The publications of the International Restless Legs Syndrome Study Group (IRLSSG) in 1995 [2] and in 2003 [3] emphasized the four essential criteria together with supportive and associated features (Tab. 1), and these have been considered the in-ternational standard for the diagnosis of RLS. Diagnostic criteria are considered mandatory for definite diagnosis, while supportive clinical features may increase the probability of diagnosing RLS in doubtful cases, and associated features are common but do not contribute to the diagnosis.
Epidemiological findings
Recent epidemiological analyses of different populations, applying the International Diagnostic Criteria for RLS, have provided more detailed information and a preva-lence rate ranging from 5 % to 15 % of the general population. Prevapreva-lence seems to increase with age, although reports of onset before 20 years of age are not uncommon in clinical studies [4, 5], and may decrease with age in elderly men and remain stable in elderly women [6]. There is a female preponderance ranging from 13 % to 17 % [6, 7]. Recent Asian surveys [8, 9] indicate a lower prevalence in those populations (1.5 % in Japan and 1 % in Singapore), but a larger body of data is necessary to
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effectively show racial differences. Two recent large epidemiological surveys in the general population and in primary care reported new and interesting data. Among 4310 German participants (20–79 years) the overall prevalence was 10.6 %, increas-ing with age, and double in females compared to males. Interestincreas-ingly, the risk of RLS increased evenly and the data confirmed the association with a lower quality of living for RLS patients [10]. In a small rural US primary care practice, 24 % of 2099 pa-tients positively responded to the four essential criteria for RLS diagnosis, and 15.3 % reported suffering from the symptoms at least weekly [11]. Methodological issues and highly selected population may explain this high rate of prevalence. Elsewhere, in a Turkish population (3234 adults interviewed) a face-to-face study indicates a lower RLS prevalence (3.2 %), highlighting the frequency (mostly> 15 days/month) and the rate increasing with age, especially in males [12]. Prevalence estimates vary considerably probably because some epidemiological studies are based on clinical patient populations and are not representative of the general population. Moreover, the influence of variable genetic susceptibility or environmental factors may de-termine regional variations. Finally, different methodological tools (questionnaires, telephone interviews, direct observations) and different diagnostic criteria may ex-plain some of these differences.
Clinical diagnostic features
An urge to move the legs usually accompanied or caused by uncomfortable and unpleasant sensations in the legs
Sometimes the urge to move is present without the uncomfortable sensations, and sometimes the arms or other body parts are involved in addition to the legs. Gener-ally sensory and motor symptoms are present together in the same patient, but the sensory or motor component may prevail, creating some difficulties in explaining the symptoms: the sensations are usually described as something uncomfortable deep in the legs, usually between knee and ankle. From 30 % to 50 % of RLS patients may complain of sensations involving the arms, although symptoms in the arms only, without involving the legs are rare and atypical, as is extension to other parts of the body. The presence of only an urge to move without sensory symptoms is unusual but may occur [3].
The urge to move or unpleasant sensations begins or worsens during periods of rest or inactivity such as lying or sitting
This criterion describes the typical arrival of symptoms when the period of rest is prolonged, and there is an increase in sensations and the urgent need to move the legs. These typical features emerge during long rest periods, lying down in bed in the evening, and made it possible to come up with a test that reflected the increase in the severity of sensory symptoms and urge to move with the length of the rest or immobile period (Suggested Immobilization Test, SIT) [13].
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The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues Generally, the relief brought about by movement is immediate and lasts as long as the activity continues. Different activities may lead to a reduction in RLS symptoms, but all patients are aware that some are better than others in providing relief: walking, stretching, massages or other actions such as hot or cold baths or putting the legs under the shower provide the most typical relief for the symptoms. In contrast, physical activity during the day, even if intense and prolonged generally does not achieve the same effect, and in many cases may exacerbate the evening/night symptoms.
The urge to move or unpleasant sensations are worse in the evening or at night than during the day, or only occur in the evening or at night. When symptoms are very severe, the worsening at night may not be noticeable but must have been previously present. The circadian effect on RLS is well documented by the reports of patients even when the symptoms are also present during the day. It seems independent from the rest and recumbent position, and it is also applicable to PLM [14]. Recent studies on circadian variation of RLS and PLM during sleep (PLMS)/PLM during wakefulness (PLMW) confirmed previous findings on prevalence between midnight and 4 am (acrophase at 3 am) and a decrease from 6 am to noon (acrophase 10–11 am) [15]. The profile of variations in leg discomfort and PLM correlate with core body temperature and salivary melatonin: most PLM occur during the falling phase of circadian temperature curve and the lowest number during the rising phase [14, 15].
Supportive clinical features Positive family history of RLS
Different clinical and epidemiological studies indicated that more than 60 % of RLS patients have a positive family history for RLS, at least for primary forms [16–18]. A definite or possible positive family history was found in 54.9 % of patients with id-iopathic RLS, but in only 17.5 % of patients with RLS associated with uremia [17].
Bimodal distribution seems to be associated with distinct etiological and clinical features: primary form, familial pattern, mild and slow progression for early onset, and secondary/primary form, sporadic pattern, moderate to severe form and frequent low serum ferritin for late onset [19]. Segregation analysis of families suggests that those families where individuals experience early onset (mean onset before age 30) demonstrate a pattern of familial distribution most consistent with a dominant inher-itance [19]. Genetic linkage studies found both recessive and dominant models of inheritance [20–22] with different disease-susceptibility loci on chromosomes 12, 14 and 9. It seems very likely that other linkages will be located, and most consider that RLS will turn out to be a genetically ‘complex disorder’ with heterogeneity in inheritance and different potential contributing genes, most with small effects and whose importance may vary from population to population [23].
Response to treatment
Several controlled studies [24–30] have shown that most people with RLS have a positive therapeutic response to dopaminergic drugs. These medications improve
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both the sensory and motor symptoms of RLS. The drugs included the precursor of dopamine [24, 25] and dopamine-receptor agonists [26–30]. Based on clinical expe-rience, more than 90 % of patients report some relief of their symptoms when treated with these agents. The positive response at a very low dose of medication indicates that when dopaminergic agents are effective, the diagnosis of RLS is confirmed. It is still necessary to define whether mimic disorders (neuropathic pain syndromes, painful legs and moving toes, leg akathisia or generalized akathisia; nocturnal leg cramps, propiospinal myoclonus, neuropathies, radiculopathies,) are also responsive to these drugs [23].
Periodic limb movements
PLMS has been classically described as a rhythmic extension of the big toe and dorsiflexion of the ankle, with occasional flexion at the knee. A PLMS index (number of movements per hour of sleep) of more than 5 present in at least 80–90 % of RLS cases during at least one of two nights of sleep recording and a PLMS index of 11 on either of the two consecutive nights of recording provide the optimal sensitivity and specificity for a diagnosis of RLS [31, 32]. This study demonstrated the night-to-night variability in the PLMS index and, therefore, the advantage of recording PLMS over several nights. Future developments in activity meters to measure PLMS may facilitate the recording of PLMS over several nights and may thereby enhance the value of this measure for supporting the diagnosis of RLS. Research results from the polysomnographic studies have shown that people with RLS frequently have PLMW. Using the SIT, the presence of PLMW in RLS patients can be considered as supporting the diagnosis [32]. Although the presence of PLMS is not RLS specific, an elevated PLMS index also supports RLS diagnosis. During both the sleep period (WASO) and the SIT, PLMW appear to be more specific for RLS, but the data for this finding remain limited [13, 33]
Associated features of RLS
Natural clinical course of the disorder
The age of onset of RLS is known to vary from childhood to more than 80 years of age [34–37]. RLS is generally a chronic condition, but it may have different phenotypic patterns of expression: mild, occurring less than once a week or even once a month, variable with long periods of remission and sometimes only occurring for a limited time of life, waxing and waning of symptoms depending on the season or the condition of the patient, moderate to severe, occurring frequently up to every evening/night. For patients who begin experiencing RLS in their young adult life, the severity and frequency of symptoms typically increase over time [34]. No long-term follow-up studies are available to establish the natural history of RLS both for primary and secondary forms. Those with disease onset in late adult life have been found to have a generally more rapid development of symptoms and to have no clear correlation between symptom severity and age [36, 37].
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Sleep disturbances
These refer to the subjective experience of disrupted sleep, including difficulty in falling asleep, reduced sleep time, increased amount of awakening with symptoms.
Thus, RLS presents two problems for sleep: falling sleep and staying sleep. Insomnia may be the only symptom that patients report because many of them do not realize that the sensory symptoms or the urge to move is the main cause for finding it hard to fall asleep or for waking up. For patients with mild RLS, sleep disturbance may be less of a problem. Sometimes patients have disturbances during the day in forced-rest conditions and slight symptoms right at the time of falling sleep, but their presence increases at night awakenings. Others describe some mild symptoms at sleep onset, which easily resolve with small movements or cease when the patients fall asleep.
Even with successful treatment of the symptoms, patients with RLS may continue to have sleep problems, perhaps due to learned responses or classical conditioning leading to insomnia [37].
Medical evaluation/physical examination
A neurological examination is normal in patients with the primary form of RLS, but patients with late-onset RLS symptoms and secondary forms may show evidence of a peripheral neuropathy or radiculopathy [38]. Apart from the established causes of secondary RLS, there are no known physical abnormalities associated with RLS.
A low to normal serum ferritin level (45–50 mg/L) has been related to increased severity of RLS, and may be associated with an increased risk of the occurrence of RLS even in patients with normal hemoglobin levels [37, 39]. Therefore, evaluations of serum ferritin levels and percentage of iron saturation are highly recommended as part of the medical evaluation for RLS.
Secondary RLS and associated pathologies
Among the pathologies associated with RLS, several groups [38, 40] have reported neuropathies and radiculopathies. Evidence of peripheral axonal neuropathy of a mild degree was found in some putative idiopathic RLS patients through electro-physiological (EMG/NCV) and psychoelectro-physiological tests, subsequently confirmed by sural nerve biopsy [41]. These data have recently been confirmed in 30 % of 22 patients by means of skin biopsy, and related to late onset associated with pain-like symptoms [42].
Rheumatoid arthritis has been reported to be associated with RLS in up to 25 % of cases [43], but serological analysis of 68 RLS patients failed to find association with rheumatological serologies [44]. The same holds true for diabetes, often reported in association with RLS; however, a recent extensive clinical study did not find a significantly higher prevalence of RLS in diabetic patients [44]. Neuropathies associated with rheumatoid arthritis and diabetes may be the cause of RLS in these patients. In patients with end-stage kidney disease, reports showed a mild or overt (from moderate to severe) RLS in up to 62 % of cases [45, 46]. No correlation with iron levels or other uremia characteristics such as a decrease in parathormone levels has been found [46]. Parkinson’s disease (PD) has frequently been associated with
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RLS, and studies have pointed to the efficacy of dopaminergic treatment for both pathologies. A recent study by Ondo et al. [47] found that 20.8 % of 303 PD patients met RLS diagnostic criteria. In contrast, a similar study conducted in Singapore among 125 PD patients did not find any case satisfying IRLSSG criteria for RLS [48]. There are no clinical studies associating RLS with myelopathies; only case descriptions have reported RLS concomitant with lesion of the spinal cord. de Mello et al. [49] found a high frequency of RLS and PLMS in spinal cord injuries (T7–
T12), with symptoms attenuated after physical activity. PLMS have frequently been reported in association with spinal cord lesions, irrespective of the nature of the lesions. We detected PLMS in 36 % of 25 patients with multiple sclerosis, correlated with high magnetic resonance imaging lesion loads in infratentorial regions [50].
Iron metabolism has been extensively evaluated in RLS, in particular by the Johns Hopkins Group in Baltimore [36, 37, 51, 52]. There is a frequent association between RLS, anemia and low serum levels of ferritin [36, 51, 52]. Recent research has shown low ferritin levels and high transferrin concentrations in CSF of patients with RLS, sometimes despite high or normal serum iron levels, suggesting an alteration of blood-brain barrier transport [51]. Pregnancy may induce RLS symptoms or make a pre-existing form of RLS worse. Pregnancy-related RLS usually reaches the highest severity during the third trimester and tends to disappear around the time of delivery.
The reasons for the association between pregnancy and RLS are unclear. Since the iron and ferritin levels physiologically decrease in late pregnancy, and lower values of plasmatic iron storage indicators have been demonstrated in pregnant women with RLS, compared to unaffected pregnant women, the pathogenetic role of iron in this RLS form has been put forward [53].