Re: 하지불안 증후군 약물치료 이해 논문..

[문형철]

Nat Sci Sleep. 2010; 2: 199–212.

Published online 2010 Sep 8. doi: 10.2147/NSS.S6946

PMCID: PMC3630948

PMID: 23616710

Update on the management of restless legs syndrome: existing and emerging treatment options

Maurizio F Facheris,1,2 Andrew A Hicks,1 Peter P Pramstaller,1,2,3 and Irene Pichler1

Author information Copyright and License information PMC Disclaimer

Abstract

Restless legs syndrome (RLS) is a sensorimotor disorder, characterized by a circadian variation of symptoms involving an urge to move the limbs (usually the legs) as well as paresthesias. There is a primary (familial) and a secondary (acquired) form, which affects a wide variety of individuals, such as pregnant women, patients with end-stage renal disease, iron deficiency, rheumatic disease, and persons taking medications. The symptoms reflect a circadian fluctuation of dopamine in the substantia nigra. RLS patients have lower dopamine and iron levels in the substantia nigra and respond to both dopaminergic therapy and iron administration. Iron, as a cofactor of dopamine production and a regulator of the expression‎ of dopamine type 2-receptor, has an important role in the RLS etiology. In the management of the disease, the first step is to investigate possible secondary causes and their treatment. Dopaminergic agents are considered as the first-line therapy for moderate to severe RLS. If dopaminergic drugs are contraindicated or not efficacious, or if symptoms are resistant and unremitting, gabapentin or other antiepileptic agents, benzodiazepines, or opioids can be used for RLS therapy. Undiagnosed, wrongly diagnosed, and untreated RLS is associated with a significant impairment of the quality of life.

요약

하지불안증후군(RLS)은 

감각 운동 장애로, 

사지(보통 다리)를 움직이고 싶은 충동과 

감각 이상을 포함하는 일주기적인 증상의 변화를 특징으로 합니다. 

일차성(가족성) 및 이차성(후천성) 형태가 있으며 

임산부, 

말기 신장 질환 환자, 

철분 결핍, 

류마티스 질환, 

약물 복용자 등 

다양한 개인에게 영향을 미칩니다. 

증상은 

흑질 흑질에서 도파민의 일주기적 변동을 반영합니다. 

RLS 환자는 

흑질 흑질에서 도파민과 철분 수치가 낮으며 

도파민 치료와 철분 투여 모두에 반응합니다. 

철분은 

도파민 생성의 보조 인자이자 

도파민 2형 수용체의 발현을 조절하는 인자로서 

RLS 병인에서 중요한 역할을 합니다. 

질병 관리의 첫 번째 단계는 

가능한 이차적 원인과 

그 치료법을 조사하는 것입니다. 

도파민성 약제는 

중등도에서 중증의 RLS에 대한 1차 치료제로 간주됩니다. 

도파민성 약물이 금기이거나 효과가 없거나 내성이 있고 증상이 지속되는 경우 

가바펜틴 또는 

기타 항전간제, 

벤조디아제핀 또는 

오피오이드가 RLS 치료에 사용될 수 있습니다. 

진단되지 않거나 잘못 진단되고 치료되지 않은 RLS는 

삶의 질을 크게 저하시키는 것과 관련이 있습니다.

Keywords: pathophysiology, quality of life

Overview of the pathology of restless legs syndrome

Diagnostic criteria

Restless legs syndrome (RLS) is a common neurological sensorimotor disorder characterized by a circadian variation of symptoms. It is counted either as a neurological movement disorder or as a “nonapnea” sleep disorder. The diagnosis is based on 4 essential clinical consensus criteria: (1) a compelling urge to move the legs (sometimes also the arms are involved), usually accompanied or caused by uncomfortable and unpleasant sensations deep in the legs (sometimes the urge to move is present without the unpleasant sensations); (2) the symptoms begin or worsen during periods of rest or inactivity; (3) they are partially or totally relieved by movement; and (4) symptoms are worse in the evening or at night or only occur in the evening or night (when symptoms are very severe, the worsening at night may not be noticeable, but must have been previously present).1 In addition to the 4 essential criteria, there are 3 criteria that can support the diagnosis: family history, response to dopaminergic treatment, and presence of periodic leg movements in sleep (PLMS; Table 1). RLS might also be present in a pediatric environment: in addition to the 4 essential adult criteria, children should be able to describe in their own words sensations that would be consistent with leg discomfort.2 Other supportive evidence for the diagnosis in children include the presence of sleep disturbance specific for age, a family history of RLS, and the presence of PLMS, after excluding other potential causes of discomfort, such as breathing disorders, medication-related side effects, neuropathies, arthritis, and certain types of dermatitis.2,3 RLS is one of the few disorders for which no laboratory or clinical test is available to confirm‎ the diagnosis; the physical examination is generally unremarkable and neurological signs, apart from PLMS, are lacking.

하지불안증후군(RLS)은

일주기적인 증상 변화를 특징으로 하는

흔한 신경학적 감각 운동 장애입니다.

신경학적 운동 장애 또는

“무호흡성” 수면 장애로 분류됩니다.

진단은 4가지 필수 임상 합의 기준을 기반으로 합니다:

(1) 다리를 움직이고 싶은 강렬한 충동(때로는 팔도 관련됨), 일반적으로 다리 깊은 곳의 불편하고 불쾌한 감각이 동반되거나 원인인 경우(때로는 불쾌한 감각 없이 움직이고 싶은 충동만 있는 경우),

(2) 휴식 또는 비활동 기간 동안 증상이 시작되거나 악화되는 경우;

(3) 움직이면 증상이 부분적으로 또는 완전히 완화되는 경우,

(4) 증상이 저녁이나 밤에 악화되거나 저녁이나 밤에만 발생하는 경우(증상이 매우 심한 경우 밤에 악화되는 것이 눈에 띄지 않을 수 있지만 이전에 증상이 있었어야 함). 1

4가지 필수 기준 외에도

가족력, 도파민 치료에 대한 반응, 수면 중 주기적인 다리 움직임의 존재 등

3가지 기준이 진단을 뒷받침할 수 있습니다(PLMS, 표 1).

RLS는

소아 환경에서도 나타날 수 있습니다.

성인에게 필수적인 4가지 기준 외에도

소아는 다리 불편감과 일치하는 감각을 자신의 말로 설명할 수 있어야 합니다.2

소아에서 진단을 뒷받침하는 다른 증거로는

호흡 장애,

약물 관련 부작용,

신경 병증,

관절염 및 특정 유형의 피부염과 같은 불편감의 다른 잠재적 원인을 배제한 후

연령에 맞는 수면 장애, RLS의 가족력, PLMS의 존재가 있습니다.2,3

RLS는 진단을 확인할 수 있는 실험실 또는 임상 검사가 없는 몇 안 되는 질환 중 하나로, 신체 검사는 일반적으로 눈에 띄지 않으며 PLMS를 제외한 신경학적 징후가 부족합니다.

Table 1

Essential clinical consensus criteria for the diagnosis of RLS and supportive criteria1

Essential diagnostic criteria

1. Uncomfortable sensations, urge to move	Urge to move the limbs (usually legs), associated to or caused by uncomfortable sensations
2. Rest brings on the symptoms	Onset of urge to move or uncomfortable sensations during periods of rest or inactivity – independent of the body position
3. Movement relieves the symptoms	Urge to move or uncomfortable sensations are partially or totally relieved by movement, such as stretching or walking
4. Evenings and night time are worse	Urge to move or uncomfortable sensations are worse in the evening or night or occur only in the evening or night (for severe RLS, the worsening at night time might not be noticeable, but must have been present previously)
Supportive criteria
5. Family history
6. Response to dopaminergic treatment
7. Periodic leg movements in sleep (PLMS)

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Abbreviations: PLMS, periodic leg movements in sleep; RLS, restless legs syndrome.

Historical perspective

RLS symptoms were described for the first time by Willis4 in 1672 as “leapings and contractions of the tendons, and so great a restlessness and tossings of their members ensue that diseased are no more able to sleep than if they were in place of greatest torture”.4 The first description of RLS as a hereditary disorder dates back to the “Textbook of Nervous Diseases” published by Oppenheim5 in 1923 and it was first clinically described by Ekbom6 in 1945.

역사적 관점
RLS 증상은 1672년 윌리스4에 의해 “힘줄의 도약과 수축, 그리고 그 부위의 심한 불안과 뒤척임으로 인해 병에 걸린 사람은 마치 큰 고문을 당한 것처럼 잠을 잘 수 없다”고 처음으로 설명되었습니다.4 유전성 질환으로서의 RLS에 대한 최초의 설명은 1923년 오펜하임5에 의해 출판된 “신경 질환 교과서”로 거슬러 올라가며 1945년 엑봄6이 임상적으로 처음 설명했습니다.

Preval‎ence of RLS

Most of the studies performed in Europe and North America report a preval‎ence between 4% and 12% in the general population.7–11 Several studies have shown a predominance in women who are affected approximately twice as often as men,9,12,13 and in the elderly with a preval‎ence of 10%–24%.14,15 A large-scale survey revealed that RLS is also common in children and adolescents with an estimated preval‎ence of 1.9% in school-aged children and 2% in adolescents, with no significant gender differences.2 Two studies show unexpectedly low preval‎ence in Asian populations: the preval‎ence in a Turkish population was 3.2% and in 2 samples of Singapore, a preval‎ence of 0.6% and 0.1%, respectively, was determined.16,17

RLS의 유병률
유럽과 북미에서 수행된 대부분의 연구는

일반 인구에서 4%에서 12% 사이의 유병률을 보고합니다.7-11

여러 연구에 따르면

여성이 남성보다 약 2배 더 자주 영향을 받고9,12,13

노인에서 10%-24%의 유병률로 우세합니다.14,15

대규모 조사에 따르면 RLS는 아동과 청소년에서도 흔하며 학령기 아동에서 1.9%, 청소년에서 2%로 추정되며 성별 차이는 없는 것으로 나타났습니다.2 터키 인구의 유병률은 3.2%, 싱가포르의 2개 샘플에서는 각각 0.6%와 0.1%의 유병률이 확인된 두 연구에서 아시아 인구의 유병률이 예상외로 낮았습니다.16,17

Primary vs secondary RLS

RLS is classified as either primary (idiopathic, familial) or secondary (acquired, symptomatic) RLS. Primary RLS has a clear genetic component: and it is estimated that approximately 50% of first-degree relatives of RLS patients will eventually develop RLS. This frequency is 3–5 times higher when compared with first-degree relatives of individuals without RLS.1 RLS-pedigrees point in most cases to an autosomal dominant transmission pattern. Also the age at onset seems to play an important role in primary RLS: patients with an age at onset before 45 years were shown to have a significantly higher number of affected relatives compared with patients with an onset after 45 years.18 Thus, RLS with an early age at onset and a positive family history points to underlying genetic factors as being responsible for the pathology.

Secondary RLS is due to other underlying clinical conditions, such as pregnancy, end-stage renal disease, iron deficiency, rheumatic disease, and drug intake. Many of these circumstances involve altered iron homeostasis. Symptomatic RLS remits with correction of the underlying condition.

일차성 및 이차성 RLS

RLS는

원발성(특발성, 가족성) 또는

이차성(후천성, 증상성) RLS로 분류됩니다.

원발성 RLS는

유전적 요소가 분명하며,

RLS 환자의 1촌 친척 중 약 50%가

결국 RLS에 걸리는 것으로 추정됩니다.

이 빈도는

RLS가 없는 사람의 1촌 친척과 비교했을 때

3~5배 더 높습니다.1

RLS 혈통은 대부분의 경우 상염색체 우성 전염 패턴을 나타냅니다. 또한 발병 연령은 원발성 RLS에서 중요한 역할을 하는 것으로 보입니다. 발병 연령이 45세 이전인 환자는 45세 이후에 발병한 환자에 비해 영향을 받은 친척 수가 훨씬 더 많은 것으로 나타났습니다.18 따라서 발병 연령이 빠르고 가족력이 양성인 RLS는 근본적인 유전적 요인이 병리의 원인으로 작용하는 것으로 보입니다.

이차성 RLS는

임신,

말기 신장 질환,

철분 결핍,

류마티스 질환,

약물 섭취와 같은 다른 기저 임상 조건으로 인해 발생합니다.

이러한 상황의 대부분은

철분 항상성 변화와 관련이 있습니다.

증상이 있는 RLS는 기저 질환을 교정하면 증상이 완화됩니다.

Rating of symptom severity

To eval‎uate the severity of symptoms, 2 rating scales were developed and validated. The Johns Hopkins restless legs severity scale provides a reliable, valid, and easily used clinical assessment for RLS severity.19 It judges severity by the time of symptom onset on a 4-point scale with 0 for no symptoms, 1 for symptoms at bedtime only, 2 for evening and bedtime symptoms, and 3 for day and night symptoms. The International Restless Legs Syndrome (IRLS) Study Group has developed a 10-item scale with questions related to the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence and impact of RLS on activities of daily living and mood.20 The responses are graded from 0 to 4 (i.e. 0 for absence of symptoms and 4 for very severe symptoms). A correlation between IRLS and objective parameters of motor dysfunction such as PLMS was demonstrated.21 The IRLS is used especially in eval‎uating treatment efficacy.

증상 심각도 평가

증상의 심각도를 평가하기 위해 두 가지 등급 척도가 개발되어 검증되었습니다. 존스홉킨스 하지불안증후군 중증도 척도는 RLS 중증도에 대한 신뢰할 수 있고 타당하며 쉽게 사용할 수 있는 임상 평가를 제공합니다.19 증상 발현 시점에 따라 4점 척도로 중증도를 판단하며, 증상이 없는 경우 0점, 취침 시에만 증상이 있는 경우 1점, 저녁 및 취침 시 증상 2점, 낮과 밤에 증상이 있는 경우 3점으로 표시합니다. 국제하지불안증후군(IRLS) 연구 그룹은 감각 및 운동 증상의 심각성, 수면 장애, 주간 졸음, 일상 생활 활동 및 기분에 대한 RLS의 영향과 관련된 질문이 포함된 10항목 척도를 개발했습니다.20 응답은 0에서 4까지(즉, 증상이 없는 경우 0, 매우 심한 경우 4) 등급이 매겨집니다. IRLS와 PLMS와 같은 운동 기능 장애의 객관적인 매개변수 간의 상관관계가 입증되었습니다.21 특히 치료 효과를 평가하는 데 IRLS가 사용됩니다.

Periodic leg movements in sleep

In about 80% of RLS patients, PLMS are associated with the syndrome.22,23 PLMS are recorded by leg actigraphy using an accelerometer,24 or by electromyography (EMG) during polysomnography, and they are defined as repetitive movements of the lower limbs (at least 4 in a series) with a duration of 0.5–10 seconds at intervals of 5–90 seconds. In addition, quantitative requirements, such as increase of the EMG amplitude to ≥8 μV above the resting level, have been defined.25 Results from the Suggested Immobilization Test have also shown that RLS patients frequently have PLM while awake (PLMW), whereas in control subjects the frequency of these movements is very low.26 PLMS are not limited to RLS alone, but occur in several other medical conditions27,28 and sleep disorders involving a dopaminergic impairment.29 PLMS lead to multiple awakenings at night and severe sleep disruption and may, at least in part, be responsible for the sleep impairment in RLS. In a polysomnographic study of 26 RLS patients, sleep efficiency was decreased by 50% and 30% of patients obtained less than 3.5 full hours of sleep per night.30

수면 중 주기적인 다리 움직임

RLS 환자의 약 80%에서

PLMS가 이 증후군과 연관되어 있습니다.22,23

PLMS는 가속도계를 사용한 다리 액티그래피,24 또는 수면다원검사 중 근전도(EMG)로 기록되며, 5-90초 간격으로 0.5-10초 지속되는 하지의 반복적인 움직임(연속 4회 이상)으로 정의됩니다. 또한 근전도 진폭이 안정 시보다 ≥8 μV로 증가하는 것과 같은 정량적 요건도 정의되어 있습니다.25 제안된 고정 검사 결과에 따르면 RLS 환자는 깨어 있는 동안 PLM이 자주 발생하는 반면(PLMW), 대조군에서는 이러한 움직임의 빈도가 매우 낮은 것으로 나타났습니다.26 PLMS는 RLS에만 국한되지 않고 여러 다른 의학적 질환27,28 및 도파민성 장애와 관련된 수면 장애에서 발생합니다.29 PLMS는 밤에 여러 번 깨어나고 심각한 수면 장애를 유발하며 적어도 부분적으로는 RLS의 수면 장애를 일으킬 수 있습니다. 26명의 RLS 환자를 대상으로 한 수면다원검사에서 수면 효율이 50% 감소했으며, 환자의 30%는 하룻밤에 3.5시간 미만의 수면을 취한 것으로 나타났습니다.30

Genetic aspects

Ekbom31 described RLS families with an autosomal dominant inheritance pattern and estimated the frequency of hereditary RLS to be one-third compared with sporadic RLS. Several studies have confirmed these early observations, and familial aggregation of RLS symptoms has been well documented. Between 40% and 90% of patients report having at least one affected first-degree relative with RLS.32,33 However, the different phenotypic expression‎ of RLS, the presence of sometimes mild and intermittent forms, and the absence of a biological marker for the diagnosis make genetic studies demanding. The presence of PLMS can support the diagnosis; however, it often occurs also in unaffected family members as an asymptomatic condition in individuals who later may develop RLS, and therefore caution needs to be taken.

Linkage studies have identified several genomic loci to be associated with RLS (RLS1 – RLS5 on chromosomes 12q, 14q, 9p, 2q, and 20p, respectively) in single families, but no gene mutation has yet been identified.34–38 Further evidence of a locus on chromosome 9p, which is probably distinct from RLS3,39 and of a locus on chromosome 16p40 was detected by linkage, and suggestive evidence exists for linkage to chromosome 19p.41 Given the subjective nature of the RLS phenotype, until specific variants are identified within the loci described above, care should be taken in interpreting their significance. The locus on chromosome 12q (RLS1) was further investigated and an association between variants in the NOS1 gene and RLS was detected, which suggests the involvement of the nitric oxide/arginine pathway in the pathogenesis of RLS.42

Genome-wide association studies with high density single nucleotide polymorphism (SNP) data have identified regions with a major contribution to RLS on chromosomes 6p (BTBD9), 2p (MEIS1), and 15q (LBXCOR1/MAP2K5).43,44 In Icelandic and American RLS patients, a common intronic variant in the BTBD9 gene was associated with RLS with PLMS.43 Interestingly, the highest odds ratio was observed in subjects with PLMS without RLS and the association disappeared completely in subjects with RLS without PLMS. A second important aspect of the Icelandic study is the association of the variant in BTBD9 with reduced serum ferritin levels (decrease of 13% per copy of the risk allele). This is the first time a clear association of a major genetic risk factor for RLS and PLMS with reduced iron in serum is described.

A second study also detected an association between RLS and an intronic variant in BTBD9, as well as 2 additional intronic SNPs in MEIS1 and a region containing the genes MAP2K5 and LBXCOR1 on chromosome 15q.44 The results were replicated in 2 further case-control samples from Germany and a French-Canadian population. Since the authors of this study did not report on PLMS, it is unclear how much of the association is due to RLS, PLMS, or the combined phenotype. An RLS-associated risk haplotype consisting of 2 SNPs in the MEIS1 gene was shown to be correlated with a decreased MEIS1 mRNA and protein expression‎ in lymphoblastoid cell lines and brains of RLS patients compared with carriers of the nonrisk haplotype, suggesting that reduced expression‎ of MEIS1 predisposes to RLS.45 Vilarino-Guell et al46 identified an arg272-to-his substitution (R272H) in MEIS1 in 4 RLS patients of 1 family, but also in 1 unaffected family member. The R272H variant was not found among 378 additional RLS cases or 528 controls from North America, but it was found in 1 of 325 European controls. This is an interesting finding, but warrants replication.

The risk variants in the 3 genomic regions have been calculated to carry a combined population attributable risk (PAR) of approximately 68.6% in the German population and 74.2% in the Canadian population.44 The PAR for the variation in the BTBD9 gene was calculated to be 50% in the combined Icelandic and American populations.43

In addition to these 3 regions, the PTPRD gene was identified as the fourth genome-wide significant locus for RLS.47 Despite the risk captured by variants at these loci, additional major susceptibility loci for the disease might still exist.

유전적 측면

Ekbom31은 상염색체 우성 유전 패턴을 가진 RLS 가족을 설명했으며 유전성 RLS의 빈도는 산발성 RLS에 비해 1/3로 추정했습니다. 여러 연구에서 이러한 초기 관찰 결과를 확인했으며, RLS 증상의 가족적 집합이 잘 문서화되어 있습니다. 환자의 40~90%는 적어도 한 명 이상의 일차 친척이 RLS에 걸린 것으로 보고합니다.32,33 그러나 RLS의 다양한 표현형 발현, 경증 및 간헐적 형태의 존재, 진단을 위한 생물학적 마커의 부재로 인해 유전자 연구가 까다롭습니다. PLMS의 존재는 진단을 뒷받침할 수 있지만, 영향을 받지 않은 가족 구성원에서도 나중에 RLS가 발생할 수 있는 무증상 상태로 발생하는 경우가 많으므로 주의가 필요합니다.

연관성 연구를 통해 단일 가족에서 RLS와 연관된 여러 게놈 유전자좌(각각 염색체 12q, 14q, 9p, 2q, 20p의 RLS1 - RLS5)가 확인되었지만 아직 유전자 변이는 확인되지 않았습니다.34 -38 RLS3와 구별되는 것으로 추정되는 9p 염색체의 유전자좌에 대한 추가 증거,39 그리고 16p40 염색체의 유전자좌가 연관성을 통해 검출되었으며, 19p 염색체와의 연관성에 대한 암시적인 증거가 존재합니다.41 RLS 표현형의 주관적인 특성을 고려할 때 위에서 설명한 유전자좌 내에서 특정 변이가 확인될 때까지 그 의미를 해석하는 데 주의를 기울여야 합니다. 염색체 12q(RLS1)의 유전자좌를 추가로 조사한 결과, NOS1 유전자의 변이와 RLS 사이의 연관성이 발견되었으며, 이는 RLS의 발병에 산화질소/아르기닌 경로가 관여한다는 것을 시사합니다.42

고밀도 단일염기다형성(SNP) 데이터를 사용한 게놈 전체 연관성 연구에서 염색체 6p(BTBD9), 2p(MEIS1), 15q(LBXCOR1/MAP2K5)에서 RLS에 크게 기여하는 영역을 확인했습니다.43,44 아이슬란드와 미국 RLS 환자에서 BTBD9 유전자의 일반적인 인트론 변이가 PLMS와 RLS와 연관되었습니다.43 흥미롭게도 RLS가 없는 PLMS 환자에서 가장 높은 오즈비가 관찰되었으며, PLMS가 없는 RLS 환자에서는 연관성이 완전히 사라졌습니다. 아이슬란드 연구의 두 번째 중요한 측면은 BTBD9의 변이가 혈청 페리틴 수치 감소(위험 대립유전자 사본당 13% 감소)와 연관성이 있다는 점입니다. RLS 및 PLMS의 주요 유전적 위험 인자와 혈청 내 철분 감소 사이의 명확한 연관성이 설명된 것은 이번이 처음입니다.

두 번째 연구에서는 RLS와 BTBD9의 인트론 변이체, 그리고 MEIS1의 2개의 추가 인트론 SNP와 염색체 15q의 MAP2K5 및 LBXCOR1 유전자를 포함하는 영역 사이의 연관성을 발견했습니다.44 이 결과는 독일과 프랑스-캐나다 인구의 추가 사례 대조 샘플 2개에서 복제되었습니다. 이 연구의 저자는 PLMS에 대해 보고하지 않았기 때문에 연관성이 RLS, PLMS 또는 복합 표현형에 의한 것인지는 불분명합니다. MEIS1 유전자에서 2개의 SNP로 구성된 RLS 관련 위험 일배체형은 비위험 일배체형 보균자에 비해 림프모구 세포주 및 RLS 환자의 뇌에서 MEIS1 mRNA 및 단백질 발현 감소와 상관관계가 있는 것으로 나타났으며, 이는 MEIS1의 발현 감소가 RLS에 걸리기 쉽다는 것을 시사합니다.45 빌라리노-구엘 등46은 한 가족 4명의 RLS 환자 1명과 영향을 받지 않은 가족 구성원 1명에게서 MEIS1에서 arg272 대 그의 치환(R272H)을 확인했습니다. R272H 변이는 북미의 378명의 추가 RLS 환자 또는 528명의 대조군에서는 발견되지 않았지만, 325명의 유럽 대조군 중 1명에서 발견되었습니다. 이는 흥미로운 발견이지만 복제할 필요가 있습니다.

3개 게놈 영역의 위험 변이는 독일 인구에서 약 68.6%, 캐나다 인구에서 74.2%의 인구 기여 위험도(PAR)를 갖는 것으로 계산되었습니다.44 아이슬란드 및 미국 인구 합산에서 BTBD9 유전자 변이에 대한 PAR은 50%로 계산되었습니다.43

이 세 가지 영역 외에도 PTPRD 유전자는 RLS의 네 번째 게놈 전체에 걸쳐 중요한 유전자좌로 확인되었습니다.47 이러한 유전자좌의 변이에 의해 포착 된 위험에도 불구하고 질병에 대한 추가 주요 감수성 유전자좌가 여전히 존재할 수 있습니다.

Association of RLS and other movement disorders

Several studies have assessed the association between Parkinson disease (PD) and RLS.48 Overall, these studies indicate that RLS is more frequent in PD patient cohorts compared with controls. However, the consensus criteria for RLS diagnosis have not been validated in PD patients,49 and symptoms of restlessness could be partially explained by the presence of parkinsonism and associated sensory complaints. On the other hand, RLS as well as PD responds to dopaminergic agents and a positive response to levodopa supports the diagnosis of both conditions. In addition, a cooccurrence of RLS and Parkin mutations (that are associated with familial parkinsonism) has been described50 and the authors were able to show that the presence of a heterozygous Parkin mutation in RLS patients linked to RLS4 can lower the age at onset of RLS.51 Taken together, these data suggest a possible connection between both diseases, although more accurate assessments are necessary.

A high frequency (33%) of RLS in patients with essential tremor has been described and these RLS patients had a high rate of familial history. In fact, in several families, essential tremor cosegregated with RLS, suggesting that these 2 conditions share some common genetic determinants.52

A higher frequency of RLS is also reported for spinocerebellar ataxia patients, compared with controls, but the probability of developing RLS did not increase with CAG repeat length53 and there was no reduction of the dopamine type 2-receptor (D2) availability in the striatum of ataxia patients with RLS.54

RLS와 다른 운동 장애의 연관성

여러 연구에서 파킨슨병(PD)과 RLS의 연관성을 평가했습니다.48 전반적으로 이러한 연구에 따르면 RLS는 대조군에 비해 PD 환자 코호트에서 더 빈번하게 발생하는 것으로 나타났습니다. 그러나 RLS 진단에 대한 합의된 기준은 PD 환자에서 검증되지 않았으며,49 불안 증상은 파킨슨병 및 관련 감각 장애의 존재로 부분적으로 설명될 수 있습니다. 반면에 RLS와 PD는 도파민성 약제에 반응하며 레보도파에 대한 양성 반응은 두 질환의 진단을 뒷받침합니다. 또한 (가족성 파킨슨병과 연관된) RLS와 파킨 돌연변이의 동시 발생이 기술되어 있으며50 저자들은 RLS4와 연관된 RLS 환자에서 이형 접합성 파킨 돌연변이가 있으면 RLS 발병 연령이 낮아질 수 있음을 보여줄 수 있었습니다.51 이러한 데이터를 종합하면 보다 정확한 평가가 필요하지만 두 질병 사이의 연관성이 있음을 시사합니다.

본태성 진전증 환자에서 RLS의 높은 빈도(33%)가 관찰되었으며, 이러한 RLS 환자는 가족력이 있는 비율이 높았습니다. 실제로 몇몇 가족에서 본태성 떨림이 RLS와 함께 나타나 이 두 질환이 몇 가지 공통된 유전적 결정 요인을 공유하고 있음을 시사합니다.52

척수 소뇌 운동 실조증 환자에서도

대조군에 비해 RLS의 빈도가 더 높은 것으로 보고되었지만,

RLS 발병 확률은 CAG 반복 길이53에 따라 증가하지 않았으며,

RLS를 가진 운동 실조증 환자의 선조체에서 도파민 2형 수용체(D2) 가용성의 감소는 없었습니다.54

Pathophysiology

The excellent response to treatment with dopamine agonists (DA) and levodopa, and the exacerbation of RLS symptoms with the use of dopamine antagonists55,56 provided the basis for the hypothesis that dopaminergic pathways are involved in RLS. The circadian nature of RLS symptoms with the worsening during the night, when dopamine levels decrease, further supports the correlation between RLS and altered dopaminergic metabolism or signaling.57 Iron has been implicated in the pathophysiology of RLS, given that several secondary causes of RLS (iron deficiency, pregnancy, and end-stage renal disease) share a common factor (i.e. iron insufficiency), and in a small nonrandomized study, intravenous iron supplementation improved symptoms of both primary and secondary RLS.58 This suggests that abnormal use and/or storage of iron is related to the development of RLS symptoms.

Positron emission tomography (PET) studies have shown mild, but significant decrease in D2-receptor binding in both the putamen and the caudate, and a decreased uptake of 18F-dopa in the striatum in patients with RLS.59,60 18F-dopa uptake was reduced by approximately 10%–12% in RLS patients compared with controls. This relatively small reduction might reflect the fact that imaging was not performed at night when RLS symptoms are most pronounced. A similar finding was reported in a study using [123I] beta-CIT and [123I] IBZM single photon emission computed tomography (SPECT).61 A study on autopsy samples from patients with very severe RLS showed a 30% decrease in D2-receptor compared with controls.62 These results are consistent with prior animal studies, where iron deficiency strongly correlates with a decrease in D2-receptor binding in the rat striatum.63 In addition, the RLS tissue showed a significant increase in tyrosine hydroxylase (TH) and phosphorylated (active) TH in the substantia nigra.62 These data are surprising, but consistent with a recent cerebrospinal fluid (CSF) study reporting greater 3-ortho-methyldopa (3-O-MD), a product of levodopa metabolism, in patients with severe RLS indicating possible increased dopamine production.64

To assess the iron status in RLS patients, magnetic resonance imaging (MRI) measures of regional brain iron and measurements of ferritin and transferrin levels in CSF have been performed. MRI studies have consistently shown decreased iron stores in the substantia nigra,65 and these data were confirmed also by different techniques, such as transcranial ultrasound.66 In a neuropathologic examination of 7 RLS brains, no histopathologic abnormalities were detected, but staining for iron and H-ferritin was reduced in the substantia nigra and transferrin receptor staining was reduced in neuromelanin-containing cells, suggesting that the iron acquisition by the neuromelanin cells may be impaired in RLS.67 Earley et al68 found significantly reduced ferritin and increased transferrin in the CSF of 16 RLS patients compared with age-matched controls. This finding, observed in the presence of normal serum iron values, is consistent with deficiencies in central nervous system (CNS) iron levels and is confirmed in a second study of Mizuno et al.69 CSF analyses also provide evidence for a dysregulation in the dopaminergic system in RLS. Both 3-O-MD and tetrahydrobiopterin, a cofactor for TH, were increased in CSF samples of RLS patients compared with controls.64 These data from CSF analyses from RLS patients support the concept of low brain iron and impaired dopaminergic function in RLS patients.

Recently, higher mitochondrial ferritin (FtMt) levels and higher numbers of mitochondria were detected in the substantia nigra of 8 RLS patients compared with 8 controls.70 Neuromelanin-containing neurons in the substantia nigra were the predominant cell type expressing FtMt. An induction of mitochondriogenesis seems to take place in RLS; this may be the result of cellular attempts to correct metabolic insufficiency and leads to cytosolic iron deficiency. This would be consistent with the previous reports of lower brain iron levels in RLS.

병리 생리학

도파민 작용제(DA)와 레보도파 치료에 대한

우수한 반응과 도파민 길항제55,56의 사용으로 인한 RLS 증상 악화는

도파민 경로가 RLS에 관여한다는 가설의 근거를 제공했습니다.

도파민 수치가 감소하는 밤에 증상이 악화되는 일주기적 특성은

RLS와 변화된 도파민 대사 또는

신호 사이의 상관관계를 더욱 뒷받침합니다.57

철분은

RLS의 여러 이차적 원인(철분 결핍, 임신, 말기 신장 질환)이

공통된 요인(즉, 철분 부족)을 공유하고 있고,

소규모 비무작위 연구에서 정맥 철분 보충제가

일차 및 이차 RLS의 증상을 모두 개선했다는 점을 고려할 때

철분이 RLS의 병리 생리와 관련이 있습니다.58

이는

철분의 비정상적인 사용 및/또는 저장과

RLS 증상 발병이 관련이 있음을 시사하는 것입니다.

양전자방출단층촬영(PET) 연구에 따르면 RLS 환자의 선조체에서 D2 수용체 결합이 경미하지만 유의하게 감소하고 선조체에서 18F 도파의 흡수가 감소한 것으로 나타났습니다.59,60 18F 도파 흡수는 대조군에 비해 RLS 환자에서 약 10%-12% 감소한 것으로 나타났습니다. 이 상대적으로 작은 감소는 RLS 증상이 가장 두드러지는 밤에 영상을 촬영하지 않았기 때문일 수 있습니다. 123I] 베타-CIT 및 [123I] IBZM 단일 광자 방출 컴퓨터 단층촬영(SPECT)을 사용한 연구에서도 비슷한 결과가 보고되었습니다.61 매우 심한 RLS 환자의 부검 샘플을 대상으로 한 연구에서는 대조군에 비해 D2 수용체가 30% 감소했습니다.62 이러한 결과는 이전의 동물 연구와 일치하며, 철분 결핍이 쥐 선조체의 D2 수용체 결합 감소와 강한 상관관계가 있는 것으로 나타났습니다.63 또한 RLS 조직은 흑질에서 티로신 하이드 록실 라제 (TH)와 인산화 된 (활성) TH가 크게 증가한 것으로 나타났습니다 .62 이러한 데이터는 놀랍지만 최근 뇌척수액 (CSF) 연구에서 레보도파 대사의 산물 인 3- 오르토 메틸 도파 (3-O-MD)가 중증 RLS 환자에서 도파민 생성 증가 가능성을 나타내는 것으로보고 한 연구와 일치합니다 .64

RLS 환자의 철분 상태를 평가하기 위해 자기공명영상(MRI)으로 국소 뇌 철분을 측정하고 CSF에서 페리틴과 트랜스페린 수치를 측정했습니다. MRI 연구에서는 흑질에 철분 저장량이 감소한 것으로 일관되게 나타났으며,65 이러한 데이터는 경두개 초음파 등 다양한 기법을 통해서도 확인되었습니다.66 7명의 RLS 뇌에 대한 신경 병리학적 검사에서 조직 병리학적인 이상은 발견되지 않았지만, 흑질에서 철과 H-페리틴 염색이 감소하고 뉴로멜라닌 함유 세포에서 트랜스페린 수용체 염색이 감소하여 RLS에서 뉴로멜라닌 세포의 철 획득이 손상될 수 있음을 시사했습니다.67 Earley 등은68 16명의 RLS 환자의 CSF에서 연령 일치 대조군에 비해 페리틴이 현저히 감소하고 트랜스페린이 증가했음을 발견했습니다. 혈청 철분 수치가 정상인 상태에서 관찰된 이 결과는 중추신경계(CNS) 철분 수치의 결핍과 일치하며, 미즈노(Mizuno) 등의 두 번째 연구에서 확인되었습니다.69 CSF 분석은 또한 RLS에서 도파민 시스템의 조절 장애에 대한 증거를 제공합니다. 3-O-MD와 TH의 보조 인자인 테트라하이드로비옵테린은 대조군에 비해 RLS 환자의 CSF 샘플에서 모두 증가했습니다.64 이러한 RLS 환자의 CSF 분석 데이터는 RLS 환자의 뇌 철분 부족과 도파민 기능 장애의 개념을 뒷받침합니다.

최근 8명의 대조군에 비해 8명의 RLS 환자의 흑질에서 더 높은 미토콘드리아 페리틴(FtMt) 수치와 더 많은 수의 미토콘드리아가 검출되었습니다.70 흑질에서 뉴로멜라닌 함유 신경세포가 FtMt를 발현하는 주된 세포 유형이었습니다. 미토콘드리아 생성 유도는 RLS에서 일어나는 것으로 보이며, 이는 대사 부족을 교정하려는 세포 시도의 결과일 수 있고 세포질 철 결핍으로 이어질 수 있습니다. 이는 RLS에서 뇌 철분 수치가 낮다는 이전 보고와 일치합니다.

Rationale of treatment options

With RLS being both a sensory and motor disorder (with the presence of PLMS), it is hard to precisely localize the anatomic areas involved in this clinical condition. Nevertheless, the responses to medication that cross the blood-brain barrier suggest the involvement of the CNS. This hypothesis is supported by 2 types of evidence the administration of metoclopramide, an antiemetic dopamine antagonist that crosses the blood-brain barrier, worsens the symptoms of RLS, while domperidone, another dopamine antagonist that does not cross the blood-brain barrier, is well tolerated and does not exacerbate any RLS symptom.71 Second, although it is still not well known whether PLMS and RLS share the same pathogenetic pathway, despite the frequent association of the 2 symptoms, it is interesting to note that dopaminergic receptors are also distributed throughout the spinal cord, both in the ventral and dorsal horns, as well as in the white matter.72 The involvement of the ventral horn might underlie some of the motor symptoms, such as PLMS, whereas the dorsal horn could address the paresthesias and pain perceptions.73,74

Several authors have shown an increased spinal flexor reflex excitability in RLS individuals during waking and sleep, and the fact that sensory and motor symptoms are usually bilateral and segmentally localized in the legs strengthens the hypothesis of spinal cord involvement. In addition, several case-reports describe the onset of RLS shortly after spinal pathologies, such as lumbosacral radiculopathy, traumatic lesions, transverse myelitis, vascular injury of the spinal cord, multiple sclerosis, and syringomyelia.75 Finally, studies that aimed to eval‎uate the cortical activity before the appearance of involuntary PLMW or PLMS showed that these movements are not preceded by a Bereitschafts-potential, thus making a cortical origin of the movements unlikely.76 However, some desynchronization in the beta activity at a cortical level is present before both voluntary and involuntary leg movements in RLS.77

As already described, an association between RLS and systemic iron deficiency has been long recognized. A possible etiologic role of iron deficiency was suggested more than 50 years ago, after the successful treatment of RLS with intravenous iron.78 Low iron storage and disturbances in iron transport or metabolism may lead to RLS,30 and abnormalities in brain iron storage are strongly associated with RLS severity. The exact mechanisms contributing to RLS development are still unknown. It has been hypothesized that although iron stores and metabolism may be sufficient for assuring normal erythrocyte production, they may be insufficient for maintaining normal brain iron stores.65,68,79 The distribution of iron in the brain is heterogeneous, but it is preval‎ent in dopaminergic regions, such as the substantia nigra and the striatum. There are several interactions between iron and dopamine: first, iron is a cofactor for TH, which is the rate-limiting step in the production of dopamine.80 Second, iron modulates the expression‎ of D2-receptors in animal brains.81 Iron deprivation in rats results in a 40%–60% reduction in postsynaptic striatal D2-receptors, but not in D1-receptors.63 In addition, in patients with RLS, ferritin concentration in the CSF was shown to be reduced, whereas transferrin concentration was increased.18 These studies support the hypothesis that local, rather than general changes in iron status may account for clinical manifestations of RLS. Ferritin provides a measure of whole body (including brain) iron storage, whereas transferrin reflects tissue requirement for iron. Since serum iron values are directly affected by diet, stress, sleep behavior, and circadian patterns, low serum ferritin levels are a better indicator of iron depletion.

Transferrin helps identifying excessive iron, but does not accurately identify reduced iron stores.

The involvement of the dopaminergic system in RLS is supported by numerous lines of evidence, including lower concentrations of dopamine metabolites and homovanillic acid levels in nocturnal urinary excretion from subjects with PLMS,82 significant differences in CSF dopamine metabolite concentrations between morning and evening from RLS patients compared with healthy controls,83 and the dramatic improvement of RLS symptoms with dopaminergic agents.

In addition to a dopaminergic system involvement, an involvement of the pain system in RLS was first highlighted in 1945 when Ekbom84 described 2 forms of RLS: one classically characterized by paresthesias and the other characterized by the presence of pain, more difficult to diagnose and to treat. Pain discrimination seems to be impaired in RLS individuals, both in idiopathic and in secondary RLS.84,85 In addition, in a sample from a psychiatric practice the occurrence of RLS was related to the intake of nonopioid pain killers, speculating therefore that central sensitization by nonopioid overuse could play a role in RLS.86 Nevertheless, as for dopaminergic drugs, the most convincing evidence supporting the involvement of the opiate system is the effectiveness of the opioid therapy in RLS patients, and most precisely those agents that specifically target opioid μ-receptors.87 In addition, there is strong evidence that endogenous opioids modulate dopamine systems in the brain and endogenous as well as exogenous opioids appear to increase extracellular dopamine levels.88

치료 옵션의 근거

RLS는 감각 및 운동 장애(PLMS가 있는 경우)이기 때문에 이 임상 상태와 관련된 해부학적 부위를 정확히 파악하기는 어렵습니다. 그럼에도 불구하고 혈액-뇌 장벽을 통과하는 약물에 대한 반응은 중추신경계가 관여하고 있음을 시사합니다. 이 가설은 두 가지 증거에 의해 뒷받침됩니다. 첫째, 혈뇌 장벽을 통과하는 구토 방지 도파민 길항제인 메토클로프라미드 투여는 RLS 증상을 악화시키는 반면, 혈뇌 장벽을 통과하지 않는 다른 도파민 길항제인 돔페리돈은 내약성이 우수하고 RLS 증상을 악화시키지 않습니다.71 둘째, PLMS와 RLS가 동일한 병인 경로를 공유하는지는 아직 잘 알려져 있지 않지만 두 증상이 자주 연관되어 있음에도 불구하고 도파민 수용체가 척수 전체, 배쪽 및 등쪽 뿔과 백질에 분포한다는 점은 흥미 롭습니다 .72 배쪽 뿔의 관여는 PLMS와 같은 일부 운동 증상의 기저가 될 수있는 반면 등쪽 뿔은 감각 이상과 통증 지각을 다룰 수 있습니다 .73,74

몇몇 저자들은 깨어 있는 동안과 수면 중에 RLS 환자의 척추 굴곡 반사 흥분성이 증가한다는 사실을 보여주었으며, 감각 및 운동 증상이 일반적으로 다리에 양측성 및 분절적으로 국한된다는 사실은 척수 침범 가설을 강화합니다. 또한 여러 사례 보고에 따르면 요천골 근병증, 외상성 병변, 횡단성 척수염, 척수 혈관 손상, 다발성 경화증, 척수 공동 증과 같은 척추 병리 직후에 RLS가 발병한 것으로 나타났습니다.75 마지막으로, 불수의적 PLMW 또는 PLMS가 나타나기 전에 피질 활동을 평가하기위한 연구에 따르면 이러한 움직임은 Bereitschafts-potential이 선행되지 않으므로 움직임의 피질 기원은 가능성이 낮습니다 .76 그러나 피질 수준에서 베타 활동의 일부 비동기화는 RLS의 자발적 및 불수의적 다리 움직임 모두 전에 존재합니다 .77

이미 설명했듯이 RLS와 전신 철분 결핍 사이의 연관성은 오랫동안 인식되어 왔습니다. 철분 결핍의 병인학적 역할 가능성은 50여 년 전 정맥 철분으로 RLS를 성공적으로 치료한 후 제안되었습니다.78 철분 저장량이 적고 철분 수송 또는 대사에 장애가 있으면 RLS가 발생할 수 있으며,30 뇌 철분 저장의 이상은 RLS 중증도와 밀접한 관련이 있습니다. RLS 발병에 기여하는 정확한 메커니즘은 아직 밝혀지지 않았습니다. 철분 저장과 대사가 정상적인 적혈구 생산을 보장하는 데는 충분할 수 있지만 정상적인 뇌 철분 저장량을 유지하는 데는 불충분할 수 있다는 가설이 제기되었습니다.65,68,79 뇌의 철분 분포는 이질적이지만 흑질과 선조체와 같은 도파민 영역에 널리 퍼져 있습니다. 첫째, 철분은 도파민 생성 속도를 제한하는 단계인 TH의 보조 인자입니다.80 둘째, 철분은 동물의 뇌에서 D2 수용체의 발현을 조절합니다.81 쥐의 철분 결핍은 시냅스 후 선조체 D2 수용체의 40%-60% 감소를 초래하지만 D1 수용체에서는 감소하지 않습니다.63 또한, RLS 환자에서 CSF의 페리틴 농도는 감소한 반면 트랜스페린 농도는 증가한 것으로 나타났습니다.18 이러한 연구는 철분 상태의 일반적인 변화가 아닌 국소적인 변화가 RLS의 임상 증상을 설명할 수 있다는 가설을 뒷받침합니다. 페리틴은 전신(뇌 포함) 철분 저장량을 측정하는 반면, 트랜스페린은 철분에 대한 조직 요구량을 반영합니다. 혈청 철분 수치는 식단, 스트레스, 수면 행동 및 일주기 패턴의 직접적인 영향을 받기 때문에 낮은 혈청 페리틴 수치는 철분 고갈을 나타내는 더 좋은 지표입니다.

트랜스페린은 철분 과다를 식별하는 데 도움이 되지만, 철분 저장량 감소를 정확하게 식별하지는 못합니다.

도파민 시스템이 RLS에 관여한다는 사실은 PLMS 환자의 야간 소변 배설에서 도파민 대사산물 및 호모바닐산 농도가 낮고,82 건강한 대조군과 비교하여 RLS 환자의 아침과 저녁 사이 CSF 도파민 대사산물 농도에 유의미한 차이가 있으며,83 도파민 제제로 RLS 증상이 극적으로 개선되는 등 수많은 증거가 뒷받침하고 있습니다.

도파민 시스템의 관여 외에도 통증 시스템의 관여는 1945년 Ekbom84이 RLS의 두 가지 형태, 즉 고전적으로 감각 이상이 특징인 경우와 진단과 치료가 더 어려운 통증이 특징인 경우를 설명하면서 처음 강조되었습니다. 특발성 및 이차성 RLS 모두에서 통증 변별력이 손상된 것으로 보입니다.84,85 또한 정신과 진료 샘플에서 RLS의 발생은 비오피오이드 진통제 섭취와 관련이 있었으며, 따라서 비오피오이드 과다 사용에 의한 중추 민감화가 RLS에서 역할을 할 수 있다고 추측합니다.86 그럼에도 불구하고, 도파민계 약물의 경우 오피오이드 시스템의 관여를 뒷받침하는 가장 설득력 있는 증거는 RLS 환자에서 오피오이드 치료의 효과, 가장 정확하게는 오피오이드 μ 수용체를 특이적으로 표적으로 하는 약제입니다.87 또한 내인성 오피오이드가 뇌의 도파민 시스템을 조절하고 내인성 및 외인성 오피오이드가 세포 외 도파민 수준을 증가시키는 것으로 보인다는 강력한 증거가 있습니다.88

Management issues: efficacy and tolerability/safety in the treatment of RLS

Nonpharmacological treatment

Figure 1 summarizes an algorithm for RLS management.89 The treatment for RLS is mainly pharmacological. Neverthe less, nonpharmacological treatment should be first tried in the management of this condition. Sleep hygiene (regular hour to go to bed at night, use of the bed only for sleep and sexual activity – not, for example, for reading or watching TV) and avoidance of stimulating substances, such as caffeine, nicotine, and alcohol, or medications such as antidepressants, antipsychotic and antihistaminic agents have been suggested to be efficacious, especially in younger patients with mild or intermittent symptoms.89,90 However, in clinical practice, nonpharmacological strategies have shown little efficacy, even if controlled studies are still lacking. Physical activity in the evening hours, although not strenuous exercise, may delay the need for pharmacologic intervention into a time later in the evening. During times of forced immobilization, such as airplane flights, patients may find that mentally stimulating or alerting activities such as playing computer games, performing intricate needlework, or reading an engaging novel may lessen their symptoms of RLS.

비약물적 치료

그림 1은 RLS 관리를 위한 알고리즘을 요약한 것입니다.89 RLS의 치료는 주로 약리학적 치료입니다. 그럼에도 불구하고 이 질환을 관리할 때는 비약물적 치료를 먼저 시도해야 합니다. 수면 위생(밤에 잠자리에 드는 시간을 규칙적으로 지키고, 침대를 독서나 TV 시청 등 다른 용도로 사용하지 않고 수면과 성행위에만 사용)과 카페인, 니코틴, 알코올과 같은 자극성 물질 또는 항우울제, 항정신병 약제, 항히스타민제와 같은 약물을 피하는 것이 특히 증상이 경미하거나 간헐적인 젊은 환자에게 효과적인 것으로 제안되었습니다.89,90 그러나 임상에서는 대조 연구가 아직 부족하더라도 비약리적 전략은 거의 효과를 보지 못한 것으로 밝혀져 있습니다. 저녁 시간대의 신체 활동은 격렬한 운동은 아니더라도 약리학적인 개입의 필요성을 저녁 늦은 시간으로 지연시킬 수 있습니다. 비행기 비행과 같이 강제로 움직이지 못하는 시간에는 컴퓨터 게임, 복잡한 바느질 작업, 흥미진진한 소설 읽기 등 정신적으로 자극을 주거나 각성 효과가 있는 활동을 하면 RLS 증상이 완화될 수 있습니다.

Figure 1

Algorithm for the management of RLS.

Source: Adapted from Silber et al.89

Notes: Dopamine agonists are the treatment choice in most patients. Low-potency opioids and gabapentin are valuable alternatives for the treatment of daily RLS, but dopamine agonists should be used if they are unsuccessful.

Abbreviation: RLS, restless legs syndrome.

Recognizing a secondary cause of RLS and targeting its specific treatment is instead of much greater importance. For example, polyneuropathies (including diabetic, alcoholic, amyloid, etc) or radiculopathies inducing dysesthesias or severe pain may worsen RLS symptoms, elevate complaints above the perception threshold in RLS individuals, or even completely mimic RLS. The exclusion of such conditions, or their treatment, is therefore essential for the correct management of RLS patients.

Uremia secondary to kidney failure is highly associated with RLS, although the mechanism by which uremia causes RLS is not known. Dialysis does not improve RLS, but it seems that RLS symptoms correlate with greater dialysis frequency. Contrarily, kidney transplantation seems to drastically improve RLS symptoms within days or weeks.91,92 Pharmacologic treatment of uremic RLS is similar to idiopathic RLS, but might require higher dosages (especially of dopaminergic agents) and these patients are more prone to be refractory. A recent study shows an association between RLS and chronic renal failure (CRF) in nondialyzed patients. Interestingly, CRF patients with RLS showed the presence of an iron deficiency compared with the CRF patients without RLS.93

Iron therapy

Iron deficiency is by far the most common cause of secondary RLS, and can account also for RLS during pregnancy, where hemoglobin levels have been found to be lower than normal.94 In order to establish whether there is an iron deficiency, serum ferritin more accurately captures whole body iron storage, as serum iron does not allow the estimation of the brain iron storage. Oral iron supplementation may improve RLS symptoms,95,96 but its usage has always been hindered by either a low efficacy97 or the poor absorption and tolerability at required doses. The absorption of oral iron supplementation is indeed inversely related to the concentration of serum ferritin, dropping to 1%–2% when ferritin levels are normal.98 Iron delivered intravenously does not have this limitation. Intravenous iron sucrose is a well-tolerated iron supplementation which has demonstrated evidence to reduce RLS symptoms in the acute phase (7 weeks) in RLS patients with variable degrees of iron deficiency.99 Still, its efficacy has been argued for the long-term follow up.100 Iron dextran has been shown to increase brain iron content and to improve refractory RLS,98 but results are inconsistent and not free of possible side effects, such as anaphylactic reactions. In addition, it has been shown that ferritin levels progressively decline in patients after high intravenous iron supplementations, maybe explaining why high iron doses do not have sustained benefits.58 Yet, iron dextran may be superior to other intravenous iron preparations for the treatment of RLS101 and supplemental iron treatments can sustain previously achieved improvements with a single intravenous iron treatment.58 Nevertheless intravenous iron supplementation has been considered likely efficacious only for the treatment of RLS secondary to end-stage renal disease and remains investigational for RLS patients with normal renal function.102

Pharmacological treatment

Pharmacological therapy is considered the most efficient form of treatment for RLS patients. As for many neurological conditions, the aim of the therapy is to provide symptomatic relief. Because RLS is a chronic condition, therapy must usually be continued indefinitely.

Dopaminergic agents

For a vast majority of individuals, moderate to severe forms of RLS can be treated with dopaminergic therapy.103–106 Both levodopa and DA are normally used and are well tolerated,106–108 as the dosage used for treatment of RLS is significantly lower than the one used for treatment of PD.73 DA should be considered as first-line therapy for moderate to severe RLS patients.109,110 Usually, the administration of the drug is limited to 2–4 hours prior to bedtime.111 However, particularly if daytime symptoms are present, DA can be given in divided dosages112 or using prolonged-release formulations,113–115 favoring the concept of low and continuous dopaminergic stimulation and increasing the benefit of therapy by reducing the risk of augmentation.

Augmentation

Augmentation is the most commonly encountered complication of long-term therapy of RLS with levodopa116,117 and probably, to a lesser extent, with DA.102,118–120 It is more likely to occur in patients with low serum ferritin levels.121,122 Augmentation is defined as an anticipation of RLS symptoms (at least 2 hours before they normally would occur prior to the initiation of drug therapy), intensification and spread to previously noninvolved parts of the body (particularly the arms). In addition, PLMW either occur for the first time or are worse than with initial therapeutic response or before treatment was started and the time from onset of quiescence to onset of symptoms is typically shortened.1 The treatment of augmentation may involve adjusting the timing or the dose of the medication or switching to another agent.

If dopaminergic drugs are contraindicated or not efficacious, benzodiazepines, gabapentin and other antiepileptic agents, or low-potency opioids, can be also proposed as therapy for RLS.89,122

Benzodiazepines

Benzodiazepines cause CNS depression by directly binding to the receptor for the inhibitory neurotransmitter gamma aminobutyric acid (GABA) and by increasing the affinity for its natural ligand. By improving sleep, benzodiazepine therapy may reduce arousals due to PLMS,123 but it could be less effective in eliminating movement and sensory abnormalities associated with RLS.89,124–126 Overall, benzodiazepines seem to have a low risk of adverse effects (mainly somnolence, decreased libido, risk of falls during the night, particularly in elderly patients, and exacerbation of comorbid obstructive sleep apnea) and to remain effective in the long term. Depending upon dosage levels, therapy with benzodiazepines may result in tolerance and dependency; in addition, if therapy is discontinued abruptly rather than through gradually tapered dosages, there may be precipitation of withdrawal. Patients with mild or intermittent symptoms of RLS, particularly young individuals, may receive the most benefit from such therapy. If combined with carbidopa/levodopa or DA, benzodiazepines may assist in the management of severe RLS symptoms and are usually administered orally shortly before or at bedtime.

Antiepileptic drugs

Gabapentin is considered efficacious for the treatment of RLS and therefore, is the most used second-line drug among the anticonvulsant medications. Although its mechanism of action is not clear, it is believed that RLS benefits from gabapentin via a combination of sedative and sensory modulating action.102,127,128 Carbamazepine, lamotrigine, valproate, levetiracetem, and pregabalin have been also used in the treatment of RLS, although their efficacy has not been confirmed, as the studies showing their efficacy included only few subjects or were open label.129–137

Opiates

Opiates seem to be the best of the second choice therapies for patients with resistant or unremitting symptoms,138 as they are supposed to decrease the release of neurotransmitters producing analgesic effects in the CNS. Some studies have shown that the use of opioids, also those with a lower potency, was able to alleviate paresthesias or dysesthesias, motor restlessness, and sleep disturbances associated with RLS.89,139–144 Opioid therapy seems to produce minimal side effects (such as nausea and constipation, but also sleep apnea via respiratory depression); however, there is always a risk of opioid addiction among RLS patients and augmentation is also reported.143,145 Nevertheless, tramadol, a weak μ-receptor agonist, may be considered as an alternative treatment of RLS,146 whereas oxycodone and methodone (the latter a very potent opioid) can be considered only for the treatment of daily and refractory RLS, respectively.102,147,148

Treatment of RLS in children

Untreated RLS in children could potentially lead to severe consequences such as cognitive deficits, attention-deficit hyperactivity disorder (ADHD), sleepwalking, nightmares, and parasomnias.149,150 Similar to the management of RLS in adults, secondary RLS should be excluded in children. When neuropathies are suspected, thyroid function, fasting blood sugar and insulin, as well as serum levels of vitamins B6, B9, and B12 should be investigated.151 Sleep hygiene and avoidance of possible triggers (such as serotoninergic drugs, diphenhydramine, metoclopramide, nicotine, caffeine, and alcohol) are essential.151 Children with low iron stores (defined by low serum ferritin) might benefit from oral iron supplementation. To date, DA agents are not approved in pediatrics and there is very little experience regarding the use of dopaminergic medications in children. Nevertheless, published case-reports show the long-term effectiveness of levodopa and other dopaminergic agents on both RLS and PLMS, as well as ADHD symptoms.152

Patient considerations, quality of life (QoL), satisfaction/preference

RLS patients present with a wide range of sensory and motor symptoms, which occur in quiet wakefulness or in sleep, and are often disabling, interfering with sleep and social functions and therefore impairing the QoL.153 The sensorimotor disorder can cause insomnia and lead to day time sleepiness. In addition, several other symptoms may occur, such as depression, fatigue, poor concentration, fidgetiness, lower limb pain, and burning feet. The onset of symptoms can be at any age; however, preval‎ence increases with age.14 The clinical course is usually chronic progressive with periodic exacerbations. However, in some individuals, symptoms occur in paroxysms or cluster. The sensory symptoms may vary so greatly, that several misdiagnoses have been posed in the course of the time. Therefore, the diagnosis is now based on the 4 essential consensus criteria.1 Most frequent sensory symptoms of RLS are general discomfort, cramps, and even pain.56,154 Lower limb involvement is the commonest presentation, but hand involvement has also been described. There is often bilateral involvement of the limbs, but the symptoms can be asymmetrical.

Motor restlessness is another specific feature of RLS.8 Patients develop an urge to move the limbs, which partially or completely resolves the unpleasant sensations.154 The most important differential diagnosis is with akathisia, a condition of constant motor restlessness secondary to neuroleptic use.154 Pain is an important aspect of symptom expression‎ and can cause difficulties for a correct RLS diagnosis. Upper limb, chin and, posterior neck pain mimicking radicular pain have been described.155

Quality of life

The QoL of patients with RLS is primarily impaired by sleep loss, extreme discomfort, reduction of job performance and job tenure, and disruption of normal activities156 mainly caused by the inability to tolerate sedentary activities. In addition, medications used to treat RLS, including dopaminergic drugs and opiates, are associated with side effects157 possibly affecting patient’s QoL. Furthermore, RLS therapy carries some limitations, for example, levodopa might lead to augmentation, especially with higher dosages.

In order to assess QoL, specific questionnaires have been developed. Both the Restless Legs Syndrome Quality of Life Instrument (RLS-QLI)158 and the Restless Legs Syndrome Quality of Life (RLSQoL)157 are specific for RLS. The latter, is an easy-to-administrate, 18-item questionnaire that only takes 10 minutes to administer, and therefore is a valuable tool for clinicians. In a specific study on QoL in RLS individuals, 85% of patients complain that RLS symptoms impair specific aspects of daytime functioning.8 The most commonly reported problems were negative influence on mood (50.5%), lack of energy (47.6%), and disturbance of normal daily activities (40.1%).8 The authors concluded that the reduced QoL in patients with RLS was comparable to that experienced by patients who had other serious medical conditions, such as diabetes and clinical depression.8

In another study, 36.3% of participants reported that RLS symptoms had a highly negative impact on their lives. Symptoms appeared to have the greatest impact on sleep: 88.4% of participants had sleep-related symptoms (eg, inability to fall asleep, inability to stay asleep, or disturbed sleep) and 43.4% rated sleep disturbance as their most troublesome symptom.56 Typically, patients with RLS do not report excessive daytime sleepiness, but they do feel tired and not fully alert.19

In addition to sleep disturbances, depression seems to be significantly more common among individuals with RLS compared with normal individuals.14,159–161 The impact that sensorimotor manifestations of RLS have on sleep disturbance (proportion of time kept awake, awakened from sleep, and prevented from falling back to sleep) seem to play the major role on emotion and alertness. Although sleep loss is a major problem for patients with RLS, these individuals tend not to complain of sleepiness but do experience cognitive impairment, in particular in exercises focused on prefrontal cortex activity that are sensitive to sleep deprivation.162 It is possible that the deficits might be a result of sleep deprivation rather than a direct effect of RLS pathology.

Future research directions

Further studies using consistent diagnostic criteria and large-scale prospective studies are needed to assess the preval‎ence and incidence of RLS across different populations. A substantial research effort is needed to develop validated diagnostic and severity measures of RLS in children. In addition, there is a strong need for further research about RLS risk factors, including socio-demographic factors, lifestyle, medical conditions, and the use of medications, as well as factors that modify the disease (eg, age at onset and family history). Large epidemiologic and laboratory studies in humans are needed to extend the understanding about the known associations between RLS/PLMS and hypertension, heart disease, and stroke. Although the candidate genes identified so far have provided some more insight into the pathophysiology of RLS, it is important to perform further functional studies and to identify additional genetic factors that modify the expression‎ of the common variants in these genes. In addition, it might be interesting to test these genes also in relation to conditions associated to RLS, such as cardiovascular disease. Genotype–phenotype correlations may be the basis for pharmacogenomic studies to identify more specific medication strategies. In addition, the definition of major genes for RLS is extremely important to gain more insight into the pathogenesis of the disease and therefore to facilitate the development of new therapeutic agents. Genetic data can also contribute to a better understanding of the possible interaction with other movement disorders, like PD, essential tremor, and ataxia. A decisive step in understanding the RLS pathogenesis would be also the development of an RLS animal model. For this attempt, reliable and objectively measurable diagnostic criteria to diagnose RLS in animals should be developed. Iron pathology is central in the disease process, and iron availability to the brain does at least contribute to the RLS symptoms. Data showing an increased mitochondriogenesis in the substantia nigra in RLS open up an interesting avenue to explain the mechanism of low brain iron levels. The role of iron supplementation, especially for patients who do not have serum iron deficiency, is another important area for future research. Clinical studies addressing iron treatment and focussing on different iron formulations will need to be conducted.

Conclusion

RLS is a sensorimotor disorder, classified either as a movement or a sleep disorder. A significant number of individuals are affected by this disorder that is associated with a substantial impairment of the QoL. It is a major cause of insomnia and has in consequence a negative impact on daytime functioning, job performance, and tenure. Therefore, and because it is still frequently undiagnosed, RLS needs more awareness among health care providers.

There is a strong genetic component, and several genetic linkages and associations that are reflected by the heterogeneity of the phenotypic expression‎ have been identified. The current understanding of the pathophysiology is a local dopaminergic dysfunction in the brain as well as insufficient levels of brain iron. Recent research has provided additional data to support the hypothesis that a primary iron deficiency leads to a dopaminergic abnormality. These data reinforce the empirical results of benefit with dopamine or DA treatment as well as iron injections in RLS. Despite these advances in our knowledge, there remain unanswered questions about the genetics, risk factors, and the pathogenesis, and further research is warranted to better dissect the complex architecture of this disorder, a prerequisite necessary for the development of new treatment strategies.

Footnotes

Disclosure

The authors report no conflicts of interest in this work.