Muscle Cramps Lecture Notes (PDF)

Muscle cramps Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the...

Muscle cramps Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the University of New South Wales in accordance with section 113P of the Copyright Act 1968 (Act).  The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.  Do not remove this notice Learning objectives - explain how scientifically based recommendations are derived (example: GRADE) - describe typical symptoms of exercise-associated muscle cramping (EAMC) - explain the hypotheses about EAMC pathophysiology - describe the rationale behind common treatment strategies - list some common treatment strategies and estimate their evidence level - describe idiopathic leg cramps - give examples for the connection of muscle cramps with serious disease Levels of evidence – how much do we know? - several systems exist, example: - GRADE: Grading of Recommendations, Assessment, Development and Evaluations - a transparent framework for developing and presenting summaries of evidence - a systematic approach for making clinical practice recommendations - a tool for grading the quality of evidence and making recommendations GRADE: certainty ratings Very low the true effect is probably markedly different from the estimated effect Low the true effect might be markedly different from the estimated effect Moderate the authors believe that the true effect is probably close to the estimated effect High the authors have a lot of confidence that the true effect is similar to the estimated effect GRADE DON’T DO treat treat - GRADE is subjective - evidence becomes less certain when: - there is a risk of bias - imprecision (does the clinical decision change when I move over the confidence interval?) - inconsistency (studies yield contradictory results) - indirectness: better!?? - publication bias (missing evidence?) treatment A treatment B x4 x2 placebo Placebo treatment A Placebo treatment B Young, BMJ Clin Evid, 2015 Muscle cramping – common symptoms - cramps = involuntary localised and painful muscle contractions - fasciculations are not cramps (few fascicles, not painful) - causality: unknown, different hypotheses (this lecture) fasciculations cramp needle EMG s - risk factors: - do not confound with causes - eliminating a risk factor is not automatically an efficient treatment => simplified and erroneous therapeutic implications Bischoff, EMG (Ge)  Muscle cramping: 4 forms 1. Benign forms a. Exercise associated muscle cramping (EAMC) b. Idiopathic leg cramps (benign nocturnal cramps) (c. Cramps associated with pregnancy) 2. Cramps and disease (neuromuscular, metabolic) Exercise-associated muscle cramping (EAMC) - cramps that occur during or immediately after exercise - pain/discomfort can have longer duration (>24 h) - prevalence up to 50%, e.g. marathon, triathlon - which muscles? multi-joint muscles (e.g. calf > foot > knee flexors) - considered benign, not a disease => unusually intense cramps may unmask other conditions Exercise-associated muscle cramping (EAMC) - cramps that occur during or immediately after exercise - pain/discomfort can have longer duration (>24 h) - prevalence up to 50%, e.g. marathon, triathlon - which muscles? multi-joint muscles (e.g. calf > foot > knee flexors) - considered benign, not a disease => unusually intense cramps may unmask other conditions - pathophysiological hypotheses: 1. neuromuscular control disorder 2. dehydration, electrolyte changes Pathophysiology – 2 hypotheses Hypothesis 1: neuromuscular control - the combination of several factors controlling muscle contraction leads to cramping - remember fatigue?...same factors! but unknown mechanisms lead to net overexcitability - factors: - myotatic reflex and Ia afferents (increased?) - GTO + Ib afferents (decreased?) => excitation of the α-motoneuron - data mostly from animal studies and electrical stimulation Katzberg, J Neurol, 2015 Pathophysiology – 2 hypotheses Hypothesis 2: dehydration / electrolytes - low evidence level - frequency seems to increase with ambient temperature and humidity - no controlled, standardized studies e.g. no fatigue measures - correlation dehydration – cramp risk has not been established - no significant differences in serum electrolyte concentrations between cramp / non-cramp subjects Katzberg, J Neurol, 2015  Pathophysiological concepts of EAMC Risk “Premature muscle factors fatigue” Nelson, Muscle & Nerve, 2016  Pathophysiological concepts of EAMC stretching? (controversy) COL5A1 CC ↓ (collagen type V) Nelson, Muscle & Nerve, 2016 Cramps: EMG correlates electrical stimulation after discharges Katzberg, J Neurol, 2015 Exercise-induced muscle cramping (EAMC) Acute interventions: - no high level (level I) evidence for any method - moderate evidence (level II-III): passive stretching - little evidence (level IV): pickle juice - no evidence: non-drug physical therapies, fluid substitution, many drugs problem: short duration of cramps, self-limiting before intervention is effective Prevention: low evidence for: - electrically induced cramps increases threshold (not practical) - quinine: no recommendation because of side-effects - TRP channel agonists - hyperventilation? Nelson, Muscle & Nerve, 2016 Idiopathic leg cramps Symptoms: - “benign nocturnal cramps” - spontaneously occurring, mostly at night, but also prolonged rest (sitting, lying) - which muscles: calf > others - more frequent with age Idiopathic leg cramps Symptoms: - “benign nocturnal cramps” - spontaneously occurring, mostly at night, but also prolonged rest (sitting, lying) - which muscles: calf > others - more frequent with age Treatment strategies: - acute: passive stretch of agonist or contract antagonist (low grade evidence) - prevention: - stretching: study protocol: 3 x 10 sec calf/hamstring stretch in the evening, 6 weeks) - quinine: level I evidence for efficacy (cramps less frequent, less intense), but: potentially serious side effects - Mg2+: probably not effective Muscle cramps: disease and medication side-effects - peripheral neuropathies: diabetes mellitus, alcohol - neuromuscular disease: amyotrophic lateral sclerosis (ALS) - metabolic disorders: thyroid, adrenal, liver, kidney disease - medication: - antidepressants (neuronal excitability?) - glucocorticoids (electrolytes? due to lower serum K+?) - diuretics (electrolytes?, renal loss of K+, Mg2+) - statins (direct effect on muscles?) Muscle cramps and disease Katzberg, J Neurol, 2015 Quinine: - natural substance, known for a long time (malaria, tonic water) - mechanism: reduces membrane excitability (neuromuscular junction, muscle fibre membrane + action potential) - level I evidence exists for efficacy against cramping (Cochrane Review) - but possibly fatal (!) side effects: - cardiac arrhythmia - thrombocytopenia (low platelets) - teratogenic (developmental malformations) => no clear recommendation https://en.wikipedia.org/wiki/Quinine Magnesium salts - theory: - Mg2+ ions are “antagonists” of Ca2+ ions - “stabilization” of the membrane potential - inhibition of intracellular Ca2+ release via RyR receptors - Garrison et al., Cochrane Review 2012: Magnesium for skeletal muscle cramps - Conclusions: - EAMC: no randomized controlled trials (RCT) - Mg2+ is unlikely to provide clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps - pregnancy related rest cramps: literature not conclusive - disease related cramps: no RCTs for e.g. amyotrophic lateral sclerosis - but: big $$$ market TRP / TRPV channel agonists - TRP = transient receptor potential channel (A-ankyrin, V-vanilloid) activators: chili, wasabi etc. - Craighead et al., Muscle & Nerve, 2017: - TRP agonists may reduce EAMC by increasing cramp threshold - cramp duration not altered, less subjective cramp soreness - no adverse effects on performance - Behringer et al., Eur J Appl Physiol, 2018: - TRPA1, TRPV1 randomized, double-blind, placebo controlled study - possible short-term effect on cramp threshold, no clear overall effect => no conclusive evidence, strong effect unlikely Pickle juice - anecdotal evidence: US football match with high ambient temperature: several players stopped with severe cramps => those that drank pickle juice improved, hypothesis: high Na+ content - Miller et al. Reflex inhibition of electrically induced muscle cramps in hypohydrated humans. Med Sci Sports Exerc 2010; 42: 953 – 961 experimental muscle cramps (3% weight loss by sweating) => treatment pickle juice vs. salt-free water => cramp duration almost -50% with pickle juice Mechanism? NaCl seems obvious… but: effect after 85 sec (pickle juice in stomach...) => reflex hypothesis (tongue, oral cavity receptors) => spinal cord => motor neuron excitability ↓ Diverse drug therapies Katzberg, J Neurol, 2015 Non-drug therapies - kinesio taping, compression garments - massage therapy - corrective exercise - stretching - hyperventilation => small samples, laboratory-based studies => lack of RCTs => low evidence Thank you!