Muscle Contracture, Pseudomyotonia, Tetanus, and Related States
Many of these states were discussed in Chap. 48 on diseases of muscle. They are reintroduced here in relation to specific diseases with which they are associated.
Physiologic Contracture Caused by Phosphorylase Deficiency (McArdle Disease) and Phosphofructokinase Deficiency (Tarui Disease)
Contractures are examples of an entirely different type of painful shortening and hardness of muscle. In both these diseases, an otherwise healthy child, adolescent, or adult begins to complain of weakness and stiffness and sometimes pain on using the limbs. Muscle contraction and relaxation are normal when the patient is in repose, but strenuous activity, especially under conditions of ischemia, causes the muscles to shorten gradually, because of a failure of relaxation. The contracted muscles in these disorders—unlike muscles in cramp, continuous muscular activity syndromes, or myotonia and other involuntary spasms—no longer use energy for which reason they are almost silent electrically in the EMG. This condition is spoken of as physiologic contracture. McArdle and Tarui diseases are discussed more fully in a later section.
This phenomenon is observed in hypothyroidism, where the muscle fibers contract and relax slowly, a response readily demonstrated in the tendon reflexes, particularly the Achilles reflex. The muscles are large and subject to myoedema. When contracted, they may show waves of slow contraction. The basis of this disorder appears to be slowness in the reaccumulation of calcium ions in the endoplasmic reticulum and in the disengagement of actin and myosin filaments. The EMG may show afterpotentials following voluntary contraction, but they do not resemble the typical waning discharges ("myotonic runs") of true myotonia.
A closely related syndrome, wherein painless contracture is induced by exercise, has been described by Lambert and Goldstein, and by Brody. Muscle contraction is normal but the relaxation phase becomes increasingly slow during exercise. Lambert and Goldstein referred to it as an unusual type of myotonia, and Brody, as a decrease of "relaxing factor"; the slow relaxation has also been attributed to a decreased uptake of calcium by the sarcoplasmic reticulum. In some cases, the disease is transmitted as a recessive trait with a mutation that impairs the function of a sarcoplasmic reticular calcium adenosine triphosphatase (ATPase). In other instances, the disease is transmitted as a dominant trait that is not genetically linked to calcium ATPase. This latter process may be more closely aligned with the muscular dystrophies and is mentioned in Chap. 48 under that heading.
Tetanus (See "Tetanus" in Chap. 43)
This toxic disorder is characterized by persistent spasms of skeletal muscles, owing to the effect of the tetanus toxin on spinal neurons (Renshaw and other cells), the natural function of which is to inhibit the motor neurons. As the condition develops, activities that normally excite the neurons (i.e., voluntary contraction and startle from visual and auditory stimulation) all evoke involuntary spasms. Sleep tends to quiet them, and they are suppressed by spinal anesthesia and curare. The EMG shows the expected interference pattern of muscle action potentials. Once the muscle is involved in persistent contraction, it is said that the shortened state is not abolished by procaine block or severance of nerve (in animals), but this type of myostatic contracture has not been demonstrated in humans.
The effect of tetanus toxin on the spinal inhibitory neurons is analogous to that of strychnine. There is also an action of the toxin at the neuromuscular junction, which has been more difficult to evaluate in the face of its powerful central action. Having injected this toxin locally in animals, Price and associates demonstrated its localization at motor endplates. It binds with ganglioside in the axon membrane and is transported by retrograde flow to the spinal cord, where it induces local tetanus effects. Neurons that innervate slow-twitch type 1 muscle fibers are more sensitive than those supplying fast-twitch type 2 fibers. Presynaptic vesicles increase in number, acetylcholine (ACh) is blocked, and terminal axon injury may paralyze muscle fibers. Fibrillation potentials and axonal sprouting follow. The similarities to stiff man syndrome are mentioned further on.
The toxin produced by this spider within a few minutes of the bite leads to a striking syndrome of cramps and spasms and then a painful rigidity of abdominal, trunk, and leg muscles. The spasms are followed by weakness. There is also vasoconstriction, hypertension, and autonomic hyperactivity. If death does not occur in the first 24 to 48 h, recovery is complete.
The spider venom has a presynaptic localization and rapidly releases quanta of ACh. The vesicles became depleted. There is some evidence that the venom prevents endocytosis of the vesicles by inserting itself into the presynaptic membranes, causing a disturbance of ionic conductance channels (Swift).
Treatment consists of calcium gluconate infusions and diazepine. Intravenous magnesium sulfate also helps to reduce the release of ACh and control the convulsions that sometimes occur. There is antiserum that is available in regions where such envenomation is frequent; it shortens the illness considerably.
Metal or other type of poisoning may simulate an inherently relapsing polyneuropathy.
States of Persistent Muscle Activity
This is an interrelated group of clinical states, all characterized by some degree of regional continuous muscular activity that in some cases cannot be fully differentiated from one another. From a clinical perspective we have found it is useful to categorize them in groups that are caused by (1) hyperexcitability of the peripheral motor nerves (fasciculations and myokymia), (2) centrally mediated hyperexcitability of motor output (Isaacs syndrome, stiff man syndrome), and (3) nonmyotonic hyperexcitability of muscle (rippling muscle disease, Schwartz-Jampel syndrome).
Hyperexcitability of Peripheral Nerve
This comprises a set of disorders in which peripheral motor nerve activity is augmented such that there are excessive, sometimes sustained contractions of the motor unit. Its mildest manifestation is benign fasciculation. In more severe form the manifestations include neuromyotonia, Isaacs disease, and a disease of potassium-gated ion channels (Morvan disease, or Morvan fibrillary chorea discussed below) that may also involve the brain. These processes are not generally familial and several lines of investigation suggest an acquired autoimmune nature (Newsom-Davis). For example, all but benign fasciculations are associated more often than might be expected with other autoimmune diseases such as myasthenia gravis and some respond to autoimmune therapies such as plasmapheresis, the patient's serum possesses antibodies to either voltage-gated potassium channels as mentioned or, less frequently, to nicotinic acetylcholine (ACh) receptors (Vernino and Lennon).
A few random fasciculations in the muscles of the calf, small muscles of the hand or of the face, or elsewhere are seen in most normal individuals. They are of little significance but can be a source of worry to physicians and patients who have read that fasciculations are an early sign of amyotrophic lateral sclerosis. A simple clinical rule is that fasciculations in relaxed muscle are not indicative of motor system disease unless there is associated weakness, atrophy, or reflex change.
Healthy individuals experience intermittent twitching of a muscle (or even part of a muscle), such as one of the muscles of the thenar eminence, eyelids, calves, or orbicularis oculi. They may continue for days. Electromyographically, benign fasciculations tend to be more constant in location and more frequent and rhythmic than the ominous fasciculations of amyotrophic lateral sclerosis but such distinctions are not entirely reliable. Quantitative study of the motor unit size may be helpful in these circumstances by demonstrating normally modeled units in the benign form and abnormally large units because of reinnervation in the case of motor neuron disease.
Occasionally, benign fasciculations are widespread and may last for months or even years. In several of our patients they have recurred in bouts separated by months and lasting several weeks. No reflex changes, sensory loss, nerve conduction, EMG abnormality (other than fasciculations), or increase in serum muscle enzymes is found. Low energy and fatigability in some of these patients may suggest an endogenous depressive illness yet the fasciculations are not explained by this mechanism. Patients commonly report a sense that the muscles affected by the twitching are weak but this cannot be confirmed by testing and several of our patients, curiously most of whom have been physicians, complained of equally troubling migratory zones of paresthesias. Pain of aching or burning type may increase after activity and cease during rest. Fatigue and a sense of weakness are frequent complaints. We suspect that this fasciculatory state reflects a disease of the terminal motor nerves, for a few of our patients have shown slowing of distal latencies, and Cöers and associates have found degeneration and regeneration of motor nerve terminals in similar cases. However, most such cases are of benign nature and settle down in a matter of weeks or months. In the cases reported by Hudson and colleagues, the condition, even after years, did not progress to spinal muscular atrophy, polyneuropathy, or amyotrophic lateral sclerosis. This conforms to our experience and to that reported from the Mayo Clinic where 121 patients with benign fasciculations, followed in some cases for more than 30 years, showed no progression of symptoms and did not acquire motor neuron disease or neuropathy (Blexrud et al). It should be acknowledged, however, that there are infrequent patients with seemingly benign fasciculations in whom the EMG shows some abnormal features (e.g., rare fibrillations) in numerous muscles and who later develop the other features of motor neuron disease. Carbamazepine, and to a lesser extent phenytoin, has been helpful in reducing the fasciculations and sensations of weakness in a proportion of cases and numerous other medications have been reportedly helpful.
This is probably a variant of the above-described benign entity in which fasciculations are conjoined with cramps, stiffness, and systemic features such as exercise intolerance, fatigability, and muscle aches. Although affected individuals may be to some degree disabled by these symptoms, the prognosis is good. The salient finding on physiologic studies is that stimulation of peripheral nerves results in sustained muscle firing due to prolonged trains of action potentials in the distal motor nerve. This phenomenon may be brought out in special electrophysiologic testing, as described by Tahmoush and colleagues. In effect, this is a mild form of neuromyotonia, which is described further on. In a small number of patients with cramp-fasciculation syndrome it is possible to demonstrate the presence of autoantibodies directed against voltage-gated axonal potassium channels. Carbamazepine or gabapentin may be beneficial.
There are, in addition to these benign states, several syndromes of abnormal muscle activity. The main ones are myokymia, a state of successive contractions of motor units imparting an almost continuous undulation or rippling of the overlying body surface, and several syndromes of continuous muscle fiber activity described below.
This state of abnormal rippling muscle activity may be generalized or limited to one part of the body such as the muscles of the shoulders or of the lower extremities. It is observed most often with demyelination of peripheral nerve following injury, and thus it is neuropathic in nature. The common underlying conditions are multiple sclerosis or Guillain-Barré syndrome affecting the facial nerve and radiation damage to the brachial or lumbar plexus. In the EMG, myokymic discharges consist of repetitive firing of one motor unit, firing at 5 to 60 Hz and recurring regularly at 0.2- to 10-s intervals. The driving impulses arise in the most peripheral parts of the axon of chronically damaged nerves. In some patients cramping is associated, and those muscles about to cramp may twitch or show premonitory spontaneous rippling contractions; the cramping may be associated with sweating. Thus, myokymia, fasciculation, and cramping seem to be related but not clinically identical conditions.
Continuous Muscle Fiber Activity (Isaacs Syndrome)
The relation of myokymia to the state called continuous muscle fiber activity is ambiguous. Sporadically in the neurologic literature there have been descriptions of patients whose muscles at some point begin to "work" continuously (see Isaacs). Terms such as neuromyotonia and widespread myokymia with delayed muscle relaxation are additional names that have been applied to what is essentially the same condition. At the moment, there is little reason to distinguish one from another except in gradations of severity. In each case the excessive and spontaneous activity can be attributed to hyperexcitability of terminal parts of motor nerve fiber, possibly as a result of a partial loss of motor innervation and compensatory collateral sprouting of surviving axons (Cöers et al; Valli et al). Twitching, spasms, and rippling of muscles (myokymia) are evident, the latter being the main clinical sign. In advanced cases there is generalized muscle stiffness and a sense of weakness. Complaints of muscle aching are usual, but severe myalgia is uncommon. The tendon reflexes may be reduced or abolished. Any muscle group may be affected. The stiffness and slowness of movement make walking laborious ("armadillo" syndrome); in extreme cases, all voluntary movement is blocked. The muscle activity persists throughout sleep. The continuous visible and painful cramps of the above-described Satoyoshi disease may be difficult to distinguish from myokymia clinically, but they represent a different phenomenon.
General and spinal anesthesia do not always suppress the muscular activity but curare does; nerve block usually has no effect or may reduce the activity, as in the case described by Lütschg and colleagues. The EMG findings are much the same as those described earlier.
Special types of myokymia arise in childhood or adult life, sometimes in association either with a polyneuropathy or rarely with an inherited type of episodic ataxia that is variably responsive to acetazolamide or remits spontaneously (see Chap. 5). An inherited form of continuous muscle fiber activity has been traced to a mutation of the peripheral nerve K channel (Gutmann and Gutmann). In addition to the association with polyneuropathy, a state of continuous muscular activity has also been described in association with lung cancer and thymoma in which cases an immune mechanism has been inferred (see reviews by Thompson and by Newsom-Davis and Mills and the discussion of paraneoplastic syndromes in Chap. 31).
Phenytoin or carbamazepine often abolish the continuous muscular activity and cause a return of reflexes. Acetazolamide has been helpful in other cases (Celebisoy et al). Many of the idiopathic cases will improve spontaneously after several years, however, plasma exchange may be tried if the symptoms are intractable.
Centrally Mediated Motor Hyperexcitability and Stiff Man (Stiff Person) Syndrome
This is a condition of persistent and intense spasms, particularly of the proximal lower limbs and lumbar paraspinal muscles. It was originally described by Moersch and Woltman in 1956 as stiff man syndrome. Since then, many examples have been reported all over the world and the term stiff person syndrome has been used to indicate its occurrence in both women and men. For lack of a better place in the book to discuss it, it is included here with other processes that cause muscular spasms and cramps.
The onset is insidious, usually in middle life. No genetic predisposition is known. At first the stiffness and spasms are intermittent, then gradually they become more or less continuously active in the proximal leg and axial trunk muscles and increasingly painful. The spasms impart a robotic appearance to walking and an exaggerated lumbar lordosis. Attempts to move an affected part passively yield an almost rock-like immobility, perceptibly different from spasticity, paratonia, or extrapyramidal rigidity. Muscles of respiration and swallowing and those of the face may be involved in advanced cases, but trismus, a common feature of tetanus, does not occur. We have observed brief periods of cyanosis and respiratory arrest during episodes of intense spasm, and one of our patients died during such an episode. The eye muscles are rarely affected.
As the illness progresses, any noise or other sensory stimulus or attempted passive or voluntary movement may precipitate painful spasms of all the involved musculature. The tendon reflexes are normal if they can be tested. The affected muscles, particularly the lumbar paraspinals and glutei, are extremely taut when palpated and eventually they become hypertrophied. It is this axial spasm that is most characteristic of the disease and gives rise to a characteristic lumbar lordosis. We have experience with one unusual instance of this disease that caused the obverse, namely, flexion spasm of the abdominal musculature with a bent-over camptocormia.
A similar stiffness of one limb ("stiff limb" syndrome) has been differentiated from the generalized variety by Barker and colleagues and others (see Saiz et al; Brown et al), but most of the localized cases have antibodies to glutamic acid decarboxylase, as described below. The limited form of the condition begins in one leg and spreads to its opposite, but remains isolated to the lower extremities, similar to localized tetanus.
A central origin of the muscle spasms is indicated by their disappearance during sleep, during general anesthesia, and with proximal nerve block. The electrophysiologic features differ from those of myokymia and continuous muscle fiber activity syndrome in that the EMG in stiff man syndrome consists entirely of activated but normally configured motor units, with no evidence of distal motor nerve disturbance.
Of interest is the finding that about two-thirds of the cases of stiff man syndrome display circulating autoantibodies that are reactive with glutamic acid decarboxylase (GAD), the synthesizing enzyme for gamma-aminobutyric acid (GABA; Solimena et al). On several occasions the test for this antibody has become positive after samples taken over 2 years were negative. An antibody to the glycine receptor (GlyR) has been identified in a subset of patients with stiff man syndrome with anti-GAD antibodies (McKeon and colleagues). The GlyR antibody, mainly expressed in the brain stem and spinal cord, has also been associated with progressive encephalomyelitis with rigidity and myoclonus, but appears to be highly specific for stiff man syndrome in patients who have anti-GAD antibodies.
Reduced spinal GABA presumably creates an imbalance between the spinal inhibitory (gabanergic) input and the excitatory input to alpha motor neurons. This interpretation is supported by the fact that the spasms worsen under the influence of drugs that enhance aminergic activity, thereby facilitating long-latency spinal reflexes, or that inhibit catecholaminergic or gabanergic transmitters. An autoimmune mechanism is further suggested by the high incidence of insulin-dependent diabetes (present eventually in almost all the cases under our care) with detectable antibodies to islet cells; a few patients have thyroiditis, pernicious anemia, or immune-mediated vitiligo.
There are rare paraneoplastic varieties of stiff man syndrome, mostly accompanying breast cancer and associated in some cases with circulating antibodies directed against amphiphysin or gephyrin, proteins associated with synaptic GABA receptors. Some of the cases related to the antiamphiphysin antibodies also display more conventional types of paraneoplastic neurologic disorder such as encephalopathy or opsoclonus (see Chap. 31).
The stiff man syndrome must be distinguished from tetanus (see "Tetanus" in Chap. 43 and further on), Isaacs syndrome, and the rare syndrome of subacute myoclonic spinal neuronitis, described in Chaps. 33 and 44. In both the stiff man syndrome and myoclonic spinal neuronitis, the intense spasms and stiffness of muscles are a result of disinhibition of interneurons in the gray matter of the spinal cord.
The syndromes of continuous muscle activity are usually distinguishable clinically and electromyographically from extrapyramidal and corticospinal abnormalities such as dystonia, dyskinesia, and rigidity, although early phases of axial dystonic disorders and stiff man syndrome have similarities.
In the stiff man syndrome, diazepam in doses of up to 50 to 250 mg/d, increased gradually, is most effective; clonazepam, vigabatrin, or baclofen is sometimes effective as well. In keeping with the presumed autoimmune mechanism of most cases, plasma exchange, high-dose corticosteroids, or intravenous gamma globulin are helpful in some patients, albeit for only several weeks or months before another infusion is required. Several of our patients have required intravenous gamma globulin for several years at intervals of 6 to 12 weeks but nevertheless became disabled if the dose of diazepam was reduced below 100 mg/d. A small randomized trial of intravenous immune globulin conducted by Dalakas and colleagues has demonstrated the efficacy of this treatment; in their study, the benefits varied in duration from 6 weeks to 1 year. The typical dose is 0.4 mg/kg daily for 4 or 5 consecutive days. Immunosuppression with rituximab is being used increasingly, on the basis of numerous case reports and small series but a small randomized trial has been negative.
Congenital Neonatal Rigidity
A "stiff infant" syndrome, observed by Dudley and colleagues in four families of mixed heritage, probably should be included in this general category. The condition came to medical attention because of respiratory distress as the result of a generalized muscular rigidity beginning at about 2 months of age. The rigidity spread slowly from cervical muscles to those of the trunk and limbs, and, as it persisted, slight hypertrophy developed. The use of respiratory aid and a feeding gastrostomy enabled the infants to survive. The rigidity slowly diminished in the second year of life. The clinical course was unlike that of tetanus. In fatal cases there were zones of fiber loss, with fibrosis in skeletal and cardiac muscles, and a greater than normal variation in fiber size. Altered Z lines were observed with electron microscope in some fibers.
Primary Hyperexcitability of Muscle
At least three varieties of primary muscle disorder are known, not myotonic in nature, that produce continuous muscle activity. The first described below is because of a defect in the muscle membrane; the second has been found to be a disease of the extracellular matrix of muscle. The third disorder, Brody disease, is only mentioned here for completeness as it is quite rare, even in comparison to the other unusual disorders in this section.
"Rippling Muscle Disease"
Ricker and Burns and their associates described a rare familial disorder (autosomal dominant) in which muscles display an unusual sensitivity to stretch, manifest by rippling waves of muscle contraction. Percussion of muscles yields a pronounced and painful local mounding. The activation is a type of myokymia. Similar familial and sporadic cases have been traced to a defect in caveolin, a protein otherwise implicated in one of the muscular dystrophies (Vorgerd). An autoimmune process was implicated in some other cases (Ashok Muley and Day). The EMG discloses neither myotonic discharges nor the action potentials of cramp, indicating that the basic abnormality is in the muscle membrane.
A syndrome characterized by continuous muscle fiber activity with stiffness and blepharospasm, accompanied by obvious dysmorphic features (dwarfism, pinched face with low-set ears, blepharophimosis, high-arched palate, receding chin, diffuse metaphyseal and epiphyseal bone dysplasia with flattened vertebrae), was described by Schwartz and Jampel in 1962. It has been reported under other names including myotonic chondrodystrophy. There may be percussion myotonia. Intelligence is usually preserved. The stiff muscles disturb gait most obviously.
The muscle stiffness is the result of frequent, almost continuous muscle activity with a combination of normal motor units and high-frequency discharges and afterdischarges similar to those seen in Isaacs syndrome. The discharges can be demonstrated to arise from muscle fibers themselves as the activity is not obliterated by curare. Agents such as procainamide, which block sodium channels in muscle, inhibit the discharges, just as they do in some other myotonic disorders. However, Spaans and associates, who have reviewed the clinical, EMG, and histologic features of 30 cases of this syndrome, report a diminished chloride conductance by the sarcolemma, which can be suppressed by procainamide or even better by mexiletine.
The disorder is usually inherited as an autosomal recessive trait that is caused by mutations in perlecan, a heparin-sulfate proteoglycan that is bound to the basement membranes of skeletal muscle and cartilage. Loss of function of the protein perturbs the organization of the basement membrane leading to an altered clustering of ACh esterase and abnormal expression of ion channels. Electron microscopic studies of muscle have yielded inconsistent findings: dilated T system, Z-band streaming, and dilatation of mitochondria; in addition, in the patient reported by Fariello and colleagues, muscle biopsy disclosed signs of denervation (group atrophy). In the latter case, treatment with procainamide, phenytoin, diazepam, and barbiturates was ineffective.
The condition, described by Aberfeld and coworkers, of two siblings in whom myotonia was combined with dwarfism, diffuse bone disease, and unusual ocular and facial abnormalities, and thought by them to represent a unique disorder, is probably a variant of the Schwartz-Jampel syndrome.