Clinical Science of Restless Legs Syndrome

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Chapter 6 Clinical Science of Restless Legs Syndrome

The masterful description of restless legs syndrome (RLS) in a monograph written over half a century ago by Ekbom,¹ even giving clues as to the pathophysiology, remains a classic in RLS literature. Perusal of the literature reveals that the great English physician Thomas Willis,² in the late 17th century, gave a tantalizing account of what appears to be the first description of RLS. What Willis described as “wherefore to some, when being a Bed, they betake themselves to sleep presently in the Arms and Legs, Leapings, and Contractions of the Tendons, and so great a Restlessness and Tossings of their Members ensue, that the diseased are no more able to sleep, than if they were in a place of the greatest Torture” seems to accurately reflect the description of an RLS patient as mentioned in the contemporary literature. The scientific community waited nearly two centuries before Wittmaack³ described RLS-like symptoms under the heading of “anxietias tibiarum.” Later, Beard⁴ in 1918 and Oppenheim⁵ in 1923 used the term neurasthenia for what appeared to be RLS-like symptoms. The description of leg movements caused by paresthesia during rest by Mussio-Fournier and Rawak⁶ in 1940 and of “leg jitters” by Allison⁷ in 1943 heralded the introduction of the term irritable legs by Ekbom in 1944,⁸ and finally restless legs in 1945.¹ Ekbom put RLS on firm footing as an organic neurological disorder and dispelled the myth of the past that RLS is of psychogenic origin. It took another 50 years to refine the diagnostic criteria⁹ for RLS with a later revision¹⁰ (four essential criteria and supportive and associated features), which were clearly enumerated by Ekbom in his classic clinical description. Clinicians and researchers are still groping for clues to understanding the pathophysiology, including the site(s) of origin of the sensorimotor components of RLS.^11,¹² An important reason for this intellectual failure is that there is no single diagnostic test for RLS. Clinical trials, epidemiological surveys, and studies to uncover the pathophysiology of RLS are hampered by the lack of a clear diagnostic test for the condition, although attempts have been made to find one by performing an overnight polysomnographic study (PSG), suggested immobilization test (SIT), and actigraphy. Clinicians and researchers have to depend on a purely clinical description, which can be extremely difficult, if not impossible in some cases, particularly in those with an atypical or uncommon presentation. There are certain conditions that may closely mimic RLS and certain conditions associated with RLS (symptomatic or comorbid), which must be recognized by clinical clues and in some cases by appropriate laboratory tests (see Chapter 18). The second reason is that RLS is almost certainly not a single disease. The heterogeneity of RLS is exemplified by phenotypical variation, linkage to different chromosomal localization, varying prevalence findings in European and North American compared with Asian epidemiological studies, differing electrophysiological and neuroimaging findings, and varying therapeutic responses to different classes of medications (e.g., dopaminergic drugs, anticonvulsants, opioids, and benzodiazepines), including iron treatment.

Phenotypical Variation

There are indications for two phenotypes for RLS:¹³ early onset (EO) (before the age of 45 years) and late onset (LO) (after the age of 45 years). But exceptions clearly occur, and for some genetic epidemiological investigations, earlier cutoffs may be meaningful. EO-RLS is more consistently associated with a possible family history, more slowly progressive course, and longer duration of the disease than LO-RLS. The latter progresses relatively rapidly, and generally patients seek medical advice within 5 years of onset of symptoms. LO-RLS is frequently secondary or symptomatic, whereas EO-RLS is primary or idiopathic. The other difference between these two phenotypes is that cerebrospinal fluid (CSF) ferritin levels are lower in EO-RLS than in LO-RLS.¹⁴ Another finding differentiating the two types is greater deficiency in brain iron in EO-RLS than in LO-RLS.¹⁵

Genetic Heterogeneity

An increased incidence of RLS (as high as 70%) has been noted in the first-degree relatives of idiopathic or primary cases.^16,¹⁷ A high concordance in monozygotic twins¹⁸ and complex segregation analysis^19,²⁰ suggest an autosomal dominant mode of inheritance. Linkage and association analyses have now documented significant RLS-associated variations in seven different chromosomes (see Chapter 8). Recently, four predispositive allelic variations in different genes have been found. One is the neuronal nitric oxide gene located near the 12q area that was first implicated in RLS.^21,²² The other identified genes (on chromosomes 2p. 6p, and 15q) are related to development and suggest that the basis for RLS may lie in the original elaboration of the nervous system.^23,²⁴

Dilemma With the Iron Deficiency Theory of Restless Legs Syndrome

The current hot topic of scientific research in RLS is the iron–dopamine connection,^11,²⁵ with clear evidence for the role of iron, and indirectly, for the role of dopamine in idiopathic RLS (see Chapter 11), at least in one major subgroup. Nordlander²⁶ first demonstrated improvement of symptoms with intravenous iron treatment. O’Keefe and associates²⁷ first reported low iron levels as measured by serum levels of ferritin, the primary storage protein for iron. The question of iron deficiency is important as such a deficiency may reduce the effective activity of the dopamine system. Various ways in which iron might influence dopamine have been suggested. Iron is needed as a cofactor for tyrosine hydroxylase, the rate-limited enzyme for dopamine synthesis, and therefore iron deficiency may impair the normal production of dopamine. Dopamine D₂ receptor is an iron-containing protein, and hence the hypofunction of D₂ receptor may be caused by iron deficiency. Both iron and dopamine show a circadian rhythm, with the lowest levels occurring at night when RLS symptoms are worse and exacerbated. The question of iron deficiency is particularly relevant in elderly patients who have low iron stores as measured by serum ferritin. RLS symptoms are often relieved by both iron and dopamine, whereas dopamine antagonists worsen RLS symptoms. Certain conditions (e.g., iron deficiency anemia, pregnancy, and end-stage renal disease) predisposing to RLS often have low iron stores. Further support for the role of iron in RLS includes the inverse correlation of body iron stores to the severity of RLS, improvement of RLS symptoms after both oral and intravenous iron treatment,^28,²⁹ and CSF^14,³⁰ and special neuroimaging findings³¹ showing decreased brain iron in RLS patients. Transcranial Doppler study³² showing hypoechogenicity in the substantia nigra (SN) also suggests reduced iron in the SN in RLS patients. The pharmacological facts complement imaging studies showing striatal dopamine abnormalities (see later). Finally, limited postmortem findings in seven cases of RLS showing no morphological abnormalities in the basal ganglia but a problem with iron acquisition and storage in the SN firmly established the role of brain iron deficiency in RLS symptomatology.³³ There are, however, some inexplicable contradictions in two different autopsy findings from the same group. The initial finding of increased transferrin receptor concentration in the SN could not be corroborated in the second quantitative autopsy study.³⁴ The second study found decreased activity of iron regulatory protein 1 (IRP1) controlling synthesis of transferrin receptors. Brain iron storage problems are not always reflected in the blood iron and ferritin levels; herein lies the dilemma. Not all iron-deficient states are associated with RLS and not all RLS patients show iron deficiency, either by laboratory techniques or by therapeutic response. There is a single report of a randomized double-blind placebo-controlled trial of oral iron supplementation failing to show any significant difference in RLS symptoms with treatment.³⁵ Should we, therefore, label the group of RLS with decreased iron or ferritin primary or comorbid (symptomatic) RLS or a special phenotypical variant of primary RLS, suggesting RLS heterogeneity? Another unanswered question is the reason for brain iron storage problems. Is it simply an epiphenomenon, a triggering factor, an incidental finding unrelated to RLS symptoms, or secondary to sleep deprivation or fragmentation disturbing iron metabolism?

Controversy Regarding the Dopamine Deficiency Theory of Restless Legs Syndrome

The dopaminergic theory of RLS is popularized predominantly on the basis of the therapeutic response noted in every patient, at least initially, and supplemented by neuroimaging findings that have been inconsistent. There is compelling indirect, but not direct, evidence that there is a dopamine deficiency in RLS. The first clue to the current popular dopaminergic deficiency theory of RLS came from Akpinar’s letter to the editor in 1982 ³⁶ showing improvement of RLS symptoms after levodopa ingestion. This brief report opened therapeutic avenues for alleviating RLS symptoms. Subsequent reports show that even a low dose of dopamine nearly always relieves RLS symptoms; this is the basis of a diagnostic test using L-dopa and looking for a response in reduced symptoms.³⁷ Several open-label and double-blind clinical trials demonstrated the efficacy of dopaminergic treatment in RLS,^38,³⁹ whereas dopamine antagonist worsened the RLS symptoms. Exacerbation of RLS symptoms in the evening when dopamine activity in the body is at its lowest level; exacerbation of RLS symptoms with iron deficiency, which may reduce the production of dopamine, and increasing frequency of RLS symptoms with increasing age when dopaminergic neurons show age-related depletion may be cited as indirect evidence in support of dopaminergic theory in the pathophysiology of RLS. CSF studies from the Johns Hopkins University group⁴⁰ show no significant differences in homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), which are dopamine metabolites between RLS patients and control subjects, but did show increased CSF tetrahydrobiopterin, whereas Stiasny-Kolster and colleagues⁴¹ found no significant differences for HVA, tetrahydrobiopterin (BH4), and several other dopamine-related metabolites between 22 RLS patients (CSF samples obtained in the evening) and 11 control subjects. A comparative study of evening and morning samples showed that the RLS subjects showed an increased circadian difference between day and night in these values, with higher concentrations found in the morning.⁴²

The pharmacological facts complement some neuroimaging studies showing evidence of presynaptic or postsynaptic dopamine deficiency, but other studies have not confirmed these conclusions (see later). Therefore, besides the therapeutic response to dopaminergic medication, the rest of the studies involving the dopamine system, including neuroimaging studies, CSF analysis of dopamine metabolites, and limited autopsy studies do not provide convincing evidence of a primary dopaminergic deficiency syndrome. Certainly, RLS is not Parkinson’s disease (PD), an example of a clear nigrostriatal dopamine deficiency (dopaminergic A9 cell degeneration) syndrome. Does this mean that RLS is due to a defect (functional or structural) in the diencephalospinal dopaminergic (A11 neurons) pathways? It is possible, but at present, this is pure speculation. What is needed is an animal model of RLS, but this is currently lacking. Ondo and associates ⁴³

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