Childhood-Onset Restless Legs SyndromeSuresh 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 onpublished criteria into probable (n � 9/32 or 28%) and definite (n � 23/32 or 78%) categories. Apart from an earlierage of diagnosis of the probable group, no differences were found between the two categories. Sleep onset or sleepmaintenance insomnia was the most common symptoms, being present in 28 of 32 subjects (87.5%). Inattentiveness wasseen in 8 of 32 subjects (25%). Serum ferritin levels were measured in 24 of 32 subjects and were below 50�g/L in 20of 24 subjects (83%). A family history of restless legs syndrome was present in 23 of 32 (72%) subjects, with mothersalmost three times more likely to be affected than fathers (p � 0.02). We conclude that iron deficiency and a strongfamily history are characteristic of childhood-onset restless legs syndrome.

Ann Neurol 2004;56:803–807

Restless legs syndrome (RLS) is a sensorimotor disordercharacterized by an irresistible urge to move the limbspredominantly in the evening or at night. This is usu-ally accompanied by a peculiar discomfort in the lowerextremities often alluded to as a “creepy” or “crawly”feeling. Insomnia and daytime fatigue result.1,2 Be-tween 38 to 45% of adult RLS subjects have onset ofsymptoms before age 20 years.3,4 Low tissue iron andcentral nervous system deficiency of dopamine may beinvolved in the pathogenesis of RLS.5 Nocturnal poly-somnography may show periodic limb movement dis-order (PLMD) which is defined as a series of four ormore limb electromyographic discharges of 0.5- to5-second duration, that are separated by intervals of 4to 90 seconds.6,7 PLMD has been documented in di-verse populations of children, including those with leu-kemia,8 fibromyalgia,9 and attention deficit hyperactiv-ity disorder.10

The recognition of RLS in childhood is not new; in1832, Duchamp11 observed that children may sufferaches and pains around puberty and labeled this symp-tom as “growing pains.” Walters and colleagues12,13

and Ekbom14 have pointed out the heterogeneous na-ture of “growing pains,” but that a subset of childrenwith growing pains indeed might have RLS. Owing tothe subjective nature of the sleep complaints, RLS maybe difficult to accurately diagnose in young or nonver-bal children. Clinical and epidemiological research intochildhood RLS therefore has been limited. The recog-

nition of childhood RLS has been facilitated by therecently published diagnostic criteria1 (Table 1).

In 1994, Walters and colleagues reported the occur-rence of RLS in a mother and her three children and inan unrelated 16-year-old boy,13 but a larger series ofchildren utilizing the most recently established diagnos-tic criteria1 is lacking. Although an association betweenchildhood-onset PLMD, RLS, and attention deficit hy-peractivity disorder was described in special popula-tions of children by Picchietti and colleagues10 andChervin and colleagues,15 the clinical features need tobe studied in a broad, less-selected population of chil-dren. We report the clinical features of RLS in childrenand adolescents who presented to our pediatric sleepdisorders program with sleep-wake complaints. Thenewly established diagnostic criteria1 were applied ret-rospectively to a group of provisionally diagnosed RLSsubjects.

Patients and MethodsThe records of all children with sleep-wake complaints eval-uated in our pediatric sleep disorders program between Jan-uary 2000 and March 2004 were reviewed for RLS after ap-proval of the study by the institutional review board. Of atotal of 538 patients below the age of 18 years, 62 had beendiagnosed as having RLS. All 538 had undergone formalsleep consultation. A review of the medical records of the 62subjects yielded 32 subjects (12 male and 20 female subjects,5.9% of the total population of 538) that met the strict,

From the 1Division of Child and Adolescent Neurology, 2Depart-ment of Neurology, and the 3Sleep Disorders Center, Mayo Clinic,Rochester, MN.

Received May 17, 2004, and in revised form Aug 11. Accepted forpublication Aug 11, 2004.

Published online Oct 25, 2004, in Wiley InterScience(www.interscience.wiley.com). DOI: 10.1002/ana.20292

Address correspondence to Dr Kotagal, Division of Child Neurol-ogy, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.E-mail: kotagal.suresh@mayo.edu

© 2004 American Neurological Association 803Published by Wiley-Liss, Inc., through Wiley Subscription Services

recently established diagnostic criteria1 for RLS. The 32 sub-jects were further subdivided based on clinical features, fam-ily history, and the diagnostic guidelines1 into definite (n �23) and probable (n � 9) RLS groups (see Table 1). Therevised classification1 recommends that definite RLS andprobable RLS criteria be used for children up to the age of 12years, beyond which the standard adult criteria apply. Theclassification, however, also recognizes that “in some casesthis age limit may need modification to meet the clinicalsituation.” Accordingly, for simplification, we applied thedefinite and probable RLS criteria to our entire patient pop-ulation of children and adolescents up to the age of 18 years.

Thirty of the 62 subjects were excluded because of insuf-ficient history (n � 14), an alternate final sleep diagnosis(n � 9), alternate systemic diagnosis such as peripheral neu-ropathy/dermatomyositis/fibromyalgia (n � 4), lack of in-

formed consent for clinical research (n � 2), and use of aselective serotonin reuptake inhibitor that is known to exac-erbate RLS (n � 1). The following information was com-piled on the remaining 32 subjects: age of onset of symp-toms, age at diagnosis of RLS, presenting symptoms, familyhistory of RLS in first-degree relatives, sex of affected rela-tive, serum ferritin levels, and complete blood count. Serumferritin levels were compared with published populationnorms for age and sex.16,17 The percentage of subjects with aserum ferritin level below 50�g/L also was calculated becauseof its association with increased severity of RLS.5

Because RLS is a clinical diagnosis that does not routinelyrequire nocturnal polysomnography, sleep studies were ob-tained only for those subjects who were suspected to havecomorbidities such as parasomnia, nocturnal seizures, orsleep-disordered breathing. Information about the periodiclimb movement index (PLMI) on the nocturnal polysomno-gram was recorded. Medications used to treat RLS(pramipexole, carbidopa–L-dopa, clonazepam, gabapentin, ororal iron) were recorded, and the response to therapy wasdetermined from chart review or contact with the families.This follow-up information was available for 22 of 32 sub-jects (68%), with an average duration of follow-up of 12.3months (range, 1–44).

Statistical AnalysisMedians were used rather than means as measures of centraltendency when the variables were not normally distributed.Age of onset of symptoms in the probable and definite RLSgroups was compared using a two-sample t test. A compari-son of the PLM index between the two groups was madeusing the Wilcoxon rank-sum test. Serum ferritin levels be-tween groups were compared using the Wilcoxon rank-sumtest. Correlation between the serum ferritin levels for bothgroups combined and periodic limb movement index forboth groups combined was made using the Spearman rankcorrelation coefficient. The �2 test was used to determine ifthe ratio of maternal: paternal transmission was significantlyunequal.

ResultsThirty-two of 538 subjects examined (5.9%) had rest-less legs syndrome, with 9 of 32 (28%) being in theprobable category and 23 of 32 (78%) in the definitecategory. Demographics, family history, periodic limbmovement index, serum ferritin levels, and treatmentprescribed for the two groups are summarized in Table2. The mean age of onset of symptoms in the probableRLS group was 7.4 years (range, 1–13; standard devi-ation [SD], 4.3) and 9.7 years (range, 1–15; SD, 4.4)in the definite group. The difference was not statisti-cally significant. The mean age at diagnosis of RLS was11.3 years (range, 6–15; SD, 3.9) in the probablegroup and 13.9 years (range, 5–17; SD, 3.2) in thedefinite group (p � 0.04). Sleep onset or sleep main-tenance insomnia was the most common complaint inboth groups, being present in 28 of 32 subjects(87.5%) and in 9 of 9 of the probable and in 19 of 23of the definite group. Inattentiveness was less common

Table 1. Diagnostic Criteria for Adult and Childhood RestlessLegs Syndrome

Essential diagnostic criteria (adults)1. An urge to move the legs, usually accompanied or

caused by uncomfortable and unpleasant sensations inthe legs

2. The urge to move or unpleasant sensations begin orworsen during periods of rest or inactivity such aslying down or sitting

3. The urge to move or unpleasant sensations are par-tially or totally relieved by movement, such as walkingor stretching, at least as long as the activity continues

4. The urge to move or unpleasant sensations are worsein the evening or night than during the day, or onlyoccur during the evening or night

Definite childhood restless legs syndrome (RLS)1. The child meets all four essential adult criteria, and2. The child relates a description in his or her own

words that is consistent with leg discomfortOR

1. The child meets all four essential adult criteria andhas two of three following

a. sleep disturbance for ageb. biological parent or sibling with definite RLSc. polysomnographically documented periodic limb

movement index of five or more per hour of sleepProbable childhood RLS

1. The child meets all four essential adult criteria forRLS except criterion 4 (the urge to move or sensa-tions are worse in the evening or at night than duringthe day), and

2. The child has a biological parent or sibling with defi-nite RLSOR

1. The child is observed to have behavioral manifesta-tions of lower extremity discomfort when sitting orlying, accompanied by motor movement of the af-fected limbs; the discomfort has characteristics ofadult criteria 2, 3, and 4, and

2. The child has a biological parent or sibling with defi-nite RLS

Adapted from: Allen RP, Pichhietti D, Hening WA, et al. Restlesslegs syndrome: diagnostic criteria, special considerations, and epide-miology. A report from the restless legs syndrome diagnosis and ep-idemiology workshop at the National Institutes of Health. SleepMedicine 2003;4:101–119.

804 Annals of Neurology Vol 56 No 6 December 2004

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 thedefinite RLS category. Involuntary limb movementsobserved by parents/guardians during sleep were a pre-senting symptom in 10 of 32 patients (31%), chronicfatigue in 9 of 32 (28%), and sleep walking in 3 of 32(9.3%). None of these symptoms was more or lessprevalent in the probable or definite categories.

The diagnosis of probable RLS mandates by defini-tion the presence of a family history of RLS in a first-degree relative, and thus the 100% positive family his-tory in this group is not surprising. There was also afamily history of RLS in first-degree relatives in 60% ofthe definite RLS category. When both definite andprobable RLS were combined, 23 of 32 subjects (71%)gave a positive family history of RLS. Overall, motherswere 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 sub-jects (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 differencesnot being statistically significant. The median serumferritin level in males and females was not significantlydifferent (23�g/L in 9 male subjects, 17�g/L in 15female subjects). There was no significant differencebetween the serum ferritin level in subjects with andwithout a family history of RLS. Serum ferritin levelsdecreased below the fifth percentile for age and sex16,17

in 8 of 24 subjects (33%) and below the median in 18of 24 (75%). The level was below 50�g/L in 20 of 24subjects (83%). Complete blood count was checked in23 subjects. The hematocrit was below the referencerange in 5 of 23 subjects (mean, 33.9; range, 32.8–35). The low number of subjects (3/23) with low meancorpuscular volumes did not allow for correlation withserum ferritin levels. The mean PLMI in 24 subjectswas 17.3 (SD, 17.9; range, 0–61). The PLMI wasgreater than 5 in 16 subjects (67%). There was no cor-

Table 2. Demographics, Clinical Features, and Treatment

PatientNo.

RLSType

SexM/F

Onset Age/DiagnosisAge (yr)

PLMIndex

SerumFerritin(�g/dl)

Hb, Hct,MCV

AffectedParent Treatment

1 Probable F 5/8 1.8 — — Mother Pramipexole2 Probable F 13/15 — 11 13.1/38/89 Mother Iron3 Probable M 11/15 33.1 — — Father Gabapentin4 Probable F 11/13 0 10 13.7/38/80 Mother Iron5 Probable M 11/13 — — — Mother —6 Probable M 1/5 21.5 — — Mother Gabapentin7 Probable F 2/14 5.3 16 — Mother Gabapentin8 Probable M 5/6 20.8 20 13.1/38/81 Father Pramipexole9 Probable F 8/13 — 47 — Mother Exercise

10 Definite M 11/13 0 21 13.3/38/77 None Iron11 Definite F 14/16 — 71 12.9/36/88 Mother Gabapentin12 Definite F 13/15 42.9 10 12.4/35/80 None Iron13 Definite M 7/13 41 17 12.1/35/80 Mother Pramipexole14 Definite M 12/15 30.8 6 11/32/75 None L-dopa–carbidopa15 Definite M 8/13 1 — — None Clonazepam16 Definite M 8/11 10 50 12.3/36/81 None —17 Definite F 4/16 5.5 — — Mother Gabapentin18 Definite F 7/14 — 17 11/33/73 Mother Gabapentin19 Definite F 11/13 — 27 12.5/36/80 None Pramipexole20 Definite F 12/14 25 25 12.2/34/80 None Pramipexole21 Definite M 15/16 13.1 — — Father Gabapentin22 Definite F 2/16 0 — — Mother Pramipexole23 Definite M 4/16 11.5 51 15.5/45/89 Father Gabapentin24 Definite F 11/11 3.5 15 14.5/43/83 Father Clonazepam25 Definite M 6/6 13.6 23 13/36/81 Mother Pramipexole26 Definite F 13/17 0 29 12.5/36/87 None Gabapentin27 Definite F 16/17 50.3 60 12.7/36/92 Mother Pramipexole28 Definite F 14/17 — 11 13.5/39/88 Mother Pramipexole, iron29 Definite F 1/5 0 12 12.4/36/82 None Pramipexole30 Definite F 15/17 — 36 — Mother Pramipexole31 Definite M 12/14 23.2 23 13.7/40/82 Father Pramipexole, iron32 Definite M 5/15 61.3 28 14.4/42/86 Mother 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).

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 of32 subjects, consisting of the dopamine receptor ago-nist 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 9of 29, clonazepam in 2 of 29, and carbidopa–L-dopa in1 of 29 (25/100mg, one tablet at bedtime). Based onrecord review or telephone query, 11 of 29 (38%)stated that their sleep was “much improved” sleep afterdrug therapy, 7 of 29 (24%) indicated that their sleepwas “somewhat improved,” whereas 4 of 29 (14%)showed no improvement; information about responseto therapy was unavailable for 7 of 29 (24%) subjects.Given the small and disparate numbers of patients ineach group, it was not possible to determine if subjectsresponded better to any one specific drug.

DiscussionOur study population was derived after applying rigor-ous selection criteria for probable and definite RLS.1 Itis the first study to our knowledge to utilize these cri-teria in the study of childhood-onset RLS. The age atdiagnosis of the probable RLS group was significantlyless than the age of the definite RLS group, but allother parameters were similar in the two groups. Thissuggests that the definite and probable criteria arelikely defining the same phenomenon.

The occurrence of RLS in 72% of biological parentsof our study population supports the familial predispo-sition of childhood RLS noted earlier by Picchietti andcolleagues10 and is consistent with an autosomal dom-inant pattern of transmission. We were surprised tofind that mothers were almost three times more likelyto be the affected parent than fathers were. A predilec-tion for mother to child transmission also has beensuggested in earlier case reports.13,14 Larger, multi-center studies are needed to determine whether geneticimprinting favoring maternal transmission is seen inchildhood RLS. It is also possible that we have a sam-pling bias because mothers may be more likely to ac-company children for the sleep center visit than fa-thers.

Normative data for serum ferritin in childhood andadolescence are dependent on age and sex. Levels de-crease in early adolescence with the onset of bodygrowth and associated expansion of red cell mass,whereas onset of menstruation causes further decreasesin girls. Levels increase again in early adulthood.16,17

Fifth percentile values vary between 8�g/L (16–17-year-old girls) and 24�g/L (8–10-year-old boys). Sim-ilarly, 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 thanexpected, decreasing below the fifth percentile in 33%

and below the median in 75% of our subjects. In ad-dition, values were below 50�g/L in 83%. This isgreater than the percentage of subjects with low serumferritin levels reported in a study of 27 adult RLS pa-tients (63%)5 and in a study of 39 children withPLMS (72%).18 The median serum ferritin level in ourpatients was also similar to the 17�g/L mean levelfound in three teenagers with RLS by Kryger and col-leagues.19 Oral iron therapy has resulted in subjectiveimprovement in sleep-wake function in children withlow serum ferritin levels.19

Decreased serum ferritin levels in our study did not,however, correlate with low hematocrit or low redblood cell mean corpuscular volume (MCV). Similarly,only one of the patients in the Kryger series19 showedmild anemia, and none showed changes in the MCV.This is to be expected, because, by the time anemiaappears, the marrow iron stores are generally negligibleand the serum ferritin is below 10�g/L.20 Sun and col-leagues5 found that serum ferritin levels below 50�g/Lin adults were associated with increased severity ofRLS. Although no comparable analysis has been per-formed in children, it seems reasonable that the sameconclusion can be applied. Indeed, adolescents may beat a greater risk of such exacerbation of RLS thanadults because of the lower iron stores in this agegroup. Our findings of serum ferritin levels below thefifth percentile in 33% and below 50�g/L in 83% ofour subjects suggest that indices of iron deficiencyshould be measured in childhood-onset RLS and maybe helpful as a supportive diagnostic criterion.

The coexistence of RLS and attention deficit disor-der that previously has been noted by Picchietti andcolleagues10 underscores the need to consider both thedaytime and nighttime features of central nervous sys-tem dopamine deficiency in children. Our series differsfrom that of Picchietti and colleagues, however, in thatour study was not restricted to children with attentiondeficit hyperactivity disorder but was composed of abroad group of subjects who presented to the pediatricsleep service with nonspecific symptoms such as insom-nia, chronic fatigue, and chronic daily headache. Theretrospective design is a weakness of our study, but thisis counterbalanced by the reasonably large sample sizeand the use of rigid and reliable selection criteria.

The Mayo Clinic Center for Patient Oriented Research providedstatistical support.

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806 Annals of Neurology Vol 56 No 6 December 2004

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