Evaluating the prevalence of PD in populations presenting with RLS is problematic, since PD symptoms would usually be more overt and precipitate an evaluation. Banno et al., however, reported that “extrapyramidal disease or movement disorders” were previously diagnosed in 17.5 % of male RLS patients vs. 0.2 % of male controls, and in 23.5 % of female patients vs. 0.2 % of female controls (p < 0.05). They did not clarify whether they felt that these prior diagnoses were correct or truly represented a different disease [3]. In an abstract, Fazzini et al. reported that 19/29 RLS patients had PD symptoms [55]. In contrast Walters et al. reported no patients presenting with RLS who had PD [56]. As part of the Health Professional Follow-up Study, employing only written questionnaires for RLS in men, Gao et al. reported a slight increased risk for PD in mild (<15 days/months) RLS of 1.1 [95 % C.I.: 0.4, 3.0] and a stronger association with more severe (>15 days/month) RLS of 3.09 [95 % C.I.: 1.5, 6.2]; p trend = 0.003 [57].

Over 15 years we collected 36 cases in which subjects developed RLS long before PD, and/or had a family history of RLS in a first-degree relative and had well-documented RLS before the onset of their PD. In this RLS/PD group, 13 were female, 18 had a positive family history of RLS, and 6 had a family history of PD. We compared these to a “control” group of idiopathic PD without RLS: N = 36, ten females, one with family history of RLS, nine with family history of PD. The age at motor onset of RLS/PD was older (64.25 ± 6.4 years vs. 56.8 ± 10.7) than for patients with idiopathic PD (p ≥ 0.001). Patients with idiopathic PD developed dyskinesia more (21/36) than RLS/PD (4/32) at last follow-up (p = 0.0001). PD phenotype and L-dopa dose were similar. We concluded that idiopathic RLS may actually delay the onset of PD, reduce dyskinesia occurrence, and possibly reduce progression of PD. This is potentially supported by aforementioned pathological studies that show increase dopamine turnover in RLS, and reduced iron, as opposed to increased iron seen in PD. Assessments of brain iron in this unique group (idiopathic RLS followed by PD) have not been done.

Recently Wong et al., using a written RLS questionnaire without interview, evaluated for incident diagnosis of PD in 22,999 U.S. male health professionals age 40–75 years enrolled in the Health Professionals Follow-up Study [58]. They found a moderate increased rate of PD diagnosis within 4 years of RLS but not after 4 years. Since the pathologic process of PD begins years before the clinical diagnosis, they postulated that RLS may be an early feature of PD, preceding motor signs, similar to REM behavioral disorder.

It is the author’s opinion that the RLS phenotype is associated with PD but that it derives from a different pathophysiology than idiopathic RLS, perhaps a consequence of reduced CNS dopamine. There is no clear evidence of reduced dopaminergic tone in RLS, despite its robust response to dopaminergics. Therefore, PD is a risk factor for RLS symptoms, but RLS pathophysiology and idiopathic RLS symptoms are not risk factors for PD.

Periodic limb movements of sleep (PLMS) are defined by the American Academy of Sleep Medicine as “at least four periodic episodes of repetitive and highly stereotyped limb movements that occur during sleep.” The incidence in the general population increases with age and is reported to occur in as many as 57 % of elderly people [59, 60]. Renal disease and a number of neurological conditions are associated with higher rates. Typically the movements involve various degrees of flexion of the toes, ankles, knees, and hips (triple flexion response), although other patterns are seen. The anterior tibialis is the most affected muscles and the one usually used to assess electromyographic signals to quantify PLM. The physiology of PLM is only partially understood but thought to result from disinhibition of the spinal cord [61]. Autonomic lability with transient hypertension and tachycardia accompany PLM and could be an argument to more aggressively treat the condition when it is not thought to otherwise cause any clinical disability [62]. An expanding body of research has epidemiologically associated PLM with cardiovascular disease [63, 64]. The term periodic limb movement disorder is appropriate when idiopathic PLMS are thought to independently result in disability.

PLMS are strongly associated with RLS. One large study reported that 81 % of RLS patients showed pathologic PLMS [65]. The prevalence increased to 87 % if two nights were recorded. Although PLMS accompany most cases of RLS, data evaluating RLS prevalence in the setting of polysomnographically documented PLMS found that only 9 of 53 (17.0 %) PLMS patients complained of RLS symptoms [66]. Therefore, most people with RLS have PLMS but many patients with isolated PLMS do not have RLS. Although the exact relationship between the two phenotypes is unclear, genetic research suggests a strong biological association [11].

PD is also associated with higher rates of PLMS in most [1, 67, 68], but not all reports [69, 70]. There is more compelling evidence that when present, PLMS correlate with the severity of PD, both clinically and on imaging studies [68, 71]. The clinical consequences of PLMS in PD are less clear. One study reported that greater PLMS was associated with more subjective sleep disturbance, and decreased Quality of Life Scales, but this was largely explained by an association of PLMS with more advanced disease. The same study found and association of PLM and REM behavioral disorder, which interestingly has also been seen in patients presenting with RBD but without PD. Other objective measures of sleep, including sleep efficiency, have not been associated with PLMS in PD [68]. Several other PSG studies, none of which primarily evaluated PLMS, have not reported an association of PLMS with daytime sleepiness. One study that performed PSG studies in PD subjects with and without RLS did find that PLMS were more common in the PPD/RLS group [48]. In contrast another study segregating PD based on the presence of PLMS did not find higher rates of RLS in the PLMS+ group [68].

The assessment of PLMS in PD is clearly confounded by dopaminergic treatment, which improves PLMS in general, and does improve PLMS specifically in PD in one prospective trial [72]. Another retrospective report in PD suggests benefit of clonazepam for PLMS [73] but there has never been any controlled treatment trial of PLMS in PD.

No formal study has ever prospectively assessed the treatment of RLS in the setting of PD. Anti-cholinergic and anti-histaminergic drugs, including amitriptyline, mirtazapine, quetiapine, and many others used in PD, can exacerbate RLS in general and should be discontinued if possible. One may consider checking serum ferritin and supplementing this if low; however, it is not known whether this could affect the PD course. Dopamine agonists and levodopa improve RLS as well as PD, so adjustment of these medications may improve RLS. A PSG study found that PD patients already treated with clonazepam had fewer PLM and less daytime sleepiness than those not treated with clonazepam [73].

Interestingly, several reports suggest that CNS surgeries for PD may affect RLS in the PD/RLS population. Rye first reported a single case of RLS symptoms improving in a PD patient following pallidotomy [74]. Driver-Dunkley et al. found RLS in 6/25 PD subjects prior to undergoing bilateral DBS of the subthalamic nucleus (STN) [42]. All six had some improvement in RLS at 3–24 months after DBS. Three had complete resolution and the mean International RLS rating scale improved by 84 %. PD medications were lowered by 56 % and the UPDRS “off” motor scores improved by 63 %, suggesting an excellent clinical response to the DBS. As part of a larger assessment of STN DBS in sleep, Chahine et al. reported improved IRLS scales in six subjects with PD/RLS [75]. In contrast, Kedia et al. reported the emergence of RLS after STN DBS postoperatively in 11 of 195 patients. The mean reduction in antiparkinsonian medication was 74 %, which they felt may have unmasked the RLS symptoms [76]. Parra et al. also reported a case of RLS emergence after DBS [77]. We recently performed a bilateral GPi DBS in a patient with idiopathic RLS without PD. She demonstrated moderate benefit [78].

The majority of studies suggest that RLS is more common in PD than in the general population. Most studies of predominately Caucasian populations demonstrate a >2× rate of RLS in PD compared to the normal population. PD/RLS rates in Asian surveys are less, as are the baseline rates of RLS but still greater than control populations. Reported risk factors for RLS in the PD population include reduced serum iron stores, older age, younger age, depression, and worse PD. RLS symptoms severity is less than those seeking treatment for idiopathic RLS but may be similar to the idiopathic RLS population in entirety. Although the data is mixed, the overall effect of RLS on daytime sleepiness and quality of life in PD is probably modest. Importantly, there is no good evidence to suggest that RLS is a forme fruste of PD, and in fact the pathophysiologies are markedly different, despite similar responses to dopaminergic medications. Therefore, it appears that RLS is one of many non-motor features intrinsic to PD, presumably secondary to dopaminergic loss, although this is not actually known.