale S, Orgill J C, Ebrahim I O, de Lacy S F, Agrawal S, Williams A J.
The association between narcolepsy and REM behavior disorder (RBD).
Sleep Med.
2005;
6(3)
253-258
- 32
Dauvilliers Y, Rompré S, Gagnon J F, Vendette M, Petit D, Montplaisir J.
REM sleep characteristics in narcolepsy and REM sleep behavior disorder.
Sleep.
2007;
30(7)
844-849
- 33
Baker T L, Guilleminault C, Nino-Murcia G, Dement W C.
Comparative polysomnographic study of narcolepsy and idiopathic central nervous system
hypersomnia.
Sleep.
1986;
9(1 Pt 2)
232-242
- 34
Mignot E, Hayduk R, Black J, Grumet F C, Guilleminault C.
HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients.
Sleep.
1997;
20(11)
1012-1020
- 35
Nishino S.
The hypothalamic peptidergic system, hypocretin/orexin and vigilance control.
Neuropeptides.
2007;
41(3)
117-133
- 36
Guilleminault C, Gelb M.
Clinical aspects and features of cataplexy.
Adv Neurol.
1995;
67
65-77
- 37
Rubboli G, d'Orsi G, Zaniboni A et al..
A video-polygraphic analysis of the cataplectic attack.
Clin Neurophysiol.
2000;
111(Suppl 2)
S120-S128
- 38
Overeem S, Reijntjes R, Huyser W, Lammers G J, van Dijk J G.
Corticospinal excitability during laughter: implications for cataplexy and the comparison
with REM sleep atonia.
J Sleep Res.
2004;
13(3)
257-264
- 39
Overeem S, Lammers G J, van Dijk J G.
Cataplexy: ‘tonic immobility’ rather than ‘REM-sleep atonia’?.
Sleep Med.
2002;
3(6)
471-477
- 40
Johns M W.
A new method for measuring daytime sleepiness: the Epworth sleepiness scale.
Sleep.
1991;
14(6)
540-545
- 41
Richardson G S, Carskadon M A, Flagg W, Van den Hoed J, Dement W C, Mitler M M.
Excessive daytime sleepiness in man: multiple sleep latency measurement in narcoleptic
and control subjects.
Electroencephalogr Clin Neurophysiol.
1978;
45(5)
621-627
- 42
Littner M R, Kushida C, Wise M Standards of Practice Committee of the American Academy
of Sleep Medicine et al.
Practice parameters for clinical use of the multiple sleep latency test and the maintenance
of wakefulness test.
Sleep.
2005;
28(1)
113-121
- 43
Mignot E, Lammers G J, Ripley B et al..
The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy
and other hypersomnias.
Arch Neurol.
2002;
59(10)
1553-1562
- 44 American Sleep Disorders Association, Diagnostic Classification Steering Committee
.International Classification of Sleep Disorders: Diagnostic and Coding Manual, ICSD-R. Westchester,
IL; American Academy of Sleep Medicine 2005
- 45 U.S. Food and Drug Administration (FDA) .InfoSheets. 2005. Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/pemolineHCP.pdf Accessed September 20, 2008
- 46
Mitler M M, Hajdukovic R, Erman M K.
Treatment of narcolepsy with methamphetamine.
Sleep.
1993;
16(4)
306-317
- 47
Kuczenski R, Segal D S.
Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine:
comparison with amphetamine.
J Neurochem.
1997;
68(5)
2032-2037
, Erratum in: J Neurochem 1997;69(3):1332
- 48
Mitler M M, Shafor R, Hajdukovich R, Timms R M, Browman C P.
Treatment of narcolepsy: objective studies on methylphenidate, pemoline, and protriptyline.
Sleep.
1986;
9(1 Pt 2)
260-264
- 49
Wisor J P, Nishino S, Sora I, Uhl G H, Mignot E, Edgar D M.
Dopaminergic role in stimulant-induced wakefulness.
J Neurosci.
2001;
21(5)
1787-1794
- 50
Qu W M, Huang Z L, Xu X H, Matsumoto N, Urade Y.
Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil.
J Neurosci.
2008;
28(34)
8462-8469
- 51
Wisor J P, Eriksson K S.
Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil.
Neuroscience.
2005;
132(4)
1027-1034
- 52
Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy.
US Modafinil in Narcolepsy Multicenter Study Group.
Ann Neurol.
1998;
43(1)
88-97
- 53
Randomized trial of modafinil as a treatment for the excessive daytime somnolence
of narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group.
Neurology.
2000;
54(5)
1166-1175
- 54
Moldofsky H, Broughton R J, Hill J D.
A randomized trial of the long-term, continued efficacy and safety of modafinil in
narcolepsy.
Sleep Med.
2000;
1(2)
109-116
- 55
Xyrem International Study Group .
Further evidence supporting the use of sodium oxybate for the treatment of cataplexy:
a double-blind, placebo-controlled study in 228 patients.
Sleep Med.
2005;
6(5)
415-421
- 56
A 12-month, open-label, multicenter extension trial of orally administered sodium
oxybate for the treatment of narcolepsy.
Sleep.
2003;
26(1)
31-35
- 57
Black J, Houghton W C.
Sodium oxybate improves excessive daytime sleepiness in narcolepsy.
Sleep.
2006;
29(7)
939-946
- 58
Mamelak M, Black J, Montplaisir J, Ristanovic R.
A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness
in narcolepsy.
Sleep.
2004;
27(7)
1327-1334
- 59
Van Cauter E, Plat L, Scharf M B et al..
Simultaneous stimulation of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate
in normal young men.
J Clin Invest.
1997;
100(3)
745-753
- 60
Schmidt H S, Clark R W, Hyman P R.
Protriptyline: an effective agent in the treatment of the narcolepsy-cataplexy syndrome
and hypersomnia.
Am J Psychiatry.
1977;
134(2)
183-185
- 61
Schachter M, Parkes J D.
Fluvoxamine and clomipramine in the treatment of cataplexy.
J Neurol Neurosurg Psychiatry.
1980;
43(2)
171-174
- 62
Vignatelli L, D'Alessandro R, Candelise L.
Antidepressant drugs for narcolepsy.
Cochrane Database Syst Rev.
2008;
(1)
CD003724
- 63
Morgenthaler T I, Kapur V K, Brown T Standards of Practice Committee of the American
Academy of Sleep Medicine et al.
Practice parameters for the treatment of narcolepsy and other hypersomnias of central
origin.
Sleep.
2007;
30(12)
1705-1711
- 64
Harsh J R, Hayduk R, Rosenberg R et al..
The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness
associated with narcolepsy.
Curr Med Res Opin.
2006;
22(4)
761-774
- 65
Lin J S.
Brain structures and mechanisms involved in the control of cortical activation and
wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons.
Sleep Med Rev.
2000;
4(5)
471-503
- 66
Fujiki N, Yoshida Y, Ripley B, Mignot E, Nishino S.
Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated
narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient
narcoleptic dog.
Sleep.
2003;
26(8)
953-959
- 67
Hanson L R, Martinez P M, Taheri S et al..
Intranasal administration of hypocretin-1 (orexin A) bypasses the blood-brain barrier
and targets the brain:a new strategy for the treatment of narcolepsy.
Drug Delivery Technol.
2004;
4
66-71
- 68
Arias-Carrión O, Murillo-Rodriguez E, Xu M, Blanco-Centurion C, Drucker-Colín R, Shiromani P J.
Transplantation of hypocretin neurons into the pontine reticular formation: preliminary
results.
Sleep.
2004;
27(8)
1465-1470
- 69
Arias-Carrión O, Drucker-Colín R, Murillo-Rodríguez E.
Survival rates through time of hypocretin grafted neurons within their projection
site.
Neurosci Lett.
2006;
404(1-2)
93-97
- 70
Mieda M, Willie J T, Hara J, Sinton C M, Sakurai T, Yanagisawa M.
Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated
model of narcolepsy in mice.
Proc Natl Acad Sci U S A.
2004;
101(13)
4649-4654
- 71
Hecht M, Lin L, Kushida C A et al..
Report of a case of immunosuppression with prednisone in an 8-year-old boy with an
acute onset of hypocretin-deficiency narcolepsy.
Sleep.
2003;
26(7)
809-810
- 72
Chen W, Black J, Call P, Mignot E.
Late-onset narcolepsy presenting as rapidly progressing muscle weakness: response
to plasmapheresis.
Ann Neurol.
2005;
58(3)
489-490
- 73
Lecendreux M, Maret S, Bassetti C, Mouren M C, Tafti M.
Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy
in a 10-year-old boy.
J Sleep Res.
2003;
12(4)
347-348
- 74
Dauvilliers Y, Carlander B, Rivier F, Touchon J, Tafti M.
Successful management of cataplexy with intravenous immunoglobulins at narcolepsy
onset.
Ann Neurol.
2004;
56(6)
905-908
- 75
Zuberi S M, Mignot E, Ling L et al..
Variable response to intravenous immunoglobulin therapy in childhood narcolepsy.
J Sleep Res.
2004;
13(Suppl 1)
828
- 76
Fronczek R, Verschuuren J, Lammers G J.
Response to intravenous immunoglobulins and placebo in a patient with narcolepsy with
cataplexy.
J Neurol.
2007;
254(11)
1607-1608
- 77
Valko P O, Khatami R, Baumann C R, Bassetti C L.
No persistent effect of intravenous immunoglobulins in patients with narcolepsy with
cataplexy.
J Neurol.
2008;
255(12)
1900-1903
- 78
Fronczek R, Overeem S, Lammers G J, van Dijk J G, Van Someren E J.
Altered skin-temperature regulation in narcolepsy relates to sleep propensity.
Sleep.
2006;
29(11)
1444-1449
- 79
Fronczek R, Raymann R JEM, Romeijn N et al..
Manipulation of core body and skin temperature improves vigilance and maintenance
of wakefulness in narcolepsy.
Sleep.
2008;
31(2)
233-240
- 80
Roth B, Nevsimalova S, Rechtschaffen A.
Hypersomnia with “sleep drunkenness”.
Arch Gen Psychiatry.
1972;
26(5)
456-462
- 81
Aldrich M S.
The clinical spectrum of narcolepsy and idiopathic hypersomnia.
Neurology.
1996;
46(2)
393-401
- 82
Bassetti C, Aldrich M S.
Idiopathic hypersomnia. A series of 42 patients.
Brain.
1997;
120(Pt 8)
1423-1435
- 83
Billiard M, Dauvilliers Y.
Idiopathic hypersomnia.
Sleep Med Rev.
2001;
5(5)
349-358
- 84
Anderson K N, Pilsworth S, Sharples L D, Smith I E, Shneerson J M.
Idiopathic hypersomnia: a study of 77 cases.
Sleep.
2007;
30(10)
1274-1281
- 85
Heier M S, Evsiukova T, Vilming S, Gjerstad M D, Schrader H, Gautvik K.
CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia
in Norway.
Sleep.
2007;
30(8)
969-973
- 86
Bové A, Culebras A, Moore J T, Westlake R E.
Relationship between sleep spindles and hypersomnia.
Sleep.
1994;
17(5)
449-455
- 87
Sforza E, Gaudreau H, Petit D, Montplaisir J.
Homeostatic sleep regulation in patients with idiopathic hypersomnia.
Clin Neurophysiol.
2000;
111(2)
277-282
- 88
Nevsímalová S, Blazejová K, Illnerová H et al..
A contribution to pathophysiology of idiopathic hypersomnia.
Suppl Clin Neurophysiol.
2000;
53
366-370
- 89
Bruck D, Parkes J D.
A comparison of idiopathic hypersomnia and narcolepsy-cataplexy using self report
measures and sleep diary data.
J Neurol Neurosurg Psychiatry.
1996;
60(5)
576-578
- 90
Montplaisir J, Fantini L.
Idiopathic hypersomnia: a diagnostic dilemma. A commentary of “Idiopathic Hypersomnia”
(M. Billiard and Y. Dauvilliers).
Sleep Med Rev.
2001;
5(5)
361-362
- 91
Critchley M, Hoffman H.
The syndrome of periodic somnolence and morbid hunger (Kleine–Levin syndrome).
BMJ.
1942;
1
137-139
- 92
Arnulf I, Zeitzer J M, File J, Farber N, Mignot E.
KleineLevin syndrome: a systematic review of 186 cases in the literature.
Brain.
2005;
128(Pt 12)
2763-2776
- 93
Arnulf I, Lin L, Gadoth N et al..
Kleine-Levin syndrome: a systematic study of 108 patients.
Ann Neurol.
2008;
63(4)
482-493
- 94
Huang Y S, Lin Y H, Guilleminault C.
Polysomnography in KleineLevin syndrome.
Neurology.
2008;
70(10)
795-801
- 95
Gadoth N, Kesler A, Vainstein G, Peled R, Lavie P.
Clinical and polysomnographic characteristics of 34 patients with KleineLevin syndrome.
J Sleep Res.
2001;
10(4)
337-341
- 96
Dauvilliers Y, Mayer G, Lecendreux M et al..
Kleine-Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses.
Neurology.
2002;
59(11)
1739-1745
- 97
Huang Y S, Guilleminault C, Kao P F, Liu F Y.
SPECT findings in the Kleine-Levin syndrome.
Sleep.
2005;
28(8)
955-960
- 98
Podestá C, Ferreras M, Mozzi M, Bassetti C, Dauvilliers Y, Billiard M.
Kleine-Levin syndrome in a 14-year-old girl: CSF hypocretin-1 measurements.
Sleep Med.
2006;
7(8)
649-651
- 99
Carpenter S, Yassa R, Ochs R.
A pathologic basis for Kleine-Levin syndrome.
Arch Neurol.
1982;
39(1)
25-28
- 100
Koerber R K, Torkelson R, Haven G, Donaldson J, Cohen S M, Case M.
Increased cerebrospinal fluid 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in
Kleine-Levin syndrome.
Neurology.
1984;
34(12)
1597-1600
- 101
Muratori F, Bertini N, Masi G.
Efficacy of lithium treatment in Kleine-Levin syndrome.
Eur Psychiatry.
2002;
17(4)
232-233
- 102
Surges R, Walker M C.
A case of late-onset Kleine-Levin syndrome responding to lamotrigine.
Sleep Med.
2009;
10(3)
394
- 103
Crumley F E.
Valproic acid for Kleine-Levin syndrome.
J Am Acad Child Adolesc Psychiatry.
1997;
36(7)
868-869
- 104 Kryger MH, Roth T, Dement WC Principles and Practice of Sleep Medicine. 4th ed. Amsterdam;
Elsevier Available at: http://www.sleepmedtext.com/content/default.cfm Accessed November 12, 2008
Eric FrenetteM.D. F.R.C.P.(C)
University of Sherbrooke Medical Center
3001 12th Avenue North, Sherbrooke, QC, Canada J1H 5N4
Email: eric.california@gmail.com
