轻微症状/无症状高肌酸激酶血症诊断方法指南解读及最新进展

基于证据导向的欧洲神经病学会联盟(European Federation of Neurological Societies,EFNS)发布的"轻微症状/无症状高肌酸激酶血症诊断方法"指南,对轻微症状/无症状高肌酸激酶血症的定义、临床表现、诊断流程和预后进行说明。轻微症状/无症状高肌酸激酶血症的定义是无任何客观肌肉疾病体征且血清肌酸激酶值高于正常值上限1.5倍。收集相关家族史并排除可能导致血清肌酸激酶水平升高的非神经肌肉源性病因是鉴别诊断首先需要解决的问题。对肌电图提示有肌源性改变、血清肌酸激酶值高于正常值3倍、年龄小于25岁或同时存在运动不耐受的患者进行肌肉活检可以提高疾病检出率。轻微症状/无症状高肌酸激酶血症的总体远期预后较好。     

单纯血清肌酶升高患者肌活检病理分析

目的 通过分析单纯血清肌酶升高患者的肌肉病理诊断,了解单纯血清肌酶升高患者的病因.方法 采用归纳分析法分析了24例单纯血清肌酶升高患者的人口学资料、血清肌酶水平、肌电图及病理特点.结果 男性16例,女性8例,年龄3岁～54岁,平均年龄(32.56±15.93)岁.血清CK波动于577.40～17720.00 U/L之间,平均(8081.83±6065.50)U/L,LDH波动于150.20～ 1643.80 U/L之间,平均(415.30±324.90) U/L.20例患者肌电图检查提示,15例为肌源性损害,3例正常,1例可疑肌源性损害,1例仅表现为运动单位时限偏短.肌肉病理提示2例为正常(8.33％)、5例(20.83％)为非特异性散在肌萎缩以及17例为肌病(70.83％),肌病包括肌营养不良13例(54.17％),炎性肌病组3例(12.50％)和Danon病1例(4.17％).结论 无症状性单纯血清肌酶升高患者的病因较多,肌肉酶组织化学和免疫组织化学可以协助多数患者的病因诊断.     

无症状高肌酸激酶血症

无症状高肌酸激酶(creatine kinase,CK)血症是一组具有显著临床异质性的疾病体,欧洲神经病学联盟将无症状高CK血症的CK值确定为大于正常高限的1.5倍。文献报道无症状高CK血症的病因多达50种以上,但仍然有约1/3的患者病因不清,肌肉活检仍然是无症状高CK血症的基础检查。随访研究结果提示无症状高CK血症是一种预后较好的综合征。本文对无症状高CK血症CK值的界定、病因、肌肉病理、肌电图、治疗和预后等方面进行综述。     

肌活检在肌病诊断准确性的临床研究-单中心1年期间56例患者的回顾性分析

目的 探讨肌肉活体组织检查(肌活检)的病理表现并结合临床、电生理、肌肉影像学及相关实验室检查在肌肉疾病中的诊断价值。方法 收集2017年7月-2018年7月在本院行肌活检的56例患者,分析肌肉病理学与人口学、肌电图、肌肉磁共振、血清肌酸激酶、相关抗体和基因检测的相关性,并评估其诊断价值。结果 ①男36例,女20例,年龄5～69岁、平均年龄(39.2±18.6)岁; ②肌电图显示肌源性损害者占83.6%(46/55),其中6例合并强直电位,6例合并神经源损害; 可疑肌源性损害12.7%(7/55); 单纯神经源性损害1.8%(1/55); 正常1.8%(1/55); ③肌肉磁共振异常率87.9%(29/33); 肌酸激酶升高者60%(33/55),中位823[349, 2505.5] U/L; 4例进行肌炎相关抗体检查者3例异常; 17例进行基因检查者12例提示肌病诊断,其中仅6例家族史阳性; ④通过肌肉组织病理检查并结合临床、抗体和基因检测80.4%的患者(45/56)能够明确肌病诊断,明显高于肌活检之前(23.2%)(P<0.01)。结论 肌活检能明显提高肌病的准确诊断率。     

氯硝西泮诱发药物性肌病1例报道及文献复习

目的加强对服用氯硝西泮引起药物性肌病的认识。方法报道1例长期口服氯硝西泮发生药物性肌病患者的临床资料,结合复习文献对其临床表现、实验室检查、肌肉病理检查结果以及可能的发病机制予以分析。结果患者系老年女性,临床仅表现为肩颈不适、四肢疲乏等非特异症状,既往有长期口服氯硝西泮治疗睡眠障碍史。实验室检查示肌酸激酶(CK)水平显著升高;肌肉病理NADH、SDH染色可见线粒体分布紊乱,COX染色见个别活性缺失纤维。停用氯硝西泮后随访患者血CK水平逐渐降低。结论氯硝西泮引起药物性肌病的病例国内未见报道,须引起临床重视;详细的病史追溯和肌肉活检病理检查对诊断具有重要意义。     

糖原累积性肌病的临床和病理学特点

目的探讨糖原累积性肌病(MGSD)患者的临床及病理特点。方法采用开放式肌肉组织活检术及肌肉酶组织化学染色方法观察29例MGSD患者的病理特点,并收集患者的一般资料、临床症状及体征、血清肌酶及EMG等临床资料进行归纳和总结。结果本组MGSD检出率为1.88%(29/1540)。29例MGSD患者中男19例,女10例。起病年龄1~67.5岁,中位数为13岁。病程3个月~41年,中位数为7年。主要的首发症状为肢体无力(65.52%)、不耐受疲劳(24.14%)和活性耐力差伴反复呼吸困难(3.45%),主要临床表现为肢体无力(96.55%)、颈肌无力(37.93%)和呼吸肌无力(13.79%)等。27例患者行肌酸激酶(CK)检查,中位数为1266.00 U/L,其中CK正常者2例(7.41%),CK升高者25例(92.59%),且以轻-中度升高为主。29例患者EMG检查均有异常,其中86.20%的患者EMG表现为肌源性损害或肌源性损害合并肌强直电位。HE染色29例患者均出现特征性的空泡样变性坏死肌纤维,空泡大小不一、形态多样,且20例空泡样变纤维中出现嗜碱性颗粒。PAS染色阳性。结论 MGSD患者发病年龄及病程波动范围大,患者均以进行性肢体无力为主要表现,部分患者有颈部肌肉及呼吸肌受累。肌肉酶组织化学染色有明显肌纤维空泡样坏死变性,有助于明确MGSD的诊断。     

血清肌酸激酶与肌萎缩侧索硬化的相关性

目的 探讨血清肌酸激酶(CK)与肌萎缩侧索硬化(ALS)疾病进展率的相关性.方法 分析144例ALS患者和100例健康体检者的临床信息,分析不同亚组ALS患者血清CK差异及与疾病进展率(△FS表示)的相关性.结果 ALS患者血清CK水平男性与女性分别为224.6± 19.3U·L-1、137.8±15.1 U·L-1,对照组分别为63.5±5.3U·L-1、60.2±4.8U·L-1,P值分别＜0.001和0.023,表明无论男性还是女性ALS患者血清CK水平均较对照组升高,差异有统计学意义.另外从年龄来看,无论是＜60岁(209.1±19.6 U·L-1)还是＞60岁(161.3±18.3U·L-1)的ALS患者血清CK水平均较对照组明显升高(P值分别为0.001和0.005).然而ALS患者血清CK水平与ALSFRS-R评分及△FS不存在相关性.对发病部位进行调整后,仅肢体起病ALS患者血清CK与△FS存在弱相关(R2=0.18,P=0.006).结论 ALS患者血清CK水平升高,与疾病进展率不存在相关性.     

分子病理确诊的肢带型肌营养不良2A型患者五例临床及病理特点

目的 通过总结5例肢带型肌营养不良2A型(LGMD2A)患者的病例资料,探讨其临床和病理特点.方法 对病理诊断排除LGMD2B(7例)之后的30例分型未明的LGMD患者的肌肉标本进行免疫组织化学染色和钙激活蛋白酶-3(calpain-3)蛋白免疫印迹分析.结果 30例患者肌肉标本中有5例calpain-3蛋白条带缺失或遗留痕迹,从而被确诊为钙蛋白酶肌病,即LGMD2A.该5例患者起病年龄10～45岁,病程2～10年.其中2例的同胞兄妹有相似的临床表现,而父母无异常,提示本病的常染色体隐性遗传方式.5例均以下肢近端肌无力起病,肌萎缩明显;血清肌酸激酶639～8237 U/L,平均2502 U/L,肌电图均为肌源性损害.5例肌肉活体组织检查病理符合典型肌营养不良的病理特点,表现为肌纤维大小明显不等,可见坏死伴吞噬及再生,内核纤维增多,还原型辅酶Ⅰ四氮唑还原酶染色2例见分叶状纤维.5例LGMD2A患者dystrophin、caveolin-3和α-、β-、γ-、δ-sarcoglycan免疫组织化学染色均正常,2例dysferlin染色减低,余3例正常.结论 LGMD2A的临床表现和肌活体组织检查病理均缺乏特异性,免疫印迹分析有助于此病的诊断和鉴别诊断.     

自噬在Duchenne型肌营养不良中的研究

目的检测Duchenne型肌营养不良症(DMD)患者骨骼肌中LC3和p62的表达情况,分析自噬在DMD骨骼肌细胞坏死中的作用。方法收集2008年1月~2015年5月在我院就诊的病理确诊为DMD的患者(DMD组,81例),另以怀疑为肌病,但肌肉病理未见明显病变者为对照组(6例)。所有入选者均行心肌酶学、肌电图、骨骼肌活检常规组织学和酶学染色、抗dystrophin-N,-C,-R和抗dysferlin免疫组织化学染色。检测其中6例DMD患者及对照组骨骼肌中LC3和p62的表达。结果 81例DMD患者均为男性,起病年龄(4.60±2.35)岁,首发症状多以双下肢起病为主。血清肌酸激酶值的高峰出现在患者年龄的6~8岁,随着肌细胞明显坏死,肌酸激酶水平下降,但仍高于正常。在DMD患者骨骼肌中,组织病理均示典型肌营养不良改变。半定量Western blot提示DMD患者骨骼肌中LC3-II的表达降低,而p62表达显著升高。结论自噬功能障碍可能参与了DMD骨骼肌细胞坏死的病理生理过程。     

老年肌肉病临床及病理学分析

目的 探讨老年肌肉病的特点。方法 采用酶组织化学和免疫组织化学方法观察62例60岁以上患者的肌肉病理,同时收集相关临床资料,进行统计学分析。结果 在1924例肌肉活检患者中,62例为老年患者,占3.22%; 其中男性27例,女性35例。男性患者平均年龄为68.26±7.003岁,女性患者平均年龄为66.63±5.621岁,二者无统计学差异(P=0.313)。48例(77.42%)患者慢性起病,57例(91.94%)患者病情缓慢进展。首发症状以双下肢无力18例(29.03%)最多见,其次为四肢无力6例(9.68%)。主要临床表现以肌无力57例(91.94%)最多见,肌萎缩、肌肉疼痛、吞咽困难均有23例(37.10%)。经肌肉酶组织化学和免疫组织化学染色显示,在62例患者中肌源性改变者24例(38.71%)、神经源性改变者7例(11.29%)、正常者3例(4.84%)和非特异性改变者28例(45.16%),前三者明确诊断共34例(54.84%),而非特异性改变者的病理结果,不能明确诊断。在24例肌源性改变者中21例为炎性肌病,其包括多发性肌炎(8例)、皮肌炎(2例)、包涵体肌炎(1例)、坏死性肌病(6例)和其他免疫性肌病(4例); 还有3例代谢性肌病。60例患者行血清肌酸激酶(CK)检查,升高者43例(71.67%)。在21例炎性肌病患者中有17例(80.95%)CK高于正常; 在28例的非特异性改变者中,有21例(75%)的CK高于正常。58例患者行肌电图(EMG)检查,有37例(63.80%)为肌源性受损,9例(15.52%)为神经源性受损,2例(3.45%)为肌源性受损合并神经源性受损,5例(5/58=8.62%)未见特征性改变,其余5例提示其他异常情况。在21例炎性肌病患者中有20例(95.24%)为肌源性受损; 而在27例的非特异性改变者中有16例(59.26%)为肌源性受损; 在6例神经源性改变者中有5例(83.33%)为神经源性受损。结论 老年肌肉病发病隐袭,临床表现无特异性,肌活检技术结合临床是诊断关键,炎性肌病占多数,可有些少见肌病; 但仍有部分患者未能明确诊断。     

Diagnostic outcome of muscle biopsy

Introduction: We reviewed the diagnostic yield of muscle biopsy according to the presence or absence of muscle weakness, hyperCKemia, and electromyogaphic (EMG) abnormalities. Methods: In a retrospective study, 698 muscle biopsy reports were analyzed. Logistic regression models for myopathy and specific myopathy were fit, and receiver‐operating characteristic (ROC) curves were generated to assess prediction accuracy. The probability of finding specific myopathy was considered the main indication of a positive muscle biopsy. Results: Isolated hyperCKemia was poorly predictive of either myopathy or specific myopathy. Combined myopathic EMG, proximal weakness, and hyperCKemia were predictive. The predictability increased proportionally to the creatine kinase (CK) level in patients with proximal weakness and myopathic EMG. Cross validation showed accuracy around 70% for a probability threshold of 50%. Conclusions: The presence of hyperCKemia, proximal weakness, and myopathic EMG together were associated with highly positive diagnostic outcome of muscle biopsy. Isolated hyperCKemia had a poor diagnostic yield. Muscle Nerve 51 :662–668, 2015     

Amelioration of ischemia‐reperfusion–induced muscle injury by the recombinant human MG53 protein

Introduction: Ischemia‐reperfusion injury (I‐R) in skeletal muscle requires timely treatment. Methods: Rodent models of I‐R injury were used to test the efficacy of recombinant human MG53 (rhMG53) protein for protecting skeletal muscle. Results: In a mouse I‐R injury model, we found that mg53,?/? mice are more susceptible to I‐R injury. rhMG53 applied intravenously to the wild‐type mice protected I‐R injured muscle, as demonstrated by reduced CK release and Evans blue staining. Histochemical studies confirmed beneficial effects of rhMG53. Of interest, rhMG53 did not protect against I‐R injury in rat skeletal muscle. This was likely due to the fact that the plasma level of endogenous MG53 protein is high in rats. Conclusions: Our data suggest that rhMG53 may be a potential therapy for protection against muscle trauma. A mouse model appears to be a better choice than a rat model for evaluating potential treatments for protecting skeletal muscle. Muscle Nerve 52 : 852–858, 2015     

CK-MM autoantibodies: prevalence, immune complexes, and effect on CK clearance

Although the blood level of creatine kinase (CK) is the most commonly used marker of muscle injury, there is marked interindividual variability in this measure. Part of this variability may be attributed to variability in the rate of CK clearance from the circulation. In this study, we assessed the possibility that CK-MM autoantibodies form immune complexes with CK following muscle injury and subsequently affect the CK clearance rate. Using an enzyme-linked immunosorbent assay, CK-MM autoantibodies were detected in all 25 human subjects studied but the levels varied greatly. Using protein A-sepharose, the percentage of the plasma CK activity found in immune complexes was determined to be correlated with the CK-MM autoantibody level at lower CK levels (<1,022 U/L). When CK-MM antibodies were administered to mice, plasma CK activity following a bolus CK injection was reduced by 11%-32%. We conclude that CK-MM autoantibodies can modulate the rate of CK clearance from the circulation. Thus, the relatively low blood CK levels seen in some individuals following injury may be attributed partly or entirely to an autoantibody-enhanced clearance of CK.     

Muscle biopsy in the evaluation of patients with modestly elevated creatine kinase levels

The utility of muscle biopsy in patients with modest elevations of serum creatine kinase (CK) level but normal neurological examinations and nondiagnostic electrodiagnostic studies is uncertain. We performed systematic, extensive studies on muscle biopsies of 20 such patients. A definitive diagnosis was arrived at in only 1 by histochemical studies, although 4 others demonstrated minor myopathic changes. Biochemical evaluation led to a diagnosis in an additional 5. Muscle biopsy is useful for evaluating such patients, but extensive studies of the muscle are necessary.     

Asymptomatic/pauci-symptomatic creatine kinase elevations (hyperckemia)

Neuromuscular clinicians are frequently asked to evaluate patients referred for asymptomatic elevations in creatine kinase (CK), a catalytic enzyme that combines creatine and ATP to form phosphocreatine and ADP. This reaction is crucial for cellular energy generation and metabolism. This laboratory finding, often referred to in simplified lexicon as asymptomatic hyperCKemia, continues to generate controversy at several levels, including definition, the extent of evaluation, and the yield of diagnostic testing. In this review, we summarize the literature based on series of patients with asymptomatic hyperCKemia and provide a rational clinical approach to reveal identifiable underlying causes. Muscle Nerve 47: 805–815, 2013     

Increased activities of MB and BB isozymes of creatine kinase in denervated neonatal and adult rat muscle

Creatine kinase (CK) activity and isozyme patterns were assessed in newborn and adult rat anterior tibial muscle in response to denervation. Total CK activity was low in the control neonatal muscle, gradually increasing to the adult level within 1 month. Denervation prevented this normal increase, and, therefore, CK activity was reduced to 25% of control at 2 months. In the denervated adult muscle, total CK activity decreased to 50% of control within 3 weeks and remained at that level. Denervation of neonatal muscle resulted in a greater conservation of MB isozyme compared with controls. The alteration in BB isozyme expression was even more dramatic with a 33-fold difference expressed at 2 months in terms of percent total CK in denervated vs. control muscle. In denervated adult muscle, MB and BB isozyme activities increased gradually, attaining levels 3-fold and 13-fold, respectively, above control muscle at the end of the experimental period.     

Increased frequency of rhabdomyolysis in familial dysautonomia

Introduction:Familial dysautonomia (FD; OMIM # 223900) is an autosomal recessive disease with features of impaired pain and temperature perception and lack of functional muscle spindles. After 3 FD patients presented with rhabdomyolysis in a short time span, we aimed to determine the frequency of rhabdomyolysis is this population. Methods: This study was a retrospective chart review of 665 FD patients. Results: Eight patients had at least 1 episode of rhabdomyolysis. Two patients had 2 episodes. The average incidence of rhabdomyolysis in FD was 7.5 per 10,000 person‐years. By comparison, the average incidence with statins has been reported to be 0.44 per 10,000 person‐years. Mean maximum creatine kinase (CK) level was 32,714 ± 64,749 U/L. Three patients had hip magnetic resonance imaging showing gluteal hyperintensities. Conclusions: Patients with FD have an increased incidence of rhabdomyolysis. We hypothesize that this may result from a combination of absent functional muscle spindles and muscle mitochondrial abnormalities. Muscle Nerve, 2015