Painful Willis-Ekbom disease: unbearable and distinct form of restless legs?

1 Introduction

In this issue of the Scandinavian Journal of Pain, Samantha Kerr and coworkers report on the clinical severity and the description of the sensations of the painful (versus painless) form of Willis-Ekbom disease or restless legs syndrome (RLS) in a sample of English-speaking South-African patients [1]. The main results of this study are that painful RLS is clinically a more severe form of RLS (as measured by the international RLS severity scale [2]) and that painful RLS patients score higher and may select different and more intense sensory and affective words when their RLS sensations are evaluated using the McGill pain questionnaire [3]. These are important findings because they replicate and confirm the results of two previous studies [4], [5] conducted in sample populations (French and South-Korean) that are linguistically, culturally, and ethnically different from each other and from the current South-African one. Therefore, the results of the current study taken together with previous studies give further credibility and generalizability to the concept of a more severe and possibly distinct painful form of RLS.

2 Mini-review of the topic

From a medical terminology standpoint, it was proposed to summarize the four-essential clinical features of RLS by “movement-responsive quiescegenic nocturnal focal akathisia usually with dysesthesias” [6]. The core RLS component is the focal akathisia (sensation of an urge to move the limbs, mainly the legs) that occurs usually at nights/evenings (nocturnal), is triggered by rest/inactivity (quiescegenic), and is alleviated by movements/activity (movement-responsive) [7]. However, most of the time, this urge to move is associated in the same limbs with uncomfortable or unpleasant sensations (dysesthesias) that can be perceived as painful (Fig. 1) by a significant number of RLS patients [1], [4], [5], [8], [9], [10], [11].

Fig. 1:

Prevalence of painful restless legs (RLS) sensations in large clinical series [1], [4], [5], [8], [9], [10], [11]. Of note, although painful RLS sensations are common across all clinical series, with at least one-fifth of patients perceiving their sensations as painful, the difference between studies could be influenced by the method used for affectation status of painful versus painless RLS (spontaneous reporting by patients, direct questioning by investigators about painful perception of RLS sensations, etc.) and by distinct ethnic and cultural backgrounds.

Despite the central role of this sensory component (focal akathisia with dysesthesias including pain) in RLS, this disorder has been classified mostly as a movement and sleep/wake disorder. It is interesting to note that, while RLS in the 18th century was classified by the French physician Boissier de Sauvages de La Croix, in his Nosologia Methodica (treaty of classes of diseases), under the 7th class of Dolores (Pains) and the 1st order of Dolores Vagi (vague pains) [12], and while there is recent evidence showing similarities between RLS sensations and pain, RLS is not mentioned currently in the international pain taxonomy book Classification of Chronic Pain [13] nor in the Wall & Melzack’s Textbook of Pain [14]. Indeed, patients with either primary RLS or secondary RLS associated with small fiber neuropathy (taken all together without distinction of associated painful or painless RLS sensations) present static hyperalgesia to pinprick on quantitative sensory testing [15] like neuropathic pain syndromes. Moreover, there is evidence of involvement of the endogenous opioid system in RLS, with opioid treatments shown to be effective in alleviating RLS symptoms [16], while this effect is reversed by the opiate receptor blocker naloxone [17]. This is further evidenced by one neuroimaging study using opiate receptor PET scanning in RLS patients compared to healthy controls and suggesting an implication of the affective medial pain system with more severe RLS symptoms possibly associated with an increase in endogenous opioid release [18].

All of the above studies reinforce the idea of the sensory component of RLS being overall a possible atypical type of chronic pain, with the painful RLS form consisting of a more severe clinical variant in a sensations continuum [5]. For example, some RLS patients may experience a fluctuation in the severity and quality of their RLS sensations that can progress over time and years or just episodically intensify and change from non-painful to painful [5]. The episodic aggravation of RLS sensations and transformation into true pain may also be induced during perioperative time by certain drugs like droperidol in conjunction with forced immobilization [19]. Karl-Axel Ekbom, the Swedish neurologist who first coined in 1945 the term restless legs, was the first also to describe a typical paresthetic form of RLS (asthenia crurum paresthetica), that is very easy to diagnose, and an atypical painful form of RLS (asthenia crurum dolorosa), that kept him “continually perplexed” on how to classify it and diagnose it [20]. He ultimately stated at the beginning of his chapter on the painful RLS form: “The two forms do not differ fundamentally, however, but are probably only variants of the same basic disease” [20].

However, some patients may perceive the RLS sensations as painful from the onset of their disease [5] and recent clinical series (including the current study by Samantha Kerr and coworkers) not only showed a more severe painful form of RLS but also some specific differences in words used to describe the RLS sensations by the painful compared to the non-painful RLS patients [1], [5]. This could imply that at least several patients in the painful RLS group may have a distinct RLS phenotype or disease. In particular, the word burning is a common sensory symptom in small fiber neuropathy and one study showed that this subgroup of painful neuropathy is more often associated with RLS [21]. There is also a paucity of objective data comparing painful and non-painful RLS except for one recent retrospective study [4] that found that painful RLS patients have, in addition to more severe RLS symptoms (with more anxiety, depression, and poorer quality of life), lower ferritin levels and decreased periodic limb movement of sleep (frequently associated with RLS) with a longer latency to sleep onset on polysomnographic studies.

3 Conclusion

In summary, with the current study by Samantha Kerr and coworkers, evidence is mounting up on the severe and unbearable nature of the painful form of RLS. Given the lack of specific sensory tool to evaluate the severity of RLS sensations and pain, it would be of primary interest to develop such a scale to be used in clinical trials as a complementary measure to the international RLS severity scale [2]. Further objective investigation is needed before considering a distinct disease in at least a subgroup of painful RLS patients. This could include exploring the presence of small fiber neuropathy in painful versus non painful RLS by mean of quantitative sensory testing and skin biopsy as well as analyzing the difference in association of the two RLS forms with several genes recently linked with RLS in genome-wide association studies [22].