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Original Contribution |

Effect of High-Dose Creatine Therapy on Symptoms of Exercise Intolerance in McArdle Disease: Double-blind, Placebo-Controlled Crossover Study FREE

Matthias Vorgerd, MD; Jochen Zange, PhD; Rudolf Kley; T. Grehl, MD; Anika Hüsing; Matthias Jäger, PhD; Klaus Müller, MD; Rolf Schröder, MD; Wilhelm Mortier, MD; Klaus Fabian, PhD; Jean-Pierre Malin, MD; Alwin Luttmann, PhD
[+] Author Affiliations

From the Departments of Neurology (Drs Vorgerd, Grehl, and Malin and Mr Kley), Medical Informatics, Biometrics, and Epidemiology (Ms Hüsing), and Pediatrics (Dr Mortier), Ruhr-University Bochum, Bochum; the German Aerospace Center, Cologne (Drs Zange and Müller); the Institute of Occupational Physiology, University of Dortmund, Dortmund (Drs Jäger and Luttmann); the Department of Neurology, University of Bonn, Bonn (Dr Schröder); and the Institute of Sports Medicine, University of Dresden, Dresden (Dr Fabian), Germany.


Arch Neurol. 2002;59(1):97-101. doi:10.1001/archneur.59.1.97.
Text Size: A A A
Published online

Background  In a recent study, we showed that administration of low-dose creatine (Cr) (60 mg/kg daily) improved work capacity in patients with McArdle disease.

Objective  To assess the efficacy of high-dose Cr therapy in McArdle disease.

Design  Randomized, double-blind, placebo-controlled crossover study.

Patients  Nineteen patients with McArdle disease.

Intervention  Treatment with Cr, 150 mg/kg daily. Each treatment phase with Cr or placebo lasted 5 weeks.

Main Outcome Measures  The patient's daily rating of symptoms of exercise intolerance. At the end of each treatment phase, serum creatine and serum creatine kinase levels, phosphorus 31 magnetic resonance spectroscopy, and surface electromyograms were assessed.

Results  Clinical end points revealed increases in the intensity of exercise-induced pain in working muscles (mean treatment-induced difference [d], 0.30 in log(score); 95% confidence interval [CI], 0.05-0.55; P = .02), the limitation of daily activities (d, 0.59; 95% CI, 0.22-0.97;P = .005), and body mass index (d, 0.33 kg/m2, 95% CI, 0.10-0.56 kg/m2; P = .008) with Cr use. Surface electromyograms revealed a smaller increase in the electromyographic amplitude over time during muscle contraction with Cr use (d, −13.52%/min; 95% CI, −23.71%/min to −3.34%/min; P = .01). There were no significant changes in phosphorus 31 magnetic resonance spectroscopy variables.

Conclusions  Administration of high-dose Cr worsened the main clinical symptoms of exercise intolerance in McArdle disease. These neurologic adverse effects represent a major dose-limiting factor in Cr therapy for McArdle disease. Taken together with results of a previous study, the indication for symptomatic therapy with Cr needs to be clarified. An effective Cr dosage without adverse effects may be between 60 and 150 mg/kg daily.

Figures in this Article

MCARDLE DISEASE (glycogenosis type V) is one of the most common metabolic myopathies and is caused by genetic defects of the muscle-specific isozyme of glycogen phosphorylase, which block adenosine triphosphate (ATP) formation from glycogen in skeletal muscle. Typically, patients with McArdle disease have exercise intolerance, with premature muscle fatigue, exercise-induced muscle pain in working muscles, and recurrent myoglobinuria. Treatment of McArdle disease has been unsatisfactory to date and therefore remains an important clinical challenge.

In a recent study, we1 showed the beneficial effects of short-term low-dose oral creatine (Cr) monohydrate (60 mg/kg daily) therapy in McArdle disease based on a trend toward subjective improvement, increased exercise capacity associated with greater depletion of phosphocreatine (PCr), and a greater slope of decline of the median frequency in surface electromyograms (S-EMGs). It was concluded that Cr may have a role in symptomatic therapy of McArdle disease, but further studies were required to find the optimal dosage.

In this follow-up study, we investigated whether use of a higher dose of Cr (150 mg/kg per day) is effective in relieving exercise intolerance. We performed a double-blind, placebo-controlled trial encompassing a quantitative approach to evaluate symptoms of exercise intolerance, phosphorus 31 magnetic resonance spectroscopy (31P-MRS), S-EMG, and laboratory studies to search for an effect of high-dose Cr therapy in McArdle disease.

PATIENTS AND STUDY DESIGN

Nineteen patients with genetically confirmed McArdle disease entered the trial (8 women and 11 men; mean [SD] age, 33.8 [11.8] years [range, 11-59 years]; mean [SD] disease duration, 27.7 [12.1] years [range, 3-53 years]). All patients had symptoms of exercise intolerance, such as exercise-induced pain in working muscles and early fatigue. They all led normal lives but were limited in daily activities, such as walking uphill and climbing stairs, and they could not carry out vigorous activities.

A double-blind, placebo-controlled crossover trial with Cr (150 mg/kg daily) was performed (Figure 1). Capsules used for administration of placebo and Cr were identical in appearance. Each study phase lasted 5 weeks, with a washout of 4 weeks between study periods. This study was approved by the local ethics committee of the Ruhr-University Bochum, Bochum, Germany. Each patient gave written informed consent before starting the trial.

Place holder to copy figure label and caption
Figure 1.

Trial profile. S-EMG indicates surface electromyogram; 31P-MRS, phosphorus 31 magnetic resonance spectroscopy.

Graphic Jump Location
CLINICAL OUTCOME MEASURES AND LABORATORY STUDIES

During both phases, patients used a diary to quantify the main symptoms of exercise intolerance and to record any adverse events. All patients were asked to note the daily frequency (bouts) of muscle pain. Duration of each bout of muscle pain was quantified in 5 grades: 1 is less than 1 minute; 2, 1 to 5 minutes; 3, greater than 5 to 10 minutes; 4, greater than 10 to 60 minutes; and 5, greater than 60 minutes. Severity of each bout of muscle pain was rated on a scale from 1 (no pain) to 10 (most severe pain), and its intensity was calculated as a product of duration and severity. Average daily early fatigability and limitation in daily activities were also rated on a scale from 1 (no complaints) to 10 (most disabling). At the beginning and end of each treatment phase, the patient's height and weight were measured and body mass index (calculated as weight in kilograms divided by the square of height in meters) was calculated. Blood samples were obtained from the antecubital vein at the end of each treatment phase. Serum creatine and serum creatine kinase levels were determined.

31P-MRS AND S-EMG

On the final day of each treatment period, the effects of treatment on muscle bioenergetics and on myoelectrical changes were measured by 31P-MRS and S-EMG using a standardized calf muscle ergometric test according to a valid protocol that has been shown to be sensitive in McArdle disease.1 In our first study,1 the target test force of 30% maximum voluntary contraction (MVC) was related to the MVC value during each session. In this follow-up study, 30% MVC was related to the patient's initial MVC value. Therefore, the target force and absolute force-time integral were the same for each patient in all test periods. This design allows interpretation of changes in S-EMG characteristics and energy metabolism independently from changes in MVC development.

STATISTICS

The sums of patient scores in both phases were compared to determine carryover effects. The differences between treatment and placebo phases in both groups were used to test for period effects. Treatment effects were analyzed using the differences between the second and first phase in each group. All comparisons were made using t tests. The scores for severity and intensity of daily muscle contractures, the time constants for oxidative PCr recovery after contractions, and the levels of serum creatine and serum creatine kinase were log-transformed for this analysis. Statistical significance was set at P<.05.

EFFECTS OF TREATMENT

Two patients in group 2 were excluded because of protocol violation (both patients limited the daily doses without occurrence of adverse events). Seventeen patients qualified for clinical outcome measures and laboratory studies. Surface EMG and 31P-MRS were evaluated in 14 patients (Figure 1). Statistical analysis showed no evidence of carryover or period effects in the selected variables (data not shown). Primary clinical end points revealed significant increases in the mean severity (Table 1) and the average daily intensity (Figure 2) of muscle pain and in the limitation of daily activities with Cr use (Figure 2). There were no significant changes in the daily frequency of muscle pain or in early fatigability (Table 1).

Table Graphic Jump LocationEffects of Creatine and Placebo Use on Clinical Outcome Measures, 31P-MRS, S-EMG, and Laboratory Studies*
Place holder to copy figure label and caption
Figure 2.

Treatment-induced differences in the average daily intensity of exercise-induced muscle pain (A) and in the limitation of daily activities (B), calculated as differences in phase 2 minus phase 1.

Graphic Jump Location

A significant elevation in body mass index with Cr therapy was found, most likely because of an increase in body fat–free mass and increased muscle water content, as demonstrated in Cr supplementation for gyrate atrophy and in athletes using Cr long term.2,3 The plasma level of creatine increased with Cr use and serum creatine kinase values remained unaltered (Table 1).

FINDINGS FROM 31P-MRS AND S-EMG

Results of 31P-MRS indicated no significant increase in the PCr/ATP ratio at rest with Cr use (Table 1). The bioenergetic efficiency of muscle contraction, measured as initial rates of [PCr] + [ATP] decrease per force-time integral during both forms of exercise, did not change significantly with Cr therapy (data not shown). There were no significant differences in the PCr and ATP consumptions during aerobic and ischemic exercise. The time constants for oxidative PCr recoveries after both contractions remained unaltered. There was no significant change in the MVC or in the force-time integrals during aerobic and ischemic exercise (Table 1).

Results of S-EMG revealed a significantly smaller increase in the EMG amplitude during muscle contraction with Cr use (Table 1 and Figure 3), which is accompanied by a nonsignificant reduction in the time-related decrease of the median frequency (Table 1).

Place holder to copy figure label and caption
Figure 3.

Treatment-induced differences in the increase in the surface electromyographic amplitude over time (indicated by the slope of the root mean square [RMS] of the gastrocnemius muscle), calculated as differences in phase 2 minus phase 1.

Graphic Jump Location

Oral Cr monohydrate is a commercially available dietary supplement and is used in a range of neuromuscular disorders.47 It has also become popular in augmentation of athletic performance in professional and amateur sports.8,9 Among the many effects of Cr, the mechanisms of ergogenic enhancement may include increased intramuscular PCr, improvement of intracellular Ca2+handling, enhanced energy shuttling, cell protection, and protein synthesis stimulation.10,11 The safety of oral Cr intake has so far been questioned in only 2 patients with renal dysfunction linked to its use.12,13

We1 recently demonstrated the beneficial effects of low-dose Cr supplementation (60 mg/kg daily) in McArdle disease. In this follow-up study, we found that higher dosages of Cr (150 mg/kg daily) worsened the main clinical features of exercise intolerance in McArdle disease. Taken together, both studies provide evidence for a dose-related effect of Cr on clinical outcome measures, S-EMG, and 31P-MRS. These findings have implications for appropriate symptomatic therapy not only for McArdle disease but also for other neuromuscular disorders for which Cr therapy is recommended. If Cr is used as symptomatic monotherapy in McArdle disease, it should be administered in a dosage well below 150 mg/kg daily to avoid adverse effects and of at least 60 mg/kg daily to enhance working capacity. Further studies are warranted to clarify the indication for Cr supplementation and to establish an optimal Cr dosage regimen.

In the present study, the absence of significant changes in the 31P-MRS variables might be explained by the failure of even high-dose Cr administration to increase the level of intramuscular Cr and thereby PCr concentration. This is in contrast to several studies mainly in trained healthy individuals that showed an improvement in muscle performance even with short-term low-dose Cr supplementation (3 g/d) associated with a higher PCr concentration and accelerated rate of PCr resynthesis as measured by 31P-MRS.1420 Human muscle cells take up Cr from blood through specific Cr transporters that are regulated by plasma Cr levels, insulin, vitamin E, high-carbohydrate loading, and exercise.16,21,22 Exercise intolerance due to blocked muscle glycogen breakdown in McArdle disease encourages a sedentary lifestyle. The absence of training-related stimuli may reduce the capacity of muscle cells to uptake Cr and thus the ability to increase muscle PCr with Cr supplementation (J. Zange, PhD, unpublished data, 2001). Individualized, force-velocity training in combination with Cr supplementation might improve exercise intolerance and increase intramuscular PCr in patients with McArdle disease, but this needs to be explored in a controlled clinical trial.

Surface EMG reveals an increase in electrical activity generated during fatiguing contractions in healthy individuals and in patients with McArdle disease because the increasing number of fatiguing muscle fibers requires additional recruitment of motor units to compensate for fatigue. Low-dose Cr therapy may lead to a shorter twitch time of muscle fibers and thereby cause a decrease in the force-time integral produced per action potential. Consequently, a greater number of action potentials is needed to hold a given force. This hypothesis is compatible with our previous findings1 of a steeper increase in the EMG amplitude with low-dose Cr use. In contrast, high-dose Cr therapy revealed an opposite effect and caused a smoother increase in the EMG amplitude, which indicates a lower level of motor unit recruitment during isometric muscle contraction. This suggests an enhanced force production per action potential, possibly because of an improvement in reduced muscle fiber membrane excitability. In patients with McArdle disease, such an impaired sarcolemmal function has been assumed because a decline in the compound muscle action potential with repetitive stimulation and reduced levels of skeletal muscle sodium/potassium-ATPases were found, which may cause a decline in muscle force generation.2325 It may be speculated that an insufficient adaption to this improved electromechanical efficacy leads to overuse of the muscle contractility in exercise and thus worsening of clinical symptoms in McArdle disease.

In conclusion, our data demonstrate that high-dose Cr administration worsens clinical symptoms of exercise intolerance in McArdle disease despite positive neurophysiological findings. We believe that administration of high-dose Cr as a symptomatic therapy for patients with McArdle disease should be approached with caution.

Accepted for publication August 28, 2001.

Author Contributions:Conception and design (Drs Vorgerd, Zange, and Luttmann); acquisition of data (Drs Vorgerd, Zange, Grehl, Jäger, Müller, Fabian, and Luttmann and Mr Kley); analysis and interpretation of data (Drs Vorgerd, Zange, Grehl, Jäger, Müller, and Luttmann; Mr Kley; and Ms Hüsing); drafting of the manuscript (Drs Vorgerd, Grehl, Jäger, Schröder, Fabian, and Luttmann and Mr Kley); critical revision of the manuscript for important intellectual content (Drs Vorgerd, Zange, Grehl, Jäger, Müller, Mortier, Malin, and Luttmann and Ms Hüsing); statistical expertise (Dr Vorgerd and Ms Hüsing); obtaining funding (Dr Vorgerd); administrative, technical, or material support (Drs Vorgerd, Zange, Grehl, Jäger, Müller, Schröder, Mortier, Fabian, Malin, and Luttmann and Mr Kley); supervision (Drs Vorgerd, Zange, and Luttmann).

This work was supported in part by a grant from the Werner Richard–Dr. Carl Dörken Stiftung (Herdecke, Germany) (Dr Vorgerd).

Corresponding author and reprints: Matthias Vorgerd, MD, Department of Neurology, Ruhr-University Bochum, Kliniken Bergmannsheil, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany (e-mail: matthias.vorgerd@ruhr-uni-bochum.de).

Vorgerd  MGrehl  TJager  M  et al Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial. Arch Neurol.2000;57:956-963.
Sipila  IRapola  JSimell  OVannas  A Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. N Engl J Med.1981;304:867-870.
Vandenberghe  KGoris  MVan Hecke  PVan Leemputte  MVangerven  LHespel  P Long-term creatine intake is beneficial to muscle performance during resistance training. J Appl Physiol.1997;83:2055-2063.
Tarnopolsky  MMartin  J Creatine monohydrate increases strength in patients with neuromuscular disease. Neurology.1999;52:854-857.
Walter  MCLochmuller  HReilich  P  et al Creatine monohydrate in muscular dystrophies: a double-blind, placebo-controlled clinical study. Neurology.2000;54:1848-1850.
Tarnopolsky  MARoy  BDMacDonald  JR A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve.1997;20:1502-1509.
Borchert  AWilichowski  EHanefeld  F Supplementation with creatine monohydrate in children with mitochondrial encephalomyopathies. Muscle Nerve.1999;22:1299-1300.
Engelhardt  MNeumann  GBerbalk  AReuter  I Creatine supplementation in endurance sports. Med Sci Sports Exerc.1998;30:1123-1129.
Bosco  CTihanyi  JPucspk  J  et al Effect of oral creatine supplementation on jumping and running performance. Int J Sports Med.1997;18:369-372.
Klivenyi  PFerrante  RJMatthews  RT  et al Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med.1999;5:347-350.
Pulido  SMPassaquin  ACLeijendekker  WJChallet  CWallimann  TRuegg  UT Creatine supplementation improves intracellular Ca2+ handling and survival in mdx skeletal muscle cells. FEBS Lett.1998;439:357-362.
Koshy  KMGriswold  ESchneeberger  EE Interstitial nephritis in a patient taking creatine. N Engl J Med.1999;340:814-815.
Pritchard  NRKalra  PA Renal dysfunction accompanying oral creatine supplements. Lancet.1998;351:1252-1253.
Balsom  PDSoderlund  KSjodin  BEkblom  B Skeletal muscle metabolism during short duration high-intensity exercise: influence of creatine supplementation. Acta Physiol Scand.1995;154:303-310.
Greenhaff  PLBodin  KSoderlund  KHultman  E Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J Physiol.1994;266:E725-E730.
Harris  RCSoderlund  KHultman  E Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Colch).1992;83:367-374.
Hultman  ESoderlund  KTimmons  JACederblad  GGreenhaff  PL Muscle creatine loading in men. J Appl Physiol.1996;81:232-237.
Snow  RJMcKenna  MJSelig  SEKemp  JStathis  CGZhao  S Effect of creatine supplementation on sprint exercise performance and muscle metabolism. J Appl Physiol.1998;84:1667-1673.
Casey  AConstantin-Teodosiu  DHowell  SHultman  EGreenhaff  PL Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol.1996;271:E31-E37.
Smith  SAMontain  SJMatott  RPZientara  GPJolesz  FAFielding  RA Effects of creatine supplementation on the energy cost of muscle contraction: a 31P-MRS study. J Appl Physiol.1999;87:116-123.
Loike  JDZalutsky  DLKaback  EMiranda  AFSilverstein  SC Extracellular creatine regulates creatine transport in rat and human muscle cells. Proc Natl Acad Sci U S A.1988;85:807-811.
Koszalka  TRAndrew  CLBrent  RL Effect of insulin on the uptake of creatine-1-14 C by skeletal muscle in normal and x-irradiated rats. Proc Soc Exp Biol Med.1972;139:1265-1271.
Dyken  MSmith  DPeake  R An electromyographic diagnostic screening test in McArdle's disease and a case report. Neurology.1967;17:45-50.
Ruff  LR Why do patients with McArdle's disease have decreased exercise capacity? Neurology.1998;50:6-7.
Haller  RGClausen  TVissing  J Reduced levels of skeletal muscle Na+K+-ATPase in McArdle disease. Neurology.1998;50:37-40.

Figures

Place holder to copy figure label and caption
Figure 1.

Trial profile. S-EMG indicates surface electromyogram; 31P-MRS, phosphorus 31 magnetic resonance spectroscopy.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Treatment-induced differences in the average daily intensity of exercise-induced muscle pain (A) and in the limitation of daily activities (B), calculated as differences in phase 2 minus phase 1.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Treatment-induced differences in the increase in the surface electromyographic amplitude over time (indicated by the slope of the root mean square [RMS] of the gastrocnemius muscle), calculated as differences in phase 2 minus phase 1.

Graphic Jump Location

Tables

Table Graphic Jump LocationEffects of Creatine and Placebo Use on Clinical Outcome Measures, 31P-MRS, S-EMG, and Laboratory Studies*

References

Vorgerd  MGrehl  TJager  M  et al Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial. Arch Neurol.2000;57:956-963.
Sipila  IRapola  JSimell  OVannas  A Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. N Engl J Med.1981;304:867-870.
Vandenberghe  KGoris  MVan Hecke  PVan Leemputte  MVangerven  LHespel  P Long-term creatine intake is beneficial to muscle performance during resistance training. J Appl Physiol.1997;83:2055-2063.
Tarnopolsky  MMartin  J Creatine monohydrate increases strength in patients with neuromuscular disease. Neurology.1999;52:854-857.
Walter  MCLochmuller  HReilich  P  et al Creatine monohydrate in muscular dystrophies: a double-blind, placebo-controlled clinical study. Neurology.2000;54:1848-1850.
Tarnopolsky  MARoy  BDMacDonald  JR A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve.1997;20:1502-1509.
Borchert  AWilichowski  EHanefeld  F Supplementation with creatine monohydrate in children with mitochondrial encephalomyopathies. Muscle Nerve.1999;22:1299-1300.
Engelhardt  MNeumann  GBerbalk  AReuter  I Creatine supplementation in endurance sports. Med Sci Sports Exerc.1998;30:1123-1129.
Bosco  CTihanyi  JPucspk  J  et al Effect of oral creatine supplementation on jumping and running performance. Int J Sports Med.1997;18:369-372.
Klivenyi  PFerrante  RJMatthews  RT  et al Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med.1999;5:347-350.
Pulido  SMPassaquin  ACLeijendekker  WJChallet  CWallimann  TRuegg  UT Creatine supplementation improves intracellular Ca2+ handling and survival in mdx skeletal muscle cells. FEBS Lett.1998;439:357-362.
Koshy  KMGriswold  ESchneeberger  EE Interstitial nephritis in a patient taking creatine. N Engl J Med.1999;340:814-815.
Pritchard  NRKalra  PA Renal dysfunction accompanying oral creatine supplements. Lancet.1998;351:1252-1253.
Balsom  PDSoderlund  KSjodin  BEkblom  B Skeletal muscle metabolism during short duration high-intensity exercise: influence of creatine supplementation. Acta Physiol Scand.1995;154:303-310.
Greenhaff  PLBodin  KSoderlund  KHultman  E Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J Physiol.1994;266:E725-E730.
Harris  RCSoderlund  KHultman  E Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Colch).1992;83:367-374.
Hultman  ESoderlund  KTimmons  JACederblad  GGreenhaff  PL Muscle creatine loading in men. J Appl Physiol.1996;81:232-237.
Snow  RJMcKenna  MJSelig  SEKemp  JStathis  CGZhao  S Effect of creatine supplementation on sprint exercise performance and muscle metabolism. J Appl Physiol.1998;84:1667-1673.
Casey  AConstantin-Teodosiu  DHowell  SHultman  EGreenhaff  PL Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol.1996;271:E31-E37.
Smith  SAMontain  SJMatott  RPZientara  GPJolesz  FAFielding  RA Effects of creatine supplementation on the energy cost of muscle contraction: a 31P-MRS study. J Appl Physiol.1999;87:116-123.
Loike  JDZalutsky  DLKaback  EMiranda  AFSilverstein  SC Extracellular creatine regulates creatine transport in rat and human muscle cells. Proc Natl Acad Sci U S A.1988;85:807-811.
Koszalka  TRAndrew  CLBrent  RL Effect of insulin on the uptake of creatine-1-14 C by skeletal muscle in normal and x-irradiated rats. Proc Soc Exp Biol Med.1972;139:1265-1271.
Dyken  MSmith  DPeake  R An electromyographic diagnostic screening test in McArdle's disease and a case report. Neurology.1967;17:45-50.
Ruff  LR Why do patients with McArdle's disease have decreased exercise capacity? Neurology.1998;50:6-7.
Haller  RGClausen  TVissing  J Reduced levels of skeletal muscle Na+K+-ATPase in McArdle disease. Neurology.1998;50:37-40.

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