Neurology_Adams

Neurology_Adams. The usual pattern of inheritance is autosomal dominant with reduced penetrance in women (male-to-female ratio of 3 or 4:1). Fontaine and coworkers (1990, 1994) localized the mutation to a region containing the gene that encodes the alpha subunit of the calcium channel of skeletal muscle and missense mutations in the responsible gene (CACNA1S) have been identified. The subunit, which is part of the dihydropyridine receptor complex, is located in the transverse tubular system. This region is believed to act both as a voltage sensor that controls calcium release from the sarcoplasmic reticulum, thus mediating muscle excitation–contraction coupling, and as a calcium- conducting pore. How precisely the reduced calcium channel function relates to hypokalemia-induced attacks of muscle weakness is not fully known but most of the mutations affect the protein in a way that would allow a cation leak (Matthews et al). Approximately 10 percent of cases, however, are due to a mutation in the


Neurology_Adams

Neurology_Adams. is not fully known but most of the mutations affect the protein in a way that would allow a cation leak (Matthews et al). Approximately 10 percent of cases, however, are due to a mutation in the earlier discussed sodium channel, SCN4A.


Neurology_Adams

Neurology_Adams. Clinical manifestations In our experience, this disease has become clinically apparent after adolescence and has been much more severe in males. We note, however, that in Talbott’s review of 152 cases, there were 40 in which symptoms began before the tenth year of life and 92 before the sixteenth year. The typical attack comes on during the second half of the night or the early morning hours, after a day of unusually strenuous exercise; a meal rich in carbohydrates favors its development. Excessive hunger or thirst, dry mouth, palpitation, sweating, diarrhea, nervousness, and a sense of weariness or fatigue are mentioned as prodromata but do not necessarily precede an attack. Usually, the patient awakens to discover a mild or severe weakness of the limbs. However, diurnal attacks also occur, especially after a nap that follows a large meal. The attack evolves over minutes to several hours; at its peak, it may render the patient so helpless as to be unable to call for assistance. Once


Neurology_Adams

Neurology_Adams. especially after a nap that follows a large meal. The attack evolves over minutes to several hours; at its peak, it may render the patient so helpless as to be unable to call for assistance. Once established, the weakness lasts a few hours if mild or several days if severe.


Neurology_Adams

Neurology_Adams. The distribution of the paralysis varies. Limbs are affected earlier and often more severely than trunk muscles, and proximal muscles are possibly more susceptible than distal ones. The legs are often weakened before the arms, but exceptionally the order is reversed. The muscles most likely to escape are those of the eyes, face, tongue, pharynx, larynx, diaphragm, and sphincters, but on occasion even these may be involved. When the attack is at its peak, tendon reflexes are reduced or abolished and cutaneous reflexes may also disappear. As the attack subsides, strength generally returns first to the muscles that were last to be affected. Headache, exhaustion, diuresis, and occasionally diarrhea may follow the attack. Myotonia is not seen; indeed, clinical or EMG evidence of myotonia essentially excludes the diagnosis of hypokalemic periodic paralysis.


Neurology_Adams

Neurology_Adams. Attacks of paralysis tend to occur every few weeks and tend to lessen in frequency with advancing age. Rarely, death may occur from respiratory paralysis or derangements of the conducting system of the heart. Mainly, such fatal cases were reported in the era before modern intensive care. Atypical forms include weakness of one limb or certain groups of muscles, bibrachial palsy (inability to lift one’s arms or to comb one’s hair), and transient weakness during accustomed activities such as walking. Some of our patients had a talipes deformity from early life. During middle adult life, a number of patients have developed a severe, slowly progressive proximal myopathy, with vacuolated and degenerated fibers and myopathic action potentials, in some instances long after attacks of periodic paralysis had ceased.


Neurology_Adams

Neurology_Adams. Laboratory findings The attacks are accompanied by reduction in serum K levels, as low as 1.8 mEq/L, but usually at levels that would not be associated with muscle weakness in normal subjects. The fall in serum K is associated with little or no increase in urinary K excretion. Presumably, large quantities of K enter the muscle fibers during an attack but this explanation may not be complete. Some episodes occur with near-normal levels of K, and weakness persists for a time after the serum level has been restored. The serum K levels return to normal during recovery. Although the shifts in K are of undoubted importance in the pathogenesis of muscle weakness, the marked sensitivity to small reductions of serum K suggests that other factors are operative and that the fall in K may be a secondary phenomenon.


Neurology_Adams

Neurology_Adams. As in hyperkalemic paralysis, the muscular weakness in this disease is associated with a decrease in the amplitude, and eventual loss, of muscle action potentials and there is failure of excitation by supramaximal stimulation of peripheral nerve or by strong voluntary effort. A decline in strength precedes the loss of motor unit potentials and the failure of propagation of action potentials over the surface of the fiber. The polarization potentials of muscle fibers measured by intracellular recordings are initially normal despite the failure of impulse propagation by the sarcolemma. One would expect the muscle fiber to be hyperpolarized as K moves into it, but it actually becomes depolarized. Rüdel and associates attribute the latter change to an increased Na conductance. The ECG changes also begin at levels of K that are slightly below normal (about 3 mEq/L); they consist of prolonged PR, QRS, and QT intervals and flattening of T waves.


Neurology_Adams

Neurology_Adams. Diagnosis at a time when the patient is normal may be facilitated by provocative tests. With the patient carefully monitored, including the use of ECG, the oral administration of 50 to 100 g of glucose or loading with 2 g of NaCl every hour for 7 doses, followed by vigorous exercise, brings on an attack, which then can be terminated by 2 to 4 g of oral KCl (the opposite of what pertains in hyperkalemic periodic paralysis).


Neurology_Adams

Neurology_Adams. Pathologic changes The muscle fibers are uniformly somewhat large but the most striking change, particularly in the late degenerative phases of the disease, is vacuolization of the sarcoplasm. The myofibrils are separated by round or oval vacuoles containing clear fluid, presumably water, and a few periodic acid-Schiff (PAS)-positive granules. There are pathologic changes in myofibrils and mitochondria as well, and focal increases in muscle glycogen. Isolated muscle fibers may undergo segmental degeneration. Electron microscopic studies have shown that the vacuoles arise as a result of proliferation and degeneration of membranous organelles within the sarcoplasmic reticulum and transverse tubules (A.G. Engel).


Neurology_Adams

Neurology_Adams. Treatment A low-sodium diet (less than 160 mEq/d), avoidance of large meals and of exposure to cold, and acetazolamide 250 mg tid may be helpful in preventing attacks. That acetazolamide reduces attacks is somewhat surprising as it is kaluretic, but it may work through the production of acidosis; a few patients have worsened with the drug. Patients who are unresponsive to acetazolamide may be treated with the more potent carbonic anhydrase inhibitor, dichlorphenamide, 50 to 150 mg/d, or with the potassium-sparing diuretics spironolactone or triamterene (both in doses of 25 to 100 mg/d), but caution must then be exercised with the simultaneous administration of oral potassium supplements. The daily administration of 5 to 10 g of KCl orally in an unsweetened aqueous solution prevents attacks in many patients and apparently, this program can be maintained indefinitely. If this approach fails, a low-carbohydrate, low-salt, high-K diet combined with a slow-release K preparation may be


Neurology_Adams

Neurology_Adams. in many patients and apparently, this program can be maintained indefinitely. If this approach fails, a low-carbohydrate, low-salt, high-K diet combined with a slow-release K preparation may be effective.


Neurology_Adams

Neurology_Adams. For an acute attack, 0.25 mEq KCl/kg should be given orally or, if this is not tolerated, some other K salt may be tried. This dose may be insufficient and if there is no improvement in 1 or 2 h, KCl may have to be given intravenously: 0.05 to 0.1 mEq/kg initially in a bolus at a safe rate, followed by 20 to 40 mEq KCl in 5 percent mannitol, avoiding glucose or NaCl as the carrier solution. For the late-progressive polymyopathy that follows many severe attacks of periodic paralysis, Dalakas and Engel report successful restoration of strength by the long-term administration of dichlorphenamide. Regular exercise (not too strenuous) to keep the patient fit is desirable.


Neurology_Adams

Neurology_Adams. In addition to the hereditary kalemic paralyses described earlier, transitory episodes of weakness are associated with a number of acquired derangements of potassium metabolism (mainly hypokalemia); these include thyrotoxicosis, aldosteronism, 17α-hydroxylase deficiency (Yazaki et al), barium poisoning (Lewi and Bar-Khayim), glycyrrhizic acid ingestion (a substance in licorice that has mineralocorticoid activity), and abuse of thyroid hormone (Layzer). Other forms of secondary hypokalemic weakness have been observed in patients suffering from chronic renal and adrenal insufficiency or disorders caused by a loss of potassium, as occurs with excessive use of diuretics or laxatives (the most common cause in practice). (Renal failure with hyperkalemia can also induce considerable weakness.)


Neurology_Adams

Neurology_Adams. This is a special form of secondary hypokalemic periodic paralysis and occurs mainly in young adult males (despite the higher incidence of thyrotoxicosis in women), with a strong predilection for those of Japanese and Chinese origin (Pothiwala). In Japan, Okinaka and associates found that 8.9 percent of men with thyrotoxicosis had periodic paralysis, but this was the case in only 0.4 percent of women; in China, the corresponding figures were 13.0 and 0.17 percent (McFadzean and Yeung). The paralytic disorder is unrelated to the severity of the hyperthyroidism. In patients with the familial forms of periodic paralysis, the induction of hyperthyroidism is said not to increase the frequency or intensity of attacks. Therefore, it seems likely that thyrotoxicosis has unmasked another type of hereditary periodic paralysis, although a familial occurrence in the thyrotoxic cases is exceptional. Clinically, the attacks of paralysis are much the same as those of familial hypokalemic type except


Neurology_Adams

Neurology_Adams. periodic paralysis, although a familial occurrence in the thyrotoxic cases is exceptional. Clinically, the attacks of paralysis are much the same as those of familial hypokalemic type except for a greater liability to cardiac irregularity. As in the familial form, the paralyzed muscles are electrically inexcitable. Potassium chloride restores power in paralytic attacks, and treatment of the hyperthyroidism prevents their recurrence.


Neurology_Adams

Neurology_Adams. Hypokalemic weakness in primary aldosteronism (Conn Syndrome) Hypokalemic weakness because of hypersecretion of the major adrenal mineralocorticoid aldosterone was first described by Conn and associates in 1955. In primary aldosteronism, the cause of the hypersecretion is in the adrenal gland itself, usually an adrenal cortical adenoma, less often adrenal cortical hyperplasia. Although the disorder is uncommon (occurring in approximately 1 percent of unselected hypertensive patients), its recognition is essential for effective treatment. Persistent aldosteronism is frequently associated with hypernatremia, polyuria, and alkalosis, which predispose to attacks of tetany as well as to hypokalemic weakness. Conn and associates (1964), in an analysis of 145 patients with primary aldosteronism, found that persistent muscular weakness was a major complaint in 73 percent; intermittent attacks of paralysis occurred in 21 percent; and tetany in another 21 percent. These manifestations were much


Neurology_Adams

Neurology_Adams. found that persistent muscular weakness was a major complaint in 73 percent; intermittent attacks of paralysis occurred in 21 percent; and tetany in another 21 percent. These manifestations were much more frequent in women than in men, in contrast to the preponderance of men among patients with hypokalemic periodic paralysis of familial type. Rarely, as already noted, primary aldosteronism is produced by the chronic ingestion of licorice; this is due to its content of glycyrrhizic acid, a potent mineralocorticoid (Conn et al, 1968).


Neurology_Adams

Neurology_Adams. The muscle fibers of patients with primary aldosteronism show necrosis and vacuolation. Ultrastructurally, the necrotic areas are characterized by dissolution of myofilaments with degenerative vacuoles; nonnecrotic fibers contain membrane-bound vacuoles and show dilatation of the sarcoplasmic reticulum and abnormalities of the transverse tubular system, suggesting that vulnerability of the latter structures may be responsible for the muscle fiber necrosis (Atsumi et al).


Neurology_Adams

Neurology_Adams. This dramatic syndrome is observed during general anesthesia in susceptible individuals, some of whom clearly have a channelopathy. It is characterized by rapidly rising body temperature, extreme muscular rigidity, and a high mortality rate. Since the original report by Denborough, as larger experience was gained with this entity, it proved in some cases to be a metabolic myopathy inherited as a dominant trait, rendering the individual vulnerable to any volatile anesthetic agent, particularly halothane, and to the muscle relaxant succinylcholine. The fundamental cause in a proportion of cases is an aberration in a component of the ryanodine calcium channel. Malignant hyperthermia has been estimated to occur approximately once in the course of every 50,000 administrations of general anesthesia.


Neurology_Adams

Neurology_Adams. The full clinical picture is striking but anesthesiologists have become adept at detecting its earliest stages and aborting the process. As halothane or a similar inhalational anesthesia is induced, or succinylcholine is given for muscular relaxation, the jaw muscles unexpectedly become tense rather than relaxed and soon rigidity extends to all of the muscles. Thereafter, the body temperature rises to 42çC or 43çC and there is tachypnea and tachycardia. Blood pH may fall to 7 or below. There may be gross myoglobinuria and serum CK reaches extraordinarily high levels. Circulatory collapse and death may ensue in approximately 10 percent of cases, or the patient may survive with gradual recovery. In some cases there is the same sequence of events (increased temperature and acidosis) without muscular spasm. In cases of early death, the muscle may appear normal by light microscopy. With survival for several days, samples of muscle reveal scattered segmental necrosis and phagocytosis of


Neurology_Adams

Neurology_Adams. muscular spasm. In cases of early death, the muscle may appear normal by light microscopy. With survival for several days, samples of muscle reveal scattered segmental necrosis and phagocytosis of sarcoplasm without inflammation. Patients with a particular congenital myopathy (central core myopathy), and those with King-Denborough syndrome mentioned later, have a propensity to malignant hyperthermia as noted in Chap. 45.


Neurology_Adams

Neurology_Adams. The pathogenesis of malignant hyperthermia has been the subject of numerous investigations. During the rigor phase, oxygen consumption in muscle increases threefold and serum lactate, 15to 20-fold. Muscle from most affected individuals is abnormally sensitive to caffeine, which induces contracture in vitro. It has been postulated that halothane acts in a manner similar to caffeine—that is, to release calcium from the sarcoplasmic reticulum and prevent its reaccumulation, thus interfering with relaxation of the muscle. The essential physiologic change is one of increased intracellular calcium.


Neurology_Adams

Neurology_Adams. Insight into the disease has been gained from a breed of pigs, inbred for muscular development, in which muscle spasm (true contracture) and hyperthermia follow the administration of anesthetic agents. These swine have an inherited defect in the ryanodine receptor, a protein component of the calcium channel of the sarcoplasm that is sensitive to both caffeine and ryanodine. However, one of several similar defects in ryanodine is found in somewhat fewer than 20 percent of people with the susceptibility to malignant hypothermia. It is presumed that other yet unidentified allelic mutations of this receptor protein or another that controls the structure of the calcium channel account for the remainder of cases. The cause of the high fever is unknown; it is probably caused by the muscle spasm, but an effect of the anesthetic on heat-regulating centers has not been excluded.


Neurology_Adams

Neurology_Adams. Clues as to which patients are at risk for this condition come from several sources. Other members of the family may have difficulties or have died during anesthesia. Some susceptible individuals exhibit myopathic and musculoskeletal abnormalities (Isaacs and Barlow). One such dysmorphic constellation consists of short stature, ptosis, strabismus, highly arched palate, dislocated patellae, and kyphoscoliosis, which have been present in several families (King-Denborough syndrome, see Denbrough, Forster and Lovell). As mentioned just above and in Chap. 45 on the congenital myopathies, central core (sometimes called multicore) myopathy is frequently complicated by malignant hyperthermia. This is understandable insofar as both disorders have been linked to the gene encoding the ryanodine receptor; the 2 diseases are a result of allelic variations (Quane et al). It has been pointed out that another rare muscle disease (Evans myopathy, named after the affected family) may also be a


Neurology_Adams

Neurology_Adams. receptor; the 2 diseases are a result of allelic variations (Quane et al). It has been pointed out that another rare muscle disease (Evans myopathy, named after the affected family) may also be a predisposing condition. It is inherited as an autosomal trait and may be asymptomatic until the anesthetic reaction but some patients have wasting of the distal thigh muscles and an elevation of serum CK concentration (see Harriman et al).


Neurology_Adams

Neurology_Adams. Diagnostic testing Various tests for susceptibility to malignant hyperthermia have undergone phases of popularity. The only currently valid one involves in vitro exposure of a muscle biopsy specimen to halothane and to caffeine and the detection of muscle contracture with both agents. This is performed only in a few centers, which are listed at http://www.mhaus.org. The review by Denborough may be consulted for further details on the testing and clinical aspects of the disease.


Neurology_Adams

Neurology_Adams. This consists of discontinuation of anesthesia at the first hint of masseter spasm or rise of temperature. The intravenous administration of dantrolene, which inhibits the release of calcium from the sarcoplasmic reticulum, may be lifesaving. An infusion of 1 mg/kg is given initially and increased slowly until symptoms subside, the total dosage not exceeding 10 mg/kg. Other measures should include body cooling, intravenous hydration, sodium bicarbonate infusion to correct acidosis, and mechanical hyperventilation to decrease acidosis. Thereafter, halothane and other volatile anesthetic agents and succinylcholine should be avoided in such individuals and surgical procedures, if necessary, should be done with other agents, such as propofol, nitrous oxide, fentanyl, thiopental (or other barbiturate), or local anesthesia. Intravenous dantrolene (2.5 mg/kg given slowly 1 h prior to anesthesia) prevents the syndrome, but this is not a preferred option in patients with the disorder.


Neurology_Adams

Neurology_Adams. This state, in which hyperthermia occurs as an idiosyncratic reaction to neuroleptic drugs, is also accompanied by widespread myonecrosis. It shares some features with malignant hyperthermia but is a distinct entity, as discussed in Chap. 41. The discovery of several types of seizure disorders based on inherited defects of the potassium channel has elicited considerable interest and only recently was it appreciated that one form of periodic paralysis, Andersen disease, is associated with the voltage-gated potassium channel.


Neurology_Adams

Neurology_Adams. Andersen and coworkers first drew attention to a distinct form of potassium-sensitive periodic paralysis characterized by the triad of periodic potassium-sensitive weakness, ventricular dysrhythmias with long QT syndrome, and dysmorphic features (micrognathia, short stature, scaphocephaly, hypertelorism, broad nose, low-set ears, and short index fingers). Sometimes called “Andersen disease,” it is not to be mistaken for the glycogen storage disease of the same name, which is discussed in Chap. 45.


Neurology_Adams

Neurology_Adams. From a study of 5 kindreds, Sansone and colleagues have pointed out that attacks of paralysis can be associated with hypo-, normo-, or hyperkalemia, and that a prolonged QT interval is an integral feature of the disease (and sometimes the only sign in a given family). Plaster and colleagues demonstrated that most cases of Andersen disease are a consequence of dominant-negative mutations in the gene KCNJ2 that encodes a type of K channel. In vitro studies indicate that the mutation impairs the ability of preformed channels to migrate to the membrane surface and also impedes the current-carrying capacity of the potassium channel system. This defect would be expected to impair repolarization of the muscle membrane, thereby making both skeletal and cardiac muscle hyperexcitable.


Neurology_Adams

Neurology_Adams. This oddly named disease is included in this chapter because an abnormality of voltage-gated potassium channels (VGKC) or circulating antibodies against the channel has been discovered in many patients (anti-VGKC). Some of the latter have the disorder as a result of a paraneoplastic reaction to thymoma and that is the context in which we have encountered it approximately 10 times over a 40 year span. It is characterized by continuous muscle fiber activity sometimes referred to as “neuromyotonia” and therefore may also be considered among similar disorders of constant muscle activity that are discussed further in the chapter. Hyperhidrosis, weight loss, insomnia, and hallucinations may occur, and most cases so far described have ended fatally in a matter of months (Serratrice and Azulay). Other antibodies may accompany the anti-VGKC, including against CASPR2 (mainly with an associated thymoma) and LGI1 and each binds to numerous brain regions as indicated in the series by Irani and


Neurology_Adams

Neurology_Adams. Other antibodies may accompany the anti-VGKC, including against CASPR2 (mainly with an associated thymoma) and LGI1 and each binds to numerous brain regions as indicated in the series by Irani and colleagues.


Neurology_Adams

Neurology_Adams. Plasma exchange reversed the syndrome in the case described by Ligouri and colleagues. Some cases have an associated thymoma and its removal may be curative. Weak oligoclonal bands are sometimes found in the spinal fluid. Whether the antibodies are responsible for the hallucinations and other cerebral symptoms is unknown, but the connection is plausible. An interesting category of disease has emerged as being caused by antibodies to the voltage-gated potassium channel (Thieben et al), sometimes parallel to an idiopathic or paraneoplastic “limbic” encephalitis, which is described in Chap. 30.


Neurology_Adams

Neurology_Adams. In addition to the above disorders, various seizure syndromes (see Chap. 15) and a category of spinocerebellar ataxias are also attributable to mutations of ion channels and are addressed in other sections of the book. Also mentioned here for completeness are several diseases that result from secondary dysfunction of these same ion channels. Most of these conditions are acquired and autoimmune in nature, for example, the Lambert-Eaton myasthenic syndrome that results from an autoimmune attack on calcium channels discussed earlier, the Isaac syndrome that results from an autoimmune attack on potassium channels, producing neuromyotonia, anti- voltage-gated potassium channel and anti-NMDA encephalitis (see Chap. 30), and erythromelalgia that implicates a sodium channel (see Chap. 10). Thus, ion channels, being ubiquitous in all excitable tissues, might be expected to produce a large variety of diseases that affect central and peripheral nervous structures. Despite this, each of the


Neurology_Adams

Neurology_Adams. ion channels, being ubiquitous in all excitable tissues, might be expected to produce a large variety of diseases that affect central and peripheral nervous structures. Despite this, each of the genetic and acquired processes has remarkably specific features that are pertinent only to the channel as expressed in a single tissue.


Neurology_Adams

Neurology_Adams. Muscle Contracture, Pseudomyotonia, Tetanus, and Related States Many of these states were discussed in Chap. 45 on diseases of muscle. They are reintroduced here in relation to specific diseases with which they are associated.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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”; Fig. 2-19) of true myotonia.


Neurology_Adams

Neurology_Adams. 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. 45 under that heading. Tetanus (See Tetanus in Chap. 41)


Neurology_Adams

Neurology_Adams. Tetanus (See Tetanus in Chap. 41) 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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).


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. The physiology of fasciculations is discussed in Chap. 2 and illustrated in Fig. 2-20. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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 and other antiepileptic drugs, has been helpful in reducing the fasciculations and sensations of weakness in a proportion of cases and numerous other medications have been reportedly helpful.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 1 motor unit, firing at 5 to 60 Hz and recurring regularly at 0.2to 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.


Neurology_Adams

Neurology_Adams. 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). The association of this type of disorder to anti-voltage gated potassium channels has been mentioned in relation to thymoma and to Morvan’s syndrome.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 as noted above in Morvan syndrome (see reviews by Thompson and by Newsom-Davis and Mills and the discussion of paraneoplastic syndromes in Chap. 30).


Neurology_Adams

Neurology_Adams. Treatment 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. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 1 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.


Neurology_Adams

Neurology_Adams. 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), rare cases of which have included a fatal encephalopathy and myoclonus (Turner et al) and a few patients with a special cervical pattern of stiffness have had anti-ampiphysin antibodies (Murinson and Guarnaccia). In all these rare cases, anti-GAD antibody is usually also present and paraneoplastic versions of each syndrome are known, as commented below.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. 30). Also reported, perhaps not surprising, have been instances of a variable cerebellar syndrome with stiff-man and high titers of anti-GAD antibodies (Rakoevic et al).


Neurology_Adams

Neurology_Adams. The stiff man syndrome must be distinguished from tetanus (see “Tetanus” in Chap. 41 and further on), Isaacs syndrome, and the rare syndrome of subacute myoclonic spinal neuronitis, described in Chaps. 32 and 42. 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.


Neurology_Adams

Neurology_Adams. 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 case reports and small


Neurology_Adams

Neurology_Adams. 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 case reports and small series but a small randomized trial has been negative (Dalakas et al, 2017). For intractable cases, particularly when 1 limb is involved, propofol has been anecdotally effective in doses that do not produce sedation (Hattan et al).


Neurology_Adams

Neurology_Adams. A “stiff infant” syndrome, observed by Dudley and colleagues in 4 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


Neurology_Adams

Neurology_Adams. Primary Hyperexcitability of Muscle At least 3 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.


Neurology_Adams

Neurology_Adams. “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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. Aberfeld DC, Hinterbuchner LP, Schneider M: Myotonia, dwarfism, diffuse bone disease, and unusual ocular and facial abnormalities (a new syndrome). Brain 88:313, 1965. Aitken RS, Allot EN, Casteldon LI, Walker M: Observations on a case of familial periodic paralysis. Clin Sci 3:47, 1937. Andersen ED, Krasilnikoff PA, Overvad H: Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. Acta Paediatr Scand 60:559, 1971. Argov Z, Mastaglia FL: Disorders of neuromuscular transmission caused by drugs. N Engl J Med 301:409, 1979. Ashok Muley S, Day JW: Autoimmune rippling muscle. Neurology 61:869, 2003.


Neurology_Adams

Neurology_Adams. Argov Z, Mastaglia FL: Disorders of neuromuscular transmission caused by drugs. N Engl J Med 301:409, 1979. Ashok Muley S, Day JW: Autoimmune rippling muscle. Neurology 61:869, 2003. Atsumi T, Ishikawa S, Miyatake T, Yoshida M: Myopathy and primary aldosteronism: Electron microscopic study. Neurology 29:1348, 1979. Bain PG, Motomura M, Newsom-Davis J, et al: Effects of intravenous immunoglobulin on muscle weakness and calcium channel auto-antibodies in the Lambert-Eaton myasthenic syndrome. Neurology 47:678, 1996. Barker RA, Reeves T, Thom M, et al: Review of 23 patients affected by the stiff man syndrome: Clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 65:633, 1998. Barth D, Nabavi Nouri M, Ng E, et al: Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology 76:2017, 2011.


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Neurology_Adams. Barth D, Nabavi Nouri M, Ng E, et al: Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology 76:2017, 2011. Becker PE: Genetic approaches to the nosology of muscle disease: Myotonias and similar diseases: Part 7. Muscle, in Bergsma D (ed): The Clinical Delineation of Birth Defects. Baltimore, MD, Williams & Wilkins, 1971. Beeson D, Higuchi O, Palace J, et al: Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science 313:1975, 2006. Bever CT Jr, Aquino AV, Penn AS, et al: Prognosis of ocular myasthenia. Ann Neurol 14:516, 1983. Blalock A, Mason MF, Morgan HJ, Riven SS. Myasthenia gravis and tumors of the thymic region: report of a case in which the tumor was removed. Ann Surg 110:544, 1939. Blexrud MD, Windebank AJ, Daube JR: Long term follow-up of 121 patients with benign fasciculations. Neurology 34:622, 1993. Bril V, Kojic J, Dhanani A: The long-term clinical outcome of myasthenia gravis in patients with thymoma. Neurology 51:1198, 1998.


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Neurology_Adams. Bril V, Kojic J, Dhanani A: The long-term clinical outcome of myasthenia gravis in patients with thymoma. Neurology 51:1198, 1998. Brody IA: Muscle contracture induced by exercise: A syndrome attributable to decreased relaxing factor. N Engl J Med 281:187, 1969. Brown P, Rothwell PJ, Marsden CD: The stiff leg syndrome. J Neurol Neurosurg Psychiatry 62:31, 1997. Buckingham JM, Howard FM Jr, Bernatz PE, et al: The value of thymectomy in myasthenia gravis: A computer-assisted matched study. Ann Surg 184:453, 1976. Burke G, Cossins J, Maxwell S, et al: Rapsyn mutation in hereditary myasthenia. Distinct early and late phenotypes. Neurology 61:826, 2003. Burns RJ, Bretag AH, Blumbergs PC, Harbord MG: Benign familial disease with muscle mounding and rippling. J Neurol Neurosurg Psychiatry 57:344, 1994. Buzzard EF: The clinical history and postmortem examination of 5 cases of myasthenia gravis. Brain 28:438, 1905.


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Neurology_Adams. Buzzard EF: The clinical history and postmortem examination of 5 cases of myasthenia gravis. Brain 28:438, 1905. Cannon SC: An expanding view for the molecular basis of familial periodic paralysis. Neuromuscul Disord 12:533, 2002. Cannon SC, Brown RH Jr, Corey DP: Theoretical reconstruction of myotonia and paralysis caused by incomplete inactivation of sodium channels. Biophys J 65:270, 1993. Celebisoy N, Cologlu Z, Akbaba Y, et al: Continuous muscle fibre activity: A case treated with acetazolamide. J Neurol Neurosurg Psychiatry 64:256, 1998. Cöers C, Telerman-Toppet N, Durda J: Neurogenic benign fasciculations, pseudomyotonia, and pseudotetany. Arch Neurol 38:282, 1981. Cogan DG: Myasthenia gravis: A review of the disease and a description of lid twitch as a characteristic sign. Arch Ophthalmol 74:217, 1965.


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Neurology_Adams. Cogan DG: Myasthenia gravis: A review of the disease and a description of lid twitch as a characteristic sign. Arch Ophthalmol 74:217, 1965. Compston DAS, Vincent A, Newsom-Davis A, Batchelor JR: Clinical, pathological, HLA antigen, and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 103:579, 1980. Conn JW, Knopf RF, Nesbit RM: Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am J Surg 107:159, 1964. Conn JW, Rovner DR, Cohen EL: Licorice-induced pseudoaldosteronism: Hypertension, hypokalemia, aldosteronopenia and suppressed plasma renin activity. JAMA 205:492, 1968. Cortes-Vicente E, Gallardo E, Martinez MA, et al: Clinical characteristics of patients with double-seronegative myasthenia gravis and antibodies to cortactin. JAMA Neurol 73:1099, 2016. Croxen R, Hattan C, Shellay C, et al: Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes. Neurology 59:162, 2002.


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Neurology_Adams. Harriman DGF, Summer DW, Ellis FR: Malignant hyperthermia myopathy. Q J Med 42:639, 1973. Hattan E, Angle MR, Chalk C: Unexpected benefit of propofol in stiff-person syndrome. Neurology 70:1641, 2008. Heatwole CR, Statland JM, Logigian EL: The diagnosis and treatment of myotonic disorders. Muscle Nerve 47:632, 2013. Hoffmann K, Muller JS, Stricker S, et al: Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. Am J Hum Genet 79:303, 2006. Hudson AJ, Brown WF, Gilbert JJ: The muscular pain-fasciculation syndrome. Neurology 28:1105, 1978. Irani SR, Pettingill P, Kleopa KA, et al: Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 72:241, 2012. Isaacs H: Continuous muscle fibre activity in an Indian male with additional evidence of terminal motor fibre abnormality. J Neurol Neurosurg Psychiatry 30:126, 1967.


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Neurology_Adams. Isaacs H: Continuous muscle fibre activity in an Indian male with additional evidence of terminal motor fibre abnormality. J Neurol Neurosurg Psychiatry 30:126, 1967. Isaacs H, Barlow MB: Malignant hyperpyrexia. J Neurol Neurosurg Psychiatry 36:228, 1973. Janssen JC, Larner AJ, Harris J, et al: Myasthenic hand. Neurology 51:913, 1998. Jaretzki A, Barohn RJ, Ernstoff RM, et al: Myasthenia gravis. Recommendations for clinical research standards. Neurology 55:16, 2000. Kakulas BA, Adams RD: Diseases of Muscle: Pathological Foundations of Clinical Myology, 4th ed. Philadelphia, Harper & Row, 1985. Kelly JJ, Daube JR, Lennon VA: The laboratory diagnosis of mild myasthenia gravis. Ann Neurol 12:238, 1982. Kerzin-Storrar L, Metcalfe RA, Dyer PA: Genetic factors in myasthenia gravis: A family study. Neurology 38:38, 1988. Koch MC, Steinmeyer K, Lorenz C, et al: The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257:797, 1992.


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Neurology_Adams. Koch MC, Steinmeyer K, Lorenz C, et al: The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257:797, 1992. Lambert EH, Eaton LM, Rooke ED: Defect of neuromuscular transmission associated with malignant neoplasm. Am J Physiol 187:612, 1956. Lambert EH, Goldstein NP: An unusual form of “myotonia.” Physiologist 1:51, 1957. Lambert EH, Lindstrom JM, Lennon VA: End-plate potentials in experimental autoimmune myasthenia gravis in rats. Ann N Y Acad Sci 274:300, 1976. Layzer RB: Neuromuscular Manifestations of Systemic Disease. Philadelphia, Davis, 1985. Lehmann-Horn F, Mailänder V, Heine R, George AL: Myotonia levior is a chloride channel disorder. Hum Mol Genet 4:1397, 1995. Lehmann-Horn F, Rüdel R, Jurkat-Rott K: Nondystrophic myotonias and periodic paralyses, in Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 1257–1300.


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Neurology_Adams. Lehmann-Horn F, Rüdel R, Jurkat-Rott K: Nondystrophic myotonias and periodic paralyses, in Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 1257–1300. Lehmann-Horn F, Rüdel R, Ricker K: Membrane defects in paramyotonia congenita (Eulenburg). Muscle Nerve 10:633, 1987. Lennon VA: Immunologic mechanisms in myasthenia gravis—a model of a receptor disease, in Franklin E (ed): Clinical Immunology Update—Reviews for Physicians. New York, Elsevier/North-Holland, 1979, pp 259–289. Lennon VA, Lindstrom JM, Seybold ME: Experimental autoimmune myasthenia gravis in rats and guinea pigs. J Exp Med 141:1365, 1975. Lewi Z, Bar-Khayim Y: Food poisoning from barium carbonate. Lancet 2:342, 1964. Ligouri R, Vincent A, Clover L, et al: Morvan’s syndrome: Peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 124:2417, 2001.


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Neurology_Adams. Ligouri R, Vincent A, Clover L, et al: Morvan’s syndrome: Peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 124:2417, 2001. Lipicky RJ, Bryant SH: Ion content, potassium flux, and cable properties of myotonic, human, external intercostal muscle. Trans Am Neurol Assoc 96:34, 1971. Lundh H, Nilsson O, Rosen I: Treatment of Lambert-Eaton syndrome: 3,4-Diaminopyridine and pyridostigmine. Neurology 34:1324, 1984. Lütschg J, Jerusalem F, Ludin HP, et al: The syndrome of “continuous muscle fiber activity.” Arch Neurol 35:198, 1978. Mason WP, Graus F, Land B, et al: Small-cell lung cancer, paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome. Brain 120:1279, 1997. Matthews E, Labrum R, Sweeney MG, et al: Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 72:1544, 2009.


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Neurology_Adams. Matthews E, Labrum R, Sweeney MG, et al: Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 72:1544, 2009. McFadzean AJS, Yeung R: Periodic paralysis complicating thyrotoxicosis in Chinese. Br Med J 1:451, 1967. McKeon B, Martinez-Hernandez E, Lancaster E, et al: Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. JAMA Neurol 70:44, 2013. McQuillen MP, Cantor HE, O’Rourke JR: Myasthenic syndrome associated with antibiotics. Arch Neurol 18:402, 1968. Meriggioli MN, Ciafaloni E, Al-Hayk KA, et al: Mycophenolate mofetil for myasthenia gravis. Neurology 61:1438, 2003. Meyers KR, Gilden DH, Rinaldi CF, Hansen JL: Periodic muscle weakness, normokalemia, and tubular aggregates. Neurology 22:269, 1972. Mills KR, Edwards RHT: Investigative strategies for muscle pain. J Neurol Sci 58:73, 1983.


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Neurology_Adams. Mills KR, Edwards RHT: Investigative strategies for muscle pain. J Neurol Sci 58:73, 1983. Milone M, Fukada T, Shen XM, et al: Novel congenital myasthenic syndromes associated with defect in quantal release. Neurology 66:1223, 2006. Moersch FP, Woltman HW: Progressive fluctuating muscular rigidity (“stiff-man syndrome”): Report of a case and some observations in 13 other cases. Mayo Clin Proc 31:421, 1956. Murinson BB, Guarnaccia JB: Stiff-person syndrome with anti-ampiphysin antibodies. Neurology 71:1955, 2008. Myasthenia Gravis Clinical Study Group: A randomized clinical trial comparing prednisone and azathioprine in myasthenia gravis: Results of the second interim analysis. J Neurol Neurosurg Psychiatry 56:1157, 1993. Newsom-Davis J: Diseases of the neuromuscular junction, in Asbury AK, McKhann GM, McDonald WI (eds): Diseases of the Nervous System, 2nd ed. Philadelphia, Saunders, 1992, pp 197–212. Newsom-Davis J: Neuromyotonia. Rev Neurol 160:85, 2004.


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Neurology_Adams. Newsom-Davis J: Neuromyotonia. Rev Neurol 160:85, 2004. Newsom-Davis J, Mills KR: Immunological associations of acquired neuromyotonia (Isaacs’ syndrome). Brain 116:453, 1993. Nissen K: Beiträge zur Kenntnis der Thomsen’schen Krankheit (Myotonia congenita), mit besonderer Berücksichtigung des hereditären Momentes und seinen Beziehungen zu den Mendelschen Vererbungsregeln. Z Klin Med 97:58, 1923. Okinaka S, Shizume K, Iinos S, et al: The association of periodic paralysis and hyperthyroidism in Japan. J Clin Endocrinol Metab 17:1454, 1957. Olanow CW, Lane RJM, Roses AD: Thymectomy in late-onset myasthenia gravis. Arch Neurol 39:82, 1982. O’Neill JH, Murray NM, Newsom-Davis J: The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 14:577, 1988. Osserman KE: Myasthenia Gravis. New York, Grune & Stratton, 1958. Palace J, Lashley D, Newsom-Davis J, et al: Clinical features of the DOK-7 neuromuscular junction synaptopathy. Brain 130:1507, 2007.


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Neurology_Adams. Palace J, Lashley D, Newsom-Davis J, et al: Clinical features of the DOK-7 neuromuscular junction synaptopathy. Brain 130:1507, 2007. Palace J, Newsom-Davis J, Lecky B: A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Neurology 50:1778, 1998. Panegyres PM, Squier M, Mills KR, Newsom-Davis J: Acute myopathy associated with large parenteral dose of corticosteroid in myasthenia gravis. J Neurol Neurosurg Psychiatry 56:702, 1993. Park HS, Shin DM, Lee JS, et al: Thymoma. A retrospective study of 87 cases. Cancer 73:2491, 1994. Pascuzzi RM, Coslett HB, Johns TR: Long-term corticosteroid treatment of myasthenia gravis: Report of 116 cases. Ann Neurol 15:291, 1984. Patrick J, Lindstrom JP: Autoimmune response to acetylcholine receptor. Science 180:871, 1973. Patrick J, Lindstrom JP, Culp B, McMillan J: Studies on purified eel acetylcholine receptor and antiacetylcholine receptor antibody. Proc Natl Acad Sci U S A 70:3334, 1973.


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Neurology_Adams. Patrick J, Lindstrom JP, Culp B, McMillan J: Studies on purified eel acetylcholine receptor and antiacetylcholine receptor antibody. Proc Natl Acad Sci U S A 70:3334, 1973. Pittinger CB, Eryase Y, Adamson R: Antibiotic-induced paralysis. Anesth Analg 49:487, 1970. Plaster NM, Tawil R, Tristani-Firouzi M, et al: Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105:511, 2001. Ponseti JM, Azem J, Fort JM, et al: Long-term results of tacrolimus in cyclosporineand prednisone-dependent myasthenia gravis. Neurology 64:1641, 2005. Poskanzer DC, Kerr DNS: A third type of periodic paralysis with normokalemia and favorable response to NaCl. Am J Med 31:328, 1961. Price DL, Griffin JW, Peck K: Tetanus toxin: Evidence for binding at presynaptic nerve endings. Brain Res 121:379, 1977. Ptácek LJ, Tawil R, Griggs RC, et al: Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77:863, 1994a.


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Neurology_Adams. Ptácek LJ, Tawil R, Griggs RC, et al: Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77:863, 1994a. Ptácek LJ, Tawil R, Griggs RC, et al: Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Neurology 44:1500, 1994b. Quane KA, Healy JMS, Keating KE, et al: Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet 5:51, 1993. Rabinstein A, Wijdicks EFM: BiPAP in acute respiratory failure due to myasthenic crisis may prevent intubation. Neurology 59:1647, 2002. Rakoevic G, Raju R, Semino-Mora C, et al: Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology 67:1068, 2006. Reman L: Zur pathogenese und therapie der myasthenia gravis pseudoparalytica. Dtsch Z Nervenheilkd 128:66, 1932.


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Neurology_Adams. Reman L: Zur pathogenese und therapie der myasthenia gravis pseudoparalytica. Dtsch Z Nervenheilkd 128:66, 1932. Ricker K, Moxley RT, Heine R, Lehmann-Horn F: Myotonia fluctuans: A third type of muscle sodium channel disease. Arch Neurol 51:1095, 1994. Ricker K, Moxley RT, Rohkamm R: Rippling muscle disease. Arch Neurol 46:405, 1989. Robertson WC, Chun RWM, Kornguta SE: Familial infantile myasthenia. Arch Neurol 37:117, 1980. Rodriguez M, Gomez MR, Howard FM: Myasthenia gravis in children: Long-term followup. Ann Neurol 13:504, 1983. Ropper AH, Gress DR, Diringer MN, et al (eds): Neurological and Neurosurgical Intensive Care, 4th ed. Baltimore, Lippincott Williams Wilkins, 2004, pp 299–311. Rosenfeld J, Sloan-Brown K, George AL: A novel muscle sodium channel mutation causes painful congenital myotonia. Ann Neurol 42:811, 1997.


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Neurology_Adams. Rosenfeld J, Sloan-Brown K, George AL: A novel muscle sodium channel mutation causes painful congenital myotonia. Ann Neurol 42:811, 1997. Rüdel R, Lehmann-Horn F, Ricker K, et al: Hypokalemic periodic paralysis: In vitro investigation of muscle fiber membrane parameters. Muscle Nerve 7:110, 1984. Russell DS: Histological changes in myasthenia gravis. J Pathol Bacteriol 65:279, 1953. Ryan DP, Ptácek LJ: Episodic neurological channelopathies. Neuron 68:282, 2010. Saiz A, Graus F, Valldeoriola F, et al: Stiff-leg syndrome: A form of stiff-man syndrome. Ann Neurol 43:400, 1998. Sanders DB, Wolfe GI, Benetar M, et al: International consensus guidelines for management of myasthenia gravis. Neurology 87:419, 2016. Sansone V, Griggs RC, Meola G, et al: Andersen’s syndrome: A distinct periodic paralysis. Ann Neurol 42:305, 1997. Santa T, Engel AG, Lambert EH: Histometric study of neuromuscular junction ultrastructure: I. Myasthenia gravis. Neurology 22:71, 1972.


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Neurology_Adams. Santa T, Engel AG, Lambert EH: Histometric study of neuromuscular junction ultrastructure: I. Myasthenia gravis. Neurology 22:71, 1972. Sansone VA, Burge J, McDermott MP, et al: Randomized placebo-controlled trial of dichlorphenamide in periodic paralysis, Neurology 86:1408, 2016, Satoyoshi E: A syndrome of progressive muscle spasm, alopecia and diarrhea. Neurology 28:458, 1978. Scadding GK, Vincent A, Newsom-Davis J, Henry K: Acetylcholine receptor antibody synthesis by thymic lymphocytes: Correlation with thymic histology. Neurology 31:935, 1981. Schluep M, Willcox N, Vincent A, et al: Acetylcholine receptors in human thymic cells in situ: An immunohistological study. Ann Neurol 22:212, 1987. Schröder JM, Adams RD: The ultrastructural morphology of the muscle fiber in myotonic dystrophy. Acta Neuropathol 10:218, 1968. Schwartz O, Jampel R: Congenital blepharophimosis associated with a unique generalized myopathy. Arch Ophthalmol 68:52, 1962.


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Neurology_Adams. Schwartz O, Jampel R: Congenital blepharophimosis associated with a unique generalized myopathy. Arch Ophthalmol 68:52, 1962. Scuderi F, Marino M, Colonna L, et al: Anti-p110 autoantibodies identify a subtype of “seronegative” myasthenia gravis with prominent oculobulbar involvement. Lab Invest 82:1139, 2002. Senanayake N, Roman GC: Disorders of neuromuscular transmission due to natural environmental toxins. J Neurol Sci 107:1, 1992. Serratrice G, Azulay JP: Que reste-t-il de la chorée fibrillaire de Morvan? Rev Neurol (Paris) 150:257, 1994. Sethi KD, Rivner MH, Swift TR: Ice pack test for myasthenia gravis. Neurology 37:1383, 1987. Simpson JA: Myasthenia gravis: A new hypothesis. Scott Med J 5:419, 1960. Solimena M, Folli F, Aparisi R, et al: Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 322:1555, 1990.


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Neurology_Adams. Solimena M, Folli F, Aparisi R, et al: Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 322:1555, 1990. Spaans F, Theunissen P, Reekers AD, et al: Schwartz-Jampel syndrome: 1. Clinical, electromyographic, and histologic studies. Muscle Nerve 13:516, 1990. Statland JM, Bundy BM, Wang Y, et al: Mexilitine for symptoms and signs of myotonia in nondystrophic myotonia. JAMA 308:1357, 2012. Streib EW: Paramyotonia congenita: Successful treatment with tocainide: Clinical and electrophysiologic findings in seven patients. Muscle Nerve 10:155, 1987. Streib EW, Rothner D: Eaton-Lambert myasthenic syndrome: Long-term treatment of 3 patients with prednisone. Ann Neurol 10:448, 1981. Subramony SH, Wee AS, Mishra SK: Lack of cold sensitivity in hyperkalemic periodic paralysis. Muscle Nerve 9:700, 1986. Sun SF, Streib EW: Autosomal recessive generalized myotonia. Muscle Nerve 6:143, 1983.


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Neurology_Adams. Sun SF, Streib EW: Autosomal recessive generalized myotonia. Muscle Nerve 6:143, 1983. Swift TR: Disorders of neuromuscular transmission other than myasthenia gravis. Muscle Nerve 4:334, 1981. Tahmoush AJ, Alonso RJ, Tahmoush GP, et al: Cramp-fasciculation syndrome: A treatable hyperexcitable peripheral nerve disorder. Neurology 41:1021, 1991. Talbott JH: Periodic paralysis: A clinical syndrome. Medicine (Baltimore) 20:85, 1941. Tawil R, McDermott MP, Brown RH Jr, et al: Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis. Ann Neurol 47:46, 2000. Thieben MJ, Lennon VA, Askanit AJ, et al: Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 62:1177, 2004. Thomas CE, Mayer SA, Gungor Y, et al: Myasthenic crisis: Clinical features, mortality, complications, and risk factors for prolonged intubation. Neurology 48:1253, 1997. Thomasen E: Myotonia, Thomsen’s Disease, Paramyotonia,


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Neurology_Adams. Thomasen E: Myotonia, Thomsen’s Disease, Paramyotonia, Dystrophia Myotonica. Aarhus, Denmark, Universitetsforlaget i Aarhus, 1948. Thomsen J: Tonische Krämpfe in willkürlich beweglichen Muskeln in Folge von ererbter psychischer disposition (Ataxia muscularis?). Arch Psychiatr Nervenkr 6:706, 1876. Tindall RSA, Phillips JT, Rollins JA, et al: A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann N Y Acad Sci 681:539, 1993. Turner MR, Irani SR, Leite MI, et al: Progressive encephalomyelitis with rigidity and Myoclonus. Neurology 77:439, 20011. Trudell RG, Kaiser KK, Griggs RC: Acetazolamide-responsive myotonia congenita. Neurology 37:488, 1987. Tyler FH, Stephens FE, Gunn FD, Perkoff GT: Studies on disorders of muscle: VII. Clinical manifestations and inheritance of a type of periodic paralysis without hypopotassemia. J Clin Invest 30:492, 1951.


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Neurology_Adams. Valli G, Barbieri S, Stefano C, et al: Syndromes of abnormal muscular activity: Overlap between continuous muscle fiber activity and the stiff-man syndrome. J Neurol Neurosurg Psychiatry 46:241, 1983. Vernino S, Lennon VA: Ion channel and striational antibodies define a continuum of autoimmune neuromuscular hyperexcitability. Muscle Nerve 26:702, 2002. Viets HR: A historical review of myasthenia gravis from 1672 to 1900. JAMA 153:1273, 1953. Vincent A, Newsom-Davis J: Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: Results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 48:1246, 1985. Vincent A, Newsom-Davis J, Martin V: Antiacetylcholine receptor antibodies in d-penicillamine associated myasthenia gravis. Lancet 1:1254, 1978. Vincent A, Wray D (eds): Neuromuscular Transmission. Basic and Applied Aspects. New York, Manchester Press, 1990.


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Neurology_Adams. Vincent A, Wray D (eds): Neuromuscular Transmission. Basic and Applied Aspects. New York, Manchester Press, 1990. Vorgerd M, Ricker K, Ziemssen W, et al: A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation. Neurology 57:2273, 2001. Walker MB: Treatment of myasthenia gravis with physostigmine. Lancet 1:1200, 1934. Weinberg DH, Rizzo JF, Hayes MT, et al: Ocular myasthenia gravis: Predictive value of single-fiber electromyography. Muscle Nerve 22:1222, 1999. Witte AS, Cornblath DR, Parry GJ, et al: Azathioprine in the treatment of myasthenia gravis. Ann Neurol 15:602, 1984. Wolfe GI, Kaminski HJ, Aban IB, et al: Randomized trial of thymectomy in myasthenia gravis. N Engl J Med 375:511, 2016. Yazaki K, Kuribayashi T, Yamamura Y, et al: Hypokalemic myopathy associated with a 17α-hydroxylase deficiency: A case report. Neurology 32:94, 1982.


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Neurology_Adams. Yazaki K, Kuribayashi T, Yamamura Y, et al: Hypokalemic myopathy associated with a 17α-hydroxylase deficiency: A case report. Neurology 32:94, 1982. Figure 46-1. A. Endplate from a patient with myasthenia gravis. The terminal axon contains abundant presynaptic vesicles, but the postsynaptic folds are wide and there are few secondary folds. The loose junctional sarcoplasm is filled with microtubules and ribosomes. The synaptic cleft (asterisk) is widened. (From Santa et al by permission.) B. Normal endplate for comparison. (Courtesy of Dr. A.G. Engel.) Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Persistent Muscle Fiber Activity Anxiety Disorders, Hysteria, and


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Neurology_Adams. The relationship between psychiatry and neurology, at one time unified specialties, has been problematic for well over a century. With the emergence of numerous theories of the nature of mental life and of the mind, came corresponding systems for the treatment of psychiatric disease. Most of these systems, typified in the past by psychoanalysis, seemed to have little in common with neurologic ideas about the structure and function of the brain. Freed from the archetype of the main mental disease that was the result of structural damage to the brain, syphilitic general paresis, psychiatry was able to turn to matters that were less anchored in medicine. With the emergence of a new biologic psychiatry based on neurochemistry, genetics, and functional imaging of the brain, it would seem that the gap between diseases of the mind and of the brain is closing. However, neurologists should view some of these modern ideas with at least some skepticism. For example, the observation of brain


Neurology_Adams

Neurology_Adams. the gap between diseases of the mind and of the brain is closing. However, neurologists should view some of these modern ideas with at least some skepticism. For example, the observation of brain function by the use of imaging methods, and disruption of that function in disease, is not the equivalent of the disease itself and certainly cannot capture the experience through which mental disease is manifest. To dissociate an individual’s personal history and experiences, aspects of life that probably cannot be quantified or visualized, from diseases of the mind remains an artifice now, as it was in the time of the classic philosophers. This potential division between mind and brain, called “dualism,” is particularly apparent when one begins to analyze the normal stream of thought that dominates daily life rather than the disordered thoughts of mental disease states. The great Hughlings Jackson was of the opinion that the brain provides a platform for thinking but is not explanatory of


Neurology_Adams

Neurology_Adams. daily life rather than the disordered thoughts of mental disease states. The great Hughlings Jackson was of the opinion that the brain provides a platform for thinking but is not explanatory of it, a property of mind he termed “emergent.” This leaves open the possibility of a science of the mind that is separate from the science of the brain. Moreover, the separation of quirks of personality and character traits, probably reflecting the biologic diversity of the development of the brain, from genuine disease will remain eternally problematic. Even the margins between the disease and mental dysfunction have been disputed and have given rise to numerous “shadow syndromes” of psychologic origin that are subject to change with popular culture and fashion. This serves as an appropriate introduction to a chapter on what was formerly termed the neuroses and have been renamed.


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Neurology_Adams. In every society, there are many troubled individuals who are neither mentally ill nor developmentally impaired. They differ from other people in being plagued by feelings of inferiority or self-doubt, suspicion about the motives of others, low energy, inexplicable fatigue, shyness, irritability, moodiness, sense of guilt, and unreasonable worries and fears. They suffer as a result of these feelings or they behave in ways that are upsetting to those around them and to society at large. Yet none of these conditions precludes partaking in the everyday life, such as attending school, working, marrying, and raising a family. As these conditions were more carefully documented in the early part of the last century, they came to be called neuroses, and those that created societal difficulties were called psychopathies, and more recently, personality disorders and sociopathies.


Neurology_Adams

Neurology_Adams. The question of the purity and homogeneity of these mental states creates an ongoing polemic in psychiatry, medicine and society. The neuroses as a group appeared to be so diverse as to require subdivision in former editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) into no less than 7 different types before the term was expunged in 1980. We take a neutral position on the value of DSM not out of iconoclasm but because the definitions in that system are changed frequently, are subject to considerable controversy, and often do not accord with neurobiologic ideas of brain function. In any case, readers may wish to consult the most current DSM-5 where appropriate, to gain insight into the evolving thinking of the psychiatric community.


Neurology_Adams

Neurology_Adams. Originally, Freud separated neuroses and psychoneuroses and both subjects became enmeshed in psychoanalytic theory. The assumption about neurosis was that an undercurrent of anxiety arising from unconscious conflict explained all the different types of neuroses as well as the psychopathies. Psychoneurosis was reserved for neurosis that had an additional aspect based in a brain (physical) trait—but the 2 differed very little. Later, psychiatrists uncommitted to psychoanalytic theory attributed these states to social forces leading to maladaptive behavior from childhood. Many of these notions were not acceptable to biologically oriented physicians, with the result that the term psychoneurosis was expunged from later editions of the DSM, and neurosis was replaced by anxiety disorders, phobic states, and obsessive-compulsive disorder. These terms are at present applied to mental disorders with the following characteristics: (1) symptoms that are distressing to the affected individual and


Neurology_Adams

Neurology_Adams. states, and obsessive-compulsive disorder. These terms are at present applied to mental disorders with the following characteristics: (1) symptoms that are distressing to the affected individual and regarded by the person as unacceptable or alien; (2) intactness of reality testing (the patient’s evaluation of the relationship between himself and the outside world); (3) symptomatic behavior that does not seriously violate social norms, although personal functioning may be considerably impaired; (4) a disturbance that has its onset early in life and is enduring—not a transitory reaction to stress; and (5) the absence of a discernible medical cause or structural disease of the brain. The foregoing definition of anxiety and its allied disorders has the virtue of being descriptive without committing one to any theory of causation.


Neurology_Adams

Neurology_Adams. The genesis of the anxiety, phobic, and obsessive states remains elusive. It is generally conceded that they do not arise de novo. The antecedents are thought in some quarters to be abnormalities in personality development, strongly influenced by genetic factors and molded by stressful events in the life of the individual (Noyes et al), introduced by Engel in 1977 as the biopsychosocial theory of mental health and mental illness. Traits of this nature undoubtedly arise in several individuals from the same family. Thus any discussion requires a brief digression into the origins of normal personality development and departures from it. Even if one is not certain of a relationship between development and psychologic disorders in the broad category of neurosis, it is clear from the interactions of daily life that minor forms of anxiety contribute to the makeup of the normal personality.


Neurology_Adams

Neurology_Adams. Chapter 27 introduced the concept of personality and its development. There it was pointed out that the term embraces the totality of a person’s mental attributes, observable behavior, and reportable subjective experience—the sum of which distinguishes one individual from all others. Thus it includes elements of what might be called the individual’s character and includes intelligence, drives, temperament, and sentiments—in short, all forces from within the organism that determine a person’s reactions to the prevailing environment. The term character is almost synonymous with personality but is less useful in medicine because of its emphasis on interpersonal and ethical aspects and its moralistic connotation. Pertinent to this subject matter is the assumption that in approximately 15 percent of the general population, certain personality traits are so pronounced as to be distressing to the individual and disturbing to others, even though the patient is not manifestly sociopathic or


Neurology_Adams

Neurology_Adams. of the general population, certain personality traits are so pronounced as to be distressing to the individual and disturbing to others, even though the patient is not manifestly sociopathic or psychotic.


Neurology_Adams

Neurology_Adams. The roots of personality features such as boldness and timidity, novelty seeking and excitability, level of energy and motor activity, fearfulness and fearlessness, social adaptability and rigidity or stubbornness are already evident in the first months of life. Monozygotic twins are alike (but not absolutely identical) in these respects, even when reared apart. Gesell and his colleagues, in their studies of infants in the middle of the last century (see Chap. 27), observed individual differences that are clearly innate; each of these characteristics is likely to be genetically determined, like intelligence. The personalities that result are as individualistic as fingerprints. One example of a biologic and genetic basis of a human personality trait, albeit to a limited degree, has been found in the expression of thrill seeking, exploration, and excitability. For example, according to the early work of Cloninger and colleagues (1996), polymorphisms of a dopamine receptor gene accounts


Neurology_Adams

Neurology_Adams. in the expression of thrill seeking, exploration, and excitability. For example, according to the early work of Cloninger and colleagues (1996), polymorphisms of a dopamine receptor gene accounts in small measure for the genetic variability of this personality type. Findings such as these have been reproduced for similar polymorphisms that contribute to the traits of timidity, anxiety, and obsessiveness. The notion, expressed by authors such as Kandel, that genetics will explain a large part of mental function and mental illness sounds reasonable enough, but the data to establish this are far from complete.


Neurology_Adams

Neurology_Adams. The interesting and related construct of a “national character” is embedded in social discourse but has not been extensively studied. It is mentioned here to allow for a more complete picture of the concept of character. A survey by Terracciano and colleagues indicates that mean personality traits in 49 cultures do not correspond to general stereotypes and are therefore probably simply contrivances for maintaining national identity. Similar comments can be proffered regarding sex differences in personality that are embedded in cultural stereotypes but these latter personality profiles have more data to suggest a degree of uniformity and validity in differences between men and women in all cultures.


Neurology_Adams

Neurology_Adams. An unsolved problem is whether each of the personality types accepted by the American Psychiatric Association is predictive or determinative of a later mental disorder. In this regard, 2 broad groups of personality disorders can be recognized. In one group—comprising the paranoid, schizoid, cyclothymic, and obsessive-compulsive personality types—there are obvious similarities to major types of psychiatric illness. Thus, among patients who develop paranoid schizophrenia, a considerable number will have had the attributes described under “paranoid personality type.” Similarly, among patients who develop schizophrenia of another type, the history will frequently disclose a preexistent “schizoid” personality. In fact, it may be difficult to judge where the personality disorder leaves off and the schizophrenic illness began. Similarly, it seems clear from several family studies that the cyclothymic personality is related to bipolar disease. Obsessive-compulsive personality is related not


Neurology_Adams

Neurology_Adams. the schizophrenic illness began. Similarly, it seems clear from several family studies that the cyclothymic personality is related to bipolar disease. Obsessive-compulsive personality is related not only to obsessive-compulsive neurosis, as one might expect, but also to depressive disease. The notion of clusters of personality traits has been introduced and may be more useful in clinical work than are the discrete personality types (see Tyrer).