Diagnostic Standards for Dopaminergic Augmentation of Restless Legs Syndrome: Report from a World Association of Sleep Medicine – International Restless Legs Syndrome Study Group Consensus Conference at the Max Planck Institute

Abstract

Objectives

Augmentation of symptom severity is the main complication of dopaminergic treatment of restless legs syndrome (RLS). The current article reports on the considerations of augmentation that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored Consensus Conference in April 2006 at the Max Planck Institute (MPI) in Munich, Germany, the conclusions of which were endorsed by the International RLS Study Group (IRLSSG) and the World Association of Sleep Medicine (WASM). The Consensus Conference sought to develop a better understanding of augmentation and generate a better operational definition for its clinical identification.

Design and methods

Current concepts of the pathophysiology, clinical features, and therapy of RLS augmentation were evaluated by subgroups who presented a summary of their findings for general consideration and discussion. Recent data indicating sensitivity and specificity of augmentation features for identification of augmentation were also evaluated. The diagnostic criteria of augmentation developed at the National Institutes of Health (NIH) conference in 2002 were reviewed in light of current data and theoretical understanding of augmentation. The diagnostic value and criteria for each of the accepted features of augmentation were considered by the group. A consensus was then developed for a revised statement of the diagnostic criteria for augmentation.

Results

Five major diagnostic features of augmentation were identified: usual time of RLS symptom onset each day, number of body parts with RLS symptoms, latency to symptoms at rest, severity of the symptoms when they occur, and effects of dopaminergic medication on symptoms. The quantitative data available relating the time of RLS onset and the presence of other features indicated optimal augmentation criteria of either a 4-h advance in usual starting time for RLS symptoms or a combination of the occurrence of other features. A paradoxical response to changes in medication dose also indicates augmentation. Clinical significance of augmentation is defined.

Conclusion

The Consensus Conference agreed upon new operational criteria for the clinical diagnosis of RLS augmentation: the MPI diagnostic criteria for augmentation. Areas needing further consideration for validating these criteria and for understanding the underlying biology of RLS augmentation are indicated.

Introduction

Dopaminergic agents have been used for the treatment of restless legs syndrome (RLS) since 1982, when Akpinar first reported on the efficacy of levodopa (l-Dopa) in treating RLS symptoms [1]. Since then, the overall long-term efficacy of these drugs has been well established by several studies [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Side effects, although frequently reported, are generally mild and transient [12], and contrary to observations made during treatment with l-Dopa in Parkinson’s disease, no cases of dyskinesias have been reported to date [4], [12], [13], [14], [15].

Despite increasingly common use of l-Dopa treatment for RLS, it was not until 14 years after Akpinar’s case report that the first published report of an unexpected new adverse effect termed “augmentation” was published [16]. In 30 RLS patients who had been treated with l-Dopa, Allen and Earley [16] characterized this adverse effect by an earlier onset of symptoms in the afternoon (100% of their patients), as well as a faster onset of symptoms when at rest (56%), an expansion of symptoms to the upper limbs and the trunk (11%), an overall increase in the severity of symptoms when present (96%), and a shorter duration of effect of the medication. They felt this condition reflected an exacerbation of the underlying disease process for RLS, producing an augmentation of all the clinical symptoms of RLS as a result of dopaminergic treatment. During treatment with l-Dopa, RLS augmentation occurred in 73% of patients, and led to change of treatment in 50% of all patients [16]. They reported a delayed onset of augmentation usually occurring at least two months after initiation of l-Dopa treatment but often not until several months after treatment initiation. Moreover, augmentation produced symptoms that were worse than those seen at baseline, a feature that differentiates it from end-of-dose rebound and from tolerance.

Despite the obvious significance and common occurrence of augmentation, few clinical descriptions have been published [16], [17], [18], [19], [20]. In the absence of a standardized operational definition, clinical studies have used similar, but not the same, criteria. Recognizing the need to standardize clinical diagnostic criteria for augmentation, the 2002 National Institutes of Health (NIH)-sponsored Workshop on RLS Diagnosis and Epidemiology defined clinical criteria for augmentation as presented in Table 1[21]. This definition relied upon the four primary features of RLS weighted by their frequency of occurrence and ease of detection as described in the initial report by Allen and Earley, as well as recognition of the relation of these symptoms to adjustments in medication doses. However, this report made no mention of assessing the severity or clinical significance of augmentation.

A measure of augmentation severity (the Augmentation Severity Rating Scale [ASRS]) has since been developed and validated in an open-label, multicenter l-Dopa study conducted by the European-RLS Study group (EURLSSG; a subgroup of the International Restless Legs Study Group [IRLSSG; www.irlssg.org]) [22]. This study also provided some empirical data for diagnostic accuracy of specific features of augmentation. Given the new data and the development of clinical experience with RLS augmentation, the EURLSSG sponsored on April 25, 2006 an International Augmentation Study Group Consensus Conference at the Max Planck Institute (MPI) of Psychiatry in Munich, Germany, where international experts met to produce an updated consensus on a clinical definition of RLS augmentation. This report summarizes the basic clinical concept of augmentation and the final new diagnostic criteria discussed by the MPI Consensus group. The conclusions of this Consensus Conference were officially endorsed by the IRLSSG, and the WASM.