Mary L. Wagner

Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome

BACKGROUND There is a need for an easily administered instrument which can be applied to all patients with restless legs syndrome (RLS) to measure disease severity for clinical assessment, research, or therapeutic trials. The pathophysiology of RLS is not clear and no objective measure so far devised can apply to all patients or accurately reflect severity. Moreover, RLS is primarily a subjective disorder. Therefore, a subjective scale is at present the optimal instrument to meet this need. METHODS Twenty centers from six countries participated in an initial reliability and validation study of a rating scale for the severity of RLS designed by the International RLS study group (IRLSSG). A ten-question scale was developed on the basis of repeated expert evaluation of potential items. This scale, the IRLSSG rating scale (IRLS), was administered to 196 RLS patients, most on some medication, and 209 control subjects. RESULTS The IRLS was found to have high levels of internal consistency, inter-examiner reliability, test-retest reliability over a 2-4 week period, and convergent validity. It also demonstrated criterion validity when tested against the current criterion of a clinical global impression and readily discriminated patient from control groups. The scale was dominated by a single severity factor that explained at least 59% of the pooled item variance. CONCLUSIONS This scale meets performance criteria for a brief, patient completed instrument that can be used to assess RLS severity for purposes of clinical assessment, research, or therapeutic trials. It supports a finding that RLS is a relatively uniform disorder in which the severity of the basic symptoms is strongly related to their impact on the patients life. In future studies, the IRLS should be tested against objective measures of RLS severity and its sensitivity should be studied as RLS severity is systematically manipulated by therapeutic interventions.

Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder

Fourteen consecutive children who were newly diagnosed with attention‐deficit hyperactivity disorder (ADHD) and who had never been exposed to stimulants and 10 control children without ADHD underwent polysomnographic studies to quantify Periodic Limb Movements in Sleep (PLMS) and arousals. Parents commonly gave both false‐negative and false‐positive reports of PLMS in their children, and a sleep study was necessary to confirm their presence or absence. The prevalence of PLMS on polysomnography was higher in the children with ADHD than in the control subjects. Nine of 14 (64%) children with ADHD had PLMS at a rate of >5 per hour of sleep compared with none of the control children (p <0.0015). Three of 14 children with ADHD (21%) had PLMS at a rate of >20 per hour of sleep. Many of the PLMS in the children with ADHD were associated with arousals. Historical sleep times were less for children with ADHD. The children with ADHD who had PLMS chronically got 43 minutes less sleep at home than the control subjects (p = 0.0091). All nine children with ADHD who had a PLMS index of >5 per hour of sleep had a long‐standing clinical history of sleep onset problems (>30 minutes) and/or maintenance problems (more than two full awakenings nightly) thus meeting the criteria for Periodic Limb Movement Disorder (PLMD). None of the control children had a clinical history of sleep onset or maintenance problems. The parents of the children with ADHD were more likely to have restless legs syndrome (RLS) than the parents of the control children. Twenty‐five of 28 biologic parents of the children with ADHD and all of the biologic parents of the control children were reached for interview. Eight of twenty‐five parents of the children with ADHD (32%) had symptoms of RLS as opposed to none of the control parents (p = 0.011). PLMS may directly lead to symptoms of ADHD through the mechanism of sleep disruption. Alternative explanations for the association between ADHD and RLS/PLMS are that they are genetically linked, they share a common dopaminergic deficit, or both.

Long-term follow-up on restless legs syndrome patients treated with opioids.

The medical records of 493 patients with restless legs syndrome (RLS) from three major centers were studied to determine the number and outcome of patients who had been treated with opioids as a monotherapy. At one time or another 113 patients (51 men, 62 women; age range, 37–88 years) had been on opioid therapy either alone (36 patients) or with opioids added secondarily to other medications used to treat RLS (77 patients). Twenty‐three of the 36 opioid monotherapy patients had failed dopaminergic and other therapeutic agents prior to the initiation of opioid monotherapy. Twenty of the 36 opioid monotherapy patients continue on monotherapy for an average of 5 years 11 months (range, 1–23 years), despite their knowledge of the availability of other therapies. Of the 16 patients who discontinued opioids as a sole therapy, the medication was discontinued in only one case because of problems related to addiction and tolerance. Polysomnography on seven patients performed after an average of 7 years 1 month of opioid monotherapy (range, 1–15 years) showed a tendency toward an improvement in all leg parameters and associated arousals (decrease in PLMS index, PLMS arousal index, and PLM while awake index) as well as all sleep parameters (increase in stages 3 and 4 and REM sleep, total sleep time, sleep efficiency, and decrease in sleep latency). Two of these seven patients developed sleep apnea and a third patient had worsening of preexisting apnea. Opioids seem to have long‐term effectiveness in the treatment of RLS and PLMS, but patients on long‐term opioid therapy should be clinically or polysomnographically monitored periodically for the development of sleep apnea.

Beyond Benzodiazepines: Alternative Pharmacologic Agents for the Treatment of Insomnia

OBJECTIVE: To review the epidemiology, etiology, and classification of insomnia and provide an overview of the pharmacologic therapy of insomnia. Novel nonbenzodiazepine hypnotics including zolpidem, zopiclone, and zaleplon, as well as nonprescription products such as valerian and melatonin, are reviewed in detail. DATA SOURCES: A MEDLINE search was performed to identify relevant clinical studies, case reports, abstracts, and review articles published between April 1992 and December 1997. Key search terms included insomnia, benzodiazepines, zolpidem, zopiclone, zaleplon, Cl 284,846, melatonin, and valerian. Additional references were obtained from the lists of review articles and textbooks. DATA EXTRACTION AND SYNTHESIS: Data concerning the safety and efficacy of the hypnotic agents were extracted from all available clinical trials and abstracts. Background information regarding insomnia, benzodiazepines, and other hypnotics was extracted from the most current literature, including review articles and textbooks. CONCLUSIONS: New developments in benzodiazepine receptor pharmacology have introduced novel nonbenzodiazepine hypnotics that provide comparable efficacy to benzodiazepines. Although they may possess theoretical advantages over benzodiazepines based on their unique pharmacologic profiles, they offer few, if any, significant advantages in terms of adverse effects. Over-the-counter agents such as valerian and melatonin may be useful in alleviating mild, short-term insomnia, but further clinical trials are required to fully evaluate their safety and efficacy.

Apomorphine for Motor Fluctuations and Freezing in Parkinson's Disease

Objective: To review the pharmacokinetics and use of apomorphine in patients with Parkinsons disease; to report a case of beneficial outcome with apomorphine in a patient with Parkinsons disease with severe levodopa “on-off” fluctuations and freezing; and to outline the types of patients or situations where apomorphine may be useful. Data Sources: Case reports, review articles, and relevant clinical studies identified by a MEDLINE search of the English-language literature published between 1975 and October 1994. Study Selection: Because all but 2 reports were of open-label design with small sample sizes, all studies identified were evaluated. Data Extraction: The following data were extracted from each study: apomorphine treatment duration, dosing, onset, duration, and adverse effects. The following efficacy variables were extracted: percent decrease in off periods, improvement in parkinsonian symptoms, and percent decrease in levodopa dosage. Data Synthesis: Efficacy of apomorphine following subcutaneous, rectal, sublingual, and intranasal dosage forms are evaluated. We also describe the use of apomorphine in a patient with Parkinsons disease who experienced on-off fluctuations and freezing. Based on these reports, recommendations for patient selection, product selection, and apomorphine dosing guidelines are presented. Conclusions: Apomorphine decreases off time, freezing, and levodopa requirements in patients with Parkinsons disease. It can be administered via a number of different nonoral routes; however, subcutaneous apomorphine is the most extensively studied. Rectal, sublingual, and intranasal routes also have been shown to provide benefit in motor fluctuations, but differ from the subcutaneous route in onset of action, duration of effect, and adverse effect profile.

“Subclinical” orthostatic hypotension is associated with dizziness in elderly patients with parkinson disease

OBJECTIVE To investigate risk factors associated with subjective complaints of dizziness in 12 elderly patients with Parkinson disease (PD), in whom no obvious cause for this symptom could be found. DESIGN A case-controlled study, with patients prospectively recruited in a nonblinded fashion. SETTING Patients were seen by one physician at a neurology outpatient clinic between August 1993 and August 1994. SUBJECTS Thirty-six patients, all over age 65 years and all with PD; 12 complained of dizziness; 24 did not. INTERVENTIONS Patients and controls were screened for blood pressure changes, postural instability, motor severity, multiple sensory deficits, drug use, cardiovascular disease, and diabetes mellitus. MAIN OUTCOME MEASURES An orthostatic decrease of systolic BP > 15 mmHg (odds ratio = 6.5; 95% confidence interval = 1.22 - 34.52; chi 2mh = 6.7; p < .01) and an orthostatic decrease of diastolic BP > 5mmHg (odds ratio = 11; 95% confidence interval = 3.15 - 38.39; chi 2mh = 7.14; p < .01) were significant risk factors for complaints of dizziness. RESULTS The only significant risk factors linked with dizziness were orthostatic decreases in systolic (15 mmHg) and diastolic (5 mmHg) blood pressure. CONCLUSIONS An orthostatic decrease in blood pressure is associated with unexplained feelings of dizziness in elderly PD patients.

A preliminary look at the percentage of patients with Restless Legs Syndrome who also have Parkinson Disease, Essential Tremor or Tourette Syndrome in a single practice

Therapeutic studies, dopamine receptor blocking studies andPositronEmissionTomographic(PET)scanstudiesimplicatethe dopaminergic system in the pathogenesis of the RestlessLegsSyndrome(RLS)(Comella,2002;Eisensehret al.,2001;Michaud et al., 2002; Ruottinen et al., 2000; Staedt et al.,1993;Trenkwalderet al.,1999;Turjanskiet al.,1999;Walterset al.,1991).Itisthereforeofinteresttodeterminewhetherawell-proven dopaminergic disorder, Parkinson Disease (PD),predisposes to RLS, but results of such inquiries have beencontroversial (Krishnan et al., 2003; Ondo et al., 2002; Tanet al.,2002)andnotincompatiblewiththelargeprevalenceofRLSinthegeneralpopulation(Phillipset al.,2000).Therehavebeennopreviousstudieslookingatthereverseprevalence, i.e. the prevalence of PD in RLS. In the currentstudywetakeapreliminarylookatthepercentageofpatientswithRLSwhohavePDinasinglepractice.Tourette Syndrome (TS) is also responsive to eitherdopamineantagonistsoragonistsandRLShasbeenreportedinupto59%ofpatientswithTS(Lipinskiet al.,1997).Thesedata also suggest a dopaminergic hypothesis for RLS. Wethereforelookatthereverseprevalence,i.e.thatofTSinRLSintheaforementionedpractice.PreviousliteraturesuggestsanincreasedprevalenceofRLSin Essential Tremor (ET) (Larner and Allen, 1997) and asubset of patients with ET may be at increased risk for PD(Jankovic,2002).ThisindirectevidencealsosuggeststhatthedopaminesystemmayalsobeinvolvedinRLS.We,thereforealsoagainlookatthereverseprevalenceofETinRLSintheaforementionedpractice.Insummary,basedupontheaforementionedliterature,theproposedaimofthecurrentstudyistotakeapreliminarylookto see if RLS predisposes to other neurologic disordersinvolving the dopaminergic system. We want to emphasizethatthecurrentstudyisnotatrueprevalencestudysinceourpopulationis(a)small,(b)notpopulationbasedand(c)wedonothaveacontrolgroup.All RLS patients currently in the practice of a singleneurologist(ASW)withexpertiseinbothMovementandSleepDisorderswereexaminedforthepresenceofPD,TS,andETatthetimeofreferralforRLS.RLSwasdiagnosedbythefourcriteria established by the International Restless Legs Syn-dromeStudyGroup(Walters,1995).PDwasdiagnosedbythepresenceofbradykinesia,rigidity,restingtremor,andposturalinstability. TS was diagnosed by the presence of motor andvocal tics. ET was diagnosed by the presence of tremor thatwas predominantly a non-intention postural action type andthe absence of any features suggesting PD or cerebellar/spinocerebellardisease.OnlypatientswhowerereferredforRLSwereenteredintothestudy.RLSpatientswereexcludedwhowerereferredforPD,TS,orET.BecauseourdatasuggestedamildincreasedpercentageofPDinRLS,wealsoexcludedtwopatientswhowerereferredforRLSorsleepdisturbance,butwhohadPDatthe time of referral. This was done to exclude the possibilitythatapatientwithbothPDandRLSwouldbemorelikelytobereferredtousthanelsewhere,asweserveasareferralcenterfor both disorders. Patients with atypical parkinsonism werealso excluded. Two patients were also excluded when thediagnosis(PDorET)wasuncertain.Forpurposesofcalculation,thesurveywasconductedatasingle time point in November, 2001. For all three disordersstudied(PD,TS,andET),wecomparedthepercentagesofourRLSpatientswhohadthesedisorderstoprevalencesfromtheliteraturetakingageandsexintoaccount(Table1).Theexactbinomialtestwasusedforcomparison.Tourette’ssyndromeisofjuvenileonsetandtheprevalencerateisfairlystableacrossadultagegroups.Therefore,TSwasdeterminedforall118ofour adult RLS patients of any age in the study (Table1).Because of the tendency for PD to be of later onset andbecause most studies in the literature use an age base of>50years, we confined our survey for PD to our 85 RLSpatients>50yearsofage(Table1).Becauseofthetendencyfor ET to be of later onset and because most studies in theliterature use an age base of >60years, we confined oursurvey for ET to our 56 RLS patients >60years of age(Table1).After exclusion, four (three males, one female) or 4.7% ofour85(47females,38males)RLSpatients>50yearsofagedevelopedPDafterbeingreferredforRLS(Table1).Allhadat least stageII PD at the time of the survey indicating

Clinically significant but unsuspected restless legs syndrome in patients with sleep apnea.

In this prospective study, the prevalence of clinically significant restless legs syndrome (RLS) with symptoms at least 2 to 3 days per week was 8.3% in 60 sequentially polysomnographically studied patients with clinically significant sleep apnea (Apnea Index score > 5 or Respiratory Disturbance Index score > 10). Age‐matched spouses were used as a control group and showed a comparable prevalence of RLS at 2.5% (not significant). Although RLS appears to be only slightly more common in sleep apnea patients than in controls, the importance of this study lies in the fact that clinically significant RLS occurred in 1 of every 12 patients with sleep apnea and, in every case, the RLS was unsuspected before polysomnography. We recommend that all patients undergoing polysomnography to rule out sleep apnea be screened for the symptoms of RLS. We have found the MEMO–NIH consensus conference questionnaire administered at the time of polysomnography to be useful in this regard.

High-Dose Clonidine in a Case of Restless Legs Syndrome

OBJECTIVE: To describe a patient with idiopathic restless legs syndrome (RLS). CASE SUMMARY: A 37-year-old man developed severe symptoms of RLS. Treatment using combinations of levodopa, opioids, benzodiazepines, and baclofen provided only partial benefit or resulted in intolerable adverse effects. Higher dosages of clonidine than previously reported in the literature (0.9 mg/d in divided doses) were needed to completely relieve his RLS symptoms. The only prominent adverse effect was dry mouth. The RLS symptoms returned after subsequent reductions in the dosage. After the dosage of clonidine was again increased, complete relief of the symptoms was achieved again. After several months, clonidine was tapered to zero and the patient entered a period of spontaneous remission. When his symptoms returned four months after clonidine had been discontinued, clonidine therapy was restarted. DISCUSSION: Clonidine alleviated RLS symptoms in 30 of 41 patients reported in the literature, indicating that the adrenergic nervous system may playa role in RLS. CONCLUSIONS: High-dose clonidine appears to be useful in treating RLS when other therapies fail. However, well-controlled, polysomnographic studies are needed.

Comparison of Internet and Community Pharmacies

Surfing the Internet for information and services is becoming a way of life. Healthcare professionals need to become aware of the advantages and disadvantages of filling prescriptions via the Internet. They should know why Internet pharmacies are growing as well as how patients can obtain prescriptions and drug information via the Internet. The prescription drug market is estimated to be