Restless Legs Syndrome Highlights From the Associated Professional Sleep Societies 19th Annual Meeting

August 15, 2005

Early Manifestations of Restless Legs Syndrome in Childhood

Picchietti D, Stevens H
Oral Abstract 0216

These investigators reviewed the records of 199 children presenting for follow-up of sleep problems (excluding sleep-disordered breathing) to a pediatric neurology/sleep practice. They identified 18 children who did not meet diagnostic criteria for RLS at initial presentation, but did meet the criteria at follow-up. Of these, 16 had reported chronic sleep-onset problems and 8 sleep-maintenance problems at the time of the initial evaluation; 10 had a history of growing pains; 12 had a parent who was diagnosed with RLS; 11 of 17 experienced at least 5 periodic limb movements of sleep/hour; and 9 of 11 responded to dopaminergic medication. Comorbidities included attention-deficit/hyperactivity disorder (ADHD) (13), anxiety disorders (6), depression (4), and oppositional defiant disorder (4). Thus, in this population, clinical sleep disturbance preceded RLS diagnosis by an average of 11.6 years. The findings of this study support the 2002 National Institutes of Health (NIH) diagnostic criteria for RLS in children.

Pharmacological Management of Childhood Restless Legs Syndrome

Sayed M, Kotagal P, Foldvary N, Bae C
Poster Abstract 0245

This retrospective review examined records of 207 children who presented at The Cleveland Clinic Sleep Center, Cleveland, Ohio, from 2000 to 2003 for evaluation of sleep disorders. In all, 10 children (5%) were diagnosed with RLS, confirmed by a full-night in-lab polysomnography. The mean age was 9.1 years, with the age of onset from birth to 10 years and mean duration of complaints of 5 years. In all, 6 of the 10 children had comorbid ADHD; 3 had a family history of ADHD; and 4 had a family history of RLS. The children received gabapentin, clonidine, or ropinirole, and all experienced amelioration of symptoms of RLS.

Ropinirole in a Child With Attention-Deficit Hyperactivity Disorder and Restless Legs Syndrome

Konofal E, Arnulf I, Cortese S, Lecendreux M, Mouren M
Poster Abstract 0285

This report describes a 6-year-old boy with concurrent ADHD and RLS. Coadministration of methylphenidate and ropinirole was found safe and effective for symptoms of both RLS and ADHD in this young child. The presenters posit that the improvement of ADHD symptoms when awake may result directly from effects of ropinirole on the dopamine dysfunction associated with ADHD, or indirectly from improvements in nocturnal sleep.

Dementia and Depression

Sleep and Restless Legs Syndrome/Periodic Limb Movement Disorder in Dementia

Richards K, Lambert C, OSullivan P, Beck C
Oral Abstract 0337

To determine how RLS/periodic limb movement disorder (PLMD) influences sleep in persons with dementia, 49 persons with dementia (mean age, 83.4 years; Mini Mental State Examination [MMSE] 14.3) underwent 1 night of attended polysomnography while sleeping in their usual nursing home environment. Diagnosis of RLS/PLMD was based on a periodic limb movement index (PLMI) greater than 20. The mean PLMI was 17.3, while the mean PLMI with arousals or awakenings was 9.0. Twelve patients (25%) had a PLMI greater than 20. When compared with those without RLS/PLMD, patients with RLS/PLMD had greater sleep disturbance, including significantly fewer minutes of nonrapid eye movement (NREM) sleep, a lower percentage of NREM sleep, and longer latency to sleep onset, compared with those without RLS/PLMD. The apnea/hypopnea index was significantly lower in those with RLS/PLMD.

Restless Legs Syndrome in Treated Depressed Outpatients: Prevalence and Clinical Correlates

Winkelman J, Johnston L, Fava M
Poster Abstract 0782

This study examined rates of RLS in depressed outpatients, either before or during treatment. A total of 113 unselected patients (75 women; average age, 42.1 years) from 2 outpatient depression clinics completed questionnaires concerning mood and somatic aspects of depression. Most described themselves as minimally depressed, and had been on their current antidepressant for a median of 9 months. Nearly half were taking at least 2 medications for depression, but none were being treated for RLS.

In all, 12 (10.6%) of the patients with treated depression experienced all 4 cardinal RLS symptoms. Of these, 10 had symptoms at least once per week, and 7 had symptoms at least twice per week. The 10 patients with at least weekly RLS were older than those without RLS symptoms (P = .02), had more difficulty falling asleep (P = .04), and trended toward higher levels of daytime fatigue (P = .06). There were no differences in sex distribution, severity of depression, or level of daytime sleepiness between those with and those without RLS. This rate of RLS in depressed patients taking antidepressants approximates the prevalence in the general population, but is much lower than previously reported rates in the only published study on this subject.

Prevalence and Correlates of Restless Legs Syndrome in the Wisconsin Sleep Cohort

Winkelman J, Finn L, Young T
Poster Abstract 0783

This study of 2779 middle-aged (40-75 years) adults in the longitudinal Wisconsin Sleep Cohort Study found an overall prevalence of at least weekly RLS of 10.6%. Prevalence was similar in men and women, but those with RLS were older than those without RLS. Regardless of the frequency of symptoms, adults with RLS were more likely to report excessive daytime sleepiness often or almost always compared with adults without RLS symptoms. Likewise, Epworth scores were higher for RLS groups than those without RLS. Adults with RLS symptoms reported poorer general health and more cardiovascular disease than those without.

Overall prevalence rates for RLS in this study were comparable to rates in other US studies, as were complaints of poor overall health. However, these investigators recommend that their finding of an association between RLS and cardiovascular disease (but not with hypertension) merits further investigation.

Prevalence, Severity and Predictors of Restless Legs Syndrome in Norway and Denmark

Bjorvatn B, Leissner L, Ulfberg J, et al
Poster Abstract 0792

This population-based, cross-sectional, epidemiologic study was designed to estimate prevalence and severity (with the International Restless Legs Scale [IRLS]) of RLS in Norway and Denmark, and explore predictors of RLS.

In all, 2005 randomly selected adults (1025 women, 980 men; mean age, 46.6 years) participated in a telephone interview in Norway and Denmark. Of these adults, 11.5% fulfilled the diagnostic criteria for RLS, and half reported moderate to very severe symptoms, as measured by the IRLS. Fewer than one third reported seeking professional help for their symptoms despite a mean duration of symptoms of 10 years, and a family history of RLS in 42%. Prevalence was 13.4% in women and 9.4% in men, and lowest in the youngest age group (18-29 years, 6.3%). From 30 years and above no clear age-related difference was seen. Main predictors of RLS in this population were insomnia and symptoms of periodic limb movements in sleep.

Epidemiological and Neuroradiological Features of Restless Legs Syndrome in Multiple Sclerosis

Ferini-Strambi L, Manconi M, Rocca M, Tortorella P, Zucconi M, Filippi M
Oral Abstract 0852

This prospective study enrolled 82 consecutive multiple sclerosis (MS) patients observed at the Neuroimaging Research Unit during the last year. Each patient underwent a medical history interview, a neurologic examination with assessment of the Expanded Disability Status Scale (EDSS), a brain and cervical cord MRI, and a structured telephone interview to verify the presence of the standard diagnostic criteria for RLS and the patient's sleep habits.

In all, 29 of 82 patients were found to be affected by RLS (prevalence rate, 35.4%). In 7 patients (8.5%), RLS preceded the onset of clinical MS; for 22 patients (24.4%), onset of RLS followed or was simultaneous with the clinical MS onset. No significant differences were found in MS duration, age, and sex in patients with RLS vs those without RLS. More patients in the RLS group had primary progressive MS. Likewise, those with RLS scored a higher EDSS, with a particular impairment of the pyramidal system.

Among the MRI metrics analyzed, brain average fractional anisotropy of normal-appearing gray matter was significantly reduced in patients without RLS (P = .01), and cervical cord average fractional anisotropy was significantly reduced in those with RLS (P = .02). Thus, RLS symptoms are common in MS patients; cervical cord damage represents a significant risk factor for RLS among MS patients.

Prevalence of Restless Legs Syndrome (RLS) in Liver Disease: An Interim Analysis

Franco R, Deshpande A, Franco J, et al
Poster Abstract 0799

RLS affects approximately 10% of the general population, but is more prevalent in certain disease states, such as iron deficiency, neuropathy, and renal insufficiency. This prospective survey and chart review examined the prevalence of RLS in patients with liver disease. Investigators used previously validated RLS survey tools and excluded patients with clinical encephalopathy. To date, 121 hepatology clinic patients have been surveyed; 76 of these were found positive, with only 2 false positives detected in follow-up interviews. This yields a prevalence estimate of 61% (P < .00001). Of the 74 positive surveys, 58% reported 4 key symptoms and 33% reported all 5 core symptoms; 32% had other risk factors, including kidney disease (3), iron deficiency (12), and/or neuropathy (14). Thus, this study found a relatively high prevalence of RLS in patients with liver disease. This can partially be explained by conditions known to cause RLS, yet a substantial number of respondents had no self-reported risk factors.

Severity of Restless Legs Syndrome and Sensory Nerve Dysfunction

Gill K, Park Y
Poster Abstract 0786

As the severity of RLS worsens, the uncomfortable sensory disturbances often become more prominent, suggesting changes in peripheral sensory processing. To examine the possible correlation between RLS symptoms and sensory dysfunction, these investigators evaluated 24 patients with high- and low-severity RLS, with ulnar and sural sensory nerve conductions, sympathetic skin response, Heart Rate Variability (R-R interval), and examination of 5 sensory modalities. They also tested hemoglobin A1c, thyroid-stimulating hormone, T4, SPEP, B12, folate, BUN, creatinine, copper, iron, and ferritin levels.

These studies found a significant correlation between the presence of RLS symptoms and both small and large sensory fiber dysfunction. In addition, greater RLS severity correlated with worsening of autonomic function and large sensory fiber function in the legs. These findings are the first to demonstrate a relationship between RLS symptoms and electrophysiologic abnormalities. The investigators suggest that early identification of autonomic and sensory (small- and large-fiber) dysfunction in RLS subjects may point to underlying etiology and/or specific symptomatic treatment.

Successful Use of Botulinum Toxin A for the Treatment of Restless Legs Syndrome: A Case Series

Rotenberg J, DiFazio M
Poster Abstract 0806

In a series of 3 patients with RLS, botulinum toxin A (BTXA) alleviated symptoms, reduced medication use, and/or reduced daytime sleepiness with minimal untoward effects. Investigators identified areas of maximal discomfort and injected them with BTXA. Symptoms improved in all 3 patients, with a duration of effect ranging from 10 to 12 weeks. None of these patients experienced any adverse events, and all also responded to subsequent BTXA injections.

Thus, these 3 patients experienced significant improvements in RLS symptoms and/or a reduction in medication use after intramuscular BTXA injections. The course of response corresponded with its typical course of efficacy in other disorders.

Augmentation During Long-term Treatment With L-DOPA in Restless Legs Syndrome: Results of a Multicentric Study in Europe

Garcia-Borreguero D, Hogl B, Gschliesser V, et al
Poster Abstract 0808

Although L-DOPA has been found effective for treating RLS symptoms; retrospective analyses have shown that augmentation (AUG) occurs during long-term treatment. The European Subgroup of the International Restless Legs Study Group performed this multicentric, prospective study to stringently evaluate the incidence and clinical characteristics of AUG during long-term L-DOPA treatment.

This preliminary analysis included 34 untreated patients from 6 European countries diagnosed with RLS according to NIH criteria. Patients received an initial dose of 100-25 mg L-DOPA-benserazide (as monotherapy). During each clinic visit (weekly for 1 month, and monthly thereafter), the dose of L-DOPA was adjusted according to clinical needs. AUG was defined as established by NIH criteria. In all, 15 patients completed the 6-month trial and 19 dropped out. AUG occurred in 17 of 34 patients (50%). AUG occurred in 68.4% of those who dropped out, and was the main reason for discontinuation in 36.8%; 52% of these patients developed AUG within the first 2 months and 76% developed AUG within 3 months. Doses of L-DOPA were higher than 300 mg daily for 88% of patients experiencing AUG. AUG developed within 2 weeks of the last dose increase in 73% of patients. The study found no relationship between RLS severity at baseline and propensity to AUG.

Failure Rates of First-line Dopaminergic Therapy for Restless Legs Syndrome (RLS)

Becker P
Oral Abstract 0810

The American Academy of Sleep Medicine (AASM) (Standards of Practice Committee [SOP]) and the RLS Foundation (algorithm) propose dopamine agonists as first-line treatment of RLS. However, dopaminergic therapy failure and the effectiveness of subsequent therapies have not been well studied. This retrospective analysis of a 2-year sample of all RLS patients from a single RLS practice describes dopaminergic failures and subsequent management during the first 3 months of treatment.

Of 138 new RLS patients, 118 were treated with dopaminergic agents (DA). Of these, 104 patients had 3 months of evaluable data, which were analyzed by descriptive group mean statistics for demographics, clinician impressions of severity and change, estimated total sleep time (TST), adverse events (AE), and changes in therapeutic regimen.

In all, 77% continued DA at 3 months, whereas 23% changed therapy. The 77% response exceeds the 50% to 60% response reported in research trials. The higher response can be explained by flexibility in DA dosing and timing. Higher adverse events, leading to DA discontinuation, might be expected in a medically ill RLS population. Because those who experienced DA failure received rapid medication change to improve efficacy or reduce side effects, only 2 of 104 patients ended therapy. Thus, roughly one quarter of RLS patients may require agents other than DA.

A Segregation Analysis of the Restless Legs Syndrome (RLS) Based on Age-of-Onset Models

Hening W, Mathias R, Allen R, et al
Oral Abstract 0815

Familial aggregation in RLS has received little formal investigation; 3 candidate loci have been reported on different chromosomes in distinct populations using different techniques and models. This study investigated segregation in the families of RLS patients enrolled in a case-control family study that used blinded diagnoses of affected status.

Probands were consecutive RLS patients presenting to neurology and sleep clinics at Johns Hopkins Bayview Medical Center, Baltimore, Maryland, who were willing to have first- and second-degree relatives contacted. The commingling analysis found 2 distributions of ages of onset; ages of onset younger than 26.35 were more likely to fall into an early distribution. Results of the REGD and REGTL models suggest that neither purely environmental nor major gene models fit these pedigrees.

This study's results were consistent with an important genetic contribution to development of RLS, but suggest that the underlying genetic model may be polygenic. Consistent with the 3 loci previously reported for this disorder, it is likely that multiple susceptibility alleles will be found and their importance may vary in different populations.

Polysomnographic Evaluation of Idiopathic Restless Legs Syndrome Patients: Effect of First Night Pramipexole-Treatment

Manconi M, Zucconi M, Oldani A, et al
Poster Abstract 0822

This study examined the first night effect of a single dose of pramipexole in consecutive, dopaminergic treatment-naive patients with idiopathic RLS. In all 16 patients, RLS symptoms subjectively improved after the first night of treatment (Visual Analog Scale).

A single, low dose of pramipexole in treatment-naive RLS patients improved symptoms and sleep parameters after 1 night of treatment. Moreover, pramipexole treatment was associated with a significant drop in periodic limb movements in sleep, without a significant change in the cyclic alternating pattern (CAP) rate. However, pramipexole seems to induce, at least acutely, a relative inhibition of REM and slow-wave sleep.

Results From the First Active Controlled Trial to Investigate Efficacy of Cabergoline Compared to Levodopa in the Treatment of Patients With Severe Restless Legs Syndrome

Trenkwalder C, Benes H, Happe S, Schwank S, Kohnen R, Caldir S
Oral Abstract 0823

This double-blind, multicenter trial compared the short-term (6-8 weeks) and long-term (30 weeks) efficacy of the dopamine agonist cabergoline (CAB) with levodopa (LEV)-benserazide for RLS.

Investigators treated patients with idiopathic RLS with fixed daily doses of 2 mg of CAB or 200 mg of LEV; after 6 weeks, the dose was raised to 3 mg of CAB or 300 mg of LEV as needed. Changes in the IRLS total score from baseline to week 6 or 8 were compared to evaluate noninferiority of CAB vs LEV; the noninferiority margin was set to more than 3 points. The long-term superiority analysis included time to discontinuation of treatment because of poor efficacy or AUG, according to investigators' assessments.

The adjusted mean change from baseline in the IRLS sum score in the short-term period was d = less than 16.4 in the CAB group and d = less than 10.1 in the LEV group. During the total treatment period of 30 weeks, 24% of patients in the LEV group and 11.9% of patients in the CAB group discontinued because of lack/loss of efficacy or AUG.

Thus, CAB again demonstrated its favorable efficacy in the treatment of RLS with a low risk for AUG or inefficacy. For LEV, the rate of AUG or poor efficacy during the 30-week period was surprisingly low (24%) in this active controlled, double-blind, comparative trial.

Anti-Histamines and Benzodiazepines Exacerbate Daytime Restless Legs Syndrome (RLS) Symptoms

Allen R, Lesage S, Earley C
Oral Abstract 0828

This double-blind study was designed to assess the effects of antihistamines and benzodiazepines on RLS. Investigators administered 3 consecutive days of drug challenges to 12 RLS patients who had reported adequate treatment with only dopamine agonists. The same dose of the same drug (diphenhydramine 25 mg or lorazepam 0.5 mg) was administered intravenously twice each day at 3:00 and 5:45 pm, and a 60-minute suggested immobilization test followed each dose. Patients received placebo on the second day, and were blinded to which day the placebo was given.

Preliminary analyses showed that periodic limb movements per hour (PLMW/hr) were greater for each patient for each of the diphenhydramine doses compared with lorazepam doses (P < .005). In contrast, the measures showed nonsignificantly greater sleepiness for lorazepam than diphenhydramine. Compared with placebo, PLMW/hr were significantly greater for diphenhydramine (P < .005) and marginally significantly greater for lorazepam (P = .10). Subjective ratings of RLS severity showed similar differences. No significant differences for the measures of sleepiness were found, although the direction of change was as expected. Thus, daytime sedating antihistamines severely exacerbated RLS more than expected for their sedating effects. Daytime benzodiazepines also moderately increase RLS symptoms.

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