Upload
giorgio-coccagna
View
218
Download
2
Embed Size (px)
Citation preview
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: [email protected] (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
References
[1] Willis T. The London practice of physic. London, England: Bassett
and Crooke; 1685.
[2] Wittmaack T. Pathologie und Therapie der Sensibilitatneurosen.
Leipzig: E. Schafer; 1861. p. 459.
[3] Beard GM. A practical treatise on nervous exhaustion. New York,
NY: William Wood; 1880. p. 41–2.
[4] Bing R. Lehrbuch der Nervenkraukheiten. Berlin: Springer; 1913. p.
522.
[5] Oppenheim H. Lehrbuch der Nervenkrakheiten. Berlin: Karger; 1923.
p. 1774.
[6] Code CF, Allen EV. Neurosis involving the legs: report of three
illustrative cases. Proc Staff Meet Mayo Clin 1936;11:60–2.
[7] Mussio Fournier JC, Rawak F. Familiares Auftreten von Pruritus,
Urtikaria und parasthetischer Hyperkinese der unteren Extremitaten.
Confinia neurol 1940;3:110–4.
[8] Mussio Fournier JC, Rawak F. Agitation paresthesique des extremites.
Rev Neurol (Paris) 1947;79:37–341.
[9] Allison FG. Obscure pains in the chest, back or limbs. Can Med Assoc
J 1943;48:36–8.
[10] Ekbom KA. Asthenia crurum paraesthetica (‘Irritable legs’). New
syndrome consisting of weakness, sensation of cold and nocturnal
paresthesia in legs, responding to certain extent to treatment with
Priscol and Doryl; note on paresthesia in general. Acta Med Scand
1944;118:197–209.
[11] Ekbom KA. Restless legs: clinical study of hitherto overlooked
disease in legs characterized by peculiar paresthesia (‘Anxietas
tibiarum’), pain and weakness and occurring in two main forms,
asthenia crurum paraesthetica and asthenia crurum dolorosa; short
review of paresthesias in general. Acta Med Scand 1945;158:1–123.
[12] Bonduelle M. Syndrome des jambes sans repos. Paresthesie agitante
nocturne des membres inferieus. Rev Rhumatisme 1947;14:188–9.
[13] Bonduelle M. Paresthesie agitante nocturne des membres inferieurs et
impatiences. Presse Medicale 1952;60:62–4.
[14] Bonduelle M, Jolivet B. Les impatiences. Bull Med 1953;12:316–8.
[15] Jolivet B. Paresthesies agitantes nocturnes des membres inferieures.
Impatiences. These de Paris: Imprimerie R Foulon; 1953.
[16] Tuvo F. Contributo clinico alla conoscenza della sindrome cosiddetta
‘irritables legs’. Minerva Med 1949;40:741–3.
[17] Bornstein B. Restless legs. Psychiat Neurol (Basel) 1961;141:
165–201.
[18] Menninger-Lerchenthal E. Ruhelosigkeit der Beine (Restless legs,
Tachyathetosis). Wien Ztschr Nervenhk 1962;19–62.
[19] Lugaresi E, Tassinari CA, Coccagna G, et al. Particularites cliniques
et polygraphiques du syndrome d’impatience des membres inferieurs.
Rev Neurol (Paris) 1965;113:545–55.
[20] Ekbom KA. Restless legs syndrome. Neurology 1960;10:868–73.
[21] Coccagna G, Lugaresi E, Tassinari CA, et al. La sindrome delle
gambe senza riposo (Restless legs). Omnia Med Therap (Nuova serie)
1966;44:619–84.
[22] Symonds CP. Nocturnal myoclonus. J Neurol Neurosurg Psychiatry
1953;16:166–71.
[23] Martinelli P, Coccagna G. Rilievi neurofisiologici sulla sindrome
delle gambe senza riposo. Rivista di Neurologia 1976;XLVI(6):
553–60.
[24] Bara-Jimenez W, Hallett M. Increased spinal cord excitability in
patients with restless legs syndrome. Mov Dis 1998;13(Suppl l2):
294.
[25] Provini F, Vetrugno R, Meletti S, et al. Motor pattern of periodic limb
movements during sleep. Neurology 2001;57(2):300–4.
[26] Lugaresi E, Cirignotta F, Coccagna G, et al. Nocturnal myoclonus and
restless legs syndrome. In: Fahn S, Marsden CD, Van Woert M,
editors. Myoclonus (Adv Neurology 43). New York: Raven Press;
1986. p. 295–307.
[27] Lugaresi E, Coccagna G, Mantovani M, et al. Some periodic
phenomena arising during drowsiness and sleep in man. Electro-
encephalogr Clin Neurophysiol 1972;32:701–5.
[28] Terzano MG, Mancia D, Salati MR, et al. The cyclic alternating
pattern as a physiological component of normal NREM sleep. Sleep
1985;8:137–45.
[29] Gorman CA, Dick PJ, Pearson JS. Symptom of restless legs. Arch
Intern Med 1965;115:155–60.
[30] Iannacone S, Zucconi M, Marchettini P, et al. Evidence of peripheral
axonal neuropathy in primary restless legs syndrome. Mov Disord
1995;10:2–9.
[31] Staedt J, Stoppe G, Kogler A, et al. Nocturnal myoclonus syndrome
(periodic movements in sleep) related to central dopamine D2-
receptor alteration. Eur Arch Psychiatry Clin Neurosci 1995;245(1):
8–10.
[32] Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic function in
restless legs syndrome: 18F-dopa and 11C-raclopride PET studies.
Neurology 1999;52(5):932–7.
[33] San Pedro EC, Mountz JM, Mountz JD, et al. Familial painful restless
legs syndrome correlates with pain dependent variation of blood flow
to the caudate, thalamus, and anterior cingulate gyrus. J Rheumatol
1998;25:2270–5.
[34] Earley CJ, Connor JR, Beard JL, et al. Abnormalities in CSF
concentrations of ferritin and transferrin in restless legs syndrome.
Neurology 2000;54(8):1698–700.
[35] Lazzarini A, Walters AS, Hickey K, et al. Studies of penetrance and
anticipation in five autosomal-dominant restless legs syndrome
pedigrees. Mov Disord 1999;14:111–6.
[36] Coccagna G, Lugaresi E. Anxietas Tibiarum and nachtliche
Myokloni. Z EEG-EMG 1978;9:155–60.
[37] Akpinar S. Treatment of restless legs syndrome with levodopa plus
benserazide (letter). Arch Neurol 1982;39:739.
[38] Akpinar S. Restless legs syndrome treatment with dopaminergic
drugs. Clin Neuropharmacol 1987;10:69–79.
[39] The International Restless Legs Syndrome Study Group (Walters AS,
group organized and correspondent), Toward a better definition of the
restless legs syndrome. Mov Disord 1995;10:634–42.
G. Coccagna et al. / Sleep Medicine 5 (2004) 279–283 283