Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Cramps, Muscle Stiffness, and Exercise Intolerance
A cramp is an involuntary painful contraction of a muscle or part of a muscle. Cramps can occur in normal children during or after vigorous exercise, and after excessive loss of fluid or electrolytes. The characteristic electromyography (EMG) finding for such cramps is the repetitive firing of normal motor unit potentials. Stretching the muscle relieves the cramp. Partially denervated muscle is particularly susceptible to cramping not only during exercise but also during sleep. Night cramps may awaken patients with neuronopathies, neuropathies, or root compression. Cramps during exercise occur also in patients with several different disorders of muscle energy metabolism. The EMG characteristic of these cramps is electrical silence.
Muscle stiffness and spasms are not cramps, but are actually prolonged contractions of several muscles that are able to impose postures. Such contractions may or may not be painful. When painful, they lack the explosive character of cramps. Prolonged contractions occur when muscles fail to relax (myotonia), or when motor unit activity is continuous ( Box 8.1 ). Prolonged, painless muscle contractions occur also in dystonia and in other movement disorders (see Chapter 14 ).
Box 8.1
Diseases With Abnormal Muscle Activity
-
Continuous motor unit activity
-
Neuromyotonia
-
Paroxysmal ataxia and myokymia (see Chapter 10 )
-
Schwartz-Jampel syndrome
-
Stiff man syndrome
-
Thyrotoxicosis a
a Denotes the most common conditions and the ones with disease modifying treatments
-
-
Cramps-fasciculation syndrome
-
Myotonia
-
Myotonia congenita
-
Myotonia fluctuans
-
-
Systemic disorders
Many normal children, especially preadolescent boys, complain of pain in their legs at night and sometimes during the day, especially after a period of increased activity. These pains are not true cramps. The muscle is not in spasm, the pain is diffuse, and aching in quality, and the discomfort lasts for an hour or longer. Stretching the muscle does not relieve the pain. This is not a symptom of neuromuscular disease and is called growing pains , for want of better understanding. One-third of the cases are associated with abdominal pain or headaches, which suggest a common ground with migraines. Mild analgesics or heat relieve symptoms.
Exercise intolerance is a relative term for an inability to maintain exercise at an expected level. The causes of exercise intolerance considered in this chapter are fatigue and muscle pain. Fatigue is a normal consequence of exercise and occurs in everyone at some level of activity. In general, weak children become fatigued more quickly than children who have normal strength. Many children with exercise intolerance and cramps, but no permanent weakness, have a defect in an enzyme needed to produce energy for muscular contraction ( Box 8.2 ). A known mechanism underlies several such inborn errors of metabolism. However, even when the full spectrum of biochemical tests is available, identification of a metabolic defect is not possible in some children with cramps during exercise.
Box 8.2
Diseases With Decreased Muscle Energy
-
Defects of carbohydrate utilization
-
Lactate dehydrogenase deficiency
-
Myophosphorylase deficiency
-
Phosphofructokinase deficiency
-
Phosphoglycerate kinase deficiency
-
Phosphoglycerate mutase deficiency
-
-
Defects of fatty acid oxidation
-
Carnitine palmitoyltransferase 2 deficiency
-
Very-long-chain acyl coenzyme A dehydrogenase deficiency
-
-
Mitochondrial (respiratory chain) myopathies
-
Myoadenylate deaminase deficiency
Myasthenia gravis is a disorder characterized by fatigability and exercise intolerance, but not covered in this chapter because the usual initial symptoms are either isolated cranial nerve disturbances (see Chapter 15 ), or limb weakness (see Chapters 6 and 7 ).
Conditions that produce some combination of cramps and exercise intolerance are divisible into three groups: diseases with abnormal muscle activity, diseases with decreased energy for muscle contraction, and myopathies. As a rule, the first and third groups are symptomatic at all times, whereas the second group is symptomatic only with exercise. The first group usually requires EMG for diagnosis. EMG is the initial diagnostic test in children with muscle stiffness that is not due to spasticity or rigidity. It usually leads to the correct diagnosis ( Box 8.3 ).
Box 8.3
Electromyography in Muscle Stiffness
Normal Between Cramps a
a Or may be myopathic
-
Brody myopathy
-
Defects of carbohydrate metabolism
-
Defects of lipid metabolism
-
Mitochondrial myopathies
-
Myoadenylate deaminase deficiency
-
Rippling muscle disease
-
Tubular aggregates
Silent Cramps
-
Brody disease
-
Defects of carbohydrate metabolism
-
Rippling muscle disease
-
Tubular aggregates
Continuous Motor Activity
-
Neuromyotonia
-
Myotonia
-
Myotonia congenita
-
Myotonic dystrophy
-
Schwartz-Jampel syndrome
-
Stiff man syndrome
Myopathy
-
Emery-Dreifuss muscular dystrophy
-
Rigid spine syndrome
-
X-linked myalgia
Abnormal muscle activity
Continuous Motor Unit Activity
The cause of continuous motor unit activity (CMUA) is the uncontrolled release of acetylcholine (ACh) packets at the neuromuscular junction. The EMG features of CMUA are repetitive muscle action potentials in response to a single nerve stimulus; high frequency bursts of motor unit potentials of normal morphology abruptly start and stop. Rhythmic firing of doublets, triplets, and multiplets occurs. During long bursts the potentials decline in amplitude. This activity is difficult to distinguish from normal voluntary activity. CMUA occurs in a heterogeneous group of disorders characterized clinically by some combination of muscle pain, fasciculations, myokymia, contractures, and cramps ( Box 8.4 ).
Box 8.4
Abnormal Muscle Activity
-
Fasciculations: spontaneous, random twitching of a group of muscle fibers
-
Fibrillation : spontaneous contraction of a single muscle fiber, not visible through the skin
-
Myotonia : disturbance in muscle relaxation following voluntary contraction or percussion
-
Myokymia: repetitive fasciculations causing a quivering or undulating twitch
-
Neuromyotonia: continuous muscle activity characterized by muscle rippling, muscle stiffness, and myotonia
The primary defect in CMUA disorder may reside within the spinal cord (stiff man syndrome), or the peripheral nerve (neuromyotonia). The original name for neuromyotonia is Isaac syndrome . These disorders may be sporadic or familial in occurrence. When familial, the usual mode of transmission is autosomal dominant inheritance.
Neuromyotonia
The primary abnormality in neuromyotonia is decreased outward potassium current of voltage-gated potassium channel function. Most childhood cases are sporadic in occurrence, but some show a pattern of autosomal dominant inheritance. An autoimmune process directed against the potassium channel may account for some sporadic cases. Some cases may be paraneoplastic, but this is rarely the case in children.
Clinical features
The clinical triad includes involuntary muscle twitching (fasciculations or myokymia), muscle cramps or stiffness, and myotonia. Excessive sweating is frequently associated with the muscle stiffness. The age at onset is any time from birth to adult life.
The initial features are muscle twitching and cramps brought on by exercise. Later these symptoms occur also at rest and even during sleep. The cramps may affect only distal muscles, causing painful posturing of the hands and feet. As a rule, leg weakness is greater than arm weakness. These disorders are not progressive and do not lead to permanent disability. Attacks of cramping are less frequent and severe with age.
In some children, cramps and fasciculations are not as prominent as stiffness, which causes abnormal limb posturing associated frequently with excessive sweating. Leg involvement is more common than arm involvement, and the symptoms suggest dystonia (see Chapter 14 ). Limb posturing may begin in one foot and remain asymmetric for months. Most cases are sporadic.
Muscle mass, muscle strength, and tendon reflexes are normal. Fasciculations are sporadic and seen only after prolonged observation.
Diagnosis
Some adult-onset cases are associated with malignancy, but this is virtually never the case in children. Muscle fibers fire repetitively at a rate of 100–300 Hz, either continuously or in recurring bursts, producing a pinging sound. The discharge continues during sleep and persists after procaine block of the nerve.
Management
Carbamazepine and phenytoin, at usual anticonvulsant doses, are both effective in reducing or abolishing symptoms. Intravenous immunoglobulin and plasmapheresis may be an option for patients refractory to symptomatic treatment with sodium channel blocking drugs.
Schwartz-Jampel Syndrome
The Schwartz-Jampel syndrome type 1 (SJS1) is a hereditary disorder transmitted by autosomal recessive inheritance. Neonatal Schwartz-Jampel syndrome type 2 (SJS2), also known as Stuve-Wiedemann syndrome, is a genetically distinct disorder with a more severe phenotype. Characteristic features of SJS1 include short stature, skeletal abnormalities, and persistent muscular contraction and hypertrophy.
Clinical features
SJS1 corresponds to the original description of Schwartz and Jampel. Bone deformities are not prominent at birth. CMUA of the face is the main feature producing a characteristic triad that includes narrowing of the palpebral fissures (blepharophimosis), pursing of the mouth, and puckering of the chin. Striking or even blowing on the eyelids induces blepharospasm. CMUA in the limbs produces stiffness of gait and exercise intolerance. Motor development during the first year is slow, but intelligence is normal.
Diagnosis
EMG shows CMUA. Initial reports suggested incorrectly that the abnormal activity seen on the EMG and expressed clinically was myotonia. Myotonia may be present, but CMUA is responsible for the facial and limb symptoms. The serum concentration of creatine kinase (CK) can be mildly elevated. The histological appearance of the muscle is usually normal but may show variation in fiber size and an increased number of central nuclei.
Management
Carbamazepine, phenytoin, and possibly other sodium channel blockers such as lamotrigine, oxcarbazepine, and lacosamide may diminish the muscle stiffness. Early treatment with relief of muscle stiffness reduces the severity of subsequent muscle deformity. Botulinum toxin injections may help.
Myotonic Disorders
Myotonia Congenita
Myotonia congenita is a genetic disorder characterized by muscle stiffness and hypertrophy. Weakness is not prominent, but stiffness may impair muscle function. The disease can be transmitted as either an autosomal dominant ( Thomsen disease ) or autosomal recessive ( Becker disease ) trait. The overlap of clinical features is considerable, and the clinical features alone cannot always determine the pattern of genetic transmission. Abnormalities in the chloride channel underlie all cases.
Clinical features
Age of onset is variable. In the dominant form, age at onset is usually in infancy or early childhood; in the recessive form, the age of onset is slightly older, but both may begin in adult life. The autosomal recessive form of myotonia congenita is often more severe than the dominant form. Individuals with the recessive form may have mild, progressive, distal weakness, and transitory attacks of weakness induced by movement after rest.
Clinical features of the dominant form are stereotyped. After rest, muscles are stiff and difficult to move. With activity, the stiffness disappears and movement may be normal (the “warm-up” effect). One of our patients played Little League baseball and could not sit while he was waiting to bat for fear that he would be unable to get up. The myotonia may cause generalized muscle hypertrophy, giving the infant a Herculean appearance. The tongue, face, and jaw muscles are sometimes involved. Cold exposure exacerbates stiffness, which is painless. Percussion myotonia is present. Strength and tendon reflexes are normal.
Diagnosis
EMG establishes the diagnosis. Repetitive discharges at rates of 20–80 cycles/sec are recorded when the needle is first inserted into the muscle and again on voluntary contraction. Two types of discharges occur: a biphasic spike potential of less than 5 msec, and a positive wave of less than 50 msec. The waxing and waning of the amplitude and frequency of potentials produces a characteristic sound (dive-bomber). Dystrophy is not present. The serum concentration of CK is normal and muscle biopsy specimens do not contain necrotic fibers.
The CLCN1 gene, encoding a chloride channel, is the only gene associated with myotonia congenita. Sequence analysis is commercially available.
Management
Myotonia does not always require treatment. Mexiletine is the most effective drug for treatment.
Myotonia Fluctuans
Myotonia fluctuans is a distinct disorder caused by mutations of the muscle sodium channel. Transmission is by autosomal dominant inheritance. Allelic disorders with overlapping clinical phenotypes include hyperkalemic periodic paralysis and paramyotonia congenita.
Clinical features
The onset of stiffness is usually in the second decade and worsens with exercise or potassium ingestion. Cramps in the toes, fingers, and eyelids, especially when tired or cold, begin in childhood. Physical examination reveals mild myotonia but normal strength. Symptoms vary from day to day. Myotonia affects the extraocular muscles as well as the trunk and limbs. The severity of myotonia fluctuates on a day-by-day basis. “Warming up” usually relieves symptoms, but exercise may also worsen symptoms. A bad day may follow a day of exercise or potassium ingestion, but neither precipitant causes immediate worsening of myotonia. Cooling does not trigger or worsen myotonia.
Diagnosis
EMG shows myotonia and a mild reduction in the amplitude of compound muscle action potential on cooling and administration of potassium. DNA analysis shows a mutation in the gene for the sodium channel subunit.
Management
Daily use of mexiletine or acetazolamide may relieve the stiffness.
Systemic Disorders
Hypoadrenalism
A small percentage of patients with Addison disease complain of cramps and pain in truncal muscles. At times, paroxysmal cramps occur in the lower torso and legs and cause the patient to double up in pain. Hormone replacement relieves the symptoms.
Hypocalcemia and Hypomagnesemia
Tetany caused by dietary deficiency of calcium is rare in modern times, except in newborns fed cows’ milk. Hypocalcemic tetany is more likely to result from hypoparathyroidism or hyperventilation-induced alkalosis.
The initial symptom of tetany is tingling around the mouth and in the hands and feet. With time the tingling increases in intensity and becomes generalized. Spasms in the muscles of the face, hands, and feet follow. The hands assume a typical posture in which the fingers extend, the wrists flex, and the thumb abducts. Fasciculations and laryngeal spasm may be present. Percussion of the facial nerve, either just anterior to the ear or over the cheek, produces contraction of the muscles innervated by that branch of the nerve (Chvostek sign).
A similar syndrome occurs with magnesium deficiency. In addition to the tetany, encephalopathy occurs. Restoring the proper concentration of serum electrolytes relieves the cramps associated with hypocalcemia and hypomagnesemia.
Thyroid Disease
Myalgia, cramps, and stiffness are the initial features in up to half of patients with hypothyroidism. Stiffness is worse in the morning, especially on cold days, and the probable cause is the slowing of muscular contraction and relaxation. This is different from myotonia, in which only relaxation is affected. Indeed, activity worsens the stiffness of hypothyroidism, which may be painful, whereas activity relieves myotonia and is painless. The slowing of muscular contraction and relaxation is sometimes demonstrated when tendon reflexes are tested. The response tends to “hang up.”
Percussion of a muscle produces a localized knot of contraction called myoedema. This localized contraction lasts for up to 1 minute before slowly relaxing.
Myokymia, CMUA of the face, tongue, and limbs, and muscle cramps develop occasionally in patients with thyrotoxicosis. Restoring the euthyroid state reverses all of the neuromuscular symptoms of hypothyroidism and hyperthyroidism.
Uremia
Uremia is a known cause of polyneuropathy (see Chapter 7 ). However, 50% of patients complain of nocturnal leg cramps and flexion cramps of the hands even before clinical evidence of polyneuropathy is present. Excessive use of diuretics may be the triggering factor. Muscle cramps occur also in approximately one-third of patients undergoing hemodialysis. Monitoring with EMG during dialysis documents a build-up of spontaneous discharges. After several hours, usually toward the end of dialysis treatment, repetitive high-voltage discharges occur associated with clinical cramps. Because standard dialysis fluid is slightly hypotonic, many nephrologists have attempted to treat the cramps by administering hypertonic solutions. Either sodium chloride or glucose solutions relieve cramps in most patients. The cramps apparently result from either extracellular volume contraction or hypo-osmolarity. Similar cramps occur in children with severe diarrhea or vomiting.
Decreased muscle energy
Three sources for replenishing adenosine triphosphate (ATP) during exercise are available: the phosphorylation of adenosine diphosphate (ADP) to ATP by phosphocreatine (PCr) within the exercising muscles; glycogen and lipids within the exercising muscles; and glucose and triglycerides brought to the exercising muscles by the blood. A fourth and less efficient source derives from ADP via an alternate pathway using adenylate kinase and deaminase. PCr stores are the main source that replenishes ATP during intense activity of short duration. During the first 30 seconds of intense endurance exercise, PCr decreases 35% and muscle glycogen stores reduce by 25%. Exercise lasting longer than 30 seconds is associated with the mobilization of substantial amounts of carbohydrate and lipid.
The breakdown of muscle glycogen (glycogenolysis) and the anaerobic metabolism of glucose to pyruvate (glycolysis) provide the energy to sustain a prolonged contraction ( Fig. 8.1 ). Anaerobic glycolysis is an inefficient mechanism for producing energy and is not satisfactory for endurance exercise. Endurance requires the further aerobic metabolism in mitochondria of pyruvate generated in muscle by glycolysis. Oxidative metabolism provides high levels of energy for every molecule of glucose metabolized (see Fig. 8.1 ).
The central compound of oxidative metabolism in mitochondria is acetyl-coenzyme A (acetyl-CoA). Acetyl-CoA derives from pyruvate, from fatty acids, and from amino acids. When exercise is prolonged, fatty acids become an important substrate to maintain muscular contraction. Oxidation of acetyl-CoA is through the Krebs cycle. Hydrogen ion release reduces nicotinamide adenine dinucleotide (NAD). These reduced compounds then enter a sequence of oxidation-reduction steps in the respiratory chain that liberate energy. Energy is stored as ATP. This process of releasing and storing energy is oxidation-phosphorylation coupling . Therefore disorders that prevent the delivery of glucose or fatty acids, prevent the oxidation process in the mitochondria, or the creation of ATP, impair the production of energy for muscular contraction.
Clinical Features of Decreased Muscle Energy
Exercise intolerance is the invariable result of any disturbance in the biochemical pathways that support muscle contraction. The common symptom is fatigue. Other symptoms are myalgia and cramps. Muscle pain is the expected outcome from unaccustomed exercise. Muscle pain develops during exercise when the mechanisms to supply energy for contraction are impaired.
The ischemic exercise test had been the first step in the diagnosis of muscle energy disorders, but it has become less important with the ease of genetic testing, tissue diagnosis by muscle biopsy, and the commercial availability of methods for measuring enzyme activity in fibroblasts.
Defects of Carbohydrate Utilization
Myophosphorylase Deficiency (McArdle Disease, Glycogen Storage Disease Type V)
Myophosphorylase deficiency exists in two forms: phosphorylase-a is the active form and phosphorylase-b is the inactive form. Phosphorylase-b kinase is the enzyme that converts the inactive form to the active form and is itself activated by a protein kinase. Deficiencies of either enzyme result in exercise intolerance.
Genetic transmission of myophosphorylase deficiency is the result of a mutation in the PYGM gene. The defective myophosphorylase enzyme fails to break down glycogen into glucose-1-phosphate, which is the first step in transforming glycogen into glucose. The muscle then has insufficient energy, at least until additional sources of glucose can be mobilized (the “second wind” effect). Myophosphorylase is found only in muscle. Liver phosphorylase concentrations are normal, and hypoglycemia does not occur.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here