NEUROMUSCULAR DISORDERS Muscle Cramps Reliable and validated outcome measures and new treatments are needed. By Hans D. Katzberg, MD, MSc, FRCPC and Hamid Sadeghian, MD, FRCPC What Is a Muscle Cramp? limb syndromes) and peripheral processes, including tetany, A muscle cramp is a hyperexcit- myokymia, myotonia, neuromyotonia (focal muscle stiff- able neurologic phenomena of ness), or myalgia.6 excessive, involuntary muscle The origin and propagation of neurogenic muscle cramps contractions.1,2 It is important localizes to peripheral and central targets (Figure 1), including to distinguish between myogen- the neuromuscular junction, where mechanical disruption ic and neurogenic muscle cramps, because each has unique and electrolyte disturbances can influence hyperexcitability pathophysiology and management.3 The conventional defi- and cramp generation. Injury to peripheral nerve components nition of a muscle cramp is a painful contraction of a muscle including the motor neuron cell bodies or the motor axons or muscle group, relieved by contraction of antagonist can result in ephaptic transmission and development of mus- muscles.4 Colloquially, muscle cramps are known by a num- cle cramps. Dysfunctional intramuscular small fiber sensory ber of different terms depending on the country, including afferents (eg, mechanoreceptors and spindles) are also pro- charley horse in the US, chopper in England, and corky in posed to be involved in cramp generation.7-10 Centrally, persis- Australia.5 Care must be taken to avoid confusing muscle tent inward currents mediated by GABAergic transmitters at cramps with other phenomena including central hyperexcit- the spinal level can amplify incoming sensory input and lead ability (eg, dystonia, spasticity, seizures, and stiff person/stiff to the propagation and amplification of cramp potentials.11 Figure 1: Pathophysiology Underlying Neurogenic Muscle Cramps. JULY/AUGUST 2019 PRACTICAL NEUROLOGY e1 NEUROMUSCULAR DISORDERS Disruption of chloride, sodium, and potassium channels and ment and morphologic features.16 Needle EMG can identify inadequate amino acids concentrations (eg, taurine) disrupt electric activity that often accompanies muscle cramps membrane currents to generate muscle cramps.12,13 (eg, fasciculations) or distinguish between other peripheral The pathophysiology of myogenic muscle cramps, in con- hyperexcitable phenomena (eg, myokymia, myotonia, or trast, is usually the result of disrupted energy production neuromyotonia). Low-frequency (1-5 Hz) repetitive nerve in muscle cells and occurs most commonly in metabolic stimulation can, on occasion, generate varying levels of post- myopathies associated with disorders of glycogen, lipid, or cramp discharges and clinical or subclinical cramp potentials mitochondrial metabolism.14 Metabolic myopathies cause (Figure 2).17 Higher frequency stimulation paradigms in the deficient ATP levels.14 Because muscle relaxation is an ade- foot using the tibial nerve and intrinsic tibial innervated foot nosine triphosphate (ATP)-dependent active process, actin muscles have been developed to induce and study muscle and myosin chains do not disengage, causing an electrically cramps; however, this is usually used in research rather silent cramp (ie, contracture). The metabolic defect may than clinical practice.18 Cramp frequency is often used to also cause accumulation of potentially toxic metabolites quantify severity because individuals affected by cramps can that further aggravate ATP deficientcy. Myopathic cramps usually count distinct episodes and distinguish these from are also a potential symptom of myopathies linked to postcramp soreness. Cramp intensity and location can also muscle membrane or intramuscular structural dysfunction be considered to quantify severity. A patient-based reliable in acquired and hereditary myopathies (eg, muscular dystro- scale to further assess muscle cramps is an unmet need. phy, congenital myopathies, and inflammatory myopathy).15 Causes of Muscle Cramps and Investigations Assessment of Muscle Cramps Table 1 outlines physiologic and pathologic processes Most often, a muscle cramp is confirmed with clinical that can lead to muscle cramps, which are nearly ubiquitous history. Although cramps are not usually induced during throughout the lifespan, occurring rarely before age 8, more motor examination or electrophysiologic tests, muscle commonly in certain physiologic states (eg, pregnancy), and cramps can rarely be seen incidentally during these assess- frequently in people more than age 65.19,20 When no underly- ments. If a cramp occurs in a muscle during needle EMG, ing cause is found, the term idiopathic muscle cramps is used. the electrically silent nature of myogenic cramps or the When idiopathic cramps occur in patients more than age characteristic high frequency (≤150 Hz) of involuntary 65—primarily nocturnally in the calves—the term nocturnal cramp potentials in neurogenic muscle cramps may be seen leg cramps of the elderly (NLCE) has been used.21 Physiologic along with classic EMG neurogenic or myopathic recruit- stressors are a common precipitant to muscle cramps. The A B C D Figure 2: Cramp-Potentials and After-Discharges in Response to Slow Repetitive Nerve Stimulation. Panels A-C indicate increasing levels of after-cramp discharges, and panel D indicates a continuous cramp potential in response to 1 Hz repetitive nerve stimulation stimulating the tibial nerve and recording from the abductor hallicus. e2 PRACTICAL NEUROLOGY JULY/AUGUST 2019 NEUROMUSCULAR DISORDERS TABLE 1. COMMON CAUSES OF MUSCLE CRAMPS spasms.27 Muscle cramps are common in the setting of diabe- Physiologic Dehydration tes through a variety of mechanisms, the most important of which are neuropathy and nephropathy.28 Medications can Exercise-induced also cause cramps, including thiazide diuretics statins, beta- Idiopathic agonists, acetylcholinesterase inhibitors (often used for treat- Nocturnal leg cramps of the elderly ment of myasthenia gravis), cimetidine, steroids, morphine, Pregnancy penicillamine, some immunosuppressants, cardiotropics, anti- retrovirals, and psychotropic medications.29 Metabolic Cirrhosis Neurologic conditions in which peripheral nerve is affect- Hypothyroidism ed are particularly prone to muscle cramps as a positive Malnutrition (vitamin B, D, Mg2+ deficiencies) motor symptom. This includes motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), where muscles cramps Uremia/hemodialysis are an early and common symptom that may eventually Medications Beta-agonists fade as denervation becomes advanced.30 Radiculopathies Diuretics can not only produce significant weakness, numbness, dys- Statins esthesia and radicular pain, but can also cause unilateral or bilateral proximal or distal muscle cramps in the affected Neuromuscular Amyotrophic lateral sclerosis myotome.31 Axonal neuropathies including hereditary disorders Charcot–Marie–Tooth disease neuropathies (eg, Charcot–Marie–Tooth disease [CMT]), Cramp-fasciculation syndrome acquired neuropathies, and idiopathic neuropathies can be associated with muscle cramps.32 Although traditionally Acquired neuropathy muscle cramps have been considered most common in neu- Radiculopathy ropathies with a high burden of motor or large fiber involve- Isaac’s syndrome (neuromyotonia) ment, muscle cramps have also been observed with similar frequency in people with predominantly sensory or small Metabolic myopathies (McArdle’s) fiber neuropathies.33,34 Acquired demyelinating neuropathies Other Parkinson’s disease (eg, acute and chronic inflammatory demyelinating polyneu- neurologic Dystonia ropathies [AIDP and CIDP]) are also associated with muscle conditions Multiple sclerosis cramps. A high proportion of individuals with nonneuro- muscular neurologic conditions (eg, stroke, multiple scle- Stroke rosis, and movement disorders) experience muscle cramps. Although the mechanism for this association is unclear, it most common is dehydration, in which electrolyte loss dis- could result from a combination of spinal or cortical dys- rupts neuromuscular junction function and membrane stabil- function, deconditioning, increased age, or medications. ity. Other physiologic stressors include unusually prolonged Myopathic cramps are common in metabolic myopathies or strenuous exercise, particularly in a deconditioned state in (eg, McArdle’s disease, phosphorylase kinase b deficiency, which muscle tendon shortening is common.22 phosphofructokinase deficiency, phosphoglycerate kinase Pathologic states that disrupt the homeostatic environ- deficiency, carnitine deficiency, or carnitine palmitoyl trans- ment or structural integrity of the neuromuscular axis or ferase 2 (CPT 2) deficiency).35 Myopathic cramps are almost spinal connections also lead to muscle cramps. People with always exertional, presenting with exercise intolerance, medical conditions in which fluid shifts occur (eg, cirrhosis or myoglobinuria, and exertional cramps. The most common renal failure) are especially vulnerable to muscle cramps.23,24 disorder of carbohydrate metabolism is McArdle’s disease For individuals being treated with hemodialysis, muscle (Type V glycogenosis),35 which presents with exercise- cramps as part of dialysis disequilibrium syndrome are com- induced myalgias and muscle cramps, pain that intensifies mon, because changes in dialysate, flow rates, and dialysis with exercise, and electrically silent contracture. The most parameters can cause fluid shifts.25 In people with cirrhosis, common disorders