History of Restless Legs Syndrome, Recently Named Willis–Ekbom Disease

IRLSSG Consensus Diagnostic Criteria for RLS (2012)

Restless legs syndrome (RLS), a neurological sensorimotor disease often profoundly disturbing sleep and quality of life, has variable expression influenced by genetic, environmental, and medical factors. The symptoms vary considerably in frequency from less than once a month or year to daily and the severity varies from mildly annoying to disabling. Symptoms may also remit for various periods of time. RLS is diagnosed by ascertaining symptom patterns that meet the following five essential criteria adding clinical specifiers where appropriate

Essential Diagnostic Criteria (all must be met)

1. An urge to move the legs usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs^{a, b}

2. The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting

3. The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues^c

4. The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day^d

5. The occurrence of the above features is not solely accounted for as symptoms primary to another medical or a behavioral condition (e.g., myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping.)^e

Specifiers for Clinical Course of RLS ^f

A. Chronic-persistent RLS: Symptoms when not treated would occur on average at least twice weekly for the past year

B. Intermittent RLS: Symptoms when not treated occured on an average of less than twice per week for the past year, with at least five lifetime events

Specifier for Clinical Significance of RLS

The symptoms of RLS cause significant distress or impairment in social, occupational, educational, or other important areas of functioning by the impact on sleep, energy/vitality, daily activities, behavior, cognition, or mood

^aSometimes the urge to move the legs is present without the uncomfortable sensations and sometimes the arms or other parts of the body are involved in addition to the legs

^bFor children, the description of these symptoms should be in the child’s own words

^cWhen symptoms are very severe, relief by activity may not be noticeable but must have been previously present

^dWhen symptoms are very severe, the worsening in the evening or night may not be noticeable but must have been previously present

^eThese conditions, often referred to as “RLS mimics,” have been commonly confused with RLS particularly in surveys because they produce symptoms that meet or at least come very close to meeting criteria 1–4. The list here gives some examples that have been noted as particularly significant in epidemiological studies and clinical practice. RLS may also occur with any of these conditions, but the RLS symptoms will then be more in degree, conditions of expression or character than those usually occurring as part of the other condition

^fThe clinical course criteria do not apply for pediatric cases nor for some special cases of provoked RLS such as pregnancy or drug induced RLS where the frequency may be high but limited to duration of the provocative condition

The IRLSSG diagnostic criteria reflect the view that WED is a neurological disease. Two other disciplines have defined WED as either a sleep-related disorder or a psychiatric disorder and in the process have unfortunately distorted the diagnosis to fit their particular discipline ignoring the neurological basis for this disease. So there is one correct set of diagnostic criteria (Table 30.1) and unfortunately two that err particularly in each having a totally arbitrary and different criterion not supported by data for frequency of symptoms required before the diagnosis can be made. RLS diagnosed independently by two neurologists experienced with RLS with 100 % agreement included 19 % who did not have symptoms at least twice a week (required by the sleep medicine diagnostic criteria) and 33 % who did not have symptoms at least three times a week [21b] .

Patient Advocacy

Since there had been little professional help available for treatment of WED, the patients themselves organized self-help groups and national organizations around the world to advocate for better recognition, treatment, and eventually a cure for the disease. The experience in the USA started with kitchen table meetings of three RLS patients: Pickett Guthrie, Virginia Wilson, and Robert Balkam. This developed into the current WED foundation with several thousand members and a regular “nightwalkers” publication. Early in this development another WED sufferer, Robert H Yoakum, a well-known humanist and author wrote an article on WED for Modern Maturity. This article produced more reader response as compared to others. More than 40,000 letters were sent to the magazine from older adults reporting relief that someone had identified the cause of their nighttime tortures. Thus, the WED foundation began its continuing campaign for recognition and acceptance of WED in the medical establishment. Today, there are active patient advocacy groups not only in the USA but also in most western European countries. They hold in conjunction with the IRLSSG an annual WED awareness day on Ekbom’s birthday.

Severity Assessment

Early in the development of WED evaluations, it became clear that a clinical scale was needed to assess WED severity. A scale called the IRLS, developed and validated in 2002 by the IRLSSG, has since provided a standard unifying clinical WED studies. This ten-item scale has scores ranging from 0 to 40, excellent psychometric properties [22, 23] and two subscales, i.e., symptoms and impact [23]. The scale has been translated into 32 or more languages and is available from Messaging Application Programming Interface (MAPI) Research Trust Patient-Reported Outcome & Quality of Life Instruments Database (Proqolid) at http://www.proqolid.org.

Epidemiology

The initial efforts to determine prevalence of WED used questionnaires asking patients about critical diagnostic symptoms. Efforts before the development of the full diagnostic criteria had a very limited set of questions missing some of the essential features of the diagnosis and produced surprisingly high prevalence, e.g., 15 % of French Canadians [24]. Subsequent better studies relied upon questions covering the four essential diagnostic criteria of IRLSSG and often added some assessment to identify clinically significant RLS. Among the best of these, the RLS epidemiology, symptoms, and treatment (REST) studies have served to define out the understanding of RLS prevalence in Europe and USA. The REST general population study documented a 7 % prevalence for RLS symptoms occurring in the past year and more significantly a 2.7 % prevalence for RLS sufferers, i.e., those with symptoms occurring in the past year usually at least twice a week with moderate to severe distress when occurring [25]. The REST study documents characteristics of the RLS sufferers including the increasing prevalence with age and a 2:1 female: male ratio. It is often misunderstood that these characteristics were not determined for all RLS but only RLS sufferers.

The developing understanding of WED mimics indicated that the questionnaire approach without any effort to correct for mimics would likely produce a low false positive rate. The 4-item questionnaire diagnosis compared in one large international study with trained physician diagnosis had, indeed, only a 58 % positive predictive value for identification of RLS sufferers [2]. In another study questions asking about the four diagnostic criteria compared to a validated questionnaire excluding mimics had only a 50 % positive predictive value [3]. It takes a very high specificity with reasonable sensitivity to obtain a reasonable positive predictive value for identification of a condition with about a 5 % prevalence. A questionnaire was then developed in a collaborative study involving Cambridge University and Johns Hopkins that included questions designed to exclude common “mimics.” The validation compared to a clinical interview found for ascertainment of WED in a population of blood donors a positive predictive value of 86 % [26]. This questionnaire has since been used in other studies and as expected showed that using questions covering only the four-diagnostic criteria has a low positive-predictive value of about 50 % [26]. Moreover, among those determined to have RLS by the Cambridge–Hopkins questionnaire about 8 % had very severe, 38 % severe, and 12 % mild WED as defined by the IRLS.

Thus, the estimated prevalence for WED in Europe and North America is about half that reported in most prior questionnaire survey studies, e.g., about 3–5 % for WED symptoms in the past year, 1–2 % for current clinically significant WED, and about 0.2–0.8 % for very severe WED. The studies conducted in Asia including India have produced conflicting results related to population and methods, but overall indicate lower prevalence than in Europe or the USA.

Biology

There have been two major historic developments in understanding the biology of WED involving iron and genetics. Iron deficiency had long been associated with increased risk of WED and oral iron treatments reversed or reduced WED symptoms [27, 28]. Most RLS patients, however, have normal blood levels of iron and iron-related proteins. This puzzle was resolved by a major breakthrough in understanding WED when magnetic resonance imaging (MRI) studies showed decreased brain iron in the substantia nigra for patients with normal peripheral iron [29] (see Fig. 30.1). This seminal work from Hopkins has since been confirmed by several other studies based on MRI [30], ultrasound [31–34], and autopsy. [35]. The biological basis for the brain iron loss remains to be determined but may reflect a metabolic disorder affecting iron transport to the brain or the distribution and maintenance of iron in the brain. An active body of research on iron metabolic disturbances and WED has been produced by Earley and Allen at Johns Hopkins in collaboration with James Conner at Penn State School of medicine. The important historic factor is that these documented a biological basis for WED involving the brain and thus WED is a neurological disease.