From 1685 to 2008: An Introduction to Restless Legs Syndrome

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Chapter 3 From 1685 to 2008: An Introduction to Restless Legs Syndrome

Restless legs syndrome (RLS) is a dysesthesia that is difficult for patients to define. There is a great variability in the wording of its description. Some patients have used phrases such as “water running under my skin” or “a snake inside my legs.” They have described twitching, burning, and irritating sensations. The result of the dysesthesia is an urge to move. The symptom appears nearly exclusively at rest and is at its peak in the evening or early part of the night.

It was very accurately described by Thomas Willis in 1685.¹ The dysesthesia disturbing the sleep of patients was characterized as follows:

“Wherefore to some, when being abed, they betake themselves to sleep, presently in the arms and legs, leapings and contractions of tendons, and so great the restlessness and tossing of their members ensure, that the diseased are no more able to sleep, than if they were in a place of greatest torture.”

Even by 1685, it was indicated that “RLS” could involve not only the legs but also the upper extremities. In a bibliographic search in 1994, we found that there had been over 150 different remedies in many different countries proposed between the 18th and 20th centuries. In many European countries, this internationally recognized syndrome was named from a word derived from the Latin term impatiens and affects more “limbs” than “leg.”

RLS was once considered to be a form of hysteria. In 1861, Wittmaack ² coined the term anxieties tibiarum. In 1923, Oppenheim³ pointed out that RLS could be described as a neurosis that could be familial or inherited. In 1940, Mussio-Fournier and Rawak⁴ affirmed the neurological origin of RLS and made the initial observation that RLS was exacerbated during pregnancy; several years later, they re-emphasized that upper limbs may be involved.⁵

The term “restless legs syndrome” was coined in 1945 by Ekbom,⁶ who also defined all the clinical features of the syndrome.^6,⁷ He maintained that there was a vascular etiology for the syndrome and recommended vasodilators as treatment. Since that time, the presence of a circulatory disturbance has been investigated. Vasodilators have demonstrated limited therapeutic success, leading some to speculate on a hypersensitivity of peripheral autonomic receptors combined with an abnormal motor response.

In 1962, Menninger-Lerchenthal ⁸ noted that RLS patients commonly had low blood iron levels. He suggested that RLS was an iron metabolism disorder with secondary dysfunction of the pallidonigral system.

In 1965, Lugaresi and colleagues ⁹ investigated RLS patients with the use of polysomnography and noted the presence of short leg jerks during their sleep. These jerks were similar to those observed earlier by Symonds,¹⁰ who named the phenomenon “nocturnal myoclonus” and had associated it with an epileptic phenomenon. But Lugaresi and colleagues¹¹ clearly demonstrated in 1968 the absence of any seizure disorder with these jerking movements. These repetitive movements are now called periodic limb movements.

The clinical neurophysiology of RLS is still unclear. Martinelli and Coccagna ¹² examined H reflexes and polysynaptic lower limb reflexes; they performed repeated stimulations and found that the polysynaptic reflexes failed to cease, persist, or even increase in response. The onset of the reflex may trigger electromyographic activity. These changes were more pronounced in the evening, and the authors interpreted their findings as suggestive of a partial spinal cord disinhibition. In 2000, Bara-Jimenez and colleagues¹³ found a sleep-related increase in the spinal flexor response on stimulation of the median plantar nerve. They noted a greater diffusion of the reflexes, which suggested some impairment of spinal activity during sleep. Provini and coauthors¹⁴ showed that periodic limb movement disorder (PLMD) in RLS patients has varying patterns of muscular recruitment and muscle inhibition. This finding was interpreted as being indicative of involvement of different and occasionally unsynchronized generators and led to the hypothesis that there was abnormal hyperexcitability along the spinal cord triggered by sleep-related, supraspinal, and unknown factors. But the clinical neurophysiological investigations in RLS patients are still limited.

Transcranial magnetic stimulation (TMS) has also been performed in RLS patients by many researchers with varying findings. Provini and coauthors ¹⁴ reported normal findings, whereas Tergau and colleagues¹⁵ and Scalise and collaborators¹⁶ observed a reduction in the intracortical inhibition for feet and hands. Varying conclusions were drawn, and it was suggested that there may be an abnormal motor excitability and disinhibition of inhibitory circuits.

Imaging Studies

Imaging studies have been performed on RLS patients ¹⁷^–²³ based on treatment response results involving iron and dopaminergic agonists. These studies used functional magnetic resonance imaging (fMRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). SPECT studies have looked at presynaptic and postsynaptic receptor bindings. Using iodine-¹²³ iodobenzamide (IBZM) binding, Michaud and collaborators²³ reported a significant reduction in the postsynaptic median striatal dopamine receptor binding in RLS patients. PET studies are rare and were never performed in the evening; results have been inconclusive to this point. Bucher and colleagues²⁰ performed the early fMRI studies in RLS patients and found an activation in the red nucleus and brainstem close to the reticular formation when patients developed involuntary periodic limb movements; the authors concluded that subcortical generators are involved in RLS. Overall, however, results obtained from imaging studies have been rather limited and mixed. There is a suggestion of mild reductions in the nigrostriatal dopaminergic system, but additional work is needed.