Udine Special Section

Restless legs syndrome: an historical note

Giorgio Coccagna*, Roberto Vetrugno, Carolina Lombardi, Federica Provini

Department of Neurological Sciences, University of Bologna, Via U.Foscolo, 7, Bologna 40123, Italy

Received 1 January 2003

Abstract

The article briefly summarizes the milestones leading to current knowledge and the possibility of treating one of the most widespread and

perhaps least known diseases, restless legs syndrome (RLS). Until the mid-twentieth century, the syndrome first described by Willis (1685),

was sporadically reported in medical literature and in most cases deemed a bizzare condition. It was only with Ekbom’s detailed clinical

description of the syndrome (1944) and the polygraphic recordings of Coccagna et al. (1962) that RLS became well-recognised clinical

entity. Since then, almost all sleep laboratories have devoted much of their research to discovering the pathogenetic mechanisms underlying

the disease and devise increasingly specific treatment. Major advances have been made in recent years, but a full understanding of RLS is still

a long way off.

q 2004 Elsevier B.V. All rights reserved.

Keywords: Restless legs syndrome (RLS); Periodic Limb Movements in Sleep (PLMS); Polysomnographic recordings (PSG); Nocturnal Myoclonus (NM)

1. The beginning of the story

In 1685, the great English physician Thomas Willis gave

the first unequivocal description of Restless Legs Syndrome

(RLS), describing a patient who had difficulty sleeping

because of discomfort in the limbs [1]. He wrote: ‘Where-

fore to some, when being abed they betake themselves to

sleep, presently in the arms and legs, leapings and

contractions of the tendons, and so great a restlessness and

tossing of their members ensue, that the diseased are no

more able to sleep, than if they were in a place of the

greatest torture’. Two centuries later a German neurologist,

Wittmaack, labelled the same clinical syndrome ‘anxietas

tibiarum’, considering it a form of hysteria [2]. Beard, Bing

and Oppenheim later mentioned ‘anxietas tibiarum’ in their

writings, again taking it to be a sign of neurosis [3–5].

Oppenheim first suggested that this form of neurosis could

be familial or hereditary.

In 1936, Code and Allen reported in the Proceedings of

the Mayo Clinic three cases of neurosis involving the legs,

the second probably being a case of RLS [6]. The first

detailed description of the clinical features of RLS was

published by Mussio, Fournier and Rawak in 1940 [7].

The authors denied the neurotic origin of the syndrome and

pointed out the exacerbating effect of pregnancy and the

hereditary nature of the disorder. In 1947 they returned to

the topic, reporting further cases and proposing the more

descriptive term of ‘agitation paresthesique des extremites’

(paresthetic restlessness of the extremities), first noting a

possible involvement of the upper limbs [8].

In 1943, Allison, a sufferer himself, described the

hallmark involuntary muscular jerks of RLS as ‘leg jitters’

and postulated a vascular origin of the syndrome [9]. Two

years later Ekbom, based on 34 personal observations,

defined all the clinical features of the syndrome and coined

the name RLS, favouring a vascular cause and hence

recommending vasodilators as prime therapy [10,11]. To

date, especially in Europe, RLS is known as Ekbom’s

Syndrome. Following Ekbom’s reports, further contributions

from the French school (Bonduelle and Jolivet 1947–1953)

suggested as the origin of RLS a circulatory disturbance in

the lumbar spine, consisting in slowing of venous flow

triggered by decubitus (bed sores) or by pregnancy [12–15].

In 1949, the Italian Tuvo wrote again of involuntary

muscular jerks accompanying motor restlessness during

sleep and, in 1961, Israeli Bornstein suggested that RLS

was linked to a disorder of muscle tone regulation in

the substantia reticularis [16,17]. Being highly topical, it is

noteworthy that in 1962 Menninger-Lerchental noted

the common finding of low blood iron levels in RLS

1389-9457/$ - see front matter q 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.sleep.2004.01.002

Sleep Medicine 5 (2004) 279–283

www.elsevier.com/locate/sleep

* Corresponding author. Tel.: þ39-051-6442132; fax: þ39-051-

6442214.

E-mail address: coccagna@neuro.unibo.it (G. Coccagna).

patients, concluding that the syndrome was a typical

extrapyramidal disease caused by an iron metabolism

disorder with secondary dysfunction of the pallidonigral

system [18].

In 1962, Coccagna and Lugaresi added the first full

polygraphic studies of the syndrome to the description of

RLS, showing that involuntary kicking movements occur

during sleep [19]. They observed a friar who complained of

not having been able to sleep for years due to a strange

sensation in his legs, which would start in the evening

whenever he sat down and, in particular, when he went to

bed. This sensation forced him to move his legs frenetically

or get out of bed and run or jump about the room. Only in the

early morning hours would the disorder subside, leaving

him exhausted, to reappear again the next evening.

No one had been able to explain his symptoms because

blood tests and repeated investigations of muscles and

nerves were normal. A specialist suggested a psychosomatic

complaint that manifested in the lower limbs, although the

friar protested that he was the calmest man in the world and

that he had embraced his religious life with enthusiasm and

had never regretted his decision. His fellow friars had

accepted the fact that one of their brothers was a bit odd.

2. Polysomnographic recordings

Coccagna and Lugaresi, having just embarked on the

study of sleep disorders, decided that the friar would make

an excellent candidate for the investigation of insomnia. A

few days later one of them remembered having read an

article by Ekbom in Neurology, describing a clinical picture

similar to that of the friar and using the term Restless Legs

Syndrome [20]. Coccagna offered to follow the sleep

recording throughout the night.

At that time, our sleep laboratory had only rudimentary

equipment and no technicians. The neurologist had to

supervise all-night recordings personally, after a nurse had

helped to position the electrodes. This do-it-yourself

situation proved fortunate because Coccagna attached an

additional two electrodes to the anterior tibialis leg muscles

when the friar complained of the need to move his legs

frenetically. This was the first PSG recording of RLS.

For the first half of the night the polygraphic tracing was

full of artefacts produced by contractions of limb muscles,

sometimes similar to myoclonic jerks. During the second

part of the night, when the patient finally began to sleep and

clear-cut K-complexes appeared on the EEG tracing,

Coccagna heard an intermittent noise, about every

20–30 s. He soon realised that the noise was produced by

the pens connected to the tibialis muscles and corresponded

to rhythmic muscular contractions that caused a triple

flexion of the lower limbs, mainly an extension of the big

toe and a dorsiflexion of the foot, and a less intense flexion

of the knee and hip (Fig. 1). The contractions went on

throughout the recording, except for one stage of slow wave

sleep (SWS), persisting during rapid eye movement (REM)

sleep, but with less intensity. Another five consecutive PSGs

were performed on the same patient and proved identical to

the first.

With these first recordings, the two key motor features of

RLS—motor agitation and periodic muscular jerks—were

outlined, and a psychogenic origin of the disorder was ruled

out [19].

3. The end of the story

When the friar observed that someone had finally taken

him seriously and that, for the first time, doctors were

interested in his case, he became very cooperative and

confessed that his mother and some of his eight siblings had

or had had a very similar disorder. We thereafter directly

examined six of his eight brothers and contacted another

two who had emigrated. All reported a typical history of

RLS and confirmed that their mother, who had died in the

meantime, had suffered from a severe form of a similar

disorder. We also obtained one or more nocturnal PSG of

three brothers, with an identical picture to the friar’s.

After the study of this family had clarified the clinical

features of the syndrome, another 10 cases were collected in

the space of a few weeks, all yielding the same PSG results.

It did not take much to convince us that RLS must be a

very common disorder. We had only to mention our research

in this connection and a long line of friends and relatives

would join the myriad of patients who experience this torture

daily, whenever they go to the cinema and theatre, relax to

watch TV, or retire to bed. We subsequently collected a

number of symptomatic cases of RLS associated with a wide

variety of neurological or other medical conditions (myelo-

pathy, peripheral neuropathy, uremia, anemia, etc.).

4. Nocturnal myoclonus and periodic limb movements

during sleep

After the friar’s first PSG, we routinely began to record

the electromyogram of the anterior tibialis muscles in nearly

all patients undergoing PSG for any reason. In particular, we

had occasion to make a PSG recording of a man whose bed

partner complained of his nightly, periodic and regular leg

jerks. He was unaware of his disorder and he did not suffer

from RLS. The recording disclosed PLMS during light

sleep, identical to those found in RLS patients. We

published this and other identical cases in 1966, grouping

them under the term ‘Nocturnal Myoclonus’ (NM) [21], a

term coined by Symonds, but not entirely appropriate [22].

Symonds had described a series of different motor

phenomena occurring in sleep, which shared the common

feature of muscular contractions, and postulated an epileptic

origin of the jerks [22]. Within these cases, the author also

included a typical case of familial RLS. The term Nocturnal

G. Coccagna et al. / Sleep Medicine 5 (2004) 279–283280

Myoclonus was subsequently replaced by Periodic Limb

Movements in Sleep (PLMS), because these muscular

contractions are not, in general, truly myoclonic, usually

lasting longer than a normal positive myoclonus.

Further recordings disclosed that PLMS were common,

especially in the elderly, and could occur throughout the

night, alternately affecting one leg or the other and even

extending to the arms. Although PLMS predominate in light

sleep, they may persist in SWS and REM sleep, when they

are less intense and less rhythmic.

5. Electrophysiological investigations

In the early 1970s, the Bologna School had completed

the clinical and polysomnographic (PSG) definition of RLS.

We subsequently performed several electrophysiological

studies, demonstrating an impaired excitability curve for

the H reflex (a spinal cord reflex) in both RLS and PLMS,

more marked during the night, with a slope similar to that

found in patients with spasticity. On repeated stimulation

the extensor and flexor polysynaptic lower limb reflexes

failed to cease, persisting or even increasing. Onset of the

reflex often triggers EMG activity lasting hundreds of milli-

seconds. These findings, more pronounced in the evening

hours, suggest partial spinal cord disinhibition [23]. Bara-

Jimenez and colleagues found evidence for specific, sleep-

related increased during sleep of the spinal flexor response,

measured by stimulation of the medial plantar nerve, and a

greater spatial diffusion of these reflexes, all much more

evident during sleep [24]. These data suggested a specific

impairment of spinal reflex activity during sleep.

We had already noted in our first patients that Babinski’s

sign was common in the evening hours in RLS. In addition,

cine-films and video recordings showed that during

PLMS there was a dorsiflexion (upgoing movement) of

the big toe with spreading of the smaller toes, similar to the

movements of Babinski’s sign, providing additional evi-

dence for a central nervous system disorder in patients with

PLMS and/or RLS [21]. More recently, we documented

that PLMS in RLS patients had a variable pattern of mus-

cular recruitment and of initiating muscles, indicating

the engagement of different, independent and sometimes

Fig. 1. Polygraphic recording done in the 1960s. During light sleep, periodic limb movements initially involve the lower limbs and subsequently spread to the

arms (L. Triceps. Br.).

G. Coccagna et al. / Sleep Medicine 5 (2004) 279–283 281

unsynchronized generators. We therefore hypothesized an

abnormal hyperexcitability along the entire spinal cord,

especially the lumbosacral and cervical segments, triggered

by sleep-related factors located at a supraspinal but still

unresolved level [25].

On the other hand, our group documented that a

cortical source was unlikely to generate PLM, because we

failed to find cortical prepotentials before waking and

sleeping PLM [26].

Another approach suggested a subcortical pacemaker,

probably located at reticular level, as the site of origin of

PLMS. In 1972, Lugaresi and colleagues first demonstrated

that PLMS may coincide with concomitant periodic

oscillations simultaneously involving EEG activity (the

cyclic alternating pattern of Terzano and Parrino), auto-

nomic functions such as heart rate, breathing rate and blood

pressure, and muscle tone [27,28]. The reticular system is

the most probable for integrating and coordinating many

autonomic and somatopsychic activities.

In 1965, Gorman and colleagues suggested that RLS

might be caused by peripheral nerve disease [29]. More

recent studies have confirmed the high frequency of RLS in

certain specific nerve disorders, such as familial amyloid

polyneuropathy and cryoglobulinemic polyneuropathy, or

have shown that RLS may follow peripheral nerve damage

of metabolic origin (uremia, diabetes). However, the role of

such peripheral neuropathies and of subtle nerve damage in

the pathogenesis of RLS remains unclear in apparently

idiopathic forms [30].

6. Imaging techniques

Functional imaging studies with SPECT and PET

techniques have recently demonstrated a central dopamin-

ergic dysfunction, particularly at the level of the striatoni-

gral system (decreased fluorodopa striatal uptake) in the

pathogenesis of the syndrome [31,32]. This hypothesis is

further supported by the beneficial effects of various

dopaminergic drugs in the treatment of RLS. Another recent

SPECT study demonstrated a decrease in cerebral blood

flow in the caudate nuclei and an increase in the anterior

cingulate gyrus during periods of increasing pain [33].

Impaired iron metabolism encountered in RLS also fits the

dopaminergic model. Studies have shown reduced ferritin

and increased transferrin concentrations in the cerebrospinal

fluid of idiopathic RLS patients, implying low brain iron

content in these patients [34]. Decreased brain iron would

lead to abnormal dopaminergic function, given the fact that

tyrosine hydroxylase, which provides the rate-limiting step

for the synthesis of dopamine, requires iron.

7. Family studies

Some family studies indicate the possibility that RLS has

a strong genetic basis. Members of the RLS study group

have examined a number of large pedigrees, including our

friar’s family, which include many members with RLS.

Informal inspection indicates that they are consistent with

an autosomal dominant form of inheritance, with variable

anticipation and penetrance, suggesting a possible genetic

heterogeneity [35].

8. Treatment

The treatments we advocated for RLS in the early 1970s

remain valid today. For the friar and his family, and other

sporadic cases of RLS, we demonstrated the efficacy of

diazepam in attenuating the sensory disorders when the drug

was taken at bedtime. For many years it remained the only

treatment available, later replaced by clonazepam. Baclo-

fen, which we also tested, also proved to be effective [36].

Some antiepileptic drugs (gabapentin, carbamazepine,

valproic acid) have also given good results. A major advance

in the medical management of RLS came with the advent of

L-dopa [37] and dopamine agonist drugs [38], further

supporting an extrapyramidal origin of the syndrome.

Appendix A

Milestones in RLS

Willis (1685) [1] First description of the syndrome

Wittmaack (1861)

[2]

‘Anxietas Tibiarum’ (a form of

hysteria)

Oppenheim (1923)

[5]

‘Anxietas Tibiarum’ (a sign of

neurosis); first report of familial

cases

Mussio Fournier and

Rawak (1940, 1947)

[7,8]

Exacerbating effect of pregnancy

and familiarity. Possible

involvement of the upper limbs

Allison (1943) [9] ‘Leg Jitters’, involuntary

muscular jerks; postulated a

vascular origin of the syndrome

Ekbom (1944–

1945) [10,11]

All the clinical features of the

syndrome; coined the name RLS

Bonduelle and

Jolivet (1947–53)

[12–15]

Motor restlessness without

paresthesias or dysesthesias.

Suggested a circulatory

disturbance in the lumbar spine,

consisting in slowing of venous

flow triggered by decubitus or

pregnancy

Symonds (1953)

[22]

Nocturnal myoclonus

Bornstein (1961)

[17]

Disorder of muscle tone

regulation in the substantia

reticularis(continued on next page)

G. Coccagna et al. / Sleep Medicine 5 (2004) 279–283282

continued

Lugaresi and

Coccagna (1962)

[19]

First full polygraphic studies of

RLS

Akpinar (1982) [37] L-dopa therapy

Walters (group

organizer) (1995)

[39]

Founder of the International RLS

study group

Staedt et al. (1995)

and Turjanski et al.

(1999) [31,32]

Functional Imaging studies;

extrapyramidal origin of the

syndrome

Earley et al. (2000)

[34]

Iron deficiency in the brain

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