Neurology_Adams

Neurology_Adams. The diagnosis of acid maltase deficiency in early-onset cases is readily confirmed by muscle biopsy, but later onset cases may show only nonspecific changes. The main features, when found, are vacuoles containing periodic acid-Schiff (PAS)–positive diastase-digestible material; they stain intensely for acid phosphatase. The glycogen particles lie in aggregates; electron microscopy shows some of them to occupy lysosomal vesicles and others, to lie free. The myofibrils are disrupted and some muscle fibers degenerate. Glycogen accumulation is more pronounced in type 1 fibers. The earlier mentioned blood-spot test is useful in cases, particularly those of late onset, that have the typical characteristics of disease but display only nonspecific histopathologic changes.


Neurology_Adams

Neurology_Adams. As indicated earlier, in the more severe infantile form of acid maltase deficiency, heart muscle and the large neurons of the spinal cord and brainstem may also accumulate glycogen and degenerate. The difference in severity between infant and adult forms relates to the completeness of enzyme deficiency, but possibly other factors are also at work as more than one of the three types may occur in the same family. Treatment The adult who is threatened by respiratory failure should be observed frequently with measurements of vital capacity and blood gases. Umpleby and coworkers reported that a low-carbohydrate, high-protein diet may be beneficial. A few of our patients died unexpectedly during sleep. Respiratory support (rocking bed, nasal positive pressure, cough-assist devices, and negative-pressure cuirass) may prolong life.


Neurology_Adams

Neurology_Adams. Enzyme replacement therapy is available to treat Pompe disease. Recombinant acid alpha-glucosidase has been shown to prolong survival in the typical infantile Pompe case, but the benefits are modest in later-onset cases, although walking was improved and pulmonary function stabilized in one series (van der Ploeg et al). The agent is injected intravenously every 2 weeks. The same approach has been used in cases of infantile onset (Kishani et al). Myophosphorylase Deficiency (Type V Glycogenosis; McArdle Disease, PYGM Mutation) and Phosphofructokinase Deficiency (Type VII Glycogenosis; Tarui Disease, PFKM Mutation)


Neurology_Adams

Neurology_Adams. These disorders are considered together because they are clinically virtually identical and both express themselves by the development of muscle cramps after exercise (actually true physiologic contractures, as described in Chap. 46). In both diseases, an otherwise normal 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 exercise, either isometric (carrying heavy weights) or dynamic (climbing stairs or walking uphill), causes the muscles to shorten (contracture), a result of their inability to relax. After vigorous exercise, episodes of myoglobinuria are common, in some cases resulting in renal failure. With mild sustained activity, the patient experiences progressive muscle fatigue and weakness, which diminish following a brief pause. The patient can then resume his activities at the original pace (“second-wind” phenomenon). During


Neurology_Adams

Neurology_Adams. patient experiences progressive muscle fatigue and weakness, which diminish following a brief pause. The patient can then resume his activities at the original pace (“second-wind” phenomenon). During the second-wind phase, the patient copes with his symptoms by increasing cardiac output and substituting free fatty acids and blood-borne glucose for muscle glycogen (Braakhekke et al).


Neurology_Adams

Neurology_Adams. The primary abnormality in McArdle disease is a deficiency of myophosphorylase, which prevents the conversion of glycogen to glucose-6-phosphate. Phosphofructokinase deficiency (Tarui disease) interferes with the conversion of glucose-6-phosphate to glucose-1- phosphate; the defect in the latter condition is also present in red blood cells (Layzer et al). The mutations for the conditions are named above and located on different chromosomes and analysis of DNA from the patient’s leukocytes can be used for genetic diagnosis. The muscle (M) subunit of the phosphofructokinase protein in Tarui disease is at fault. This defect predominates in Ashkenazi Jewish men.


Neurology_Adams

Neurology_Adams. Clinical variations of these disorders, particularly in severity and age of onset, are well known. Some patients, with no previous symptoms of cramps or myoglobinuria, develop progressive weakness of limb muscles in the sixth or seventh decade. One of these older patients came to our attention because of chronically elevated levels of CK and mild muscle cramping after climbing stairs. In others, rapidly progressive weakness became evident in infancy, with early death from respiratory failure. Curiously, these extreme forms are not directly related to severity of the enzyme deficiencies.


Neurology_Adams

Neurology_Adams. The contracted muscles, unlike muscles in other involuntary spasms, no longer use energy and they are more or less electrically silent (i.e., no electrical activity is recorded from maximally contracted muscle during the cramps). Moreover, the muscle does not produce lactic acid. The shortened state is spoken of as physiologic contracture as discussed in the introductory sections of this chapter. Ischemia contributes to this condition by denying glucose to the muscle, which then cannot function adequately on fatty acids and nonglucose substrates. These features are the basis of the forearm ischemic exercise test, which, although controversial in its use and sensitivity, may be helpful if performed carefully. An indwelling catheter is placed in the antecubital vein and a basal blood sample is obtained. Above the elbow, a sphygmomanometer cuff is inflated to exceed arterial pressure. After 1 min of vigorous hand exercise (30 hand closures against an ergometer), blood samples are


Neurology_Adams

Neurology_Adams. sample is obtained. Above the elbow, a sphygmomanometer cuff is inflated to exceed arterial pressure. After 1 min of vigorous hand exercise (30 hand closures against an ergometer), blood samples are obtained at 1 and 3 min. Normal individuals show a 3to 5-fold increase in blood lactate. In patients with either McArdle or Tarui disease, the lactate fails to rise. This procedure has reportedly caused a localized rhabdomyolysis (Meinck et al), for which reason Griggs and associates recommend that the test be carried out without a blood pressure cuff. Problems with consistency in conducting the test and in processing blood samples for lactate limit its validity unless it is performed by experienced individuals and laboratories. Definitive diagnosis depends more on the histochemical stains of biopsied muscle, which reveal an absence of phosphorylase activity (in McArdle disease) or of phosphofructokinase activity (in Tarui disease). Genetic analysis, can be used to corroborate the


Neurology_Adams

Neurology_Adams. of biopsied muscle, which reveal an absence of phosphorylase activity (in McArdle disease) or of phosphofructokinase activity (in Tarui disease). Genetic analysis, can be used to corroborate the diagnosis, but it is unnecessary if the histochemical tests are definitive.


Neurology_Adams

Neurology_Adams. Treatment The main treatment is a planned reduction and intermittency in physical activity. Sucrose, taken as 75 g in a beverage, has been shown by Vissing and Haller to cause a short-lived improvement in exercise tolerance, and they propose that exercise-induced rhabdomyolysis can be avoided by a well-timed drink. Fructose and creatine taken orally are also said to be helpful in some cases, but the reported results are not as impressive as they are for sucrose. Improvement has also been described after the administration of glucagon (Kono et al) and with a high-protein diet (Slonim and Goans), but these effects are not consistent. Other Forms of Glycogenosis (See Table 45-5)


Neurology_Adams

Neurology_Adams. Of the remaining glycogen storage diseases, type III (debranching enzyme deficiency; Cori-Forbes disease, AGL Mutation) affects muscle but only inconsistently. The childhood form is characterized mainly by a benign hepatopathy, sometimes accompanied by diminished muscle strength and tone. An adult form beginning in the third and fourth decades presents with proximal and distal myopathy. The course is slowly progressive and may be associated with wasting of the leg and hand muscles. Several patients have developed weakness during adult life complained of rapid fatigue and aching of muscles, occurring with exertion and first noticed at an early age. Serum CK values were elevated and the EMG showed a myopathic picture as well as increased insertional activity, pseudomyotonic discharges, and fibrillation potentials. Rarely in the adult form, glycogen also accumulates in the peripheral nerves, giving rise to mild symptoms of polyneuropathy. The enzymatic defect is one of


Neurology_Adams

Neurology_Adams. discharges, and fibrillation potentials. Rarely in the adult form, glycogen also accumulates in the peripheral nerves, giving rise to mild symptoms of polyneuropathy. The enzymatic defect is one of amylo-1,6-glucosidase deficiency.


Neurology_Adams

Neurology_Adams. Disturbance of skeletal muscle is even less prominent in type IV glycogenosis (branching enzyme deficiency, or Andersen disease, which is also implicated in the polyglucosan disease that causes a special neuropathy discussed in Chap. 43, a motor system disease with flaccid bladder, or a leukoencephalopathy with dementia). This is a progressive disease of infancy and early childhood, characterized by cirrhosis and chronic hepatic failure, usually with death in the second or third year. Hepatomegaly as a result of accumulation of an abnormal polysaccharide is a universal finding. Muscle weakness and atrophy, hypotonia, and contractures occur less regularly and are overshadowed by the liver disease. The diagnostic hallmark of the myopathy is the presence of basophilic, intensely PAS-positive polysaccharide granules in skin and muscle.


Neurology_Adams

Neurology_Adams. The remaining nonlysosomal glycogenoses (types VIII through XI) need only be mentioned briefly. They are all rare and clinically heterogeneous, and a myopathy— characterized by intolerance to exercise, cramps, myoglobinuria, elevated CK, and, sometimes, renal failure—has been observed in a small proportion of them. Phosphoglycerate kinase deficiency (type IX glycogenosis, PGK1 mutation) differs in that it is inherited as a sex-linked recessive trait localized to chromosome Xq13. Hemolytic anemia—becoming evident soon after birth—mental retardation, seizures, and tremor are other features that set this glycogenosis apart from the others. The myopathic features of the lysosomal and nonlysosomal glycogenoses are listed in Table 45-5 and detailed accounts can be found in the monographs by Griggs and associates and of Engel and Franzini-Armstrong. Disorders of Lipid Metabolism Affecting Muscle (Lipid Myopathies)


Neurology_Adams

Neurology_Adams. Disorders of Lipid Metabolism Affecting Muscle (Lipid Myopathies) Although it has long been known that lipids are an important source of energy in muscle metabolism (along with glucose), it was only in 1970 that W.K. Engel and associates reported the abnormal storage of lipid in muscle fibers attributable to a defect in the oxidation of long-chain fatty acids. The subjects of their report were twin sisters who had experienced intermittent cramping of muscles associated with myoglobinuria after vigorous exercise. In 1973, A.G. Engel and Angelini described a young woman with progressive myopathy, lipid storage predominantly in type 1 muscle fibers, and a deficiency of muscle carnitine, a cofactor required for the oxidation of fatty acids. Since that time, highly sophisticated biochemical techniques have greatly expanded the study of fatty acid metabolism and the identification of many of the primary defects.


Neurology_Adams

Neurology_Adams. Carnitine (b-hydroxy-gamma-N-trimethylamino-butyrate), derived from lysine and methionine, plays a central role in the metabolism of fatty acids. Approximately 75 percent of carnitine comes from dietary sources (red meat and dairy products); the remainder is synthesized in the liver and kidneys. Practically all of the body carnitine is stored in muscle, where it has two main functions: (1) transporting long-chain fatty acylcoenzyme As (CoAs) from the cytosol compartment of the muscle fiber into the mitochondria, where they undergo beta-oxidation, and (2) preventing the intramitochondrial accumulation of acyl-CoAs, thus protecting the muscle cell from the membrane-destabilizing effects of these substances.


Neurology_Adams

Neurology_Adams. To be oxidized, the long-chain fatty acids undergo a series of biochemical transformations. First they are activated to corresponding acyl-CoA esters by acyl-CoA synthetase, which is located on the outer mitochondrial membrane. Because the inner mitochondrial membrane is impermeable to acyl-CoA esters, they are transferred into the mitochondria as acylcarnitine esters. This is accomplished by carnitine palmitoyltransferase I (CPT I), also located on the outer mitochondrial membrane. A second carnitine palmitoyltransferase (CPT II), bound to the inner face of the inner mitochondrial membrane, reconverts the acylcarnitines to fatty acyl-CoAs, which undergo beta-oxidation within the mitochondrial matrix. The steps in the transport of long-chain fatty acids into the mitochondrial matrix (the carnitine cycle) are described in detail in the reviews of DiMauro and colleagues (1973), and DiDonato and Taroni. Isoforms of CPT are critically involved in this process at the inner and outer


Neurology_Adams

Neurology_Adams. (the carnitine cycle) are described in detail in the reviews of DiMauro and colleagues (1973), and DiDonato and Taroni. Isoforms of CPT are critically involved in this process at the inner and outer membranes of the mitochondria.


Neurology_Adams

Neurology_Adams. Despite the many biochemical abnormalities that have been identified in the fatty acid metabolic pathways, there are essentially 3 clinical patterns by which these defects are expressed: 1. One constellation of symptoms referred to as the encephalopathic syndrome has its onset in infancy or early childhood. Its very first manifestation may be sudden death (sudden infant death syndrome [SIDS]), or there may be vomiting, lethargy and coma, hepatomegaly, cardiomegaly, muscular weakness, and hypoketotic hypoglycemia, with prominent hyperammonemia, that is, a Reye-like syndrome. Undoubtedly, instances of this syndrome have not been recognized as abnormalities of fatty acid metabolism but have been designated incorrectly as the Reye syndrome or as SIDS. They are discussed in Chap. 36 with other inherited metabolic disorders.


Neurology_Adams

Neurology_Adams. 2. A second (myopathic) syndrome appears in late infancy, childhood, or adult life and takes the form of a progressive myopathy, with or without cardiomyopathy. The myopathy may follow episodes of hypoketotic hypoglycemia or may develop de novo. 3. The third syndrome is one that usually begins in the second decade of life and is induced by a sustained period of physical activity or fasting. It is characterized by repeated episodes of rhabdomyolysis with or without myoglobinuria. 4. Summarized in the following text are the main disorders of fatty acid metabolism that affect skeletal muscle; these are rare but interesting diseases.


Neurology_Adams

Neurology_Adams. 4. Summarized in the following text are the main disorders of fatty acid metabolism that affect skeletal muscle; these are rare but interesting diseases. To date, this is the only form of carnitine deficiency that can be considered primary (see further on for discussion of the secondary types). Its main clinical features are progressive lipid storage myopathy and cardiomyopathy, sometimes associated with the signs of hypoketotic hypoglycemia. There is no dicarboxylic aciduria, in distinction to the secondary beta-oxidation defects, in all of which dicarboxylic aciduria is present. The cardiomyopathy, which is fatal if untreated, responds to oral administration of l-carnitine, 2 to 6 g/d. This disorder is inherited as an autosomal recessive trait. In these families there is frequently a history of sudden unexplained death in siblings, so that early identification of affected children is essential.


Neurology_Adams

Neurology_Adams. This disease is also inherited as an autosomal recessive trait and the gene encoding carnitine palmitoyltransferase (CPT) has been identified. There are three types: types I, IIA, and IIB. Type I is the most common. It affects males predominantly, beginning in the second decade of life. Attacks of myalgia, cramps, and muscle weakness, “tightness,” and stiffness are precipitated by sustained (although not necessarily intense) exercise and less often by a prolonged period of fasting. Fever, anesthesia, drugs, emotional stress, and cold have been additional but rare precipitating events. The attacks vary greatly in frequency. They are usually accompanied by myoglobinuria, with resultant renal failure in about one-fourth of cases (DiMauro et al, 1973). Rest does not abort the attacks and, once initiated, there is no second-wind phenomenon. There are no warning signs of an impending attack. Any muscle group may be affected. Persistence of weakness after an attack is uncommon. Serum CK


Neurology_Adams

Neurology_Adams. once initiated, there is no second-wind phenomenon. There are no warning signs of an impending attack. Any muscle group may be affected. Persistence of weakness after an attack is uncommon. Serum CK rises to high levels not only during attacks but also after vigorous exercise without myoglobinuria. A mild form is more likely to occur in females.


Neurology_Adams

Neurology_Adams. In type I deficiency, necrosis of muscle fibers, particularly type I fibers, occurs during attacks, followed by regeneration. Between attacks, the muscle appears normal. In type IIA, lipid bodies accumulate in the liver, and in type IIB, excess lipid is detected in heart, liver, kidneys, and skeletal muscle. CPT is either undetectable or greatly reduced in muscle, and assays are now available for the measurement of CPT I and II in circulating lymphocytes and cultured fibroblasts. Testing for the mutation is available. Treatment A high-carbohydrate, low-fat diet, ingestion of frequent meals, and additional carbohydrate before and during exercise appear to reduce the number of attacks. Patients need to be instructed about the risks of prolonged exercise and skipped meals. Recently, the use of bezafibrate, a drug used for dyslipidemia, has been helpful in patients with mild CPT II.


Neurology_Adams

Neurology_Adams. This is occasionally the result of severe dietary deprivation or impaired hepatic and renal function. Such instances have been observed in patients with alcoholic–nutritional diseases and kwashiorkor, in premature infants receiving parenteral nutrition, in patients with chronic renal failure undergoing dialysis, and rarely, as a complication of valproate therapy. However, most cases of systemic carnitine deficiency are a result of defects of beta-oxidation, described as follows. Carnitine acylcarnitine translocase deficiency This condition causes muscular weakness, cardiomyopathy, hypoketotic hypoglycemia, and hyperammonemia, which develop in early infancy and usually lead to death in the first month of life.


Neurology_Adams

Neurology_Adams. Long-chain acyl-CoA dehydrogenase deficiency (ACLDVL mutation) The presentation is in infancy, with recurrent episodes of fasting hypoglycemic coma, muscle weakness, and myoglobinuria, and sometimes sudden death. Survivors may develop a progressive myopathy. Administration of carnitine improves the cardiac disorder and prevents metabolic attacks. Medium-chain acyl-CoA dehydrogenase deficiency (ACADM mutation) This is a cause of SIDS and a Reye-like syndrome. About half of survivors develop a lipid-storage myopathy in childhood or adult life. The abnormal gene has been mapped to chromosome 1p31. Oral l- carnitine may be of therapeutic value. Short-chain acyl-CoA dehydrogenase deficiency This myopathy in a limb-girdle distribution may appear initially in older children and adults, or it may follow episodic metabolic disorders in infancy.


Neurology_Adams

Neurology_Adams. Short-chain acyl-CoA dehydrogenase deficiency This myopathy in a limb-girdle distribution may appear initially in older children and adults, or it may follow episodic metabolic disorders in infancy. deficiency This is a disease of infancy marked by episodes of Reye-like syndrome, hypoketotic hypoglycemia, lipid storage myopathy, cardiomyopathy, and sometimes sudden death. deficiency This presents as an episodic disorder such as the one described previously, long-chain hydroxyacyl-CoA dehydrogenase deficiency (HAD), but its onset is in adolescence. Recurrent attacks may be associated with myoglobinuria.


Neurology_Adams

Neurology_Adams. Multiple acyl-CoA dehydrogenase deficiency; glutaric aciduria type II Some cases are caused by a deficiency of electron transfer flavoprotein (ETF) and others by a deficiency of electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). In the severest form of multiple acyl-CoA dehydrogenase deficiency (MADD), infants are born prematurely and many die within the first week of life; added to the common metabolic abnormalities are multiple congenital defects and a characteristic “sweaty feet” odor. In less severe cases, the congenital anomalies are absent. In the least severe form, the onset may be in late infancy (with episodic metabolic disturbances) or in childhood or adult life (with a lipid storage myopathy and a deficiency of serum and muscle carnitine). The prenatal diagnosis of glutaric aciduria type II (GA II) is suggested by the finding of large amounts of glutaric acid in the amniotic fluid. In the milder forms of the disease, oral riboflavin (100 to 300 mg/d) may be


Neurology_Adams

Neurology_Adams. of glutaric aciduria type II (GA II) is suggested by the finding of large amounts of glutaric acid in the amniotic fluid. In the milder forms of the disease, oral riboflavin (100 to 300 mg/d) may be helpful.


Neurology_Adams

Neurology_Adams. Muscle coenzyme Q10 deficiency This condition presents as a slowly progressive lipid storage myopathy from early childhood. The basic defect is in coenzyme Q10 in the respiratory chain of muscle mitochondria. The administration of coenzyme Q10 has improved the myopathic weakness. Neutral lipid storage diseases (Chanarin-Dorfman disease, PNPLA2 mutation) These abnormalities of lipid metabolism are distinct from the beta-oxidation defects; they occur in 2 forms, Chanarin disease, which is characterized by ichthyosis, and a form without skin changes. A progressive myopathy is combined with neurologic manifestations, such as developmental delay, ataxia, neurosensory hearing loss, and microcephaly. The lipid material is stored in muscle as triglyceride droplets that are nonlysosomal and non–membrane-bound.


Neurology_Adams

Neurology_Adams. Several myopathic diseases are related to alterations in thyroid function: (1) chronic thyrotoxic myopathy; (2) exophthalmic ophthalmoplegia (infiltrative orbital ophthalmopathy—Graves disease); (3) myasthenia gravis associated with thyrotoxicosis; (4) periodic paralysis associated with thyrotoxicosis; and (5) muscle hypertrophy and slow muscle contraction and relaxation associated with myxedema and cretinism. Although they are not common, we have encountered up to several examples of these diseases in a single year in our general hospital.


Neurology_Adams

Neurology_Adams. This disorder, first noted by Graves and Basedow in the early nineteenth century, is characterized by progressive weakness and wasting of the skeletal musculature, occurring in conjunction with overt or covert (“masked”) hyperthyroidism. The thyroid disease is usually chronic and the goiter is usually of the nodular rather than the diffuse type. Exophthalmos and other classic signs of hyperthyroidism are often present but need not be. This complication of hyperthyroidism is most frequent in middle age, and men are more susceptible than women. Some degree of myopathy has been found when sought in more than 50 percent of thyrotoxic patients, although the manifestations may be subtle. The onset is insidious, and the weakness progresses over weeks and months. The muscular disorder as noted is most often mild in degree, but it may be so severe as to suggest progressive spinal muscular atrophy (motor system disease). Muscles of the pelvic girdle and thighs are weakened more than others


Neurology_Adams

Neurology_Adams. is most often mild in degree, but it may be so severe as to suggest progressive spinal muscular atrophy (motor system disease). Muscles of the pelvic girdle and thighs are weakened more than others (Basedow paraplegia), although all are affected to some extent, even the bulbar muscles and, albeit rarely, the ocular ones. However, the shoulder and hand muscles show the most conspicuous atrophy (not an obligatory feature). Tremor and twitching during contraction may occur, but we have not seen fasciculations. The tendon reflexes are of average briskness, possibly more lively than normal. Both the contraction and relaxation phases of the tendon reflexes are shortened, but usually this cannot be detected by the clinician.


Neurology_Adams

Neurology_Adams. Serum concentrations of muscle enzymes are not increased and may be reduced. The EMG is typically normal, although the action potentials may be abnormally brief or polyphasic. Biopsies of muscle, except for slight atrophy of both types 1 and 2 fibers and an occasional degenerating fiber, have been normal. Muscle power and bulk are gradually restored when thyroid hormone levels are reduced to normal levels. Exophthalmic Ophthalmoplegia (Graves Ophthalmopathy) (See discussion in Chap. 13)


Neurology_Adams

Neurology_Adams. Exophthalmic Ophthalmoplegia (Graves Ophthalmopathy) (See discussion in Chap. 13) This refers to the cooccurrence of weakness of the ocular muscles and exophthalmos in patients with Graves disease (pupillary and ciliary muscles are always spared). The exophthalmos varies in degree, sometimes being absent at an early stage of the disease, and it is not in itself responsible for the muscle weakness. Often there is some degree of orbital pain. Both the exophthalmos and the weakness of the extraocular muscles may precede the signs of hyperthyroidism, be associated with the other classic features of hyperthyroidism (tachycardia, weight loss, tremor), or may follow effective treatment of the disorder.


Neurology_Adams

Neurology_Adams. The eye signs, both ocular paresis and exophthalmos, become apparent over days or weeks and may occasionally be unilateral, especially at the onset. Any of the external eye muscles may be infiltrated, usually one more than others, accounting for strabismus and diplopia; the inferior and medial recti are the most frequently affected, but upward movements are usually limited as well. The typical but not invariable sign of lid retraction imparts a staring appearance. Subtle exophthalmos can be appreciated by standing above and behind the seated patient and observing the relative positions of the lids and the eyelashes. Conjunctival edema and vascular engorgement over the insertions of the medial and lateral rectus muscles can be appreciated by inspecting and palpating the globe in its extreme lateral positions. These swollen muscles are easily visible on orbital ultrasonography, CT, and MRI. The differential diagnosis of this imaging appearance is from orbital pseudotumor, a usually


Neurology_Adams

Neurology_Adams. lateral positions. These swollen muscles are easily visible on orbital ultrasonography, CT, and MRI. The differential diagnosis of this imaging appearance is from orbital pseudotumor, a usually painful condition, which is discussed in Chap. 13.


Neurology_Adams

Neurology_Adams. Examination of the eye muscles in biopsy and autopsy material has shown prominent fibroblasts, many degenerated fibers, and infiltrations of lymphocytes, mononuclear leukocytes, and lipocytes; hence the term infiltrative ophthalmopathy. These histopathologic findings are suggestive of an autoimmune disease—a hypothesis supported by the finding of serum antibodies that react (inconsistently) with extracts of eye muscles (Kodama et al). Possibly the antibodies target glycosaminoglycans of the orbital fibroblasts. A sensitivity of muscle fibers to beta-adrenergic activity caused by excessive thyroid hormone has also been postulated. Other factors are almost certainly involved, such as the small size of oculomotor motor units, the absence of dystrophin, and the rich mitochondrial content.


Neurology_Adams

Neurology_Adams. Treatment Because the ophthalmoparesis often runs a self-limited course, as does the exophthalmos, therapy is difficult to evaluate. Certainly the maintenance of a euthyroid state seems desirable (Dresner and Kennerdell). If the exophthalmos is slight, topical applications of adrenergic blocking agents (guanethidine eye drops, 5 percent) and ophthalmic ointment to prevent corneal drying are adequate. Severe exophthalmos, marked by periorbital and conjunctival edema, and the extraocular muscle weakness may be partially controlled by high doses of corticosteroids (about 80 mg/d prednisone). Because of the hazards of protracted corticosteroid therapy, this approach should be reserved for patients who would otherwise require surgical intervention to decompress the contents of the orbit. In a number of such cases, it has been possible for the patient treated with corticosteroids to weather the crisis for several weeks or more and avoid the damaging effects of extreme exophthalmos and risks


Neurology_Adams

Neurology_Adams. of such cases, it has been possible for the patient treated with corticosteroids to weather the crisis for several weeks or more and avoid the damaging effects of extreme exophthalmos and risks of surgery. Exophthalmos of a degree that threatens to injure the cornea or cause blindness requires tarsorrhaphy or decompression by removal of the roof of the orbit.


Neurology_Adams

Neurology_Adams. This disorder closely resembles familial hypokalemic periodic paralysis (as described in Chap. 46). It consists of attacks of mild to severe weakness of the muscles of the trunk and limbs; usually the cranial muscles are spared. The weakness develops over a period of a few minutes or hours and lasts for part of a day or longer. In some series of patients with periodic paralysis, as many as half have had hyperthyroidism and most of them have been Asian males. Unlike the typical hypokalemic form, thyrotoxic periodic paralysis is not a familial disorder and its onset is usually in early adult life. Nevertheless, in most of the thyrotoxic cases, the serum potassium levels have been low during the attacks of weakness and the administration of 100 to 200 mg of potassium chloride has terminated the episodes. Propranolol in doses of 160 mg daily in divided doses is also helpful in preventing the episodes. More importantly, effective treatment of the hyperthyroidism abolishes the periodic


Neurology_Adams

Neurology_Adams. the episodes. Propranolol in doses of 160 mg daily in divided doses is also helpful in preventing the episodes. More importantly, effective treatment of the hyperthyroidism abolishes the periodic attacks of weakness in more than 90 percent of cases. A mutation in the potassium channel, Kir2.6, has been found to confer susceptibility to the disease. Other aspects of periodic paralysis are discussed in Chap. 46.


Neurology_Adams

Neurology_Adams. Myasthenia is discussed fully in Chap. 46. Here only a few remarks are made on its special relationship to thyrotoxicosis. Myasthenia gravis in its typical autoimmune, anticholinesterase-responsive form may accompany hyperthyroidism or rarely, hypothyroidism, which are also autoimmune in nature. Approximately 5 percent of patients with myasthenia have hyperthyroidism and the frequency of myasthenia gravis in patients, while low, is 20 to 30 times higher in hyperthyroidism than in the general population. Either condition may appear first, or they may coincide. The weakness and atrophy of chronic thyrotoxic myopathy may be added to that of the myasthenia without appearing to affect the requirement for or response to anticholinesterase medications. By contrast, hypothyroidism, even of mild degree, seems to aggravate the weakness of myasthenia gravis, greatly increasing the need for pyridostigmine and at times inducing a myasthenic crisis. In these cases, thyroxine is beneficial and, with


Neurology_Adams

Neurology_Adams. seems to aggravate the weakness of myasthenia gravis, greatly increasing the need for pyridostigmine and at times inducing a myasthenic crisis. In these cases, thyroxine is beneficial and, with respect to myasthenia, restores the patient to the status that existed before the onset of thyroid insufficiency. The myasthenia should probably be regarded as an autoimmune disease independent of the thyroid disease and each must be treated separately.


Neurology_Adams

Neurology_Adams. Abnormalities of skeletal muscle consisting of diffuse myalgia and increased volume, stiffness, and slowness of contraction and of relaxation are common manifestations of hypothyroidism, whether in the form of myxedema or cretinism. These changes probably account for the relatively large tongue and dysarthria that one observes in myxedema. Weakness, however, is not a prominent feature. The presence of action myospasm and myokymia (both of which are rare) and of percussion myoedema and slowness of both the contraction and relaxation phases of tendon reflexes assists the examiner in making a bedside diagnosis. The administration of thyroxine corrects the muscle disturbance.


Neurology_Adams

Neurology_Adams. Cretinism in association with these muscle abnormalities is known as the Kocher-Debré-Semelaigne syndrome, and myxedema in childhood or adult life with muscle hypertrophy is the Hoffmann syndrome; the latter simulates hypertrophia musculorum vera and myotonia congenita. In neither cretinism nor myxedema, however, is there evidence of true myotonia, either by clinical testing or by EMG, although muscle action potentials are myopathic and often show bizarre high-frequency discharges. Serum transaminase values are normal but CK levels are usually elevated, often markedly so. Muscle biopsies have disclosed only the presence of large fibers or an increase in the proportion of small fibers (either type 1 or 2) and slight distention of the sarcoplasmic reticulum and subsarcolemmal glycogen (probably all a result of disuse atrophy). Pathogenesis of the Thyroid Myopathies


Neurology_Adams

Neurology_Adams. Pathogenesis of the Thyroid Myopathies How thyroid hormone affects the muscle fiber is still a matter of conjecture. Clinical data indicate that thyroxine influences the contractile process in some manner but does not interfere with the transmission of impulses in the peripheral nerve across the myoneural junction or along the sarcolemma. In hyperthyroidism an undefined functional disorder enhances the speed of the contractile process and reduces its duration, the net effect being fatigability, weakness, and loss of endurance of muscle action. In hypothyroidism, muscle contraction is slowed, as is relaxation, and its duration is prolonged.


Neurology_Adams

Neurology_Adams. The speed of the contractile process is related to the quantity of myosin adenosine triphosphatase (ATPase), which is increased in hyperthyroid muscle and decreased in hypothyroid muscle. The speed of relaxation depends on the rate of release and reaccumulation of calcium in the endoplasmic reticulum. This is slowed in hypothyroidism and increased in hyperthyroidism (Ianuzzo et al). The myopathic effects of hypothyroidism need to be distinguished from those of a neuropathy, which may rarely complicate hypothyroidism (see Chap. 43). The widespread use of adrenal corticosteroids has created a class of muscle diseases similar to the one that occurs in the Cushing disease as described many decades ago by Müller and Kugelberg. A deficiency of corticosteroids, as occurs in Addison disease, also causes generalized weakness and asthenia, but without an identifiable muscle disease.


Neurology_Adams

Neurology_Adams. The prolonged use of corticosteroids causes the proximal limb and girdle musculature to become weak to the point of causing difficulty in elevating the arms and arising from a sitting, squatting, or kneeling position; walking upstairs may also be hampered. Some individuals seem to be more susceptible than others. The problem often arises of distinguishing an iatrogenic steroid-induced myopathy from the weakness produced by a primary neuromuscular disorder that is being treated with these medications such as one of the myositides or myasthenia. In some of our myasthenic patients, the use of high-dose corticosteroids has resulted in a selective, rapid, and severe weakness of the hip flexors.


Neurology_Adams

Neurology_Adams. The EMG is normal or mildly myopathic, with small and abundant action potentials but no fibrillations. Biopsies disclose only a slight variation in fiber size with atrophic fibers, mainly of type 2b, but little or no fiber necrosis and no inflammatory cells. Under electron microscopic examination there are aggregates of mitochondria, accumulations of glycogen and lipid, and slight myofibrillar loss that suggest more disuse atrophy than they do a primary muscle disorder. The serum CK and aldolase are usually normal. These changes are the same in Cushing disease and an otherwise unexplained proximal myopathy with these features suggests that diagnosis (Cushing disease and Cushing syndrome).


Neurology_Adams

Neurology_Adams. There is an imprecise correlation between the total dose of corticosteroid administered and the severity of muscle weakness. Nevertheless, in patients who develop this type of myopathy, the corticosteroid dosage has usually been high and sustained over a period of months or years. All corticosteroids may produce the disorder, although fluorinated ones, on uncertain evidence, are said to be more culpable than others. Discontinuation or reduction of corticosteroid administration leads to gradual improvement and recovery; alternate-day regimens may also allow recovery, albeit gradually. As the foregoing discussion implies, the mechanism by which corticosteroids cause muscle weakness is not known. In corticosteroid-treated animals, there is a measurable decrease in the uptake of amino acids and protein synthesis by muscle, but the underlying pathways have not been elucidated. This has even greater bearing on the next discussed subject.


Neurology_Adams

Neurology_Adams. In addition to the proximal myopathy induced by the long-term use of steroids, an acute and far more severe myopathy has been recognized in critically ill patients. It was described initially with cases of severe asthma in patients who were exposed to high doses of steroids for treatment. Subsequently, this acute myopathy has been recognized with all types of critical systemic diseases and organ failure, again, usually in the context of the administration of high doses of corticosteroids but in a few cases, with sepsis and shock without exposure to this class of medication. Moreover, the use of neuromuscular blocking agents appears to play an important complementary role in the genesis of the myopathy, being reported as a factor in more than 80 percent of cases; it is uncertain whether these agents alone, without sepsis or organ failure, can produce a similar process (see reviews by Gorson and Ropper, Lacomis et al, and Barohn et al).


Neurology_Adams

Neurology_Adams. Ropper, Lacomis et al, and Barohn et al). Patients who acquire this problem may have been exposed to high doses of corticosteroids for only brief periods. Exceptional instances have been reported in which the myopathy was induced by doses as low as 60 mg prednisone administered for 5 days, but we have not encountered such a case. The degree and type of simultaneous exposure to neuromuscular blocking agents have varied, but the doses have generally also been quite high, falling in the range of a total dose of 500 to 4,000 mg of pancuronium or an equivalent, over several days.


Neurology_Adams

Neurology_Adams. The severe generalized muscle weakness usually becomes evident when the systemic illness subsides, often as attempts are made to wean the patient from the ventilator. The tendon reflexes are normal or diminished, and there may be confounding features of a “critical illness polyneuropathy,” which is discussed in Chap. 43. Most of our patients with acute myopathy have recovered over a period of 6 to 12 weeks after the corticosteroid agent has been greatly reduced in dose or withdrawn, but a few have remained weak for as long as a year.


Neurology_Adams

Neurology_Adams. Serum CK is elevated, at least early in the process. The EMG discloses the characteristic features of a myopathy; often there are fibrillations as well, theorized to be a result of separation of the motor endplate region from intact segments of muscle fibers. A concurrent polyneuropathy and any residual effects of neuromuscular blockade can be excluded by appropriate electrophysiologic studies. Muscle biopsy shows varying degrees of necrosis and vacuolation affecting mainly type 2 fibers. The identifying histologic feature is a striking loss of thick (myosin) filaments. Severe degrees of muscle necrosis occur and have been accompanied by massively elevated CK levels and by myoglobinuria with renal failure.


Neurology_Adams

Neurology_Adams. Several experimental observations may explain the apparent additive effect on muscle of corticosteroids and neuromuscular blocking agents. Animals exposed to high doses of steroids soon after experimental denervation of a muscle display a selective loss of myosin, the characteristic finding of acute steroid myopathy. Myosin depletion is reversed by reinnervation but not by withdrawal of the corticosteroids. Furthermore, denervation of muscle has been found to induce an increase in glucocorticoid receptors on the surface of the muscle. On this basis, Dubois and Almon have postulated that exposure to neuromuscular blocking agents creates a functional denervation, rendering the muscle fiber vulnerable to the damaging effects of steroids. It is curious that this myopathy has not been seen after high-dose corticosteroid administration for neurologic diseases such as multiple sclerosis, but the observation of Panegyres and colleagues of a patient with myasthenia who developed a severe,


Neurology_Adams

Neurology_Adams. after high-dose corticosteroid administration for neurologic diseases such as multiple sclerosis, but the observation of Panegyres and colleagues of a patient with myasthenia who developed a severe, myosin-depleted myopathy following high doses of methylprednisolone supports such a dual action of denervation (at the postsynaptic membrane) and glucocorticoids. Whether it also explains the more common circumstance of clinical worsening of myasthenia gravis that sometimes accompanies the initial administration of corticosteroid treatment is also not clear.


Neurology_Adams

Neurology_Adams. Generalized weakness and fatigability are characteristic of adrenocortical insufficiency, whether primary in type, that is, because of Addison disease (infectious, neoplastic, or autoimmune destruction of the adrenal glands or adrenal hemorrhage), or secondary to a pituitary deficiency of adrenocorticotropic hormone (ACTH). The weakness and fatigability, however, are probably related to mostly water and electrolyte disturbances and hypotension, not to a primary disorder of muscle. Perhaps there is also an element of reduced central drive of motor activity. Biopsy has not disclosed any abnormalities of muscle and postmortem examination in one case showed no changes. Likewise, the EMG is normal, and the tendon reflexes are retained. Addisonian weakness responds (as does hyperkalemic paralysis) to glucocorticoid and mineralocorticoid replacement.


Neurology_Adams

Neurology_Adams. Production of excess aldosterone by adrenal adenomas has been the subject of many articles, one of the earliest and most notable being that of Conn muscular weakness has been observed in 75 percent of the reported cases of hyperaldosteronism. In nearly half of those with muscle weakness there was either hypokalemic periodic paralysis or tetany. Chronic potassium deficiency may express itself either by periodic weakness or by a chronic myopathic weakness. An associated severe alkalosis causes the tetany. As in the weakness of Addison disease, there is no structural disorder of muscle, except perhaps for vacuolation, which is the result of severe hypokalemia. Diseases of Parathyroid Glands and Vitamin D Deficiency


Neurology_Adams

Neurology_Adams. Diseases of Parathyroid Glands and Vitamin D Deficiency A proportion of patients with parathyroid adenomas complain of weakness and fatigability. Vicale described the first example of this disorder and remarked on the muscular atrophy and weakness and the pain on passive or active movement. The tendon reflexes were retained. A few scattered muscle fibers had undergone degeneration, but claims for a denervative muscle process are disputed. We have not been impressed with either a myopathy or neuropathy in this disease. In hypoparathyroidism, muscle cramping is prominent, but there are no other neuromuscular manifestations. In both hypoparathyroidism and pseudohypoparathyroidism—the latter with characteristic skeletal abnormalities and, in some instances, mental slowness—the most important muscle abnormality is tetany. This is a result of low ionized serum calcium, which depolarizes axons more than muscle fibers.


Neurology_Adams

Neurology_Adams. Osteomalacia, as a result of vitamin D deficiency and disorders of renal tubular absorption, often includes muscle weakness and pain as common complaints, similar to those in patients with primary hyperparathyroidism and with uremia (see Layzer for further comment).


Neurology_Adams

Neurology_Adams. More striking than any of the foregoing disturbances, in our view, has been a chronic proximal myopathy in conjunction with hypophosphatemia associated with solitary bone cysts. In two of our patients, removal of the cyst restored serum phosphorus levels and cured the generalized muscle weakness. Also known is an uncommon syndrome of severe hypophosphatemia and generalized bone pain in association with usually benign mesenchymal tumors of soft tissue and bone (oncogenic hypophosphatemia). These tumors express a fibroblast growth factor that induces renal wasting of phosphorous. Hypophosphatemic myopathic weakness has been noted in our and other critical care units, precipitated by hyperalimentation solutions; the onset of weakness can be so abrupt in this circumstance, as to simulate the Guillain-Barré syndrome. The oral administration of phosphates to raise serum phosphorus cures the nonneoplastic cases. Presumably phosphorus depletion limits the phosphorylation reactions and the


Neurology_Adams

Neurology_Adams. Guillain-Barré syndrome. The oral administration of phosphates to raise serum phosphorus cures the nonneoplastic cases. Presumably phosphorus depletion limits the phosphorylation reactions and the synthesis of ATP in muscle.


Neurology_Adams

Neurology_Adams. Proximal muscle weakness and atrophy have been recorded as late developments in many acromegalic patients. Formerly thought to be caused by neuropathy, these symptoms in acromegaly have been convincingly shown by Mastaglia and colleagues to be the result of a generalized myopathy. The serum CK is slightly elevated in some cases, and myopathic potentials are observed in the EMG. Biopsy specimens have shown atrophy and reduced numbers of type 2 fibers, but necrosis of only a few fibers. Treatment of the pituitary adenoma and correction of the hormonal changes restores strength. A mild peripheral neuropathy of sensorimotor type has also been reported in a few patients with acromegaly but is far less frequent than carpal tunnel syndrome and other focal entrapments in this disease. MITOCHONDRIAL MYOPATHIES (SEE CHAP. 36)


Neurology_Adams

Neurology_Adams. MITOCHONDRIAL MYOPATHIES (SEE CHAP. 36) The genetic aspects of mitochondrial diseases and the diverse and overlapping clinical syndromes that constitute this category—including the myopathic ones—are discussed in Chap. 37. The histologic change termed ragged red fibers reflects the mitochondrial changes of this class of diseases and is common to many of them, even without manifest symptoms of muscle disease. MYOPATHIES CAUSED BY DRUGS AND TOXINS; RHABDOMYOLYSIS (SEE CHAP. 41)


Neurology_Adams

Neurology_Adams. MYOPATHIES CAUSED BY DRUGS AND TOXINS; RHABDOMYOLYSIS (SEE CHAP. 41) A vast number of drugs and other chemical agents have been identified as myotoxic. In 1989, Curry and colleagues found reports (in the English literature alone) of approximately 100 drugs that had caused rhabdomyolysis and myoglobinuria, mostly acting in an idiosyncratic manner, and the list continues to grow. Additional myotoxic agents that can be expected to appear as new drugs are introduced. Because it is impractical to describe all the implicated drugs and toxins individually, they are broadly categorized and their main features listed in Chap. 41.


Neurology_Adams

Neurology_Adams. Exogenous agents may produce myopathic changes in several ways. They may act directly on muscle cells, either diffusely or locally, as occurs with intramuscular injections, or the muscle damage can be a result of diverse secondary factors—electrolyte disturbances (hypokalemia), renal failure, excessive energy requirements of muscle (as occur with drug-induced seizures and malignant hyperthermia), or inadequate delivery of oxygen and nutrients. Of course, there is a derivative category of drug-induced coma with compressive-ischemic injury to muscle. However, the most important group is that of direct toxic effects on the muscle membrane on the internal apparatus of the cell.


Neurology_Adams

Neurology_Adams. Several clinical features mark a myopathy as toxic in nature: lack of preexisting muscular symptoms; a predictable delay in onset of symptoms after exposure to a putative toxin; the lack of any other cause for the myopathy; and often, complete or partial resolution of symptoms after withdrawal of the toxic agent. Pathologically, this group of disorders is characterized by nonspecific myopathic changes, which in most severe degrees take the form of myonecrosis (rhabdomyolysis) and resultant myoglobinuria. This necrotizing muscle syndrome is the most frequent and serious myotoxic syndrome.


Neurology_Adams

Neurology_Adams. In any disease that results in rapid destruction of striated muscle fibers (rhabdomyolysis), myoglobin and other muscle proteins enter the bloodstream and appear in the urine. The latter is “cola”-colored (burgundy red or brown), much like the urine in hemoglobinuria. In hemoglobinuria, however, the serum is pink, because hemoglobin (but not myoglobin) is bound to haptoglobin, and this complex is not excreted in the urine as readily as myoglobin; also in addition, the hemoglobin molecule is three times as large as the myoglobin molecule. (The hemoglobin–haptoglobin complex is removed from the blood plasma over a period of hours and haptoglobin may be depleted, so that hemoglobinuria is present without grossly evident hemoglobinemia.) Differentiation of the two pigments in urine is difficult; both are guaiac-positive and may be detected by the “dipstick” test that can be used to advantage at the bedside in appropriate circumstances. Only small differences are seen on spectroscopic


Neurology_Adams

Neurology_Adams. both are guaiac-positive and may be detected by the “dipstick” test that can be used to advantage at the bedside in appropriate circumstances. Only small differences are seen on spectroscopic examination. The most sensitive means of detecting myoglobin is by radioimmunoassay. It should be mentioned that porphyrins are another cause of discoloration of the urine. The clinical picture in porphyria is one of a polyneuropathy and not a myopathy.


Neurology_Adams

Neurology_Adams. Many of the causes of myonecrosis have already been mentioned in this chapter, including acute inflammatory myopathy, several types of glycogenoses, CPT deficiency, and as a result of poisoning or therapeutic use of a vast array of drugs (including the combination of steroids and pancuronium in critically ill patients, discussed earlier), environmental toxins, and venoms. Myoglobinuria is an important feature of many other medical conditions: crush injury; extensive infarction of muscle that occurs in cases of vascular disease and of diabetes; in cases of severe acute alcohol intoxication, excessive use or repeated injury to muscles in status epilepticus, generalized tetanus, malignant hyperthermia, malignant neuroleptic syndrome, prolonged marching, electrical and lightning injuries; or simply excessive exercise—although muscle necrosis after exercise suggests an underlying metabolic disease of muscle.


Neurology_Adams

Neurology_Adams. Regardless of the cause of the rhabdomyolysis, the affected muscles become painful and tender within a few hours and their power of contraction is diminished. Sometimes, the skin and subcutaneous tissues overlying the affected muscles (nearly always of the limbs and sometimes of the trunk) are swollen and congested. There is a marked elevation of CK in the serum and there may be a low-grade fever and a reactive leukocytosis. If myoglobinuria is mild, recovery occurs within a few days and there is only a residual albuminuria. When severe, renal damage may ensue and lead to anuric renal failure requiring dialysis. The mechanism of the renal damage is not entirely clear; it is not simply a mechanical obstruction of tubules by precipitated myoglobin (although this does occur).


Neurology_Adams

Neurology_Adams. Treatment of myoglobinuria Alkalinization of the urine by ingestion or infusion of sodium bicarbonate is said to protect the kidneys by preventing myoglobin casts, but in severe cases it is of doubtful value and the sodium may actually be harmful if anuria has already developed. Diuresis induced by mannitol or by loop diuretics such as furosemide and by the administration of intravenous fluids reduces the chances of anuric renal failure if given in time. Therapy is much the same as for the anuria that follows shock (see Harrison’s Principles of Internal Medicine). In cases of focal muscle injury, for example, as occurs in diabetics or from vascular occlusion, surgical decompression of the overlying fascia and skin may be necessary to prevent ongoing ischemia, the “compartment syndrome.”


Neurology_Adams

Neurology_Adams. With the widespread use of these lipid-lowering medications, myotoxicity has become a well-described but possibly overrated problem. Symptoms range in severity from mild muscular aches with slightly elevated CK concentrations in the serum to a rare but potentially fatal rhabdomyolytic syndrome. (Myalgias alone are as common in patients taking placebo as in those taking stains). The incidence of true myopathy with statins has been estimated to be approximately 1 in 10,000 people treated per year. There appear to be two types of mypathy—one idiosyncratic and associated with direct toxicity and another, now thought to be more common, due to an antibody reaction. The first generation of these drugs were fungal metabolites (lovastatin, pravastatin, simvastatin) and were infrequently implicated in muscle damage, but the newer synthetic ones (atorvastatin, fluvastatin, cerivastatin) are more frequently toxic, especially when given with gemfibrozil (which has reportedly led to a small number


Neurology_Adams

Neurology_Adams. in muscle damage, but the newer synthetic ones (atorvastatin, fluvastatin, cerivastatin) are more frequently toxic, especially when given with gemfibrozil (which has reportedly led to a small number of deaths from myoglobinuric renal failure and has been removed from the market). Few cases are this dramatic. The subject has been reviewed by Thompson and associates and by Mammen. Drugs in the statin class with higher lipid solubility appear to have a greater potential for toxicity as a result of their increased muscle penetration.


Neurology_Adams

Neurology_Adams. In addition to the direct toxicity, there is an autoantibody syndrome directed against HMGCo-A reductase, which may be induced by statins (of any type) or occur spontaneously and may cause necrotizing myopathy as discussed in an earlier section and as reviewed by Mammen. The mechanism of directly toxic muscle damage is not well understood, but it is likely that inherent enzymatic defects are present in a proportion of the severe cases (see the brief review by Farmer) and that others are due to the aforementioned autoimmune process. A novel insight derived from genome-wide screening has been that variants in a gene (SLCO1B1) that codes for an organic anion-transporting polypeptide confers a risk of statin myopathy (4.5-fold for a heterozygous state and 17 times for the homozygous state; see the study by The SEARCH


Neurology_Adams

Neurology_Adams. Collaborative Group). In addition, the chronic use of statin drugs reduces levels of both ubiquinone and small guanosine triphosphate (GTP)–binding proteins, also plausible factors in statin-induced muscle toxicity.


Neurology_Adams

Neurology_Adams. A clinical problem arises when the CK level is elevated, but the patient taking one of these medications has no muscular symptoms. It has been our general practice to continue the medication if the elevation of CK is in the low range and does not rise over time, and if the medication is considered necessary. If alternative and safe means of lowering the lipid level are available, they should be tried in lieu of a statin, but each patient’s circumstances differ. In a small series, Phillips and colleagues have called attention to a similarly vexing and not uncommon problem: myopathic symptoms such as muscle stiffness, tenderness, and weakness with normal CK concentrations in patients taking a drug in this class. A trial of discontinuing the medication might be appropriate. Finally, we have encountered a number of patients whose CK levels have remained high for months or longer after the medications have been stopped. In a few, CK elevations have remained over years, but we have had no


Neurology_Adams

Neurology_Adams. encountered a number of patients whose CK levels have remained high for months or longer after the medications have been stopped. In a few, CK elevations have remained over years, but we have had no way to ensure that the test was not abnormal before taking the statin. Noted in


Neurology_Adams

Neurology_Adams. Chap. 43 is a polyneuropathy in which statin drugs have been very tentatively implicated. As a rule, statins should be discontinued if the muscle disorder is serious. Treatment of the immune type of myopathy is complex as the syndrome may persist after discontinuation of the drug. In some instances, discontinuation is followed by spontaneous improvement but others may require glucocorticoids administration or an immunosuppressive agent such as mycophenylate or azathioprine. If there is no response, intravenous immunoglobulin or rituximab may be tried. These approaches have been reviewed by Mammen but there have not been adequate trials to determine the best course of action.


Neurology_Adams

Neurology_Adams. This condition is included here as much for its curious histopathologic features as for its clinical interest. The drug, used widely in the treatment of gout, often gives rise to a mild subacute proximal muscular weakness but has also produced an acute necrotizing myopathy. Most instances of the latter have occurred in patients with a degree of renal failure, which allows accumulation of the drug (even though the drug is metabolized predominantly by the liver). In rare instances the myopathy has affected the cranial musculature and the diaphragm. Many cases also show clinical or electrophysiologic evidence of a polyneuropathy, as pointed out by Kuncl and colleagues, leading to the term colchicine myoneuropathy. The reflexes are diminished and there is mild distal sensory loss. Rare cases of colchicine-induced hypokalemic periodic paralysis and also of myotonia have been reported.


Neurology_Adams

Neurology_Adams. The serum CK concentration may be elevated or normal. The muscle biopsy shows elements of both myopathic and neuropathic disease, with the special feature in muscle of rimmed vacuoles on the Gomori trichrome stain that are more central in the muscle fibers than those seen with inclusion body myositis. The mechanism of the muscle damage is unknown but is probably attributable to the drug’s interference with tubulin, a protein required for the polymerization of microtubules in muscle and nerve. Weakness resolves in a matter of days or weeks when the drug is discontinued, but the neuropathic features may remain. Other drugs that cannot be compactly summarized but may produce a toxic myopathy or neuromyopathy include amiodarone, chloroquine, and hydroxychloroquine as mentioned in Chap. 41. Alcohol Myopathy (See Also Chap. 41)


Neurology_Adams

Neurology_Adams. Alcohol Myopathy (See Also Chap. 41) Several forms of muscle weakness have been ascribed to alcoholism. In one type, a painless and predominantly proximal weakness develops over a period of several days or weeks in the course of a prolonged drinking bout and is associated with severe degrees of hypokalemia (serum levels <2 mEq/L). The urinary excretion of potassium is not significantly increased, and depletion is probably the result of vomiting and diarrhea. In addition, serum levels of liver and muscle enzymes are markedly elevated. Biopsies from severely weakened muscles show single-fiber necrosis and vacuolation. Treatment consists of the administration of potassium chloride intravenously (about 120 mEq daily for several days), after which oral administration suffices. Strength returns gradually in 7 to 14 days, and enzyme levels return to normal concomitantly.


Neurology_Adams

Neurology_Adams. A more dramatic myopathic syndrome, occurring acutely at the height of a prolonged drinking bout and appropriately termed acute alcoholic myopathy, is manifest by severe pain, tenderness, and edema of the muscles of the limbs and trunk, accompanied in severe cases by renal damage (see Hed et al). Hypokalemia is not implicated. The myonecrosis is generalized in some patients, and remarkably focal in others. A swollen, painful, tender limb or part of a limb may give the appearance of a deep venous thrombosis or lymphatic obstruction. Myonecrosis is reflected by high serum levels of CK and aldolase and the appearance of myoglobin in the urine, leading in the most severe cases to fatal myoglobinuric renal failure. Indeed, in a general hospital, alcoholism is one of the most common causes of rhabdomyolysis and myoglobinuria, rivaled only by status epilepticus and trauma. Some patients recover within a few weeks, but others require several months, and relapse during another drinking spree


Neurology_Adams

Neurology_Adams. rhabdomyolysis and myoglobinuria, rivaled only by status epilepticus and trauma. Some patients recover within a few weeks, but others require several months, and relapse during another drinking spree occurs frequently. Restoration of motor power occurs with muscle regeneration but may be hindered by polyneuropathy and other syndromes of neuromuscular disability associated with alcoholism. Haller and Drachman have produced rhabdomyolysis in rats by subjecting the animals to a brief fast following a 2to 4-week exposure to alcohol, suggesting that a similar mechanism may be operative in alcoholic individuals.


Neurology_Adams

Neurology_Adams. Perkoff and his associates described what is presumably a third form of acute muscular disorder in alcoholics, characterized by severe muscular cramps and diffuse weakness in the course of a sustained drinking bout. They noted a number of biochemical abnormalities in these patients, as well as in asymptomatic alcoholics who had been drinking heavily for a sustained period before admission to the hospital: elevated serum levels of CK, myoglobinuria, and a diminished rise in blood lactic acid in response to ischemic exercise. The status of this syndrome and its relation to the conventional acute alcoholic myopathy are unclear to us.


Neurology_Adams

Neurology_Adams. From time to time in alcoholics one observes the subacute or chronic evolution of painless weakness and atrophy of the proximal muscles of the limbs, especially of the legs, with only minimal signs in the distal segments of the legs and feet. Cases such as these have been referred to as chronic alcoholic myopathy, implying a direct toxic effect of alcohol on muscle, but the data are insufficient to warrant such an assumption. Some of these cases have shown necrosis of individual muscle fibers and other signs of polymyositis; most cases seen by the authors have proved to be neuropathic in nature. This has been the experience of others as well (Faris and Reyes). Treatment follows along the lines indicated for nutritional-alcoholic neuropathy, and complete recovery can be expected if the patient abstains from alcohol and maintains adequate nutrition.


Neurology_Adams

Neurology_Adams. Included under this section are two sizable groups of muscle diseases: one is an assemblage of congenital deformities that involve muscle and the other is a unique class of congenital myopathies. Insofar as all of the disorders comprising these categories are congenital, it may be helpful by way of introduction to refer briefly the main facts about the natural development and aging of muscle in the introductory section of this chapter. These diseases are of particular importance in pediatric neurology, for most of them attract notice at an early age. Congenital Deformities of Muscle


Neurology_Adams

Neurology_Adams. Congenital Deformities of Muscle This disorder of multiple congenital contractures, now referred to as arthrogryposis (literally, curved joints), has been estimated to occur once in 3,000 births. The deformities result from a lack of movement during fetal development and are therefore produced by any disorder that immobilizes the developing embryo, whether from a lack of anterior horn cells, peripheral nerves, the motor end plate (as in an infant born to a myasthenic mother), or diseases of muscle. Often, there are associated developmental defects of the nervous system and somatic structures, low-set ears, wide and flat nose, micrognathia, and high-arched palate; less often, there are short neck, congenital heart disease, hypoplasia of the lungs, and cryptorchidism. Of the many conditions that underlie arthrogryposis, developmental abnormalities of the anterior horn cells, mainly Werdnig-Hoffmann disease as discussed in


Neurology_Adams

Neurology_Adams. Chap. 38, is by far the most common. A failure in development of anterior horn cells results in an uneven smallness and paresis of limb muscles. The unopposed contraction of relatively normally innervated muscles sets the fixed deformities. In a less common group of myopathic causes of arthrogryposis, the nervous system is usually intact and the disease is that of a congenital myopathy or congenital dystrophy. It has been observed that in the myopathic variety the limbs are fixed in a position of flexion at the hips and knees and adduction of the legs, in contrast to the variable postures of the myelopathic (anterior horn cell) form. In addition to these two well-recognized causes of arthrogryposis, occasional cases are attributable to a neonatal neuropathy, neonatal myasthenia gravis, or to the Prader-Willi syndrome (causing intrauterine hypotonia).


Neurology_Adams

Neurology_Adams. An infant with arthrogryposis should be evaluated with an EMG that is interpreted by an experienced electromyographer, and by a biopsy of muscle for the detection of group atrophy and of the congenital myopathies described further on in this chapter. Both these tests are difficult to interpret in the incompletely formed nervous system of the premature infant. In many circumstances, it is valuable to delay the tests until several weeks of postterm development when the results are usually clearer. Sometimes, the electrophysiologic and biopsy tests may have to be repeated after several weeks or more to give a definitive diagnosis. If the initial evaluations are unrevealing, an imaging study of the brain to detect cerebral malformations (and sequencing of the PWCR locus chromosome 5 for Prader-Willi syndrome) may prove useful.


Neurology_Adams

Neurology_Adams. This term refers to a fixation of limb posture as a result of a developmental lack or destruction of muscles, with shortening and fibrosis of supporting tissue and ligaments. A surprising number of deformities in infants and children are traceable to this type of defect. The most common are congenital clubfoot (talipes), congenital torticollis (wryneck), congenital elevation of the scapula (Sprengel deformity), and congenital dislocation of the hips. In all these conditions, the postural distortion is produced and maintained either by a weakened, fibrotic muscle or by a normal one that is contracted and shortened because of the absence of a countervailing antagonist. Trauma to a muscle during intrauterine life or at birth may lead to fibrosis and to fibrous contracture in some cases.


Neurology_Adams

Neurology_Adams. Congenital clubfoot Here the deformity may be one of plantar flexion of the foot and ankle (talipes equinus), inversion (talipes varus or clubfoot), eversion (talipes valgus or splayfoot), or dorsiflexion of foot at the ankle (talipes calcaneus). Approximately 75 percent of cases are of the equinovarus clubfoot variety (i.e., the foot turns downward and inward). Usually both feet are affected. Multiple incidences may occur in one family. Several explanations of cause and pathogenesis have been offered: fetal malposition, an embryonic abnormality of tarsal and metatarsal bones, a primary defect in nerves or anterior horn cells of the spinal cord, or a congenital dystrophy of muscle. No one theory explains all cases, and available pathologic data exclude a single cause and pathogenesis. In some instances, clubfoot is the only recognizable congenital abnormality, but as often it occurs as a manifestation of generalized arthrogryposis (see later) and is an indicator of a more widespread


Neurology_Adams

Neurology_Adams. some instances, clubfoot is the only recognizable congenital abnormality, but as often it occurs as a manifestation of generalized arthrogryposis (see later) and is an indicator of a more widespread intrauterine involvement of the CNS. (See Kakulas and Adams and also Banker for pertinent literature on the subject.)


Neurology_Adams

Neurology_Adams. Congenital torticollis (Wryneck) This disorder begins during the first months of life and, unlike the torticollis of adults discussed in Chap. 4, it is not the result of a dystonia but instead is caused by congenital shortening of the sternocleidomastoid muscle, which is firm and taut. The head is inclined to one side and the occiput slightly rotated to the side of the affected muscle. This disorder is nonfamilial and is ascribed to injury to the sternocleidomastoid at birth. Whether the injury is a purely mechanical one to the muscle itself or is caused by ischemia stemming from arterial or venous occlusion (or an entirely different cause) is not clear. Congenital torticollis often gives rise to a sternocleidomastoid enlargement (a pseudotumor) that appears, on exploration, as a pale, spindle-shaped swelling of the muscle belly. The histologic findings are similar to those of Volkmann contracture, that is, replacement of the muscle fibers by relatively acellular connective tissue,


Neurology_Adams

Neurology_Adams. spindle-shaped swelling of the muscle belly. The histologic findings are similar to those of Volkmann contracture, that is, replacement of the muscle fibers by relatively acellular connective tissue, suggesting that an ischemic mechanism underlies the defect in at least some cases.


Neurology_Adams

Neurology_Adams. Congenital Absence of Muscles (Amyoplasia) It is well known that some individuals are born without certain individual muscles. This pertains not only to certain inconstant and functionally unimportant muscles, such as the palmaris longus, but also to more substantial ones. The muscles found to be absent most frequently are the pectoralis, trapezius, serratus anterior, and quadriceps femoris, but many single muscles may be missing in isolated cases.


Neurology_Adams

Neurology_Adams. Congenital absence of muscle is usually associated with congenital anomalies of neighboring nonmuscular tissues. For example, congenital absence of the pectoral muscle is accompanied by aplasia or hypoplasia of the mammary structures or of syndactyly and microdactyly. Agenesis of the pectoral muscle may also be associated with scoliosis, webbed fingers, and underdevelopment of the ipsilateral arm and hand (Poland syndrome). Another unusual constellation consists of congenital absence of portions of the abdominal muscles (“prune belly”), often in association with arthrogryposis and a defect of ureters, bladder, and genital organs. Amyoplasia also occurs in a few cases of facioscapulohumeral dystrophy.


Neurology_Adams

Neurology_Adams. In another group of restricted palsies, the essential abnormality is in the CNS (nuclear amyotrophies). One of the most frequent is congenital ptosis as a result of an inborn defect of the innervation of the levator palpebrae muscles. Complete paralysis of all muscles supplied by the oculomotor nerve, apparently a result of hypoplasia of the third nerve nuclei, may be observed in several members of a family and occasionally in only one member. Bilateral abducens palsy is often associated with bifacial palsy in the newborn and is known as the Möbius syndrome; this usually nonfamilial anomaly, the cause of which is thought to be a nuclear hypoplasia or aplasia, is discussed with the developmental disorders in Chap. 37. In these familial nuclear amyotrophies, the muscles develop independently of the nervous system but have no prospect of surviving because of failure of innervation. It is, therefore, a kind of congenital denervation hypotrophy. Of course, a primary dystrophy may also give


Neurology_Adams

Neurology_Adams. of the nervous system but have no prospect of surviving because of failure of innervation. It is, therefore, a kind of congenital denervation hypotrophy. Of course, a primary dystrophy may also give rise to bifacial weakness, as in FSHD.


Neurology_Adams

Neurology_Adams. Beginning in 1956, with the account by Shy and Magee of a patient whose muscle fibers showed a peculiar central densification of sarcoplasm (“cores”), a new class of hereditary diseases of muscle was delineated. The more common and better-defined members of this group are the central core, nemaline (rod-body), myotubular, and centronuclear myopathies. A variety of other types of congenital myopathy have been described, but they are relatively uncommon and some are of dubious specificity; they are mentioned only briefly. As the names imply, in each of these diseases there is no loss of muscle fibers, but within each fiber there is a distinctive morphologic abnormality. These processes usually express themselves early in life by a lack of muscle bulk, hypotonia, weakness of the limbs, and often, with additional but subtle dysmorphic features of other parts of the body.


Neurology_Adams

Neurology_Adams. Further study has revealed that the diseases of this group are not confined to infancy and early childhood and some of them, especially those present at birth, are not as benign as their early descriptions implied. Each of the entities mentioned earlier has been observed at a later age, even in middle adult life. Indeed, if the disease is mild, there is often no way of deciding whether it has been present since birth.


Neurology_Adams

Neurology_Adams. The characteristic feature of most of these myopathies, in addition to usual early onset, is lack of progression or extremely slow progression, in contrast to the more rapid pace of many muscular dystrophies, Werdnig-Hoffmann disease, and of other forms of hereditary motor system disease of childhood and adolescence. Exceptionally, an example of more rapid progression of a congenital myopathy has been reported, and prior to the use of histochemical and electron microscopic techniques such patients were usually considered to have a “benign muscular dystrophy.” Familial occurrence has also been established in some types, so the clinical line of separation between this group of diseases and some of the more slowly progressive muscular dystrophies may in certain cases remain ambiguous. There is no specific treatment for any of the congenital myopathies.


Neurology_Adams

Neurology_Adams. The characteristic lesions in the congenital myopathies are revealed most clearly by the systematic application of histochemical stains to frozen sections of muscle biopsy tissue and by phase and electron microscopy. Some of the abnormalities are also disclosed by the conventional stains used in light microscopy, but as a group their identification has been the product of newer histologic techniques.


Neurology_Adams

Neurology_Adams. A word of caution is in order about the specificity of some of the morphologic changes and the classifications of the congenital myopathies based on these changes. It is inadvisable to assume that a change in a single organelle or a subtle change in the sarcoplasm of a muscle fiber can be relied on to characterize a pathologic process. Indeed, as more careful studies have been made of this class of disease, the specificity of some of the changes has come to be questioned. For example, central cores are sometimes found in the same muscle as nemaline bodies, and so on, and each of the denotative lesions has been reported in association with other systemic diseases and even as a result of certain medications. Nevertheless, the prominence of the morphologic change in any individual case, along with certain characteristic clinical features, permits an accurate diagnosis to be made.


Neurology_Adams

Neurology_Adams. In the original family described by Shy and Magee, 5 members (4 males) in 3 successive generations were affected, suggesting an autosomal dominant pattern of inheritance. The youngest was 2 years old; the oldest, 65 years. In each there was weakness and hypotonia soon after birth (again, “floppy infant”) and a general delay in motor development, particularly in walking, which was not achieved until the age of 4 to 5 years. These patients had difficulty in rising from a chair, climbing stairs, and running. The weakness was greater in proximal than in distal muscles, although the latter did not escape, and shoulder-girdle muscles were affected less than those of the pelvic girdle. Facial, bulbar, and ocular muscles were spared. The tendon reflexes were hypoactive and symmetrical. Muscle atrophy was not a prominent feature, although poor muscular development was present in 1 patient and has since been reported in others. There were no fasciculations, cramps, or myotonia, but cramps


Neurology_Adams

Neurology_Adams. atrophy was not a prominent feature, although poor muscular development was present in 1 patient and has since been reported in others. There were no fasciculations, cramps, or myotonia, but cramps following exercise have been described in other families. The ECGs were normal.


Neurology_Adams

Neurology_Adams. Almost all cases studied in the modern era have been due to variants in the ryanodine receptor 1 (RYR1), which is also implicated in the causation of a small number of cases of malignant hyperthermia (see Chap. 41) and of the rare recessively inherited condition of minicore disease (multiple, or multi-minicore), a congenital myopathy that may include ophthalmoplegia. The disease therefore has remarkable attribute in that every patient is a potential candidate for the development of malignant hyperthermia and should wear a bracelet or be otherwise identified to indicate vulnerability to this anesthetic-induced complication.


Neurology_Adams

Neurology_Adams. The disease is rare, but as additional cases have been discovered, milder forms have come to be recognized, and in some of them the symptoms first appeared in adult life. Originally these patients were thought to have limb-girdle dystrophy because of the disproportionate involvement of proximal muscles. In other families, such as the one reported by Patterson and colleagues, the disease was first recognized in middle adult life with the rapid evolution of a proximal myopathy. Dislocation of the hips, pes cavus or pes planus, and kyphoscoliosis has been found in a few children, but arthrogryposis is rare. In the majority of cases, the progress of the disease is extremely slow, with slight worsening over many years. These represent the two extremes of the process. The EMG reveals brief, small-amplitude motor unit potentials with a normal interference pattern. Serum concentration of CK is normal or only slightly elevated, as it is in all the congenital myopathies.


Neurology_Adams

Neurology_Adams. Pathologically, the majority of the muscle fibers appears normal in size or enlarged, and no focal destruction or loss of fibers can be found. The unique feature of the disease is the presence in the central portion of each muscle fiber of a dense, amorphous condensation of myofibrils or myofibrillar material. This altered zone characteristically lacks mitochondria and other organelles and gives a reduced positive PAS reaction and a dark blue coloration with the Gomori trichrome stain, contrasting with the normal blue-green color of the peripheral myofibrils. Within the core, there is a lack of phosphorylase and oxidative enzymes. Most of the cores are in type 1 fibers, which predominate in muscle biopsies. These cores run the length of the muscle fiber, thus differing from the multiple cores or minicores that are seen in oculopharyngeal and multiminicore myopathy.


Neurology_Adams

Neurology_Adams. This disorder also expresses itself by hypotonia and impaired motility in infancy and early childhood, but unlike the case in central core disease, the muscles of the trunk and limbs (proximal greater than distal), as well as the facial, lingual, and pharyngeal muscles, are strikingly thin and hypoplastic. Several forms have been observed. One is congenital, with generalized weakness in the neonatal period, making breathing and feeding difficult. The limbs are flaccid and flexic (again “floppy” infant). Pneumonia and death occur within weeks to months. In forms that permit longer survival, the weakness is less severe, involving mainly the proximal muscles. Tendon reflexes are diminished or absent. The young child with this disease usually suffers from inanition and frequent respiratory infections, which may shorten life. Strength slowly improves with growth, the latter process evidently counteracting the advance of the disease.


Neurology_Adams

Neurology_Adams. A slender appearance, narrow face, open mouth, narrow, arched palate, and kyphoscoliosis are regular but not invariable accompaniments of nemaline myopathy. These dysmorphic features are not typical of the other congenital polymyopathies. Pes cavus or clubfoot may be added. Some of the milder cases reach adulthood, at which time a cardiomyopathy may threaten life. A.G. Engel, as well as W.K. Engel and Reznick, observed individuals who first showed signs of the disease in middle age; the weakness was mainly in proximal muscles and the dysmorphic and skeletal abnormalities of the childhood form were lacking. The EMG is “myopathic,” and serum enzymes are normal or only slightly elevated.


Neurology_Adams

Neurology_Adams. Cases of nemaline myopathy have come to attention during adulthood because of disproportionate involvement of the respiratory muscles, a feature shared with the adult appearance of acid maltase deficiency. Usually these patients have had a history of poor physical performance throughout their earlier life. An unexplained accompanying monoclonal gammopathy has appeared in case reports of late-onset nemaline myopathy and probably represents a separate process that is more than chance occurrence. In the series of late-onset cases described by Chahin and colleagues, 7 of 14 cases had an abnormal blood protein and these authors suggested that the prognosis may be less favorable than in those lacking the protein. The patients who have been shown with this combination of adult proximal weakness and monoclonal protein had no dysmorphic features, suggesting that these cases are different from the typical genetically determined nemaline myopathy described as follows.


Neurology_Adams

Neurology_Adams. Nemaline myopathy appears to be genetically heterogeneous but about 20 percent are due to mutations in ACTA1. The pattern of inheritance is most often autosomal dominant with variable penetrance. In some families there has been an autosomal recessive or an X-linked pattern of inheritance. Studies of the various gene defects have begun to clarify the uncertainties about inheritance and explain the relationships between the different forms of the disease. The genes implicated in nemaline myopathy include those for alpha-tropomyosin, beta-tropomyosin, alpha-actin, nebulin, troponin, coflin-1, and the ryanodine receptor (the last of these is more commonly implicated in central core disease, as mentioned above).


Neurology_Adams

Neurology_Adams. The disease is so named for the rods or coils of threadlike structures in pathology material. Frozen muscle tissue stained with Gomori trichrome discloses the characteristic lesion, which can be seen under the light microscope. Myriads of bacillus-like rods, singly and in small packets, are seen beneath the plasma membrane of the muscle fiber. They are composed of material that resembles that of Z bands under the electron microscope, and often actin filaments are attached, just as they are to Z bands. The type 1 fibers, which usually predominate, are smaller than normal, as in central core disease. The size of the motor neurons has been reported to be reduced. Weakness is probably related to a smallness and reduction in the number of muscle fibers and possibly to focal interruption of their cross-striations, particularly of the Z bands.


Neurology_Adams

Neurology_Adams. In this familial disease, hypotonia and weakness become manifest soon after birth or in infancy or early childhood. In the mildest form, the diagnosis does not become evident until adult years. All the striated skeletal muscles are involved to some degree, but distinctive features are ptosis and ocular palsies combined with weakness of facial, masticatory, lingual, pharyngeal, laryngeal, and cervical muscles in most of the infants with this disease, but not in adults. In the limbs, distal weakness keeps pace with proximal weakness. The limbs remain thin and are flexic throughout life. Motor development is secondarily slowed, though some improvement with maturation can occur. Later, however, motor functions that had been acquired may be lost as the disease slowly advances. Several patients have shown signs of cerebral abnormality with seizures and an abnormal electroencephalogram (EEG), but it is not clear whether this is truly part of the disease. Needle EMG examination shows the


Neurology_Adams

Neurology_Adams. have shown signs of cerebral abnormality with seizures and an abnormal electroencephalogram (EEG), but it is not clear whether this is truly part of the disease. Needle EMG examination shows the usual myopathic pattern as well as both positive sharp waves and fibrillation potentials in some cases. Abundant spontaneous activity should suggest the diagnosis of centronuclear myopathy (Griggs et al).


Neurology_Adams

Neurology_Adams. Heckmatt and colleagues classified this disorder into three types, based on severity, mode of presentation, and genetic pattern: (1) a severe neonatal X-linked recessive type, now known to be associated mainly with mutations in myotubularin, MTM1; (2) a less severe early infantile, late-infantile, or childhood autosomal recessive type associated with BIN1, RYR1, or titin; and (3) a still milder late childhood–adult autosomal dominant type associated in some cases with mutations in DYN2 (dynamin) or MYF6, a helix-loop-helix protein that appears to function as a myogenic transcription factor.


Neurology_Adams

Neurology_Adams. The outstanding pathologic features of the disease are the smallness of muscles and their constituent fibers and central nucleation. In one group of centronuclear myopathies, there is hypotrophy of type 1 fibers (Bethlem et al; Karpati et al). Surrounding most of the centrally placed nuclei is a clear zone, in which there is a lack of organization of contractile elements. Because of central nucleation, the disease has incorrectly been referred to as myotubular myopathy, implying an arrest in development of muscle at the myotubular stage. Actually, the nature of the pathologic process is obscure. The small, centrally nucleated fibers do not really resemble typical myotubes. There is evidence from electron microscopic studies of changes in the central parts of the fibers (lack of enzymatic activity in the clear zones surrounding the nuclei), leading in all probability to fiber loss. Such changes argue against a purely developmental abnormality.


Neurology_Adams

Neurology_Adams. The accumulation of tubular aggregates in the subsarcolemmal or more interior regions of muscle fibers was first observed in patients with hypokalemic periodic paralysis and myotonia congenita, and later with a number of diverse conditions, such as chronic drug intoxication, hypoxia, and congenital myasthenic syndromes. However, tubular aggregates are also the defining feature of several rare and purely myopathic syndromes: (1) a slowly progressive muscular weakness, in a limb-girdle distribution, with onset in childhood or early adult life; inheritance is either autosomal dominant or recessive in type; (2) a childhood onset of proximal weakness, easy fatigability, and myasthenic features; heredity is autosomal recessive. This syndrome may respond to pyridostigmine; and (3) muscle pain, cramps, and stiffness induced by exercise; the cases to date have been sporadic.


Neurology_Adams

Neurology_Adams. The histologic changes are readily overlooked in paraffin sections. Frozen sections show masses of material that is basophilic with hematoxylin and eosin and bright red with Gomori trichrome and shows an intense reaction with reduced form of nicotinamide adenine dinucleotide (NADH) dehydrogenase. By electron microscopy, the bundles of tubular aggregates are sharply demarcated from myofibrils.


Neurology_Adams

Neurology_Adams. The foregoing congenital myopathies—central core, nemaline, centronuclear, and tubular aggregate types—are fairly well-defined clinicopathologic entities. Other less common types have been described, each named according to a distinctive morphologic alteration of organelles in muscle fibers in histochemical and electron microscopic preparations. In none of these additional types has the pattern of inheritance or the gene locus been identified. Some of these myopathies (multicore [minicore], fingerprint body, sarcotubular) have been reported in only a few cases, quite insufficient to allow their categorization as disease entities. Two other types, congenital fiber type disproportion and congenital fiber type predominance, originally designated as congenital myopathies, have proved to be nonspecific histochemical alterations observed in many infants and children with congenital developmental abnormalities, delays in motor development, and other conditions. Other putative congenital


Neurology_Adams

Neurology_Adams. nonspecific histochemical alterations observed in many infants and children with congenital developmental abnormalities, delays in motor development, and other conditions. Other putative congenital myopathies include so-called reducing body, trilaminar, and cap disease; zebra body; and familial myopathy with lysis in type 1 fibers, among others. They most likely also represent nonspecific reactions in muscle or fixation artifacts; as yet there is no evidence that any one of them represents a clinicopathologic entity.


Neurology_Adams

Neurology_Adams. This entity, more a group of myopathies, was formerly included among the congenital myopathies but now clearly belongs in the category of dystrophies and is discussed in an earlier section on that class of diseases. As stated in the introductory section, there is currently no treatment for any of the congenital myopathies. THE SPINAL MUSCULAR ATROPHIES OF INFANCY AND CHILDHOOD (SEE CHAP. 38)


Neurology_Adams

Neurology_Adams. As stated in the introductory section, there is currently no treatment for any of the congenital myopathies. THE SPINAL MUSCULAR ATROPHIES OF INFANCY AND CHILDHOOD (SEE CHAP. 38) Obviously this important group of diseases, appearing as they do in the same periods of life as the congenital myopathies and of certain of the congenital muscular dystrophies, must figure in the differential diagnosis of early-onset muscle weakness, hypotonia, and of arthrogryposis. Indeed, they represent the main problems faced by the clinician studying neuromuscular diseases of the infant. Their hereditary nature, their progression to fatal outcome or delayed motor attainments, and their tendency in certain instances to produce disabling contractures are shared with the primary muscle diseases. The proper application of current laboratory techniques sets them apart in most instances. In deference to their neuronal origin, we have placed them with the other degenerative diseases in Chap. 38.


Neurology_Adams

Neurology_Adams. DISORDERS OF MUSCLE CHARACTERIZED BY CRAMP, SPASM, PAIN, AND LOCALIZED MASSES (SEE ALSO CHAP. 46)


Neurology_Adams

Neurology_Adams. Quite apart from spasticity and rigidity, which are caused by a disinhibition of spinal motor mechanisms, there are forms of muscular stiffness and spasm that can be traced to abnormalities of the lower motor neuron and its spinal inhibitory mechanisms or to the sarcolemma of the muscle fiber. Muscles may go into spasm because of an unstable depolarization of motor axons, sending volleys of impulses across neuromuscular junctions—as occurs in myokymia, hypocalcemic tetany, and pseudohypoparathyroidism. In other states, the innervation of muscle is normal, but contraction persists despite attempts at relaxation (myotonia). Or, after one or a series of contractions, the muscle may be slow in decontracting, as occurs in paradoxical myotonia and hypothyroidism. In the contracture of McArdle phosphorylase deficiency and phosphofructokinase deficiency, muscle, once contracted, lacks the energy to relax. In yet another type of muscle stiffness, the muscle may ripple or respond to percussion


Neurology_Adams

Neurology_Adams. deficiency and phosphofructokinase deficiency, muscle, once contracted, lacks the energy to relax. In yet another type of muscle stiffness, the muscle may ripple or respond to percussion by mounding and rapidly contrasting and relaxing. Cramping should also be differentiated from restless leg syndrome (see Chap. 18), which is primarily a nocturnal disorder but may carry over into the daytime hours.


Neurology_Adams

Neurology_Adams. Each of these conditions evokes the complaint of cramp or spasm, which is variably painful and interferes with free and effective voluntary activity. Each condition has its own identifying clinical and EMG characteristics and most of them respond favorably to therapy. Muscle Cramp (See Also Chap. 46)


Neurology_Adams

Neurology_Adams. This subject was introduced at the beginning of this chapter, where it is pointed out that everyone at some time or other experiences muscle cramps. Cramps often occur during the night, after a day of unusually strenuous activity; less frequently they occur during the day, either during a period of relaxation or occasionally after a strong voluntary contraction or postural adjustment. A random restless or stretching movement may induce a hard contraction of a single muscle (most frequently of the foot or leg) that cannot be voluntarily relaxed. The muscle is visibly and palpably taut and painful, and the condition is readily distinguished from an illusory cramp, in which the sensation of cramp is experienced with little or no contraction of muscle. The latter phenomenon may occur in normal persons as well as in those with peripheral nerve diseases. Massage and vigorous stretch of the cramped muscle will cause the spasm to yield, although for a time the muscle remains excitable and


Neurology_Adams

Neurology_Adams. persons as well as in those with peripheral nerve diseases. Massage and vigorous stretch of the cramped muscle will cause the spasm to yield, although for a time the muscle remains excitable and subject to recurrent cramps. Visible fasciculations may precede and follow the cramp, indicating excessive excitability of the terminal branches of motor neurons supplying the muscle. Sometimes the cramp is so intense that the muscle is injured; it remains sore to touch and painful upon use for a day or longer. Cramps of precordial chest muscles or diaphragm may arouse fear of heart or lung disease. In the EMG, the cramp is marked by bursts of high-frequency, high-voltage action potentials, and the precramp phase shows runs of activity in motor units. Why cramps should be painful is not known; probably the demands of the overactive muscle exceed metabolic supply, causing a relative ischemia and accumulation of metabolites. Overwork of muscle with or without impairment of circulation is also


Neurology_Adams

Neurology_Adams. the demands of the overactive muscle exceed metabolic supply, causing a relative ischemia and accumulation of metabolites. Overwork of muscle with or without impairment of circulation is also painful. Between cramps, the muscles are normal clinically and electromyographically.