**2. RLS description and diagnosis**

RLS is described by the RLS foundation as a neurological condition that is characterized by the irresistible urge to move the legs. Patients will describe an uncomfortable itching or "creepy-crawling" sensation on the legs in the evenings and report that it feels like "bugs crawling under the skin." The IRLSSG has listed 4 essential criteria to clinically diagnose RLS. Physical examination is usually normal. There is no single test used which will make the diagnosis although many patients suffer from iron deficiency with low ferritin levels. While overnight polysomnography (PSG) in a sleep laboratory is helpful to assess periodic limb movements of sleep (PLMS), a PSG is not necessary to make the clinical diagnosis of RLS. PLMS are defined as a repetitive or periodic bursts of leg (or arm) electromyographic (EMG) activity during sleep associated with discrete, stereotypical movements of the legs or arms. PLMS are felt to be a related but separate disease from RLS. Although most (80%) patients with RLS with have PLMS on PSG testing, approximately 12-20% of RLS patients will not have evidence for PLMS (Montplaisir J et al., 1997). Approximately 30% of patients with PLMS will have RLS symptoms. The revised 2003 IRLSSG essential criteria include 1) An urge to move the legs accompanied or caused by uncomfortable sensations in the legs, 2) The urge to move or unpleasant sensations beginning or worsening during periods or rest or inactivity such as lying or sitting, 3) The urge to move or unpleasant sensations are partially or totally relieved by movements such as walking or stretching, at least as long as

Risk Factors and Treatment of Restless Legs Syndrome in Adults 161

After an initial 2002 meeting presentation where data from 100 multiple sclerosis (MS) patients with a prevalence of RLS of 32%was described, Auger et al reported a prevalence of 37.5% in their 200 French-Canadian MS patients meeting the 2003 IRRLSG criteria. Interestingly, in their patient population, more women than men met RLS criteria and 30% of patients reported that RLS symptoms started or worsened during pregnancy. A positive family history for RLS was reported by 36% of these French-Canadian patients meeting RLS criteria. They speculated whether MS plaque formation and involvement in the basal ganglia may be pathogenic for RLS in these patients. This concept may be supported by the therapeutic effect of dopaminergic therapeutic agents. The concept of potential common susceptibility genes for both MS and RLS is raised by the authors (Auger C et al, 2005). The following year, Kilfoyle et al reported a myelin protein zero (MPZ) mutation which was associated in the individuals studied with various neurological manifestations including

In 2007, Manconi et al examined prevalence of RLS in an Italian population of MS patients. In this population of 156 patients, 100 were female and a prevalence of 32.7% was found who met the 2003 IRRLSG diagnostic criteria. However, in contrast to the French-Canadian population, a positive family history for RLS was only reported by 5% of the (total) population. In the majority of these patients (> 90%), RLS symptoms followed or were simultaneous in onset with MS clinical features onset. The authors speculate that the coexistence of MS and RLS may be the result of a particular lesional pattern (Manconi et al, 2007). In a subsequent study of 82 MS patients of whom 30 patients had co-existing RLS, brain and cervical spinal cord MRIs were done. The MS and RLS patients were observed to have a greater degree of cervical cord involvement than those MS patients without RLS. The authors state that cervical cord damage represents a significant risk factor for RLS in MS

The Italian REMS Study Group, published the 'REstless legs syndrome in Multiple Sclerosis' or REMS study in 2008 in the journal SLEEP. This group reported a prospective, multicenter case-control epidemiologic survey which involved 20 sleep centers certified by the Italian Association of Sleep Medicine and included 861 MS patients and 649 control patients. They reported a 19% prevalence of RLS, using the IRRLSG criteria, in the MS patients compared to a 4.2% in the control population. This provided a relative risk for RLS in the MS patients of 5.4. Risk factors associated with RLS in the MS patients were identified as older age, longer duration of MS, the primary progressive form of MS, higher global, pyramidal, and sensory disability and the presence of leg jerks before sleep onset. Additionally, RLS symptom severity was reported to be worse in the MS patient group compared to symptoms of control group patients with RLS. The authors comment that their results strengthen the hypothesis that MS inflammatory lesions may induce a secondary form of RLS (The Italian

In a study of French patients with MS by Douay et al, the authors report a prospective evaluation of 242 MS patients and found 18% met the international RLS criteria, consistent with the REMS study report. In this French population, the authors reported RLS symptoms to be more frequent in patients with the relapsing-remitting form of MS (Douay et al. 2009). A Brazilian study of 44 MS patients reported by Moreira et al, found 27% of their patients met the RLS criteria. The authors did not observe any association of specific patient

**6. Clinical associations with RLS or secondary RLS** 

**6.1 RLS and multiple sclerosis** 

RLS and MS (Kifoyle DH, et al, 2006).

patients (Manconi et al, 2008).

REMS Study Group, 2008).

the activity continues, 4) The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night (Allen RP et al., 2003). Despite these revised guidelines, there are still difficulties in excluding mimics such as leg cramps that can confound the diagnosis and the specificity of the 4 diagnostic criteria is 84% (Hening WA et al., 2009). It has been suggested that the validated self-completed Cambridge-Hopkins RLS questionnaire (CH-RLSq) is more useful with a sensitivity of 87.2% and a specificity of 94.4%. (Allen RP et al., 2008). In addition to the diagnostic criteria, the IRLSSG developed a validated, patient-completed 10 item severity rating scale called the IRLS severity scale or IRLSSS (Walters AS et al., 2003).
