不安腿综合征 临床研究和治疗进展 复旦大学华山医院 王坚 仅是抛砖引玉。感兴趣，与大家探讨。 NEUROLOGY.

Presentation on theme: "不安腿综合征 临床研究和治疗进展 复旦大学华山医院 王坚 仅是抛砖引玉。感兴趣，与大家探讨。 NEUROLOGY."— Presentation transcript:

1 不安腿综合征 临床研究和治疗进展 复旦大学华山医院 王坚 仅是抛砖引玉。感兴趣，与大家探讨。 NEUROLOGY

2 概况 不安腿综合征(Restless legs Syndrome，RLS)在临床上并不少见．
对健康虽然没有直接威胁，但重的病人十分痛苦．而轻的病人又经常延误诊断。 是临床上的一个难题。

3 概况 最早于1672年一位英国医生Thomas Willis用拉丁文作了描述．至1685年才翻成英文发表。
1945年由瑞典神经病学家Ekbon首先对8例病人进行了详细描述后并于1945后正式称之为不安腿综合征。也称为Ekbom综合征。 1995年国际不安腿综合征研究组确定了诊断标准

4 不安腿综合征，Ekbom综合症 原来没有得到重视。与抽动症一样，bizza。老年社会，重视了。

5 流行病学 老年好发 女性 > 男性 不同人种的患病率 西方人种：4－15％ 东方人种：21岁以上 0.1% 55岁以上 0.6%
东方人种：21岁以上 0.1% 55岁以上 0.6% 就象肝炎好发于东方人，多发性硬化好发于西方人一样。 Epidemiological studies have shown that, at least in populations derived from the North and West of Europe, symptoms of RLS are quite common (Lavigne and Montplaisir, 1994; Phillips et al., 2000; Rothdach et al., 2000; Ulfberg et al., 2001a,b) and that there is likely family aggregation (Montplaisir et al., 1997; Winkelmann et al., 2000). Onset may be at any age and a substantial fraction of patients report onset in childhood and youth (Montplaisir et al., 1997; Walters et al., 1996).

6 流行病学 阳性家族史：65％，常染色体显性遗传。 40岁前起病：常有家族史 50岁后起病：家族史少，常伴周围神经病
RLS患者一级亲属患RLS的风险增加3.3倍

7 病因和发病机制 原发性。病因不明，部分属于遗传性。 继发性。相关因素： 淀粉样变性 干燥综合征 巨球蛋白血症 慢性阻塞性肺疾病
主要的易感基因的位点：12q，首先从法国大家系发现 意大利家系：14q 继发性。相关因素： 淀粉样变性 干燥综合征 巨球蛋白血症 慢性阻塞性肺疾病 怀孕 周围神经病 慢性肾功能衰竭 缺铁性贫血 腰骶根性神经病 糖尿病 叶酸缺乏 脊髓病 风湿性关节炎 维生素B12缺乏 帕金森病 甲状腺功能低下 胃部分切除术后 肿瘤 周围微栓塞 咖啡、酒精等 三环类抗抑郁剂 H2受体阻滞剂 镇静剂或 血管扩张剂的停药等

8 RLS主要相关病因 成人 原发性 主要的继发性 缺铁 怀孕 尿毒症 儿童： ADHD
Pregnant women have at least two or three times higher risk of experiencing restless legs syndrome (RLS) than the general population. These data come from few epidemiological studies finding an 11–27% prevalence of RLS during pregnancy. The causes of the association between RLS and pregnancy are unknown. The most debated hypotheses are: metabolic alterations, with particular regard to iron and folate deficiency; hormonal influences related to the increase of prolactin, progesterone and estrogens during late pregnancy; and the changing motor habits and psychological state of pregnant women. RLS is very frequent among uremics, particularly if affected by polyneuropathy. It is unclear which factors of dialysis are implicated in the development of RLS in uremic patients.

9 根据对治疗的反应，推测RLS机制： 铁代谢异常 多巴胺功能异常

10 发病机制 中枢多巴胺能系统障碍 证据 中枢多巴胺能系统功能障碍 多巴胺受体阻断剂胃复安会加重症状 多巴胺D2和D3受体激动剂疗效好

11 发病机制 铁缺乏对RLS具有重要影响 缺铁时RLS症状明显加重，口服铁剂症状明显减轻 孕妇RLS发病率增加可能与缺铁有关
65％脑脊液中铁含量减少而转铁蛋白增加3倍以上 特殊的MRI和PET A9(黑质纹状体区)、A11、A14区铁含量明显减少 多巴胺能神经元铁转运和铁储备能力下降

12 发病机制 缺铁引起RLS的可能机制 －影响多巴胺能神经元的代谢 铁是酪氨酸羟化酶的辅酶
该酶控制酪氨酸代谢特别是线粒体中的氧化代谢有关，从而影响多巴胺的合成 多巴胺能受体及多巴胺转运体合成及功能与铁的关系尚未完全明了

13 发病机制 引起RLS的其他可能机制 周围神经异常： 血管因素 腿部代谢产物堆积，运动促进血液循环，症状减轻 感觉和运动神经传导速度异常
多无神经体征和周围神经紊乱 电镜没有发现神经末梢结构异常 血管因素 腿部代谢产物堆积，运动促进血液循环，症状减轻 血管扩张剂可以减轻症状 其实，我的理解，RLS是一个不折不扣的综合症。病因和机制不同，都可以表现为相似的临床症状。

14 临床表现及诊断 诊断取决于病史 重视患者及家庭成员的主诉 症状不典型或合并其他运动障碍和睡眠障碍时，诊断则有一定的难度

15 主要诊断标准 1. 活动腿部的冲动 常伴腿部难以描述的不适感 异常感觉位于肌肉或骨骼深部，很少位于关节
蠕动感 蚁走感 搔 痒 烧灼感 灼痛感 牵拉感 冷热感 触电感 坐立不安 疼痛感 比如，病人描述：汽水在静脉中的感觉。 异常感觉位于肌肉或骨骼深部，很少位于关节 感觉异常以下肢为主，半数患者也可影响上肢 单侧或双侧肢体均可累及 Objective tests can be helpful in doubtful cases, but have not become accepted as diagnostic criteria 难以名状。即便好不容易表达出了，也是一种怪异的感觉。 The most recent standards emphasize the presence of one main symptom—the urge to move—and three key modulators: rest, activity, and time of day.

16 RLS英文描述性术语

17 主要诊断标准 2.休息或静止时症状出现或加重 越是舒适，越易出现症状 病人觉得躺在硬邦邦的地板上反而容易睡着。躺在床上不易睡着。

18 主要诊断标准 3.活动后症状可部分或完全缓解 轻症者可能不必起来走动，在床上和椅子上伸展一下肢体即可。
重症者常来回踱步、搓揉下肢、伸屈肢体以减轻症状。 症状减轻或消失后，当患者平躺或坐下时，数分钟至1小时后，症状会再次出现。 Movement immediately relieves the symptoms, and continued movement (such as walking) provides ongoing relief. However, if patients stop moving their legs, the symptoms may return. Ignoring the urge to move the legs may lead to progressive intensification of the akathisia, until patients either move their legs or the legs jerk involuntarily.

19 主要诊断标准 4.症状常在傍晚或夜间出现或加重 典型患者： 症状最重：23点至次日4点间 症状最轻：早晨6点至12点
周期性的规律受药物治疗的影响，也受“三班倒”、睡眠疾病和睡眠不规则的影响 一般而言，症状总是在夜间加重 Although initially the symptoms occur at bedtime or during the night, as the syndrome progresses, symptoms start to occur earlier in the day and become more intense at night. Even when they occur throughout the day, the symptoms are always worst in the evening or at night.

20 支持标准  1.多巴胺能药物治疗有效 2.有家族史 Sometimes the patient’s bed partner reports having seen frequent leg or limb movements during sleep years before the patient recognized sensory symptoms. Not all patients with RLS have periodic limb move ments of sleep, and not all patients with such movements have RLS, making the identification of these movements of questionable value in diagnosis. RLS 是引起PLM最常见的原因。

21 支持标准 定义：相同的发作，在一定的时间内（5-90秒）中发作4次或4次以上，每次持续0.5-5秒。 腿部刻板、重复的屈曲运动
3.伴发周期性肢体运动（Periodic limb movement，PLM）:RLS 是引起PLM最常见的原因。 定义：相同的发作，在一定的时间内（5-90秒）中发作4次或4次以上，每次持续0.5-5秒。 腿部刻板、重复的屈曲运动 单侧或双侧，对称或不对称 多发生在快动眼相睡眠期 有时呈节律性发作，间歇期20-40秒 老年人多发，RLS以外的其它疾病也会伴发 通常发生于睡眠时，但也会发生觉醒时，尤其是RLS合并的PLM可发生在觉醒时。 Sometimes the patient’s bed partner reports having seen frequent leg or limb movements during sleep years before the patient recognized sensory symptoms. Not all patients with RLS have periodic limb move ments of sleep, and not all patients with such movements have RLS, making the identification of these movements of questionable value in diagnosis.

22 支持标准 初期病情呈波动性，以后持续性或慢性进展性 睡眠节律紊乱 90％以上入睡难或多醒 神经科体检正常 要特别重视脊髓和周围神经功能的检测
  ％以上入睡难或多醒 睡眠质量下降，白天常疲惫不堪。 神经科体检正常 一直进展。除非药物干预。 RLS is generally a chronic condition [21–23,25]. This is true not only of patients, but of affected family members who have not yet come to medical attention for the condition [41]. Over 95% of family members of RLS patients who have experienced RLS symptoms continue to have them through time of interview. While patients generally report a progressive course, family members may not. Instead, they may report stable manifestations or even a decrease in symptoms. 影响睡眠。Whether because of the sensory symptoms or associated periodic limb movements of sleep, RLS may have profound negative effects on sleep. Symptoms of insomnia or fatigue may be the problem that is initially reported; in addition, reduced concentration and memory, decreased motivation and drive, and depression and anxiety may be reported. While one theory of RLS suggests that this condition is similar to Parkinson’s disease (PD) in having an underlying dopamine abnormality [44], the sensory [45] and motor [46] findings characteristic of PD are not found in RLS. However, if RLS is due to another condition, such as a peripheral neuropathy [47], uremia [48], or anemia [49], findings typical of those disorders may be present in the RLS patient. 要特别重视脊髓和周围神经功能的检测

23 RLS的自然进程 变数很大 目前的研究均来源于严重病例，不能反映真实的情况
继发性RLS：当病因去除后，多数RLS持续缓解。 Clinical experience, which is gained primarily from more-severe cases of RLS, has previously contributed to the conclusion that RLS is generally a chronic condition. This may be the case, but for patients with milder RLS, the pattern of expression of the disorder appears to be variable with long periods of remission and sometimes with expression only for a limited time of life. Certainly the natural course varies greatly for milder RLS, but for the patients whose symptoms start in young adult life and who eventually seek treatment, the severity and frequency of symptoms typically increases over time [9]. Because many people with RLS never seek treatment, little is known about the course of the disorder in mild or intermittent cases. One particularly interesting finding in Lee et al.’s study of RLS during pregnancy is that one of the seven women who developed RLS during pregnancy continued to experience symptoms postpartum, suggesting that pregnancy may be a risk factor for developing RLS. Nonetheless, RLS that occurs during pregnancy remits for most women postpartum.

24 NIH筛选RLS的询问表

25 特殊时期可发生RLS 临床其他特点 有报道，20％孕妇出现RLS 20％－62％透析者出现RLS 与周围神经病关系密切

26 PD中的RLS 一项303例的PD患者研究发现19．5％患者同时存在不安腿综合征
Clinical experience, which is gained primarily from more-severe cases of RLS, has previously contributed to the conclusion that RLS is generally a chronic condition. This may be the case, but for patients with milder RLS, the pattern of expression of the disorder appears to be variable with long periods of remission and sometimes with expression only for a limited time of life. Certainly the natural course varies greatly for milder RLS, but for the patients whose symptoms start in young adult life and who eventually seek treatment, the severity and frequency of symptoms typically increases over time [9]. Because many people with RLS never seek treatment, little is known about the course of the disorder in mild or intermittent cases. One particularly interesting finding in Lee et al.’s study of RLS during pregnancy is that one of the seven women who developed RLS during pregnancy continued to experience symptoms postpartum, suggesting that pregnancy may be a risk factor for developing RLS. Nonetheless, RLS that occurs during pregnancy remits for most women postpartum.

27 儿童RLS 症状与成人患者类似 下肢轻至中度的感觉异常及烦躁不安 症状多呈间歇性发作。而且由于语言描述困难，常易误诊为疼痛发作。
睡眠时间常较正常儿童明显缩短，常导致精神运动发育损害，特别是注意力和行为等

28 儿童RLS的诊断标准（definite）

29 儿童RLS诊断标准中的支持性标准

30 实验室检查 除外继发性因素 血液生化学检测 血清铁蛋白、转铁蛋白和血清铁 甲状腺和甲状旁腺功能测定 EMG,NCV EEG
血中叶酸和维生素B12浓度 甲状腺和甲状旁腺功能测定 EMG,NCV EEG

31 PLM的脑电图 Series of periodic limb movements in a sleeping patient. These occur almost exclusively in the left leg. Burst at arrow shows several initial high amplitude brief components. Middle burst in record is prolonged, consistent with an arousal leading to voluntary prolongation of movement. After this burst, there is an altered EEG rhythm and EMG activity spreading to chin and right leg, as well as altered respiratory rhythm. (Chin EMG has respiratory artifacts through tracing). The bursts recur in a nearly periodic fashion. Top four traces—EEG from vertex (top two traces) and occiput (third and fourth traces) referenced to the opposite ear. Fifth and sixth traces, left and right EOG (electrooculograms). Seventh trace, chin EMG. Eighth trace, EKG. Ninth and tenth traces, left and right tibialis anterior EMGs. Eleventh trace, oral air flow. Twelve and Thirteenth traces, thoracic and abdominal respiratory effort. Bottom trace, sound recording. Trace superimposed on Abdominal effort is a displaced oximeter tracing indicating oxygen saturation. Thick vertical lines indicate 16 s divisions.

32 鉴别诊断 静坐不能（Akathisia） 均有用多巴胺能受体阻断剂的病史 常有轻度锥体外系症状 内在的不安宁感 少有昼夜规律，睡眠也少有影响
常无家族史

33 鉴别诊断 多发性周围神经病 肢体的感觉异常和疼痛 同一病人中同时出现 常不出现坐立不安 运动后症状不改善 没有明显的昼夜规律 与PLMs无关
共性 肢体的感觉异常和疼痛 同一病人中同时出现 常不出现坐立不安 运动后症状不改善 没有明显的昼夜规律 与PLMs无关 睡眠障碍较RLS少见 不同

34 鉴别诊断 动脉供血不足 症状在运动后加重，休息后减轻 B超、血管造影等有助于区分

35 鉴别诊断 周期性腿部运动(PLM) 除了RLS外，还可以出现在： 睡眠呼吸暂停 神经变性疾病 脊髓损坏 中风 发作性睡病
抗抑郁剂、精神类药物 n the absence of the core clinical features of RLS, the diagnosis of RLS cannot be made, and other causes of periodic limb movements of sleep or isolated periodic limb movement disorder must be considered. The relation between periodic limb movement disorder and RLS is unclear, but treatments used for RLS may be effective in this disorder as well.

36 鉴别诊断 夜间腿肌痛性痉挛（Cramp） 通常也是夜间起病 伸展腿部、站立、走动时症状缓解 有类似的昼夜规律，并干扰睡眠 起病更突然
共性 in most cases cramps are easily distinguished from RLS by the presence of a clear knotting of a muscle and the presence of severe local muscle pain in the former. 起病更突然 常累及单侧肢体，呈局灶性 发病时常可触及肌肉的挛缩 不同

37 治 疗 一般治疗 包括少用咖啡及含咖啡的饮料，因其可加 重或诱发RLS． 戒烟可减轻RLS病人的症状， 少饮酒或睡前热水浴对改善症状有效；

38 （pramipexole、ropinirole、pergolide、溴隐亭）
治 疗 多巴胺受体激动剂首选 （pramipexole、ropinirole、pergolide、溴隐亭） 药物的半衰期长，无需夜间重复给药 耐受性好 长期应用较少出现并发症 The dopaminergic agents are considered the first line of treatment in idiopathic RLS.Levodopa, bromocriptine, pergolide, and pramipexole have been studied in randomized, placebo-controlled trials and have been shown to provide clinically and statistically significant improvement in symptoms of RLS, periodic limb movements of sleep, or both. These agents have provided 90 to 100 percent relief of symptoms in RLS and have reduced the frequency of periodic limb movements of sleep by 70 to 100 percent. 能够缓解90－100%RLS症状 能够缓解70－100％PLM症状

39 治 疗 多巴胺受体激动剂剂量切换 1 mg of pergolide 协良行 1 mg of lisuride
治 疗 多巴胺受体激动剂剂量切换 1 mg of pergolide 协良行 1 mg of lisuride   1 mg of pramipexole  5 mg of ropinirole  10 mg of bromocriptine 溴隐亭 20 mg of dihydroergocriptine克瑞帕 The dopaminergic agents are considered the first line of treatment in idiopathic RLS.Levodopa, bromocriptine, pergolide, and pramipexole have been studied in randomized, placebo-controlled trials and have been shown to provide clinically and statistically significant improvement in symptoms of RLS, periodic limb movements of sleep, or both. These agents have provided 90 to 100 percent relief of symptoms in RLS and have reduced the frequency of periodic limb movements of sleep by 70 to 100 percent.

40 治 疗 复方多巴制剂的疗效 多个临床对照研究验证了疗效 常用剂量是左旋多巴50－250mg，睡前1小时顿服 严重病例tid或qid给药

41 治 疗 多巴胺能治疗的问题 反跳（rebound） 恶化（augmentation） 每天发病的时间提早 发作间隙期变短
治 疗 多巴胺能治疗的问题 反跳（rebound） 恶化（augmentation） 每天发病的时间提早 发作间隙期变短 症状加重与L-DA有关 扩展到上肢和躯干 药效持续时间缩短 L-DA半衰期短 症状在凌晨复现 临时加服一次 改用半衰期长的多巴制剂 A very common problem with the long-term use of dopaminergic drugs is augmentation of the symptoms of RLS, which takes the form of an onset of symptoms progressively earlier in the day. Increases in the dose of medication to cover the expanded symptomatic period relieve the symptoms in the short term, but ultimately, symptoms begin to appear even earlier, accompanied by a noticeable decrease in the duration of action and the effectiveness of the drug. Some patients have an augmentation in the form of an extension of the symptoms from the legs to the arms or trunk. Patients may present with total-body restlessness that is unrelenting even when they are walking. The symptoms are indistinguishable from those of acute akathisia induced by neuroleptic drugs. Augmentation has been reported less frequently with dopamine agonists (in 20 to 30 percent of patients) than with levodopa (in 80 percent of patients). this difference may reflect the pattern of use of dopamine agonists in clinical studies, which have involved relatively low doses and short durations of treatment. It is possible that longer-term use and higher doses of dopamine agonists may result in rates of augmentation similar to those reported with levodopa. All patients will have some withdrawal symptoms when treatment with any of the dopaminerdopaminergic agents is discontinued. Withdrawal manifests itself as an intensification of the symptoms of RLS that is often quite severe for the first 48 hours; the symptoms then slowly return to their base-line level after four to seven days. In general, the longer the drug has been used and the higher the dose, the worse the withdrawal syndrome. An increased overall intensity of the urge to move or sensation is temporally related to an increase in the daily medication dosage. A decreased overall intensity of the urge to move or sensations is temporally related to a decrease in the daily medication dosage. The latency to RLS symptoms at rest is shorter than the latency with initial therapeutic response or before treatment was instituted. The urge to move or sensations are extended to previously unaffected limbs or body parts. The duration of treatment effect is shorter than the duration with initial therapeutic response. Periodic limb movements while awake either occur for the first time or are worse than with initial therapeutic response or before treatment was instituted.

42 治 疗 多巴胺受体激动剂的用法

43 羟可酮oxycodone、美沙酮、丙氧吩propoxyphene
治 疗 阿片制剂 羟可酮oxycodone、美沙酮、丙氧吩propoxyphene 许多病人有效 其他药物无效、症状持续者有肯定疗效 副作用和潜在的成瘾性限制其应用 羟可酮有卖吗？Opiates mostly in open-label studies, to improve subjective ratings of the symptoms of RLS. They have also reduced the occurrence of periodic limb movements of sleep on polysomnography. Early-morning sedation is an issue of particular concern with the bedtime use of clonazepam, which has a long half-life. None of these agents have been linked to an augmentation of symptoms.

44 治 疗 抗痫药 卡马西平 加巴喷丁 尤其适用于伴疼痛或与多发性周围 神经病有关的RLS 安定只能诱导睡眠，不能直接消除症状

45 治 疗 可乐亭 最近的对照研究中，可乐亭能缓解RLS病人的症状 常见的副作用有：口干、识别力降低、头晕 治疗以0.1mg/天开始。
治 疗 可乐亭 最近的对照研究中，可乐亭能缓解RLS病人的症状 常见的副作用有：口干、识别力降低、头晕 治疗以0.1mg/天开始。 羟可酮有卖吗？Opiates mostly in open-label studies, to improve subjective ratings of the symptoms of RLS. They have also reduced the occurrence of periodic limb movements of sleep on polysomnography. Early-morning sedation is an issue of particular concern with the bedtime use of clonazepam, which has a long half-life. None of these agents have been linked to an augmentation of symptoms.

46 治 疗 抗痫剂等治疗RLS的具体用法

47 治 疗 补铁 血清铁低于45－50mcg/l时需补充铁剂 研究表明：血清铁正常的RLS患者补铁，多数患者症状也能显著缓解。
治 疗 补铁 血清铁低于45－50mcg/l时需补充铁剂 研究表明：血清铁正常的RLS患者补铁，多数患者症状也能显著缓解。 速力菲（琥珀酸亚铁 ） 0.1 QD-TID。 In patients with a serum ferritin level of less than 18 μg per liter, treatment with oral iron supplements resulted in improvements in the severity of the symptoms of RLS and, in some patients, the complete resolution of the symptoms. The use of oral iron therapy in subjects with normal-to-high ferritin levels, in contrast, was ineffective but similarly had little effect on the serum ferritin level. In one report, 21 of 22 subjects who had normal serum iron levels had a resolution of symptoms of RLS after highdose intravenous iron supplementation. The findings support the treatment of iron deficiency as a potential therapy for symptoms of RLS.

48 治 疗 积极治疗原发病 如果能找到病因，原发病的治疗和加重因 素的去除对于减轻病人的症状往往奏效。 如肾功能障碍，帕金森病等。

49 谢 谢 NEUROLOGY