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Childhood-onset restless legs syndrome.

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Childhood-Onset Restless Legs Syndrome
Suresh Kotagal, MD,1–3 and Michael H. Silber, MD2,3
The clinical characteristics of childhood-onset restless legs syndrome are described. Thirty-two of 538 subjects (5.9%)
examined in our sleep disorders center received diagnoses of restless legs syndrome. They were classified based on
published criteria into probable (n ⴝ 9/32 or 28%) and definite (n ⴝ 23/32 or 78%) categories. Apart from an earlier
age of diagnosis of the probable group, no differences were found between the two categories. Sleep onset or sleep
maintenance insomnia was the most common symptoms, being present in 28 of 32 subjects (87.5%). Inattentiveness was
seen in 8 of 32 subjects (25%). Serum ferritin levels were measured in 24 of 32 subjects and were below 50␮g/L in 20
of 24 subjects (83%). A family history of restless legs syndrome was present in 23 of 32 (72%) subjects, with mothers
almost three times more likely to be affected than fathers (p ⴝ 0.02). We conclude that iron deficiency and a strong
family history are characteristic of childhood-onset restless legs syndrome.
Ann Neurol 2004;56:803– 807
Restless legs syndrome (RLS) is a sensorimotor disorder
characterized by an irresistible urge to move the limbs
predominantly in the evening or at night. This is usually accompanied by a peculiar discomfort in the lower
extremities often alluded to as a “creepy” or “crawly”
feeling. Insomnia and daytime fatigue result.1,2 Between 38 to 45% of adult RLS subjects have onset of
symptoms before age 20 years.3,4 Low tissue iron and
central nervous system deficiency of dopamine may be
involved in the pathogenesis of RLS.5 Nocturnal polysomnography may show periodic limb movement disorder (PLMD) which is defined as a series of four or
more limb electromyographic discharges of 0.5- to
5-second duration, that are separated by intervals of 4
to 90 seconds.6,7 PLMD has been documented in diverse populations of children, including those with leukemia,8 fibromyalgia,9 and attention deficit hyperactivity disorder.10
The recognition of RLS in childhood is not new; in
1832, Duchamp11 observed that children may suffer
aches and pains around puberty and labeled this symptom as “growing pains.” Walters and colleagues12,13
and Ekbom14 have pointed out the heterogeneous nature of “growing pains,” but that a subset of children
with growing pains indeed might have RLS. Owing to
the subjective nature of the sleep complaints, RLS may
be difficult to accurately diagnose in young or nonverbal children. Clinical and epidemiological research into
childhood RLS therefore has been limited. The recog-
nition of childhood RLS has been facilitated by the
recently published diagnostic criteria1 (Table 1).
In 1994, Walters and colleagues reported the occurrence of RLS in a mother and her three children and in
an unrelated 16-year-old boy,13 but a larger series of
children utilizing the most recently established diagnostic criteria1 is lacking. Although an association between
childhood-onset PLMD, RLS, and attention deficit hyperactivity disorder was described in special populations of children by Picchietti and colleagues10 and
Chervin and colleagues,15 the clinical features need to
be studied in a broad, less-selected population of children. We report the clinical features of RLS in children
and adolescents who presented to our pediatric sleep
disorders program with sleep-wake complaints. The
newly established diagnostic criteria1 were applied retrospectively to a group of provisionally diagnosed RLS
subjects.
From the 1Division of Child and Adolescent Neurology, 2Department of Neurology, and the 3Sleep Disorders Center, Mayo Clinic,
Rochester, MN.
Address correspondence to Dr Kotagal, Division of Child Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
E-mail: kotagal.suresh@mayo.edu
Patients and Methods
The records of all children with sleep-wake complaints evaluated in our pediatric sleep disorders program between January 2000 and March 2004 were reviewed for RLS after approval of the study by the institutional review board. Of a
total of 538 patients below the age of 18 years, 62 had been
diagnosed as having RLS. All 538 had undergone formal
sleep consultation. A review of the medical records of the 62
subjects yielded 32 subjects (12 male and 20 female subjects,
5.9% of the total population of 538) that met the strict,
Received May 17, 2004, and in revised form Aug 11. Accepted for
publication Aug 11, 2004.
Published online Oct 25, 2004, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20292
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
803
Table 1. Diagnostic Criteria for Adult and Childhood Restless
Legs Syndrome
Essential diagnostic criteria (adults)
1. An urge to move the legs, usually accompanied or
caused by uncomfortable and unpleasant sensations in
the legs
2. The urge to move or unpleasant sensations begin or
worsen during periods of rest or inactivity such as
lying down or sitting
3. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking
or stretching, at least as long as the activity continues
4. The urge to move or unpleasant sensations are worse
in the evening or night than during the day, or only
occur during the evening or night
Definite childhood restless legs syndrome (RLS)
1. The child meets all four essential adult criteria, and
2. The child relates a description in his or her own
words that is consistent with leg discomfort
OR
1. The child meets all four essential adult criteria and
has two of three following
a. sleep disturbance for age
b. biological parent or sibling with definite RLS
c. polysomnographically documented periodic limb
movement index of five or more per hour of sleep
Probable childhood RLS
1. The child meets all four essential adult criteria for
RLS except criterion 4 (the urge to move or sensations are worse in the evening or at night than during
the day), and
2. The child has a biological parent or sibling with definite RLS
OR
1. The child is observed to have behavioral manifestations of lower extremity discomfort when sitting or
lying, accompanied by motor movement of the affected limbs; the discomfort has characteristics of
adult criteria 2, 3, and 4, and
2. The child has a biological parent or sibling with definite RLS
Adapted from: Allen RP, Pichhietti D, Hening WA, et al. Restless
legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep
Medicine 2003;4:101–119.
recently established diagnostic criteria1 for RLS. The 32 subjects were further subdivided based on clinical features, family history, and the diagnostic guidelines1 into definite (n ⫽
23) and probable (n ⫽ 9) RLS groups (see Table 1). The
revised classification1 recommends that definite RLS and
probable RLS criteria be used for children up to the age of 12
years, beyond which the standard adult criteria apply. The
classification, however, also recognizes that “in some cases
this age limit may need modification to meet the clinical
situation.” Accordingly, for simplification, we applied the
definite and probable RLS criteria to our entire patient population of children and adolescents up to the age of 18 years.
Thirty of the 62 subjects were excluded because of insufficient history (n ⫽ 14), an alternate final sleep diagnosis
(n ⫽ 9), alternate systemic diagnosis such as peripheral neuropathy/dermatomyositis/fibromyalgia (n ⫽ 4), lack of in-
804
Annals of Neurology
Vol 56
No 6
December 2004
formed consent for clinical research (n ⫽ 2), and use of a
selective serotonin reuptake inhibitor that is known to exacerbate RLS (n ⫽ 1). The following information was compiled on the remaining 32 subjects: age of onset of symptoms, age at diagnosis of RLS, presenting symptoms, family
history of RLS in first-degree relatives, sex of affected relative, serum ferritin levels, and complete blood count. Serum
ferritin levels were compared with published population
norms for age and sex.16,17 The percentage of subjects with a
serum ferritin level below 50␮g/L also was calculated because
of its association with increased severity of RLS.5
Because RLS is a clinical diagnosis that does not routinely
require nocturnal polysomnography, sleep studies were obtained only for those subjects who were suspected to have
comorbidities such as parasomnia, nocturnal seizures, or
sleep-disordered breathing. Information about the periodic
limb movement index (PLMI) on the nocturnal polysomnogram was recorded. Medications used to treat RLS
(pramipexole, carbidopa–L-dopa, clonazepam, gabapentin, or
oral iron) were recorded, and the response to therapy was
determined from chart review or contact with the families.
This follow-up information was available for 22 of 32 subjects (68%), with an average duration of follow-up of 12.3
months (range, 1– 44).
Statistical Analysis
Medians were used rather than means as measures of central
tendency when the variables were not normally distributed.
Age of onset of symptoms in the probable and definite RLS
groups was compared using a two-sample t test. A comparison of the PLM index between the two groups was made
using the Wilcoxon rank-sum test. Serum ferritin levels between groups were compared using the Wilcoxon rank-sum
test. Correlation between the serum ferritin levels for both
groups combined and periodic limb movement index for
both groups combined was made using the Spearman rank
correlation coefficient. The ␹2 test was used to determine if
the ratio of maternal: paternal transmission was significantly
unequal.
Results
Thirty-two of 538 subjects examined (5.9%) had restless legs syndrome, with 9 of 32 (28%) being in the
probable category and 23 of 32 (78%) in the definite
category. Demographics, family history, periodic limb
movement index, serum ferritin levels, and treatment
prescribed for the two groups are summarized in Table
2. The mean age of onset of symptoms in the probable
RLS group was 7.4 years (range, 1–13; standard deviation [SD], 4.3) and 9.7 years (range, 1–15; SD, 4.4)
in the definite group. The difference was not statistically significant. The mean age at diagnosis of RLS was
11.3 years (range, 6 –15; SD, 3.9) in the probable
group and 13.9 years (range, 5–17; SD, 3.2) in the
definite group ( p ⫽ 0.04). Sleep onset or sleep maintenance insomnia was the most common complaint in
both groups, being present in 28 of 32 subjects
(87.5%) and in 9 of 9 of the probable and in 19 of 23
of the definite group. Inattentiveness was less common
Table 2. Demographics, Clinical Features, and Treatment
Patient
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
RLS
Type
Sex
M/F
Onset Age/Diagnosis
Age (yr)
PLM
Index
Serum
Ferritin
(␮g/dl)
Hb, Hct,
MCV
Affected
Parent
Treatment
Probable
Probable
Probable
Probable
Probable
Probable
Probable
Probable
Probable
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
Definite
F
F
M
F
M
M
F
M
F
M
F
F
M
M
M
M
F
F
F
F
M
F
M
F
M
F
F
F
F
F
M
M
5/8
13/15
11/15
11/13
11/13
1/5
2/14
5/6
8/13
11/13
14/16
13/15
7/13
12/15
8/13
8/11
4/16
7/14
11/13
12/14
15/16
2/16
4/16
11/11
6/6
13/17
16/17
14/17
1/5
15/17
12/14
5/15
1.8
—
33.1
0
—
21.5
5.3
20.8
—
0
—
42.9
41
30.8
1
10
5.5
—
—
25
13.1
0
11.5
3.5
13.6
0
50.3
—
0
—
23.2
61.3
—
11
—
10
—
—
16
20
47
21
71
10
17
6
—
50
—
17
27
25
—
—
51
15
23
29
60
11
12
36
23
28
—
13.1/38/89
—
13.7/38/80
—
—
—
13.1/38/81
—
13.3/38/77
12.9/36/88
12.4/35/80
12.1/35/80
11/32/75
—
12.3/36/81
—
11/33/73
12.5/36/80
12.2/34/80
—
—
15.5/45/89
14.5/43/83
13/36/81
12.5/36/87
12.7/36/92
13.5/39/88
12.4/36/82
—
13.7/40/82
14.4/42/86
Mother
Mother
Father
Mother
Mother
Mother
Mother
Father
Mother
None
Mother
None
Mother
None
None
None
Mother
Mother
None
None
Father
Mother
Father
Father
Mother
None
Mother
Mother
None
Mother
Father
Mother
Pramipexole
Iron
Gabapentin
Iron
—
Gabapentin
Gabapentin
Pramipexole
Exercise
Iron
Gabapentin
Iron
Pramipexole
L-dopa–carbidopa
Clonazepam
—
Gabapentin
Gabapentin
Pramipexole
Pramipexole
Gabapentin
Pramipexole
Gabapentin
Clonazepam
Pramipexole
Gabapentin
Pramipexole
Pramipexole, iron
Pramipexole
Pramipexole
Pramipexole, iron
Pramipexole
Data for hematocrit and the mean corpuscular volume have been rounded off to the nearest full figure.
RLS ⫽ restless legs syndrome; PLM ⫽ periodic limb movement; MCV ⫽ mean corpuscular volume (cubic micrometers).
as a symptom, being present in 8 of 32 subjects (25%)
and in 4 of 9 of the probable and in 4 of 23 of the
definite RLS category. Involuntary limb movements
observed by parents/guardians during sleep were a presenting symptom in 10 of 32 patients (31%), chronic
fatigue in 9 of 32 (28%), and sleep walking in 3 of 32
(9.3%). None of these symptoms was more or less
prevalent in the probable or definite categories.
The diagnosis of probable RLS mandates by definition the presence of a family history of RLS in a firstdegree relative, and thus the 100% positive family history in this group is not surprising. There was also a
family history of RLS in first-degree relatives in 60% of
the definite RLS category. When both definite and
probable RLS were combined, 23 of 32 subjects (71%)
gave a positive family history of RLS. Overall, mothers
were significantly more likely to be the affected relative
(17/23) than fathers (6/23; p ⫽ 0.02).
Serum ferritin levels were available for 24 of 32 subjects (75%). The median serum ferritin level in the
probable RLS group was 16␮g/L (n ⫽ 4) and 23␮g/L
(n ⫽ 20) in the definite group, with these differences
not being statistically significant. The median serum
ferritin level in males and females was not significantly
different (23␮g/L in 9 male subjects, 17␮g/L in 15
female subjects). There was no significant difference
between the serum ferritin level in subjects with and
without a family history of RLS. Serum ferritin levels
decreased below the fifth percentile for age and sex16,17
in 8 of 24 subjects (33%) and below the median in 18
of 24 (75%). The level was below 50␮g/L in 20 of 24
subjects (83%). Complete blood count was checked in
23 subjects. The hematocrit was below the reference
range in 5 of 23 subjects (mean, 33.9; range, 32.8 –
35). The low number of subjects (3/23) with low mean
corpuscular volumes did not allow for correlation with
serum ferritin levels. The mean PLMI in 24 subjects
was 17.3 (SD, 17.9; range, 0 – 61). The PLMI was
greater than 5 in 16 subjects (67%). There was no cor-
Kotagal and Silber: Childhood-Onset RLS
805
relation between serum ferritin levels and the PLMI
(r ⫽ 0.16).
Pharmacotherapy for RLS was prescribed in 29 of
32 subjects, consisting of the dopamine receptor agonist pramipexole alone in 11 of 29 (dose,
0.125– 0.25mg at bedtime), oral iron alone in 4 of 29,
pramipexole plus oral iron in 2 of 29, gabapentin in 9
of 29, clonazepam in 2 of 29, and carbidopa–L-dopa in
1 of 29 (25/100mg, one tablet at bedtime). Based on
record review or telephone query, 11 of 29 (38%)
stated that their sleep was “much improved” sleep after
drug therapy, 7 of 29 (24%) indicated that their sleep
was “somewhat improved,” whereas 4 of 29 (14%)
showed no improvement; information about response
to therapy was unavailable for 7 of 29 (24%) subjects.
Given the small and disparate numbers of patients in
each group, it was not possible to determine if subjects
responded better to any one specific drug.
Discussion
Our study population was derived after applying rigorous selection criteria for probable and definite RLS.1 It
is the first study to our knowledge to utilize these criteria in the study of childhood-onset RLS. The age at
diagnosis of the probable RLS group was significantly
less than the age of the definite RLS group, but all
other parameters were similar in the two groups. This
suggests that the definite and probable criteria are
likely defining the same phenomenon.
The occurrence of RLS in 72% of biological parents
of our study population supports the familial predisposition of childhood RLS noted earlier by Picchietti and
colleagues10 and is consistent with an autosomal dominant pattern of transmission. We were surprised to
find that mothers were almost three times more likely
to be the affected parent than fathers were. A predilection for mother to child transmission also has been
suggested in earlier case reports.13,14 Larger, multicenter studies are needed to determine whether genetic
imprinting favoring maternal transmission is seen in
childhood RLS. It is also possible that we have a sampling bias because mothers may be more likely to accompany children for the sleep center visit than fathers.
Normative data for serum ferritin in childhood and
adolescence are dependent on age and sex. Levels decrease in early adolescence with the onset of body
growth and associated expansion of red cell mass,
whereas onset of menstruation causes further decreases
in girls. Levels increase again in early adulthood.16,17
Fifth percentile values vary between 8␮g/L (16 –17year-old girls) and 24␮g/L (8 –10-year-old boys). Similarly, median values range between 29 and 52␮g/
L.16,17 When age and sex were taken into account,
serum ferritin levels in our subjects were lower than
expected, decreasing below the fifth percentile in 33%
806
Annals of Neurology
Vol 56
No 6
December 2004
and below the median in 75% of our subjects. In addition, values were below 50␮g/L in 83%. This is
greater than the percentage of subjects with low serum
ferritin levels reported in a study of 27 adult RLS patients (63%)5 and in a study of 39 children with
PLMS (72%).18 The median serum ferritin level in our
patients was also similar to the 17␮g/L mean level
found in three teenagers with RLS by Kryger and colleagues.19 Oral iron therapy has resulted in subjective
improvement in sleep-wake function in children with
low serum ferritin levels.19
Decreased serum ferritin levels in our study did not,
however, correlate with low hematocrit or low red
blood cell mean corpuscular volume (MCV). Similarly,
only one of the patients in the Kryger series19 showed
mild anemia, and none showed changes in the MCV.
This is to be expected, because, by the time anemia
appears, the marrow iron stores are generally negligible
and the serum ferritin is below 10␮g/L.20 Sun and colleagues5 found that serum ferritin levels below 50␮g/L
in adults were associated with increased severity of
RLS. Although no comparable analysis has been performed in children, it seems reasonable that the same
conclusion can be applied. Indeed, adolescents may be
at a greater risk of such exacerbation of RLS than
adults because of the lower iron stores in this age
group. Our findings of serum ferritin levels below the
fifth percentile in 33% and below 50␮g/L in 83% of
our subjects suggest that indices of iron deficiency
should be measured in childhood-onset RLS and may
be helpful as a supportive diagnostic criterion.
The coexistence of RLS and attention deficit disorder that previously has been noted by Picchietti and
colleagues10 underscores the need to consider both the
daytime and nighttime features of central nervous system dopamine deficiency in children. Our series differs
from that of Picchietti and colleagues, however, in that
our study was not restricted to children with attention
deficit hyperactivity disorder but was composed of a
broad group of subjects who presented to the pediatric
sleep service with nonspecific symptoms such as insomnia, chronic fatigue, and chronic daily headache. The
retrospective design is a weakness of our study, but this
is counterbalanced by the reasonably large sample size
and the use of rigid and reliable selection criteria.
The Mayo Clinic Center for Patient Oriented Research provided
statistical support.
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Kotagal and Silber: Childhood-Onset RLS
807
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