소아 기면증의 진단과 치료

Vol. 17, No. 2, November, 2009 □ 종 설 □

1)

서 론

,

, (hypnagogic) (hypnapompic) ,

: 2009 10 20 , : 2009 10 28

: , CHA

Tel : 031)780-5229, Fax : 031)780-5239 Email : barnabas@cha.ac.kr

. (excessive daytime sleepiness)

,

.

. 2 (International Clas-

소아 기면증의 진단과 치료

, CHA ^*

방 양 원 채 규 영*․

= Abstract =

Pediatric Narcolepsy - Diagnosis and Treatment

Yang Weon Bang, M.D. and Kyu Young Chae, M.D., Ph.D.

Division of Child and Adolescent Psychiatry, Department of Psychiatry, Keyo Hospital Division of Pediatric Neurology, Department of Pediatrics, CHA University

Narcolepsy is chronic devastating disease that characterized by excessive daytime slee- piness, cataplexy, which often precipitated by intense emotion or excitement, hypnagogic, or hypnapompic hallucinations, sleep paralysis and nocturnal disrupted sleep. In child onset narcolepsy, the presentations of narcolepsy can be very variable, making misdiagnosis as seizure disorders or delaying diagnosis as much as several years after disease onset. For the diagnosis of narcolepsy, overnight polysomnography(PSG) and multiple sleep latency test(MSLT) should be evaluated. Test for Cerebrospinal fluid hypocretin(orexin) concentra- tion and human leukocyte antigens(HLA) would be great helpful to confirm the narcolepsy with cataplexy even in early stage of disease in children. The mainstays of treatment are that reducing the excessive daytime sleepiness, preventing the intrusion of the REM related phenomena including cataplexy and consolidating the nighttime sleep. Central nervous sys- tem stimulators such as methylphenidate or amphetamine decrease excessive daytime slee- piness and tricyclic antidepressant(TCA) or selective serotonin reuptake inhibitors(SSRI) can prevent cataplexy. Recently, new therapeutic agents such as modafinil and sodium oxybate are emerging in clinical practice with much effectiveness. Counseling for poor school performance, social isolation and depression should be provided. Early diagnosis and treatment can greatly improve the quality of life. Awareness of excessive daytime sleepi- ness in children or adolescent will allow pediatricians to effectively identify hypersomnia such as narcolepsy.

Key Words : Narcolepsy, Diagnosis, Treatment, Children, Adolescents

sification of Sleep Disorder, ICSD-2)

1) , 2)

, 3)

4)

.

.

본 론

기면증의 임상적인 특징 1.

과다 졸음증

1) (Excessive sleepiness)

2)

.

.

.

, 10-30

.

. 5 ,

. 탈력발작

2) (Cataplexy)

3)

. ,

.

.

.

. . (status cataplec-

ticus) .

10-20%

4)

. 5

(atonic seizure)

5, 6)

.

, . 수면마비

3) (Sleep paralysis)

.

. 40-80%

7)

.

.

4) 입면 출면시 / 환각(Hypnagogic/hypnapo mpic hallucination)

40-80%

.

(cenesthopathic feeling)

4)

.

. 기타 증상

5)

(sleep frag-

mentation)

.

.

(ex- cessive twitching),

9)

.

(REM sleep behavior disorder,

RBD)

.

,

10-12)

. 유병률

6)

.

0.05%, 0.18%

0.02%

.

1/4 .

0.04%

14)

.

. 10

20 30 10

(Fig. 1)

. 14.7 35

, 23.5 24.5

. 원 인

7)

1990 hypocretin(orexin)

18)

4)

. Hypocretin

19)

. Hypocretin hypocretin-1 hypo-

cretin-2 pre-

prohypocretin

.

(dorsolateral

hypothalamus) (locus coeru-

leus), (dorsal raphe), (amygdale), (basal forebrain), (suprachias-

Fig. 1. Age of onset of sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis in 469, 438, 210 and 189 patients, respectively. The number of subjects with onset at each age range is plotted. Note that sleepiness onset is generally earlier than the other symptoms(Cited from Okun ML, Sleep 2002).

matic nucleus), (cholinergic brain- stem nuclei)

21)

. Hypocretin

serotonin, histamine, acetylcholine, dopamine, GABA(gamma-aminobutyric acid)

(glutamate)

22, 23)

. Hypocretin

/ hypo-

cretin-2

hypocretin

24, 25)

. 2001

hy-

pocretin-1

hypocretin- 1 110 pg/mL

27)

.

200 pg/mL (Fig.

2)

.

(sleep-onset REM periods, SOREMPs)

26)

. hypocretin-1 88.5%, 99.1%

.

(idiopathic hypersomnolence), Klein-Levin

28)

. Hypocretin-1

27)

. Hypocretin

(Fig.

3)

,

Fig. 2. Cerebrospinal fluid(CSF) hypocretin-1(Hcrt-1) concentrations are plot- ted for individuals across various control and sleep disorders. Each point represents the crude concentration of Hcrt-1 in a single person. The cutoffs for normal(>200 pg/mL) and low(<110 pg/mL) Hcrt-1 concentrations are shown. The median value in each group is shown as a

horizontal bar

31)

hy- pocretin

32)

.

(human leukocyte antigen: HLA)

, HLA

DQB1*0602

. 40%

24%

33)

. HLA DQB1*0602 Hcrt-1

.

.

10-40

34)

. 25-31%

35)

. 진 단

8)

, (fragmented sleep), .

, (circadian rhythm sleep disor-

ders), .

(sleep-onset association disorders),

( ,

), (parasomnia),

( , ),

.

,

. 6

10 2

4-5 (multiple

sleep latency test, MSLT)

. 15

(Fig. 4).

60-90 .

15-20 8

36)

.

8

(Table 1). 5

70%, 97%

.

36, 38)

.

hypocretin-1 HLA

. DQB1*

0602 76-90

% DQB1*0602

hypocretin-1 110 pg/mL

(Fig. 5)

.

(in situ hybridization) in a narcoleptic human brain hypothalamus (A) contrasted with control (B). Each dot in the control represents a hypo- cretin-producing cell. Note that most of these cells are located close to the fornix area, a white matter tract (f). The dramatic loss of the hypo- cretin signal is evident in the narcoleptic brain (Cited from Peyron C, brains. Nat Med 2000).

1/5-1/3 . 6

1/4 (status cataplecticus)

39)

.

(Prader Willi , Niemann Pick C , Myotonic dystrophy type I, Norrie ,

Coffin-Lowry ), ( ,

),

40)

.

.

.

Kleine-

Levin

.

50%

42)

.

. Klein-Levin

, ,

41)

. 치 료

2.

비약물 치료 1)

. ,

. ,

.

4-5 15

.

,

, .

.

43)

. 2) 약물치료

Fig. 4. Example of a multiple sleep latency test in narcolepsy. At the 10 a.m., 2 p.m., and 4 p.m.

sleep opportunities, the patient had a period of REM sleep(thick line) near sleep onset(SOREM).

Mean sleep latency is 8 min(Cited from Wilson S: Narcolepsy. In: Sleep Disorders. 2008).

Table 1. Diagnostic Criteria for Narcolepsy by the International Classification of Sleep Disorders Narcolepsy with cataplexy

Excessive daytime sleepiness almost daily for at least 3 months Definite history of cataplexy

Diagnosis should be confirmed, whenever possible, by one of the following:

PSG and MSLT; mean sleep latency should be ≤8 minutes and at least 2 SOREMPS CSF hypocretin level ≤110 pg/mL or 1/3 of mean normal controls

Hypersomnia is not better explained by another disorder or medication Narcolepsy without cataplexy

Excessive daytime sleepiness almost daily for at least 3 months Definite cataplexy is not present

Diagnosis must be confirmed by one of the PSG and MSLT; mean sleep latency should be≤8 minutes and at least 2 SOREMPS

Hypersomnia is not better explained by another disorder or medication Secondary narcolepsy (narcolepsy due to medical condition)

Excessive daytime sleepiness almost daily for at least 3 months One of the following is present:

Definite history of cataplexy

If cataplexy is not present, diagnosis must be confirmed by PSG and MSLT; mean sleep latency should be ≤8 minutes and at least 2 SOREMPS

CSF hypocretin level ≤110 pg/mL

Underlying medical or neurological condition accounts for the sleepiness Hypersomnia is not better explained by another disorder or medication

Cited from American Academy of Sleep Medicine, international classification of sleep disorders, 2^nded.:

diagnostic and coding manual. 2005

Fig. 5. Diagnostic flow chart for clinical evaluation of hypersomnia.

.

, , ,

,

.

, . . methylphenidate amphe- tamine

. Ampheta- mine

methylpheni-

date . Methylphenidate

5 mg

5-10 mg 60 mg

. 25 kg

45 mg

.

, , ,

, .

Modafinil

45)

. Modafinil

(mo-

noamine) (amygdale)

histamine

. 100

mg 100-200 mg

(200-400 mg/day) .

2

. , ,

. Stevens-Johnson .

.

(Tricyclic antidepressant)

. norepine-

phrine serotonin

. Clomipramine

. 25 mg

200 mg 3 mg/kg

. desipramine, imi- pramine, protryptylin

.

, , , ,

, ,

5)

.

(selective serotonin reuptake in- hibitor)

. Fluoxetine

10 mg 20 mg

. , , ,

, . Venlafaxine serotonin norepinephrine

. 37.5 mg

75-300 mg

. atomoxetine

47)

. modafinil

serotonin

9)

. Sodium oxybate 16

GABA(gamma-aminobutyric

acid) B .

.

. seroto-

nin, dopamine, opioid

48)

. 0.5-1 2.5-4

. 4.5 g

6-9 g .

49)

.

.

50)

.

결 론

, ,

,

. 15

. 10

. ,

. 90%

HLA DQB1 0602 hypocretin

(Hypocretin-1) 110 pg/mL .

.

.

.

.

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