Restless Legs Syndrome

William G. Ondo

INTRODUCTION

Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is clinically defined by the presence of four positive criteria: (1) an urge to move the limbs with or without sensations, (2) worsening at rest, (3) improvement with activity, and (4) worsening in the evening or night. The diagnosis of RLS is exclusively based on those symptoms. The diagnostic criterion for children relies mostly of description from the child’s perspective, family history of RLS, and sleep disturbance. There is also an expanding literature linking RLS in children to attention deficit disorders.

Patient subjective semantic descriptions can be quite varied and tend to be suggestible and education dependent. The sensation is always unpleasant but not necessarily painful. It is usually deep within the legs and commonly between the knee and ankle. The key is to rephrase their description into a question asking if that sensation makes you want to move your legs. Essentially, all patients report transient symptomatic improvement from walking, although other movements also help. In general, harsh sensory stimuli can also mitigate RLS. Other clinical features typical for RLS include the tendency for symptoms to gradually worsen with age, improvement with dopaminergic treatments, a positive family history, and periodic limb movements while asleep (PLMS). Traditionally, the neurologic examination is normal in RLS; however, leg/feet stereotypies are sometimes present later in the day although usually suppressible.

In most cases, only a simple evaluation is justified for clinically typical RLS. Serum ferritin and iron-binding saturation for serum iron deficiency and electrolytes for renal failure should be obtained. It should be noted that severe iron deficiency may exist in the setting of a normal ferritin level because it is an acute phase reactant and increases with age. Nerve conduction velocities may be performed in atypical presentations (i.e., sensations beginning in the feet or superficial pain) or when physical symptoms and signs are consistent with a peripheral neuropathy. Polysomnographic evaluation is not generally needed. Several confounding diagnosis need to be considered (Table 75.1).

EPIDEMIOLOGY

Studies in predominantly Caucasian populations consistently show that between 5% and 15% of people have RLS, which is clinically significant in 2% to 3%. In general, northern European countries demonstrated the highest prevalence, followed by Germanic/Anglo-Saxon, then Mediterranean countries. The prevalence tends to decline the farther east one progresses, with lower rates in Asia. People from Africa have never been specifically studied but anecdotally, African-Americans only rarely present with RLS. Women usually have higher RLS rates; however, this female predisposition is lost in nulliparous women.

TABLE 75.1 Differential Diagnosis of Restless Legs Syndrome

Condition	How Different from RLS
Akathisia	Whole body urge to move, associated with dopamine blockers, not as circadian
Cramp	Chaotic visible/palpable muscle contraction, can be stopped by stretching muscle, no urge to move
Myalgia	Muscle ache, may be worse at night but no true urge to move
Neuropathic pain	Usually superficial, burning, electric, feet most involved
Radiculopathy	Usually asymmetric, more position dependent but not urge to move other than to move from painful position
Body positional discomfort	Can’t get comfortable in any position but not a true urge to move
Moving toes, painful legs	Slow writhing dystonic movement of toes/feet, not suppressible
RLS, restless legs syndrome.

PATHOBIOLOGY

Pathophysiologic studies show a number of objective abnormalities in RLS; however, our understanding is incomplete. The most robust observation is reduced central nervous system (CNS) iron stores, even in the setting of normal systemic iron studies. RLS patients show reduced cerebrospinal fluid CSF) ferritin, reduced iron on magnetic resonance imaging (MRI), especially in the striatum and red nucleus, reduced iron on CNS ultrasonography in the substantia nigra, and most importantly, reduced iron and ironrelated proteins at autopsy, including reduced H-ferritin staining, iron staining, and increased transferrin stains, but also reduced transferrin receptors. Researches also demonstrate reduced Thy-1 expression, which is regulated by iron levels. Substantia nigra dopaminergic cells are neither reduced in number nor are there markers associated with neurodegenerative diseases, such as tau or α-synuclein abnormalities.

Brain dopaminergic systems are also implicated in RLS by the dramatic improvement from dopaminergics. However, dopaminergic brain imaging studies are inconsistent and show modest or no abnormalities in a pattern that defies simple explanation and is interpreted by some to actually suggest increased dopamine turnover.

Iron and dopamine are intricately related. Although a number of theories explain the relationship, human data is lacking. The neural localization of RLS is also unknown. Functional involvement of the medial thalamus, cerebellum, and brain stem has been implicated
using functional MRI techniques. Spinal cord lesions often result in RLS and PLMS and animal models that lesion the diencephalospinal dopaminergic (A11) nucleus, which descends the spinal cord, mimic features of RLS in mice and rats, mostly increasing locomotor activity. Iron deprivation augments the phenotype.

Opioid pathways are implicated by clinical improvement seen with narcotics and pathologic data that shows reduced beta-endorphin-positive cells and Met-enkephalin-positive cells in six RLS patients compared to six controls. Glutaminergic activity is increased in the thalamus of RLS patients and correlates with arousal but not PLMS. Afferent systems are also implicated as shown by increased sensitivity to pinprick pain ratings (static hyperalgesia). These researchers felt this type of hyperalgesia was probably mediated by central sensitization to A-delta fiber high-threshold mechanoreceptor input, a hallmark sign of the hyperalgesia type of neuropathic pain.

In 40% to 60% of cases, a family history of RLS can be found, although this is often not initially reported by the patient. Twin studies also show a very high concordance rate. Many linkages have been identified in traditional familial studies but in no case has a specific gene mutation been identified. To date, six risk factor genes identified through genome-wide association studies have been published. The most robust associations include BTBDP, MEIS1, and PTPRD.

TABLE 75.2 Medications and Doses Used for Restless Legs Syndrome

Drug	Amount per Dose (mg)	Duration of Effect (h)	Comment
Dopaminergics: immediate effect, considered first-line therapy
L-Dopa	100-250	2-6	Positive class 1 trials, fast onset, can use PRN, highest augmentation rates
Pramipexole	0.125-1	5-12	Positive class 1 trials, commonly used, slower onset but longer duration, extended release available
Ropinirole	0.25-4	4-8	Positive class 1 trials, extended release preparations available
Rotigotine	1-4	24	Positive class 1 trials, commonly used patch preparation
Pergolide	0.125-1	6-14	Well studied (class 2) but seldom used due to risk of cardiac valve fibrosis and other possible ergot adverse events (AE)
Apomorphine	1-3	1	Injection of short-acting powerful drug, anecdotal PRN use
Cabergoline	0.25-2	>24	Longest acting but may have same AEs as other ergot DAs
Bromocriptine	5-20	4-6	Rarely used in RLS
Opioids: Numerous opioids are used.
Methadone	2-15	8-12	Open label data only, very good long-term tolerability and efficacy, several-day latency to benefit
Hydrocodone	5-10	4-10	Faster acting, shorter duration
Oxycodone	5-20	5-10	Best studied opioid
Alpha-2 delta blockers
Gabapentin	300-1,200	4-8	Small controlled trials, may help painful component of RLS
Pregabalin	50-300	6-12	Positive class 1 and 2 trials, not approved
Gabapentin enacarbil	600-1,800	8-16	Gabapentin prodrug with better absorption/bioavailability; positive class 1 trials, approved in the United States
Benzodiazepines: more beneficial for sleep than RLS, can be used in combination with other RLS medications. Clonazepam (0.5-2.0 mg) is traditionally used.
Oral iron	>50	?	No specific iron salt superior, titrate up as tolerated; minimal data of efficacy
IV iron	1,000	?	Usually not repeated before 3 months, several-day latency to benefit, long-term safety unknown, patients with normal serum ferritin equally responsive. Anecdotal evidence favors iron dextran preparations.
PRN, as necessary; DAs, dopamine agonists; RLS, restless legs syndrome; IV, intravenous.