Characteristics of Narcolepsy in Preteenaged Children

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Characteristics

of Narcolepsy

in Preteenaged

Children

Suresh Kotagal, MD; Kristyna M. Hartse, PhD; and

James K. Walsh, PhD

From the Department of Neurology, Sleep Disorders Center, St Louis University Medical Center, and the Sleep Disorders Center, Deaconess Hospital, St Louis, Missouri

ABSTRACT. Narcolepsy is rarely diagnosed in

preteen-aged children. Its clinical and polysomnographic mani-festations, some of which are unusual, are described in four children who were observed prospectively. The mean age at onset of hypersomnia was 10.2 years (range 8.4 to 11.2 years). Daytime naps among these children were lengthy, ranging from 20 to 120 minutes, and generally were considered unrefreshing. Cataplexy was present at the onset in all four children. Three of the four children

were obese, with the concurrent nocturnal snoring

prompting a misleading concern about obstructive sleep apnea syndrome in two children. The histocompatibility DR2 antigen was present in all four children. Significant behavioral manifestations appeared in all of them. The response to stimulant medications was, at best, modest. Narcolepsy may be difficult to diagnose in this age group. However, a careful history eliciting sleep/wake dysfunc-tion (including cataplexy), leukocyte assays for the his-tocompatibility DR2 antigen, and serial polysomno-graphic studies may enable early recognition and treat-ment of this disease. Pediatrics 1990; 85:205-209; preteenaged children, narcolepsy.

Narcolepsy is a lifelong disorder characterized by

excessive daytime sleepiness, and abnormal

fea-tunes of rapid eye movement (REM) sleep such as

cataplexy, sleep paralysis, and hypnagogic

halluci-nations.”2 The onset of symptoms generally occurs

in the late second on third decade.3’4 Young et al3

and Guilleminault4 emphasized that narcolepsy is

rare in the prepubertal years, ie, through 1 1 years of age, but is commonly seen in the second decade.

The clinical and polysomnographic features of a

group of narcoleptic children less than 15 years of

age were only recently reported.3 Additionally, there

Received for publication Jan 30, 1989; accepted Apr 4, 1989. Reprint requests to (S.K.) Dept of Neurology, St Louis Univer-sity Medical Center, 3660 Vista Aye, St Louis, MO 63110. PEDIATRICS (ISSN 0031 4005). Copyright © 1990 by the

American Academy of Pediatrics.

are three single case reports in the litenature.57 In only one of these four studies was the clinical course

of narcolepsy prospectively documented in a child.7

The purpose of this report is to describe the clinical

and polysomnographic features of narcolepsy in

preteenaged children, with an emphasis on the

characteristic findings at this age and the steps one needs to take to establish an early, definitive

diag-nosis.

METHOD

Between 1982 and 1987, 4 of approximately 4000

new patients evaluated by the neurology service at

a pediatric tertiary cane institution were diagnosed

as having narcolepsy following investigation of a

chief complaint of excessive daytime sleepiness.

The diagnosis of narcolepsy was based on a history

of hypensomnia, cataplexy, and polygraphically

de-fined sleep-onset REM periods in daytime naps.”2

All subjects underwent leukocyte histocompatibil-ity antigen typing. After an interview in which the

history of excessive daytime sleepiness was

pro-vided by the patients and their families, all patients

underwent nocturnal polysomnography, followed

the next day by the multiple sleep latency test. The

multiple sleep latency test is a standard measure of

sleep tendency that consists of four or five daytime nap opportunities at 2-hour intervals with

polysom-nographic measurement of sleep/wake states.8

Pol-ygraphic data were scored in 30-second epochs with

standard criteria.9 Sleep latency was defined as the

time from commencement of the opportunity to

nap until the first epoch of sleep. Each nap attempt

was terminated after 15 minutes of sleep or 20

minutes of wakefulness if sleep did not occur.

Sleep-onset REM periods were defined as those with the

presence of REM sleep within 15 minutes of the

start of the nap opportunity.3 Three of the four

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polysom-nography and multiple sleep latency tests for the

definitive establishment of the diagnosis of

narco-lepsy.

CASE REPORTS

Patient 1

Patient 1, a 9-year-old boy, was evaluated for an 8-month history of taking naps both before and after noon, varying in frequency between two to three per day and in duration from between 30 and 45 minutes each. He began falling asleep while eating, reading, and riding on his father’s tractor. They were not followed by the

re-freshed feeling typically described by most adult narco-leptics. On some occasions when he laughed or became excited, his legs felt “weak” and he would partially col-lapse to the floor. There was no history of drug or alcohol abuse. He had undergone tonsillectomy and

adenoidec-tomy at age 7 years for nocturnal snoring and suspected upper airway obstruction, with resolution of the snoring. There was no history of sleep paralysis, hypnagogic hal-lucinations, head trauma, or central nervous system

in-fections. The family history was negative for narcolepsy. He was moderately obese, with a weight of 60.8 kg (>95th percentile). Neurologically, he appeared normal. Noctur-nal polysomnography (Table 1) and the multiple sleep

TABLE 1. Nocturnal P olysomn ographic Features*

Polysomnographic Feature

Patient No.

1 2 3 4

TRT 546.5 (579.5) (647.5)

445.0 611

(589)

603.5

TST 458.5 (547) (524.5)

365.0 559

(483.5) 567

Sleep latency 0 (3.0) (18.5)

0.5 5

(0.5) 0.5

LatencytoREM 0 (58) (154.0)

0.5 3.5

(220) 5.5 Sleep efficiency 83.8 (94) (81.0) (82.1)

TRT/TST 82 91.5 94

Stage 1 sleep (%) 27.3 (19.5) (19.7)

20.3 18.6

(30.1) 22.7

Stage 2 (%) 27.0 (37.4) (23.4)

37.9 30.1

(26.6) 31.8

Stage 3-4 (%) 22.5 (20.2) (23.8)

21.9 23.6

(14.5) 14.7

Stage REM (%) 23.3 (22.9) (16.5)

19.9 20.0 (11.1)

24.9

Periodic leg movements 0 (0) (15.0) (0)

in sleep (#{176}) 0 16.2 0

Respiratorydisturbance 4.36 (5.8) (2.6) (17.9)

index (apnea/hypop- 4.1 8.2 1.2

nea/h of sleep)

* Data from initial studies are in parentheses, whereas

those not included in parentheses are from the definitive

polysomnogram. Time intervals between the studies for

patients 2, 3, and 4 were 9, 12, and 3 months, respectively. Results are given as minutes unless indicated otherwise.

Abbreviations: TRT, total recording time; TST, total

sleep time; REM, rapid eye movement.

latency test (Table 2) were diagnostic for narcolepsy. Therapy with pemoline sodium was begun with a result-ant satisfactory decrease in daytime somnolence. At psy-chiatnic consultation obtained 1 year later for irritability and low frustration tolerance, the boy was found not to have dysphoric mood, appetite change, suicidal thoughts, or feelings of worthlessness suggestive of depression. A leukocyte histocompatibility study was found positive for

the DR2 antigen 2 years later. The hypersomnia

re-mained controlled with pemoline 112.5 mg/d.

Patient 2

Patient 2, a 12-year-old boy, was referred because of a 7 month history of morning and afternoon napping.

These 10 to 50-minute unrefreshing naps occurred one

to two times per day. The child fell asleep while reading books or being driven in a car. He had outbursts of anger for no obvious reason. Laughter or anger provoked

epi-sodes of weakness in the lower extremities without asso-ciated impairment in consciousness. Hypnagogic hallu-cinations were also present. There was no history of sleep paralysis, snoring, head trauma, or central nervous sys-tern infection. Birth, early development, and neurologic examination were normal. Because the initial polysom-nogram (Table 1) was suggestive of narcolepsy, the boy was given methylphenidate 10 mg twice a day for hyper-somnia and protniptyline 2.5 mg/d for treatment of ca-taplexy. To establish a definitive diagnosis of narcolepsy, sleep studies were repeated 10 months later following withdrawal of all medications. The time interval between withdrawal of medications and sleep studies was 2 weeks. The nocturnal polysomnogram and multiple sleep latency test results were once again consistent with the diagnosis

of narcolepsy (Tables 1 and 2). Three years after the

onset of symptoms, both the hypersomnia and cataplexy remain controlled with the same medications. The clini-cal course has been disturbed, however, by periods (last-ing days) of waxing and waning in the severity of daytime sleepiness, without associated changes in appetite or be-havior.

TABLE 2. Multiple Sleep Latency Test Findings*

No. of Sleep Onset Rapid Eye Movement Mean Sleep Latency (mm) Periods

Patient 1 4/4 9.1

Patient 2

Initial study 4/4 3.8

Repeated study 4/4 4.5

Patient 3

Patient 4

* The time intervals between first and repeated studies

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Patient 3

Patient 3, an 8-year, 8-month-old girl, was evaluated

for a 3-month history of falling asleep while riding as a passenger in a car, reading books, or talking. The naps

were 60 to 120 minutes in length and unrefreshing.

Whenever she laughed suddenly or became excited, she

fell to the floor or, if seated at a table, she collapsed, striking her head on the table. Consciousness was

pre-served during these episodes. Hypnagogic hallucinations and sleep paralysis were absent. The patient also snored

at night. She was moderately obese (weight 60 kg, above the 95th percentile). Results ofpolysomnography and the

multiple sleep latency test were suggestive of narcolepsy (Tables 1 and 2). Because of this child’s young age, particularly with the absence of sleep onset REM periods in daytime naps, a definite diagnosis of narcolepsy was not initially established. Also, mild sleep-related respi-ratory disturbance, which can potentially contribute to

daytime sleepiness, was present. Therefore, weight loss, a conservative approach to resolving this form of respi-ratory disturbance was recommended, but not achieved. The sleep studies were repeated 1 year later, and, at that time, a sleep-onset REM period was seen at night as well as during each of the four daytime naps (Tables 1 and 2). The mean sleep latency on the multiple sleep latency test had decreased to 0.4 minutes. A human leukocyte antigen

assay was positive for the DR2 antigen. As of 38 months after the onset of symptoms, gradual upward titration in

pemoline to the current 150 mg/d has led to a satisfactory control of the hypersomnia. However, the girl still takes

a nap when she returns from school every afternoon.

There are times when she becomes depressed and cries

for no obvious reason. Cataplectic attacks occur occasion-ally but are not severe enough to warrant drug therapy. Recently, the child began to have hypnagogic hallucina-tions.

Patient 4

Patient 4, an 11-year, 3-month-old boy was evaluated for a history of falling asleep while reading books or watching television. These unintentional, unrefreshing naps occurred one to two times per day and lasted be-tween 5 and 90 minutes each. He had also curtailed his physical activity and interaction with peers. He typically went to bed by 9 PM and did not have difficulty falling asleep. He snored at night and generally awoke by about 7 AM. His legs became weak when he laughed. On one occasion, he fell to the ground when his friends made him laugh. At other times, when he was emotionally upset, he had to lean against a supporting object for a few moments until his legs regained their strength. Con-sciousness was always preserved during these episodes.

He frequently had vivid, frightening dreams when he

went to sleep but no sleep paralysis. According to the parents he had been hyperactive since he was 4 years of

age. His tonsils were moderately enlarged. Neurologically, he was found to be normal. Nocturnal polysomnography performed 5 weeks after the onset of symptoms showed mild obstructive sleep apnea. Additionally, the multiple

sleep latency test demonstrated pathologic sleepiness and

presence of two sleep-onset REM periods (Table 1). Soon thereafter, the patient underwent tonsillectomy for relief of sleep apnea. However, the hypersomnia persisted un-changed despite effective treatment of sleep apnea as determined by sleep studies 3 months postoperatively. Pathologic sleepiness and sleep onset REM periods char-acteristic of narcolepsy were now unequivocal (Table 2).

Methylphenidate, 10 mg twice a day was started, with satisfactory control of the hypersomnia. According to

results of psychologic evaluation carried out 1 year later because of abnormal conduct at home and school, he was

found to be withdrawn and alienated.

DISCUSSION

The clinical features of the four children are

summarized in Tables 3 and 4, and

polysomno-graphic and multiple sleep latency data are given

in Tables 1 and 2, respectively. The mean age at

onset of hypensomnia was 10.2 years (range 8.4 to

11.2 years). The patients had been excessively

sleepy for a mean period of 9.5 months prior to

diagnosis (range 4 to 19 months).

The diagnosis of narcolepsy in these four patients

was based on the presence of excessive daytime

sleepiness, cataplexy, markedly reduced sleep

la-tency, and sleep onset REM periods in the multiple

sleep latency tests. However, the definitive

diag-nosis could be established in three of the four

patients only after repeated clinical and

polysom-nographic evaluation for a period of 3 to 12 months. The polygraphic features became especially obvious after repeated sleep studies in three patients.

Ca-taplexy was evident in all four subjects. The four

patients fell asleep readily during the nocturnal

sleep studies (Table 1). Although all four patients

eventually had sleep onset REM periods at night,

in patients 2, 3, and 4, these became apparent only after repeated studies.

The finding of disturbed nocturnal sleep and

reduced night sleep efficiency (mean 90.8%, range

83% to 94%, normal value 97% to ± 2%; increased

stage 1 percentage) is similar to that noted in adult

patients with narcolepsy. In patient 3, periodic leg

movements may have additionally contributed to

the sleep disruption.

According to the multiple sleep latency tests

(Table 2), there was marked daytime sleepiness in

all four patients, with mean sleep latencies ranging

from 0.4 to 9.1 minutes in the final multiple sleep

latency test. The age-matched normative value for

sleep latency is 19 minutes.7 Sleep onset REM

periods eventually developed in the multiple sleep

latency test of all four patients.

Among adults with narcolepsy,’#{176}2 the DR2

an-tigen was found in 82% to 100% of patients, as

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Age at Diagnosis of Symptoms (y)

Duration of Follow-up

HLA DR2 Antigen

(mo)

1 M 9 9.7 31 Present

2 F 11.5 12.0 36 Present

3 F 8.4 10.1 31 Present

4 M 11.2 11.6 54 Present

TABLE 3. Patient Characteristics

Patient Sex Age at Onset of

No. Symptoms (y)

TABLE 4. Clinical Features

Patient No.

Hypersomnia Cataplexy Hypnagogic Hallucinations

Sleep Paralysis

Obesity Nocturnal Snoring

Behavior

1 + + - - + + Depressed, feelings of

alienation

2 + + + - - - Outbursts of anger

3 + + + - + + Depressed, frequent crying

4 + + + - + - Withdrawn, “hyperactive” since age

4 y; conduct disorder

* Symbols: +, present; -, absent.

control subjects.” The association between

narco-lepsy and the DR2 antigen is further extended into

the pediatric age group by our study. Because

nan-colepsy is a familial disorder, through HLA DR2

studies, children of narcoleptics who are at risk of

narcolepsy developing may be identified at an

ear-lien age. The pathogenetic mechanisms underlying

the association between this antigen and narcolepsy remain uncertain.

Sleep apnea syndrome was a preliminary

diag-nostic consideration in patients 3 and 4. However

the associated features of cataplexy, hypnagogic

hallucinations, and the HLA DR2 antigen studies

were helpful in establishing the diagnosis of

nan-colepsy.

The duration of daytime naps was long, ranging

from 10 to 120 minutes. The unrefreshed feeling

when awakening described by these children may

be consequent to the relatively long naps and

pos-sible entry into slow wave sleep following initial

REM sleep in these prolonged naps. It is not

Un-usual for patients to complain of confusion,

diso-nientation, tiredness, and “sleep drunkedness”

when arousing from slow wave sleep.4

Carskadon and Dement’3 demonstrated that

non-mal adolescents tend to sleep less during school

nights than during nonschool nights. As a

conse-quence of this self-imposed sleep deprivation, they

may be sleepy in the daytime. Superimposition of

this additional factor can have a major impact on

cognitive, academic, and behavioral function of the adolescent narcoleptic. Significant behavioral

prob-lems were present in all four of the patients

de-scnibed and may have also been secondary to

frus-trations stemming from chronic sleepiness. In

net-rospect, obesity in these sleepy children could also

have been related to their sedentary habits.

The decrease in daytime sleepiness following

treatment with stimulants (pemoline 75 to 150 mg

or methylphenidate 30 to 60 mg) was satisfactory, but not striking. Lack of a better response to

stim-ulants may have been related to the development

of tolerance, a phenomenon that has been observed in adults with narcolepsy.’4 Whether drug holidays

will have a salutory effect on responsiveness to

stimulants still needs to be determined.

The onset of cataplexy was closely related to the

development of excessive daytime sleepiness in all

four patients. In narcolepsy of adult onset,

cata-plexy has been reported to develop 5 to 10 years

later than somnolence.2 Our findings in this regard are similar to those described by Young et al.3

IMPLICATIONS

Cataplexy is an early clinical manifestation of

childhood narcolepsy. Careful attention should

therefore be paid toward eliciting its presence in

children with excessive daytime sleepiness. HLA

DR2 antigen assays and serial polysomnographic

studies for a period of months may be necessary to

establish a definite diagnosis. The management

should address the hypersomnia and cataplexy as

well as behavioral problems.

REFERENCES

1. Zarcone V. Narcolepsy. N EngI J Med. 1973;288:1156-1166 2. Kales A, Cardieux RJ, Soldatos CR, et al.

Narcolepsy-cataplexy, I. Clinical and electrophysiological

characteris-tics. Arch Neurol. 1982;39:164-168

3. Young D, Zorick F, Wittig R, et al: Narcolepsy in a pediatric population. Am J Dis Child. 1988;142:210-213

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1987:181-194

5. Wittig R, Zorick F, Roehrs T, et al. Narcolepsy in a

7-year-old child. J Pediatr. 1983;102:725-727

6. Chisolm RC, Brook CJ, Harrison GF, et al. Prepubescent

narcolepsy in a 6-year-old child. Sleep Res. 1985;15:113 7. Carskadon MA, Harvey K, Dement WC. Multiple sleep

latency tests in the development of narcolepsy. West J Med. 1981;135:414-418

8. Carskadon MA, Dement WC, Mitler MM, et al. Guidelines for the multiple sleep latency test (MSLT): A standard measure of sleepiness. Sleep. 1986;9:519-524

9. Rechtschaffen A, Kales A, eds. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Los Angeles, CA: UCLA Brain

Information Service/Brain Research Institute; 1968

10. Mitler MM, Shafor R, Sobers M, et al. Human leukocyte

antigen (HLA) studies in excessive daytime somnolence: narcolepsy versus sleep apnea. Sleep Res. 1986;15:148

11. Billiard M, Seignalet J, Besset A, Cadilhac J. HLA-DR2 and

narcolepsy. Sleep. 1986;9:49-152

12. Langdon N, Welsh KI, Van Dam M, et al. Genetic markers in narcolepsy. Lancet. 1984;2:1178-1180

13. Carskadon MA, Dement WC. Sleepiness in the normal

adolescent. In: Guilleminault C, ed. Sleep and Its Disorders. New York, NY: Raven Press;1987:53-66

14. Mitler MM, Nelson 5, Hajdukovic R. Narcolepsy. Diagnosis,

treatment, and management. Psychiatr Clin North Am. 1987;10:593-606

NOT TAKING TABLETS

Compliance with treatment, for many reasons, is often rather worse than

doctors like to think-even for life-threatening illnesses such as epilepsy, where

the importance of treatment is well known to the patient and for which pill

counts and blood anticonvulsant levels may be used to double-check the history.

A novel way to monitor compliance with treatment is described by Cramer et

al,’ who studied newly treated and long-term patients on anticonvulsants. They

used Medication Event Monitor Systems (Aprex, Fremont,

California)-stand-and pill bottles which have a microprocessor in the lid that records whenever

the bottle is opened. With every opening counted as a dose taken, compliance

with treatment averaged 76% oven 3428 patient-days of observation-or 87%

for once daily treatment, 81% for twice daily, and 77% for three times daily,

but a mere 39% for doses four times a day. If compliance with treatment is poor

in epileptic patients (who are only too aware of the importance of remaining

fit-free to be able to drive), what is it like in others?

REFERENCES

1.

Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellete VL. How often is medication taken

as prescribed? A novel assessment technique. JAMA. 1989;261:3273-3277

From Not taking the tablets. Lancet. 1989;2:118

Noted by J.F.L., MD

THOUGHT FOR THE FIN DE SIECLE

What pledge can be afforded that the boasted remedies of the present day

will not, like their predecessors, fall into disrepute and in their turn serve only

as a humiliating memorial of the credulity and infatuation of the physicians

who recommended and prescribed them?

From Paris Pharmacologia of 100 Years Ago. Quoted by: Shapiro AK. A contribution to a history of the placebo effect. Beh Sci. 1960;4:111-135

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1990;85;205

Pediatrics

Suresh Kotagal, Kristyna M. Hartse and James K. Walsh