Restless Legs Syndrome and Nocturnal Myoclonus (Periodic Limb Movements During Sleep)

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Chapter 5 Restless Legs Syndrome and Nocturnal Myoclonus (Periodic Limb Movements During Sleep)

An Historical Review

Elio Lugaresi, Federica Provini

In a lecture on the predormitum (or sleepening, as Gowers, cited in Critchley,¹ liked to call it), Critchley¹ mentioned a predormitum restlessness, which, he said, is by no means a rarity, although physicians may not be consulted specifically on this score. He acknowledged that Ekbom²^–⁴ was responsible for drawing attention to the condition, calling it restless legs syndrome (RLS). Few medical men, Critchley added, knew that the Ekbom syndrome was graphically described in the 17th century by the great clinical neurologist Thomas Willis.⁵ Ekbom²^–⁴ admitted that Willis had been the first to describe the disorder, but in 1685, not 1695 as Critchley had suggested. In fact, a description of the syndrome seems to date back to a text Willis wrote in 1683, which was in turn a translation from a paper written in Latin in 1672.⁶

In 1861, Wittmaack ⁷ named the disorder “anxietas tibiarum,” misconstruing it as a particular form of hysteria. Beard⁸ also considered the condition to be a form of nervous exhaustion, but specified that it was “one of the myriad results of spinal irritation.” Oppenheim⁹ included the RLS among the forms of neurasthenia, pointing out that it may sometimes appear as a family trait.

For these clinicians, the terms “nervous exhaustion,” “hysteria,” and “neurasthenia” did not have the modern meaning of psychogenic disease or syndrome but simply a clinical condition lacking a well-defined anatomical basis. However, semantic confusion has led the authors of more recent reports to mistake RLS for a form of “neurosis” in the modern sense.

Mussio-Fournier and Rawak ¹⁰ in 1940 published a full report of a patient with an inherited familial form of RLS. They pointed out that the clinical symptoms worsened during pregnancy and then improved during the puerperium. Their patient also presented with acroparaesthesia and motor agitation associated with pruritis and urticaria.

Allison ¹¹—a sufferer himself—wrote, “This is a common ailment, which I have never seen described,” adding “I have observed this condition mainly in myself, relatives, and friends, as patients do not often complain of it unless it occurs frequently enough to cause loss of sleep.” Allison defined the motor disorder as “a combination of voluntary and involuntary jerks,” using the term “leg jitters.”

Without a doubt, Ekbom has the merit of having extensively illustrated the clinical aspects of the syndrome, dedicating an important series of publications to the subject between 1944 and 1960 and beyond.²^–⁴

Bonduelle ¹² and Jolivet¹³ described the first French observations; Tuvo,¹⁴ the first Italian case; and Barraquer-Ferre,¹⁵ the Spanish patient. A major contribution was made by Nordlander,¹⁶ who documented that iron deficiency anemia exacerbated RLS and that intravenous administration of iron compounds “proved very effective, regardless of whether or not the patient had anemia or sideropenia.” The fact that RLS may arise after acute anemia and regress with appropriate treatment was subsequently also reported by Murphy.¹⁷

Heralding more modern pathophysiological theories on the origin of RLS, Menninger-Lerchenthal ¹⁸ deemed it a kind of extrapyramidal disease related to an iron metabolism disorder with a secondary dysfunction of the pallidonigral system.

The notion that anemia and iron deficiency underlie the RLS arising in end-stage renal disease and pregnancy has also been proposed by others.¹⁹^–²²

The treatment of RLS owes much to the work of Walters, Hening, and colleagues ²³ on the efficacy of opioids and to Akpinar,^24,²⁵ who paved the way to the use of L-dopa and dopamine agonists.

Polysomnographic Recordings of Restless Legs Syndrome and the Discovery of Periodic Limb Movements or Nocturnal Myoclonus

In the early 1960s, we used polysomnography (PSG) to record our first patient with RLS. Our aim was to assess insomnia provoked by acroparaesthesias and motor agitation and the efficacy of drug treatment. We documented the adverse effects of vasodilators, barbiturates, and Desyrel previously proposed by others. Valium (diazepam) proved effective, shortening the time taken by patients to fall asleep, but given at high doses, the drug caused muscle weakness.

PSG recordings also disclosed a hitherto undescribed phenomenon.²⁶ On falling asleep, all our patients demonstrated involuntary muscle jerks recurring every 20 to 30 seconds.²⁶ In this very first observation, we noted that the simplest most common movement consisted of dorsiflexion of the big toe and/or the foot. When, more rarely, the movement became more intense and diffuse, there appeared a flexion of the leg on the thigh and of the thigh on the trunk. More seldom, the forearm would flex at the elbow. The muscle jerks, especially those of the foot and leg, could also be tonic-clonic-polyclonic. The same muscles on both sides would contract asynchronously and asymmetrically or leg muscles would contract alternately on both sides.²⁷ The periodic jerks were preceded or accompanied by electroencephalographic signs of arousal (reappearance of the alpha rhythm in stage 1 non−rapid eye movement [NREM] sleep and K complexes in stage 2 NREM sleep). In a patient with startle disease (hyperekplexia), we documented for the first time that periodic limb movements during sleep (PLMS) may also arise irrespective of RLS.^28,²⁹ By subjecting patients with neurological disorders to nocturnal PSG, we also demonstrated that RLS and PLMS are particularly common in acute and chronic neuropathies and myelopathies, either alone or in association.³⁰ Although we recognized the polymorphic features of PLMS, we proposed the term nocturnal myoclonus in honor of Charles Symonds, who first reported “involuntary movements at night” in five patients, deeming them epileptic in origin.³¹ Symonds’ fourth patient was a typical case of RLS. Ian Oswald, recording a physiological event he called “sudden bodily jerks,” claimed that nocturnal myoclonus was the same manifestation.³² Oswald’s patient, W, was another typical case of RLS.³²

Coleman and colleagues ³³ subsequently showed that PLMS can also arise in healthy subjects, and Bixler and associates³⁴ emphasized that they are age related. When PLMS are present, they appear concomitantly with other signs of electroencephalographic, motor, and autonomic activation³⁵ but are not preceded by cortical prepotentials.³⁶ Plantar stimulation would trigger a typical Babinski sign in more than one third of our cases, readily evoked in the evening when patients complain of this disorder.²⁷^–²⁹ According to Martinelli and Coccagna,³⁷ the study of monosynaptic and polysynaptic reflexes, performed in the evening when the Babinski sign is more readily evoked, suggested that RLS and PLMS are linked to motor disinhibition, favored by drowsiness. These pioneering findings were subsequently confirmed and well documented by Wechsler and coworkers³⁸ and Bara-Jimenez and coworkers³⁹ In our laboratory, Fabio Cirignotta found that direct repetitive stimulation of the peroneal nerve during sleep in RLS patients evokes myoclonic jerks similar to those arising spontaneously at frequencies ranging from one jerk every 30 seconds to one jerk every 4 to 5 seconds (Lugaresi and coworkers³⁶). At that time, all these findings were difficult to interpret: some seem to indicate that PLMS are regulated by a supraspinal (subcortical) pacemaker, whereas others reflect a hyperexcitability of the spinal motor neurons as being responsible for the disorder.³⁶