Normalization of creatine kinase level during pregnancy in idiopathic hyperCKemia

A 34-year-old previously healthy woman with no remarkable family history developed asymptomatic hyperCKemia at age 26. Over the next 6 years, hyperCKemia persisted (502-2562 IU/l; normal range<180). A muscle biopsy showed minimal nonspecific myopathy. Genetic analysis of blood and muscle samples showed no abnormality in the dystrophin gene. At age 33, she became pregnant for the first time and serum creatine kinase (CK) was normal at 170 IU/l in the third trimester. After delivery, hyperCKemia reappeared (715-2620) while her baby tested normal for CK. This is the first report of idiopathic hyperCKemia associated normalization of serum CK level during pregnancy, which has been reported in carriers of Duchenne muscular dystrophy.     

Single-fiber electromyography in hyperCKemia: the value of fiber density

Although persistently raised serum creatine kinase (sCK), or hyperCKemia, is considered the biological hallmark of neuromuscular diseases, pauci- or asymptomatic- or isolated-hyperCKemia can often be found. Single-fiber electromyography (SFEMG) is an electrophysiological technique of great value in the assessment of neuromuscular, neuropathic and myopathic disorders. We hypothesize that SFEMG fiber density (FD) evaluation is able to detect subclinical electrophysiological abnormalities indicating a myopathic process in subjects with hyperCKemia. Nineteen subjects with hyperCKemia without evident clinical signs of muscle involvement and 15 healthy controls were studied. Electrophysiological investigations including nerve conduction studies (NCS), quantitative EMG (QEMG), SFEMG with focus on FD measurements, and muscle biopsy were performed. NCS, QEMG, SFEMG were normal in all controls. In subjects with hyperCKemia, NCS were normal; QEMG was abnormal in 5, while both SFEMG and muscle biopsy disclosed abnormalities in 12 subjects. The mean FD value was 2.6 ± 0.5 in the control and 4 ± 1.4 (p = 0.003) in the hyperCKemia group. SFEMG revealed subclinical changes in the majority of subjects with hyperCKemia. To the best of our knowledge, this is the first study demonstrating that SFEMG FD evaluation is able to detect the presence of muscle diseases, which are in a subclinical phase and would remain unidentified otherwise. SFEMG may be used to distinguish hyperCKemia associated to asymptomatic muscle disorders from idiopathic hyperCKemia. We believe that SFEMG FD evaluation should be added to the routine examinations in the screening of idiopathic hyperCKemia.     

HyperCKemia as the only sign of McArdle's disease in a child

An asymptomatic 13-year-old boy, who never complained of exercise intolerance or myalgia, was found to have markedly elevated serum creatine kinase (CK) levels during a routine check-up. General physical and neurologic examinations were normal. Surprisingly, histochemical and biochemical analysis of muscle showed myophosphorylase deficiency and genetic analysis showed that the patient was homozygous for the most common mutation encountered in McArdle's disease (R49X). This case illustrates the fuzzy correlation between molecular defect and clinical phenotype in patients with McArdle's disease, and suggests that a thorough study of the muscle biopsy is important in patients with idiopathic hyperCKemia for correct diagnosis and careful follow-up.     

Electrodiagnosis and muscle biopsy in asymptomatic hyperckemia

Purpose/aim of the study: An increased serum level of creatine kinase (CK) in asymptomatic individuals is a diagnostic challenge, as it may be associated with either physiological conditions, such as exercise or even signal an ominous neuromuscular disease at a presymptomatic stage. The electromyogram (EMG) and the muscle biopsy play a key role in the evaluation of asymptomatic hyperckemia. The objective of this study was to investigate asymptomatic individuals with increased CK levels. Materials and methods: We comparatively studied EMG, quantitative EMG and muscle biopsy in asymptomatic clinically normal individuals with repeatedly increased CK levels. Results: Conventional EMG was abnormal in 76% of patients, while quantitative EMG showed abnormal results in 88.9%. Muscle biopsy was diagnostic in 28%, one patient had neurogenic findings, 40% showed non-specific changes and 28% had normal results. Conclusions: EMG and especially quantitative EMG are highly sensitive in detecting subclinical neuromuscular diseases, whereas muscle biopsy may better contribute in the final diagnosis. No strong correlations were found between histological abnormalities and electrophysiological data, but further research is needed.     

Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects

Six years befor the present study we performed a retrospective study of 114 subjects presenting with asymptomatic / oligosymptomatic hyperckemia (raised creatine kinase blood levels), a diagnosis being made in 21 of them. We now present the results of a long-term follow-up in 55 of the still undiagnosed 93 individuals. Most of them have remained asymptomatic and did not develop specific neuromuscular disorders. One subject became frankly symptomatic manifesting limb-girdle weakness. A diagnosis of dystrophinopathy carrier and one of possible type I SMA carrier were indirectly made in another two subjects. Almost all subjects still have hyperckemia, though the mean creatine kinase (CK) value is lower than before. CK levels have become normal in 12 subjects. Two died of neoplasia, and six developed non-neuromuscular disorders. We noted no follow-up differences in terms of CK modifications between subjects with pathological EMG and/or muscle biopsy findings and those with normal findings at first examination. Received in revised form: 5 August 2005     

Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study

In this cross-sectional study we assessed the prevalence of hyperCKemia, defined as persistent CK values ?210 U/L in women, ?400 U/L in men <50 years and ?280 U/L in men ?50 years (reference values according to the Nordic Reference Interval Project).Blood samples were obtained from 12,828 participants in the 6th survey of The Tromsø Study. We identified 686 (5.3%) individuals with incidentally elevated CK. After a standardized control test, 169 persons (1.3%) had persistent hyperCKemia, i.e. 69.9% normalization. Use of statins or other causes of hyperCKemia were detected in 78 individuals (46.2%), giving a prevalence of “idiopathic hyperCKemia” of 0.71%. CK variation was highest in younger men and in females between 60 and 69 years. This study has identified persistent hyperCKemia in 1.3% of the normal population, and demonstrates the importance of performing controlled CK analyses, also in those with identified risk factors.     

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。     

Familial idiopathic hyper-CK-emia: an underrecognized condition

Persistent elevation of serum creatine kinase (CK) in individuals with normal neurological and laboratory examinations has been called idiopathic hyperCKemia (IH). IH has been reported in rare families and was recently ascribed to caveolin-3 gene mutations. We retrospectively found that IH was familial in 13 of 28 subjects in whom serum CK was measured in relatives. These 13 families had a total of 41 subjects with IH, including six over 60 years of age. In eight families there was male-to-male transmission and a higher prevalence of males with hyperCKemia. Muscle biopsy in one member of all families was normal or showed minimal, nonspecific changes. Morphometric examination disclosed different patterns of changes in fiber size and distribution. Caveolin-3 expression was normal and in five families molecular genetics excluded caveolin-3 gene mutations. Our findings suggest that IH is familial in 46% of cases. Familial IH is a benign genetically heterogeneous condition that is autosomal-dominant in at least 60% of cases, with a higher penetrance in men.     

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     

Screening test for malignant hyperthermia in patients with persistent hyperCKemia: A pilot study

Introduction: Persistently elevated serum creatine kinase (CK) is frequently associated with predisposition to malignant hyperthermia (MH). We investigated whether a minimally invasive metabolic test is suitable to diagnose MH susceptibility among patients with hyperCKemia. Methods: Thirty‐nine participants were included: 10 were MH susceptible (MHS); 21 MH were non‐susceptible (MHN); and 8 had MHN with persistent hyperCKemia >500 U/L. Microdialysis probes were inserted into the vastus lateralis muscle, and halothane or caffeine was injected via an attached microtubing catheter. Lactate concentrations in dialysis samples were measured spectrophotometrically. Results: Baseline lactate did not differ between the groups. After local application of halothane or caffeine, a significant lactate increase was detected only in the MHS group. Conclusions: Test results were not influenced by hyperCKemia. To avoid risks and complications of a surgical muscle biopsy this microdialysis test might be a useful screening tool for MH susceptibility among patients with persistent CK elevation. Muscle Nerve 47: 677–681, 2013     

Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia

Mutations in the caveolin-3 (CAV3) gene are associated with autosomal dominant limb-girdle muscular dystrophy (LGMD1C). The authors report a novel sporadic mutation in the CAV3 gene in two unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia) without muscle weakness. Immunohistochemistry and quantitative immunoblot analysis of caveolin-3 showed reduced expression of the protein in muscle fibers. Our data indicate that a partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia.     

EFNS guidelines on the diagnostic approach to pauci‐ or asymptomatic hyperCKemia

Objective: To provide evidence‐based guidelines to general neurologists for the assessment of patients with pauci‐ or asymptomatic hyperCKemia. Background: Recent epidemiologic studies show that up to 20% of ‘normal’ individuals have an elevated creatine kinase activity in the serum (sCK). The possibility of a subclinical myopathy is often raised, and patients may be unnecessarily denied treatment with statins. Search strategy: Electronic databases including Medline, the Cochrane Library and the American Academy of Neurology were searched for existing guidelines. Articles dealing with series of patients investigated for asymptomatic/pauci‐symptomatic hyperCKemia and articles dealing with myopathies that can present with asymptomatic hyperCKemia were identified and reviewed. Results: The only guidelines found were those approved by the Italian Association of Myology Committee, and the only relevant articles identified describe class IV studies. Recommendations: HyperCKemia needs to be redefined as values beyond 1.5 times the upper limit of normal (which itself needs to be appropriately defined). Pauci‐ or asymptomatic hyperCKemia with no apparent medical explanation may be investigated with a muscle biopsy if one or more of the following are present; the sCK is ≥3× normal, the electromyogram is myopathic or the patient is <25 years of age. In addition, women with sCK<3 times normal may be offered DNA testing because of the possibility of carrying a dystrophin mutation.     

Hypertension risk in idiopathic hyperCKemia

Patients with idiopathic hyperCKemia are usually reassured and discharged. However, these subjects may have increased hypertension risk, based on data from our population study, which showed that the population tertile with the highest serum creatine kinase activities had the highest systolic and diastolic blood pressure levels. Therefore, we assessed whether subjects with idiopathic hyperCKemia have greater occurrence of hypertension than controls.We included 46 participants aged 18 to 67 years, diagnosed with idiopathic hyperCKemia at the departments of Neurology of the Universities of Amsterdam and Utrecht, The Netherlands. We found that 48% of the subjects with idiopathic hyperCKemia were hypertensive, as compared to 19% of the random population controls (n = 22,612, aged 20 to 65 years), an odds ratio of 3.9 (95 % CI, 2.2 to 6.9) before, and 2.0 (1.1 to 3.8) after adjustment for sex, age, and body mass index.In accord with our previous finding of an association between creatine kinase and blood pressure in the general population, the data reported here suggest that subjects with idiopathic hyperCKemia have greater hypertension risk than controls. This may be due to relatively high tissue creatine kinase activity, resulting in greater ATP buffer capacity to create and sustain high blood pressure levels.Larger, prospective studies are needed to further assess this association, but as active case finding is important in the diagnosis of hypertension, subjects with idiopathic hyperCKemia should be screened and monitored for the presence of hypertension.     

Clinical impact of persistent hyperCKemia in a Norwegian general population: A case-control study

In this case-control study we assessed the clinical impact of persistent hyperCKemia in a Norwegian general population. HyperCKemia was defined according to the NORIP- references (women 35–210 U/L, men <50 years 50–400 U/L, and men ?50 years 40–280 U/L). We compared the frequency of muscular symptoms and function, neuromuscular diseases and risk factors between 120 cases with persistent hyperCKemia and 130 age- and sex-matched controls with normal CK values, all recruited from the single-centre, population-based prospective Tromsø Study. The participants underwent a standardized interview assessing muscle symptoms, physical activity, use of statins and presence of other CK risk factors, prior to clinical neurological and neurophysiological examination. Knee extensor muscle strength (Cybex NORM dynamometer) and dominant hand grip strength (Martin Vigorimeter) was assessed. A total of 85 cases (71%) reported either muscle pain, muscle stiffness or cramps, compared to 70 controls (54%) (p = 0.017) There were no differences in muscle strength between the groups. In men, weight, Body Mass Index and muscle symptoms were significantly higher in the group with persistent hyperCKemia. In women, no differences between the groups were detected. Use of statins was similar in cases and controls. We diagnosed 3 women with previously unknown myopathy, all in the group with persistent hyperCKemia. This study support that CK may be used as a marker of muscular symptoms in the general population.     

Asymptomatic hyper-CK-emia: an electrophysiologic and histopathologic study

Since the popularization of routine creatine kinase (CK) measurement, an increasing number of patients with unexplained CK elevation ("asymptomatic hyper-CK-emia") are being identified. We studied 19 patients with persistent CK elevation of unknown etiology with electromyography (EMG) and muscle biopsy. Needle EMG was abnormal in 14 patients. Muscle biopsy was positive in all individuals with abnormal EMG and in one patient with normal EMG. Diagnoses included polymyositis in five patients, morphologically nonspecific myopathy in three, mitochondrial myopathy in two, and sarcoid myopathy, central core disease, multicore disease, inclusion body myopathy, and McArdle's disease in one case, respectively. Five patients with abnormal biopsies developed weakness within 1 year of presentation. We conclude that persistent asymptomatic CK elevation represents mild or early myopathy in a majority of cases.     

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     

Asymptomatic elevation of serum creatine kinase leading to the diagnosis of 4q35 facioscapulohumeral muscular dystrophy

Persistent, asymptomatic (hyperCKemia) may be the prelude to, or the sole manifestation of, a neuromuscular disease. However, the clinical spectrum of facioscapulohumeral muscular dystrophy (FSHD) ranges from asymptomatic individuals with minimal clinical signs to patients who are wheelchair-bound. We describe a patient with persistent, asymptomatic hyperCKemia who received the diagnosis of 4q35 FSHD after a thorough stepwise investigation.     

Grandpa and I have dystrophinopathy?: approach to asymptomatic hyperCKemia

This report describes three males from a single kinship, ages 7, 8, and 67 years with clinically asymptomatic dystrophinopathy. The index case was an 8-year-old male evaluated for asymptomatic but persistently elevated serum creatine kinase levels. Muscle biopsy demonstrated a mild myopathy, without necrotic fibers. Immunostaining for dystrophin revealed a slight reduction in sarcolemmal reactivity for the amino terminus of dystrophin. Dystrophin gene analysis revealed a deletion of exon 45 to exon 51. Genetic analysis identified two other affected males (age 7 years and 67 years), as well as four female carriers in the same family. The 7-year-old male had mildly increased creatine kinase levels with normal muscle strength. The 67-year-old grandfather had normal neuromuscular examination and serum creatine kinase levels. Asymptomatic dystrophinopathy in late adulthood is exceptionally rare, and highlights the importance of consideration of dystrophin mutation analysis in patients with hyperCKemia, even in the absence of muscle weakness.     

Asymptomatic familial hyperCKemia associated with desmin accumulation in skeletal muscle

We describe a family, two brothers and their mother, who came to our observation because of slight to moderate hyperCKemia. The younger brother, who had the highest CK values, was only suffering from episodic myalgia, the other two members of the family were asymptomatic. Neurological examination was normal. Both brothers underwent muscle biopsy which was significant for the presence of abnormal sarcoplasmic areas of desmin accumulation. So far, desmin abnormalities have never been reported in patients with such a mild neuromuscular pattern. We discuss possible correlations between severity of clinical phenotype and degree of desmin accumulation.     

Persistent hyperCKemia: fourteen patients studied in retrospect

Fourteen patients with persistently raised serum creatine kinase activity (hyperCKemia) were studied in retrospect. Clinical and laboratory findings did not point to any established neuromuscular disorder. In 8, manual occupation with local muscle strain apparently caused the hyperCKemia despite a low total work load. One patient had subclinical hypothyroidism with a normal serum thyroxine and and elevated thyroid-stimulating hormone level. CK normalized with L-thyroxine therapy. In 2, including one manual worker, myoadenylate deaminase was deficient. The hyperCKemia remained unexplained in 4 patients.