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InternalMed_Harrison. Laboratory Features Serum CK levels, results of EMG, and muscle biopsy findings closely resemble those in Duchenne dystrophy. The diagnosis of Becker muscular dystrophy requires Western blot analysis of muscle biopsy samples, demonstrating a reduced amount or abnormal size of dystrophin or mutation analysis of DNA from peripheral blood leukocytes. Genetic testing reveals deletions or duplications of the dystrophin gene in 65% of patients with Becker dystrophy, approximately the same percentage as in Duchenne dystrophy. In both Becker and Duchenne dystrophies, the size of the DNA deletion does not predict clinical severity; however, in ~95% of patients with Becker dystrophy, the DNA deletion does not alter the translational reading frame of messenger RNA. These “in-frame” mutations allow for production of some dystrophin, which accounts for the presence of altered rather than absent dystrophin on Western blot analysis.


InternalMed_Harrison

InternalMed_Harrison. The use of glucocorticoids has not been adequately studied in Becker dystrophy. The syndrome of LGMD represents more than one disorder. Both males and females are affected, with onset ranging from late in the first decade to the fourth decade. The LGMDs typically manifest with progressive weakness of pelvic and shoulder girdle musculature. Respiratory insufficiency from weakness of the diaphragm may occur, as may cardiomyopathy.


InternalMed_Harrison

InternalMed_Harrison. A systematic classification of LGMD is based on autosomal dominant (LGMD1) and autosomal recessive (LGMD2) inheritance. Superimposed on the backbone of LGMD1 and LGMD2, the classification uses a sequential alphabetical lettering system (LGMD1A, LGMD2A, etc.). Disorders receive letters in the order in which they are found to have chromosomal linkage. This results in an ever-expanding list of conditions summarized in Tables 462e-6 and 462e-7. None of the conditions is as common as the dystrophinopathies; however, prevalence data for the LGMDs have not been systematically gathered for any large heterogeneous population. In referral-based clinical populations, Fukutin-related protein (FKRP) deficiency (LGMD2I), calpainopathy (LGMD2A), anoctaminopathy (LGMD2L), and to a lesser extent dysferlinopathy (LGMD2B) have emerged as the most common disorders.


InternalMed_Harrison

InternalMed_Harrison. There are at least five genetically distinct forms of Emery-Dreifuss muscular dystrophy (EDMD). Emerin mutations are the most common cause of X-linked EDMD, although mutations in FHL1 may also be associated with a similar phenotype, which is X-linked as well. Mutations involving the gene for lamin A/C are the most common cause of autosomal dominant EDMD (also known as LGMD1B) and are also a common cause of hereditary cardiomyopathy. Less commonly, autosomal dominant EDMD has been reported with mutations in nesprin-1, nesprin-2, and TMEM43.


InternalMed_Harrison

InternalMed_Harrison. Clinical Features Prominent contractures can be recognized in early childhood and teenage years, often preceding muscle weakness. The contractures persist throughout the course of the disease and are present at the elbows, ankles, and neck. Muscle weakness affects humeral and peroneal muscles at first and later spreads to a limb-girdle distribution. The cardiomyopathy is potentially life threatening and may result in sudden death. A spectrum of atrial rhythm and conduction defects includes atrial fibrillation and paralysis and atrioventricular heart block. Some patients have a dilated cardiomyopathy. Female carriers of the X-linked variant may have cardiac manifestations that become clinically significant.


InternalMed_Harrison

InternalMed_Harrison. Laboratory Features Serum CK may be elevated twoto tenfold. EMG is myopathic. Muscle biopsy usually shows nonspecific dystrophic features, although cases associated with FHL1 mutations have features of myofibrillar myopathy. Immunohistochemistry reveals absent emerin staining of myonuclei in X-linked EDMD due to emerin mutations. ECGs demonstrate atrial and atrioventricular rhythm disturbances.


InternalMed_Harrison

InternalMed_Harrison. X-linked EDMD usually arises from defects in the emerin gene encoding a nuclear envelope protein. FHL1 mutations are also a cause of X-linked scapuloperoneal dystrophy, but can also present with an X-linked form of EDMD. The autosomal dominant disease can be caused by mutations in the LMNA gene encoding lamin A and C; in the synaptic nuclear envelope protein 1 (SYNE1) or 2 (SYNE2) encoding nesprin-1 and nesprin-2, respectively; and most recently in TMEM43 encoding LUMA. These proteins are essential components of the filamentous network underlying the inner nuclear membrane. Loss of structural integrity of the nuclear envelope from defects in emerin, lamin A/C, nesprin-1, nesprin-2, and LUMA accounts for overlapping phenotypes (Fig. 462e-7).


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InternalMed_Harrison. Supportive care should be offered for neuromuscular disability, including ambulatory aids, if necessary. Stretching of contractures is difficult. Management of cardiomyopathy and arrhythmias (e.g., early use of a defibrillator or cardiac pacemaker) may be life saving. This is not one entity but rather a group of disorders with varying degrees of muscle weakness, CNS impairment, and eye abnormalities. Clinical Features As a group, CMDs present at birth or in the first few months of life with hypotonia and proximal or generalized muscle weakness. Calf muscle hypertrophy is seen in some patients. Facial muscles may be weak, but other cranial nerve–innervated muscles are spared (e.g., extraocular muscles are normal). Most patients have joint contractures of varying degrees at elbows, hips, knees, and ankles. Contractures present at birth are referred to as arthrogryposis. Respiratory failure may be seen in some cases.


InternalMed_Harrison

InternalMed_Harrison. The CNS is affected in some forms of CMD. In merosin and FKRP deficiency, cerebral hypomyelination may be seen by magnetic resonance imaging (MRI), although only a small number of patients have mental retardation and seizures. Three forms of congenital muscular dystrophy have severe brain impairment. These include Fukuyama’s congenital muscular dystrophy (FCMD), muscle-eye-brain (MEB) disease, and Walker-Warburg syndrome (WWS). Patients are severely disabled in all three of these conditions. In MEB disease and WWS, but in the nuclear membrane and sarcomere. As shown in the exploded view, emerin and lamin A/C are constituents of the inner nuclear membrane. Several dystrophy-associated proteins are represented in the sarcomere including titin, nebulin, calpain, telethonin, actinin, and myotilin. The position of the dystrophin-dystroglycan complex is also illustrated.


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InternalMed_Harrison. not in FCMD, ocular abnormalities impair vision. WWS is the most severe congenital muscular dystrophy, causing death by 1 year of age. Laboratory Features Serum CK is markedly elevated in all of these conditions. The EMG is myopathic and muscle biopsies show nonspecific dystrophic features. Merosin, or laminin α2 chain (a basal lamina protein), is deficient in surrounding muscle fibers in merosin deficiency. Skin biopsies can also demonstrate defects in laminin α2 chain. In the other disorders (FKRP deficiency, FCMD, MEB disease, WWS), there is abnormal α-dystroglycan staining in muscle. In merosin deficiency, cerebral hypomyelination is common, and a host of brain malformations are seen in FCMD, MEB disease, and WWS.


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InternalMed_Harrison. All forms of CMD are inherited as autosomal recessive disorders. Chromosomal linkage and specific gene defects are presented in Table 462e-8. With the exception of merosin, the other gene defects affect posttranslational glycosylation of α-dystroglycan. This abnormality is thought to impair binding with merosin and leads to weakening of the dystrophin-glycoprotein complex, instability of the muscle membrane, and/or abnormalities in muscle contraction. CMDs with brain and eye phenotypes probably involve defective glycosylation of additional proteins, accounting for the more extensive phenotypes. There is no specific treatment for CMD. Proper wheelchair seating is important. Management of epilepsy and cardiac manifestations is necessary for some patients.


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InternalMed_Harrison. There is no specific treatment for CMD. Proper wheelchair seating is important. Management of epilepsy and cardiac manifestations is necessary for some patients. Myotonic dystrophy is also known as dystrophia myotonica (DM). The condition is composed of at least two clinical disorders with overlapping phenotypes and distinct molecular genetic defects: myotonic dystrophy type 1 (DM1), the classic disease originally described by Steinert, and myotonic dystrophy type 2 (DM2), also called proximal myotonic myopathy (PROMM). Merosin deficiency Onset at birth with hypotonia, joint contractures, delayed milestones, generalized muscle weakness Cerebral hypomyelination, less often cortical dysplasia Normal intelligence usually, some with MR (~6%) and seizures (~8%) Partial deficiency leads to milder phenotype (LGMD picture) Weakness of proximal muscles, especially shoulder girdles Hypertrophy of leg muscles Joint contractures Cognition normal


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InternalMed_Harrison. Partial deficiency leads to milder phenotype (LGMD picture) Weakness of proximal muscles, especially shoulder girdles Hypertrophy of leg muscles Joint contractures Cognition normal Hypotonia, joint contractures Generalized muscle weakness Hypertrophy of calf muscles Seizures, MR Cardiomyopathy Muscle-eye-brain disease Onset at birth, hypotonia Eye abnormalities include: progressive myopia, cataracts, and optic nerve, glaucoma, retinal pigmentary changes Progressive muscle weakness Joint contractures Seizures, MR Walker-Warburg syndromeb Onset at birth, hypotonia Generalized muscle weakness Joint contractures Microphthalmos, retinal dysplasia, buphthalmos, glaucoma, cataracts Seizures, MR Serum CK 5–35× normal EMG myopathic NCS abnormal in some cases MRI shows hydrocephalus, cobblestone lissencephaly, corpus callosum and cerebellar hypoplasia, cerebral hypomyelination


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InternalMed_Harrison. MRI shows hydrocephalus, cobblestone lissencephaly, corpus callosum and cerebellar hypoplasia, cerebral hypomyelination MRI shows cobblestone lissencephaly, hydrocephalus, encephalocele, absent corpus callosum aAll are inherited as recessive traits. bThere is phenotypic overlap between disorders related to defective glycosylation. In muscle, this is a consequence of altered glycosylation of dystroglycans; in brain/eye, other glycosylated proteins are involved. Clinically, Walker-Warburg syndrome is more severe, with death by 1 year. Abbreviations: CK, creatine kinase; EMG, electromyography; LGMD, limb-girdle muscular dystrophy; MR, mental retardation; MRI, magnetic resonance imaging; NCS, nerve conduction studies.


InternalMed_Harrison

InternalMed_Harrison. Clinical Features The clinical expression of DM1 varies widely and involves many systems other than muscle. Affected patients have a typical “hatchet-faced” appearance due to temporalis, masseter, and facial muscle atrophy and weakness. Frontal baldness is also characteristic of the disease. Neck muscles, including flexors and sternocleidomastoids, and distal limb muscles are involved early. Weakness of wrist extensors, finger extensors, and intrinsic hand muscles impairs function. Ankle dorsiflexor weakness may cause footdrop. Proximal muscles remain stronger throughout the course, although preferential atrophy and weakness of quadriceps muscles occur in many patients. Palatal, pharyngeal, and tongue involvement produce a dysarthric speech, nasal voice, and swallowing problems. Some patients have diaphragm and intercostal muscle weakness, resulting in respiratory insufficiency.


InternalMed_Harrison

InternalMed_Harrison. Myotonia, which usually appears by age 5 years, is demonstrable by percussion of the thenar eminence, the tongue, and wrist extensor muscles. Myotonia causes a slow relaxation of hand grip after a forced voluntary closure. Advanced muscle wasting makes myotonia more difficult to detect. Cardiac disturbances occur commonly in patients with DM1. ECG abnormalities include first-degree heart block and more extensive conduction system involvement. Complete heart block and sudden death can occur. Congestive heart failure occurs infrequently but may result from cor pulmonale secondary to respiratory failure. Mitral valve prolapse also occurs commonly. Other associated features include intellectual impairment, hypersomnia, posterior subcapsular cataracts, gonadal atrophy, insulin resistance, and decreased esophageal and colonic motility.


InternalMed_Harrison

InternalMed_Harrison. Congenital myotonic dystrophy is a more severe form of DM1 and occurs in ~25% of infants of affected mothers. It is characterized by severe facial and bulbar weakness, transient neonatal respiratory insufficiency, and mental retardation. DM2, or PROMM, has a distinct pattern of muscle weakness affecting mainly proximal muscles. Other features of the disease overlap with DM1, including cataracts, testicular atrophy, insulin resistance, constipation, hypersomnia, and cognitive defects. Cardiac conduction defects occur but are less common, and the hatchet face and frontal baldness are less consistent features. A very striking difference is the failure to clearly identify a congenital form of DM2.


InternalMed_Harrison

InternalMed_Harrison. Laboratory Features The diagnosis of myotonic dystrophy can usually be made on the basis of clinical findings. Serum CK levels may be normal or mildly elevated. EMG evidence of myotonia is present in most cases of DM1 but may be more patchy in DM2. Muscle biopsy shows muscle atrophy, which selectively involves type 1 fibers in 50% of cases, and ringed fibers in DM1 but not in DM2. Typically, numerous internalized nuclei can be seen in individual muscle fibers as well as atrophic fibers with pyknotic nuclear clumps in both DM1 and DM2. Necrosis of muscle fibers and increased connective tissue, common in other muscular dystrophies, are less apparent in myotonic dystrophy.


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InternalMed_Harrison. DM1 and DM2 are both autosomal dominant disorders. New mutations do not appear to contribute to the pool of affected individuals. DM1 is transmitted by an intronic mutation consisting of an unstable expansion of a CTG trinucleotide repeat in a serine-threonine protein kinase gene (named DMPK) on chromosome 19q13.3. An increase in the severity of the disease phenotype in successive generations (genetic anticipation) is accompanied by an increase in the number of trinucleotide repeats. A similar type of mutation has been identified in fragile X syndrome (Chap. 451e). The unstable triplet repeat in myotonic dystrophy can be used for prenatal diagnosis. Congenital disease occurs almost exclusively in infants born to affected mothers; it is possible that sperm with greatly expanded triplet repeats do not function well.


InternalMed_Harrison

InternalMed_Harrison. DM2 is caused by a DNA expansion mutation consisting of a CCTG repeat in intron 1 of the ZNF9 gene located at chromosome 3q13.3q24. The gene is believed to encode an RNA-binding protein expressed in many different tissues, including skeletal and cardiac muscle. The DNA expansions in DM1 and DM2 almost certainly impair muscle function by a toxic gain of function of the mutant mRNA. In both DM1 and DM2, the mutant RNA appears to form intranuclear inclusions composed of aberrant RNA. These RNA inclusions sequester RNA-binding proteins essential for proper splicing of a variety of other mRNAs. This leads to abnormal transcription of multiple proteins in a variety of tissues/organ systems, in turn causing the systemic manifestations of DM1 and DM2.


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InternalMed_Harrison. The myotonia in DM1 rarely warrants treatment, although some patients with DM2 are significantly bothered by the discomfort related to the associated muscle stiffness. Phenytoin and mexiletine are the preferred agents for the occasional patient who requires an antimyotonia drug; other agents, particularly quinine and procainamide, may worsen cardiac conduction. A cardiac pacemaker should be considered for patients with unexplained syncope, advanced conduction system abnormalities with evidence of second-degree heart block, or trifascicular conduction disturbances with marked prolongation of the PR interval. Molded ankle-foot orthoses help stabilize gait in patients with foot drop. Excessive daytime somnolence with or without sleep apnea is not uncommon. Sleep studies, noninvasive respiratory support (biphasic positive airway pressure [BiPAP]), and treatment with modafinil may be beneficial.


InternalMed_Harrison

InternalMed_Harrison. This form of muscular dystrophy has a prevalence of ~1 in 20,000. There are two forms of FSHD that have similar pathogenesis, as will be discussed. Most patients have FSHD type 1 (95%), whereas approximately 5% have FSHD2. FSHD1 and FSHD2 are clinically and histopathologically identical. FSHD is not to be confused with the genetically distinct scapuloperoneal dystrophies.


InternalMed_Harrison

InternalMed_Harrison. Clinical Features The condition typically has an onset in childhood or young adulthood. In most cases, facial weakness is the initial manifestation, appearing as an inability to smile, whistle, or fully close the eyes. Weakness of the shoulder girdles, rather than the facial muscles, usually brings the patient to medical attention. Loss of scapular stabilizer muscles makes arm elevation difficult. Scapular winging (Fig. 462e-3) becomes apparent with attempts at abduction and forward movement of the arms. Biceps and triceps muscles may be severely affected, with relative sparing of the deltoid muscles. Weakness is invariably worse for wrist extension than for wrist flexion, and weakness of the anterior compartment muscles of the legs may lead to footdrop.


InternalMed_Harrison

InternalMed_Harrison. In most patients, the weakness remains restricted to facial, upper extremity, and distal lower extremity muscles. In 20% of patients, weakness progresses to involve the pelvic girdle muscles, and severe functional impairment and possible wheelchair dependency result. Characteristically, patients with FSHD do not have involvement of other organ systems, although labile hypertension is common, and there is an increased incidence of nerve deafness. Coats’ disease, a disorder consisting of telangiectasia, exudation, and retinal detachment, also occurs. Laboratory Features The serum CK level may be normal or mildly elevated. EMG usually indicates a myopathic pattern. The muscle biopsy shows nonspecific features of a myopathy. A prominent inflammatory 462e-11 infiltrate, which is often multifocal in distribution, is present in some biopsy samples. The cause or significance of this finding is unknown.


InternalMed_Harrison

InternalMed_Harrison. An autosomal dominant inheritance pattern with almost complete penetrance has been established, but each family member should be examined for the presence of the disease, since ~30% of those affected are unaware of involvement. FSHD1 is associated with deletions of tandem 3.3-kb repeats at 4q35. The deletion reduces the number of repeats to a fragment of <35 kb in most patients. Within these repeats lies the DUX4 gene, which usually is not expressed. In patients with FSHD1 these deletions in the setting of a specific polymorphism leads to hypomethylation of the region and toxic expression of the DUX4 gene. In patients with FSHD2, there is no deletion, but a mutation in SMCHD1. Interestingly, in the setting of the same polymorphism, there again is seen hypomethylation of the region and the permissive expression of the DUX4 gene. In both FSHD1 and FSHD2, there is overexpression of the DUX4 transcript.


InternalMed_Harrison

InternalMed_Harrison. No specific treatment is available; ankle-foot orthoses are helpful for footdrop. Scapular stabilization procedures improve scapular winging but may not improve function. This form of muscular dystrophy represents one of several disorders characterized by progressive external ophthalmoplegia, which consists of slowly progressive ptosis and limitation of eye movements with sparing of pupillary reactions for light and accommodation. Patients usually do not complain of diplopia, in contrast to patients having conditions with a more acute onset of ocular muscle weakness (e.g., myasthenia gravis).


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InternalMed_Harrison. Clinical Features Oculopharyngeal muscular dystrophy has a late onset; it usually presents in the fourth to sixth decade with ptosis and/ or dysphagia. The extraocular muscle impairment is less prominent in the early phase but may be severe later. The swallowing problem may become debilitating and result in pooling of secretions and repeated episodes of aspiration. Mild weakness of the neck and extremities also occurs. Laboratory Features The serum CK level may be two to three times normal. Myopathic EMG findings are typical. On biopsy, muscle fibers are found to contain rimmed vacuoles, which by electron microscopy are shown to contain membranous whorls, accumulation of glycogen, and other nonspecific debris related to lysosomes. A distinct feature of oculopharyngeal dystrophy is the presence of tubular filaments, 8.5 nm in diameter, in muscle cell nuclei.


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InternalMed_Harrison. Oculopharyngeal dystrophy has an autosomal dominant inheritance pattern with complete penetrance. The incidence is high in French-Canadians and in Spanish-American families of the southwestern United States. Large kindreds of Italian and of eastern European Jewish descent have been reported. The molecular defect in oculopharyngeal muscular dystrophy is a subtle expansion of a modest polyalanine repeat tract in a poly-RNA-binding protein (PABP2) in muscle. Dysphagia can lead to significant undernourishment and inanition, making oculopharyngeal muscular dystrophy a potentially life-threatening disease. Cricopharyngeal myotomy may improve swallowing, although it does not prevent aspiration. Eyelid crutches can improve vision when ptosis obstructs vision; candidates for ptosis surgery must be carefully selected—those with severe facial weakness are not suitable.


InternalMed_Harrison

InternalMed_Harrison. A group of muscle diseases, the distal myopathies, are notable for their preferential distal distribution of muscle weakness in contrast to most muscle conditions associated with proximal weakness. The major distal myopathies are summarized in Table 462e-9.


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InternalMed_Harrison. Clinical Features Welander’s, Udd’s, and Markesbery-Griggs type distal myopathies are all late-onset, dominantly inherited disorders of distal limb muscles, usually beginning after age 40 years. Welander’s distal myopathy preferentially involves the wrist and finger extensors, whereas the others are associated with anterior tibial weakness leading to progressive footdrop. Laing’s distal myopathy is also a dominantly inherited disorder heralded by tibial weakness; however, it is distinguished by onset in childhood or early adult life. Nonaka’s distal myopathy and Miyoshi’s myopathy are distinguished by autosomal recessive inheritance and onset in the late teens or twenties. Nonaka’s and Williams’ myopathy entails anterior tibial weakness, whereas Miyoshi’s myopathy is unique in that gastrocnemius muscles are preferentially affected at onset. Finally, the myofibrillar myopathies (MFMs) are a clinically and genetically heterogeneous group of disorders that can be associated with


InternalMed_Harrison

InternalMed_Harrison. gastrocnemius muscles are preferentially affected at onset. Finally, the myofibrillar myopathies (MFMs) are a clinically and genetically heterogeneous group of disorders that can be associated with prominent distal weakness; they can be inherited in an autosomal dominant or recessive pattern. Of note, Markesbery-Griggs myopathy (caused by mutations in ZASP) and LGMD1B (caused by mutations in myotilin) are in fact subtypes of myofibrillar myopathy.


InternalMed_Harrison

InternalMed_Harrison. Laboratory Features Serum CK level is particularly helpful in diagnosing Miyoshi’s myopathy because it is very elevated. In the other conditions, serum CK is only slightly increased. EMGs are myopathic. In the MFMs, myotonic or pseudomyotonic discharges are common. Muscle biopsy shows nonspecific dystrophic features and, with the exception of Laing’s and Miyoshi’s myopathies, often shows rimmed vacuoles. MFM is associated with the accumulation of dense inclusions, as well as amorphous material best seen on Gomori trichrome and myofibrillar disruption on electron microscopy. Immune staining sometimes demonstrates accumulation of desmin and other proteins in MFM, large deposits of myosin heavy chain in the subsarcolemmal region of type 1 muscle fibers in Laing’s myopathy, and reduced or absent dysferlin in Miyoshi’s myopathy. The affected genes and their gene products are listed in Table 462e-9.


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InternalMed_Harrison. The affected genes and their gene products are listed in Table 462e-9. Occupational therapy is offered for loss of hand function; ankle-foot orthoses can support distal lower limb muscles. The MFMs can be associated with cardiomyopathy (congestive heart failure or arrhythmias) and respiratory failure that may require medical management. Laing’s-type distal myopathy can also be associated with a cardiomyopathy. These rare disorders are distinguished from muscular dystrophies by the presence of specific histochemical and structural abnormalities in muscle. Although primarily disorders of infancy or childhood, three forms that may present in adulthood are described here: central core disease, nemaline (rod) myopathy, and centronuclear (myotubular) myopathy. Sarcotubular myopathy is caused by mutations in TRIM-32 and is identical to LGMD2H. Other types, such as minicore myopathy (multi-minicore disease), fingerprint body myopathy, and cap myopathy, are not discussed.


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InternalMed_Harrison. Patients with central core disease may have decreased fetal movements and breech presentation. Hypotonia and delay in motor milestones, particularly in walking, are common. Later in childhood, patients develop problems with stair climbing, running, and getting up from the floor. On examination, there is mild facial, neck-flexor, and proximal-extremity muscle weakness. Legs are more affected than arms. Skeletal abnormalities include congenital hip dislocation, scoliosis, and pes cavus; clubbed feet also occur. Most cases are nonprogressive, but exceptions are well documented. Susceptibility to malignant hyperthermia must be considered as a potential risk factor for patients with central core disease. Recent series have demonstrated that many cases of late-onset axial myopathy in which patients manifest with bent spine (camptocormia) or neck extensor weakness (neck extensor myopathy) are caused by mutations in the ryanodine receptor gene (RYR1). This illustrates the interesting spectrum


InternalMed_Harrison

InternalMed_Harrison. manifest with bent spine (camptocormia) or neck extensor weakness (neck extensor myopathy) are caused by mutations in the ryanodine receptor gene (RYR1). This illustrates the interesting spectrum of RYR1 mutations.


InternalMed_Harrison

InternalMed_Harrison. The serum CK level is usually normal. Needle EMG demonstrates a myopathic pattern. Muscle biopsy shows fibers with single or multiple central or eccentric discrete zones (cores) devoid of oxidative enzymes. Cores occur preferentially in type 1 fibers and represent poorly aligned sarcomeres associated with Z disk streaming. Autosomal dominant inheritance is characteristic; sporadic cases also occur. As alluded above, this myopathy is caused by point mutations of RYR1, encoding the calcium-release channel of the sarcoplasmic reticulum of skeletal muscle; mutations of this gene also account for some cases of inherited malignant hyperthermia (Chap. 23). Malignant hyperthermia is an allelic condition; C-terminal mutations of the RYR1 gene predispose to this complication. Specific treatment is not required, but establishing a diagnosis of central core disease is extremely important because these patients have a known predisposition to malignant hyperthermia during anesthesia.


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InternalMed_Harrison. The term nemaline refers to the distinctive presence in muscle fibers of rods or threadlike structures (Greek nema, “thread”). Nemaline myopathy is clinically heterogeneous. A severe neonatal form presents with hypotonia and feeding and respiratory difficulties, leading to early death. Nemaline myopathy usually presents in infancy or childhood with delayed motor milestones. The course is nonprogressive or slowly progressive. The physical appearance is striking because of the long, narrow facies, high-arched palate, and open-mouthed appearance due to a prognathous jaw. Other skeletal abnormalities include pectus excavatum, kyphoscoliosis, pes cavus, and clubfoot deformities. Facial and generalized muscle weakness, including respiratory muscle weakness, is common. An adult-onset disorder with progressive proximal or distal weakness may be seen. Myocardial involvement is occasionally present in both the childhood and adult-onset forms. The serum CK level is usually normal or slightly


InternalMed_Harrison

InternalMed_Harrison. with progressive proximal or distal weakness may be seen. Myocardial involvement is occasionally present in both the childhood and adult-onset forms. The serum CK level is usually normal or slightly elevated. The EMG demonstrates a myopathic pattern. Muscle biopsy shows clusters of small rods (nemaline bodies), which occur preferentially, but not exclusively, in the sarcoplasm of type 1 muscle fibers. Occasionally, the rods are also apparent in myonuclei. The muscle often shows type 1 muscle fiber predominance. Rods originate from the Z disk material of the muscle fiber.


InternalMed_Harrison

InternalMed_Harrison. Six genes have been associated with nemaline myopathy. Five of these code for thin filament–associated proteins, suggesting disturbed assembly or interplay of these structures as a pivotal mechanism. Mutations of the nebulin (NEB) gene account for most cases, including both severe neonatal and early childhood forms, inherited as autosomal recessive disorders. Neonatal and childhood cases, inherited as predominantly autosomal dominant disorders, are caused by mutations of the skeletal muscle a-actinin (ACTA1) gene. In milder forms of the disease with autosomal dominant inheritance, mutations have been identified in both the slow a-tropomyosin (TPM3) and β;-tropomyosin (TPM2) genes accounting for <3% of cases. Muscle troponin T (TNNT1) gene mutations appear to be limited to the Amish population in North America. Mutations may also be seen in NEM6 that encodes a putative BTB/Kelch protein. No specific treatment is available.


InternalMed_Harrison

InternalMed_Harrison. Three distinct variants of centronuclear myopathy occur. A neonatal form, also known as myotubular myopathy, presents with severe hypotonia and weakness at birth. The late infancy–early childhood form presents with delayed motor milestones. Later, difficulty with running and stair climbing becomes apparent. A marfanoid, slender body habitus, long narrow face, and high-arched palate are typical. Scoliosis and Myofibrillar myopathies Onset in fifth decade Weakness begins in hands Slow progression with spread to distal lower extremities Lifespan normal Onset fourth to eighth decade Distal lower extremity weakness (tibial Onset fourth to eighth decade Distal lower extremity weakness (tibial distribution) with progression to distal arms and proximal muscles Onset childhood to third decade Onset: second to third decade Progression to other muscles sparing quadriceps Ambulation may be lost in 10–15 y Onset: second to third decade Lower extremity weakness in posterior


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InternalMed_Harrison. Onset: second to third decade Progression to other muscles sparing quadriceps Ambulation may be lost in 10–15 y Onset: second to third decade Lower extremity weakness in posterior Progression leads to weakness in other muscle groups Ambulation lost after 10–15 y in about one-third of cases Distal lower extremity weakness (anterior tibial distribution) Onset from early childhood to late adult life Weakness may be distal, proximal, or generalized Cardiomyopathy and respiratory involvement is not uncommon features and rimmed vacuoles Titin absent in M-line of muscle Serum CK is usually mildly elevated EMG reveals irritative myopathy Muscle biopsies demonstrate rimmed vacuoles and features of MFM Serum CK is normal or slightly elevated Muscle biopsies do not typically show rimmed vacuoles, but may show hyaline bodies with accumulation of myosin Large deposits of myosin heavy chain are seen in type 1 muscle fibers Serum CK 3–10× normal EMG myopathic


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InternalMed_Harrison. Large deposits of myosin heavy chain are seen in type 1 muscle fibers Serum CK 3–10× normal EMG myopathic Muscle biopsy shows nonspecific dystrophic features often with prominent inflammatory cell infiltration; no rimmed vacuoles Muscle biopsy may show rimmed vacuoles and features of MFM EMG is myopathic and often associated with myotonic discharges Muscle biopsy demonstrates abnormal accumulation of desmin and other proteins, rimmed vacuoles, and myofibrillar degeneration AD Titin AR (associated with more proximal GNE gene: UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase Allelic to hereditary inclusion body myopathy AR Allelic to LGMD2B (see Table 462e-7) Dysferlin Myotilin (also known as LGMD 1A) aMiyoshi’s myopathy phenotype may also be seen with mutations in ANO-5 that encodes for anoctamin 5 (allelic to LGMD2L).


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InternalMed_Harrison. Myotilin (also known as LGMD 1A) aMiyoshi’s myopathy phenotype may also be seen with mutations in ANO-5 that encodes for anoctamin 5 (allelic to LGMD2L). Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CK, creatine kinase; EMG, electromyography; MFM, myofibrillar myopathy; NCS, nerve conduction studies. clubbed feet may be present. Most patients exhibit progressive weakness, some requiring wheelchairs. Progressive external ophthalmoplegia with ptosis and varying degrees of extraocular muscle impairment are characteristic of both the neonatal and the late-infantile forms. A third variant, the late childhood–adult form, has an onset in the second or third decade. Patients have full extraocular muscle movements and rarely exhibit ptosis. There is mild, slowly progressive limb weakness that may be distally predominant (some of these patients have been classified as having Charcot-Marie-Tooth disease type 2 [CMT2; Chap. 459]).


InternalMed_Harrison

InternalMed_Harrison. Normal or slightly elevated CK levels occur in each of the forms. Nerve conduction studies may reveal reduced amplitudes of distal compound muscle action potentials, in particular in adult-onset cases that resemble CMT2. EMG studies often give distinctive results, showing positive sharp waves and fibrillation potentials, complex and repetitive discharges, and rarely myotonic discharges. Muscle biopsy specimens in longitudinal section demonstrate rows of central nuclei, often surrounded by a halo. In transverse sections, central nuclei are found in 25–80% of muscle fibers.


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InternalMed_Harrison. A gene for the neonatal form of centronuclear myopathy has been localized to Xq28; this gene encodes myotubularin, a protein tyrosine phosphatase. Missense, frameshift, and splice-site mutations predict loss of myotubularin function in affected individuals. Carrier identification and prenatal diagnosis are possible. Autosomal recessive forms are caused by mutations in BIB1 that encodes for amphyphysin-2, whereas some autosomal dominant cases, which are allelic to a form of CMT2, are associated with mutations in the gene that encodes dynamin-2. No specific medical treatments are available at this time. There are two principal sources of energy for skeletal muscle—fatty acids and glucose. Abnormalities in either glucose or lipid utilization can be associated with distinct clinical presentations that can range from an acute, painful syndrome with rhabdomyolysis and myoglobinuria to a chronic, progressive muscle weakness simulating muscular dystrophy.


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InternalMed_Harrison. gLYCOgEN STORAgE AND gLYCOLYTIC DEFECTS Disorders of glycogen Storage Causing Progressive Weakness • α-Glucosidase, or acid maltase, deficiency (PomPe’s disease) Three clinical forms of α-glucosidase, or acid maltase, deficiency (type II glycogenosis) can be distinguished. The infantile form is the most common, with onset of symptoms in the first 3 months of life. Infants develop severe muscle weakness, cardiomegaly, hepatomegaly, and respiratory insufficiency. Glycogen accumulation in motor neurons of the spinal cord and brainstem contributes to muscle weakness. Death usually occurs by 1 year of age. In the childhood form, the picture resembles muscular dystrophy. Delayed motor milestones result from proximal limb muscle weakness and involvement of respiratory muscles. The heart may be involved, but the liver and brain are unaffected. The adult form usually begins in the third or fourth decade but can present as late as the seventh decade. Respiratory failure and diaphragmatic


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InternalMed_Harrison. be involved, but the liver and brain are unaffected. The adult form usually begins in the third or fourth decade but can present as late as the seventh decade. Respiratory failure and diaphragmatic weakness are often initial manifestations, heralding progressive proximal muscle weakness. The heart and liver are not involved.


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InternalMed_Harrison. The serum CK level is 2–10 times normal in infantile or childhood-onset Pompe’s disease but can be normal in adult-onset cases. EMG examination demonstrates a myopathic pattern, but other features are especially distinctive, including myotonic discharges, trains of fibrillation and positive waves, and complex repetitive discharges. EMG discharges are very prominent in the paraspinal muscles. The muscle biopsy in infants typically reveals vacuoles containing glycogen and the lysosomal enzyme acid phosphatase. Electron microscopy reveals membrane-bound and free tissue glycogen. However, muscle biopsies in late-onset Pompe’s disease may demonstrate only nonspecific abnormalities. Enzyme analysis of dried blood spots is a sensitive technique to screen for Pompe’s disease. A definitive diagnosis is established by enzyme assay in muscle or cultured fibroblasts or by genetic testing.


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InternalMed_Harrison. Pompe’s disease is inherited as an autosomal recessive disorder caused by mutations of the α-glucosidase gene. Enzyme replacement therapy (ERT) with IV recombinant human α-glucosidase has been shown to be beneficial in infantile-onset Pompe’s disease. Clinical benefits in the infantile disease include reduced heart size, improved muscle function, reduced need for ventilatory support, and longer life. In late-onset cases, ERT has not been associated with the dramatic response that can be seen in classic infantile Pompe’s disease, yet it appears to stabilize the disease process.


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InternalMed_Harrison. other GlycoGen storaGe diseases with ProGressive weakness In debranching enzyme deficiency (type III glycogenosis), a slowly progressive form of muscle weakness can develop after puberty. Rarely, myoglobinuria may be seen. Patients are usually diagnosed in infancy, however, because of hypotonia and delayed motor milestones, hepatomegaly, growth retardation, and hypoglycemia. Branching enzyme deficiency (type IV glycogenosis) is a rare and fatal glycogen storage disease characterized by failure to thrive and hepatomegaly. Hypotonia and muscle wasting may be present, but the skeletal muscle manifestations are minor compared to liver failure.


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InternalMed_Harrison. Disorders of glycolysis Causing Exercise Intolerance Several glycolytic defects are associated with recurrent myoglobinuria: myophosphorylase deficiency (type V glycogenosis), phosphofructokinase deficiency (type VII glycogenosis), phosphoglycerate kinase deficiency, phosphorylase kinase deficiency (type IX glycogenosis), phosphoglycerate mutase deficiency (type X glycogenosis), lactate dehydrogenase deficiency (glycogenosis type XI), and β-enolase deficiency. Myophosphorylase deficiency, also known as McArdle’s disease, is by far the most common of the glycolytic defects associated with exercise intolerance. These glycolytic defects result in a common failure to support energy production at the initiation of exercise, although the exact site of energy failure remains controversial.


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InternalMed_Harrison. Clinical muscle manifestations in these conditions usually begin in adolescence. Symptoms are precipitated by brief bursts of high-intensity exercise such as running or lifting heavy objects. A history of myalgia and muscle stiffness usually precedes the intensely painful muscle contractures, which may be followed by myoglobinuria. Acute renal failure accompanies significant pigmenturia. Certain features help distinguish some enzyme defects. In McArdle’s disease, exercise tolerance can be enhanced by a slow induction phase (warm-up) or brief periods of rest, allowing for the start of the “second-wind” phenomenon (switching to utilization of fatty acids). Varying degrees of hemolytic anemia accompany deficiencies of both phosphofructokinase (mild) and phosphoglycerate kinase (severe). In phosphoglycerate kinase deficiency, the usual clinical presentation is a seizure disorder associated with mental retardation; exercise intolerance is an infrequent manifestation.


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InternalMed_Harrison. In all of these conditions, the serum CK levels fluctuate widely and may be elevated even during symptom-free periods. CK levels >100 times normal are expected, accompanying myoglobinuria. All patients with suspected glycolytic defects leading to exercise intolerance should undergo a forearm exercise test. An impaired rise in venous lactate is highly indicative of a glycolytic defect. In lactate dehydrogenase deficiency, venous levels of lactate do not increase, but pyruvate rises to normal. A definitive diagnosis of glycolytic disease is made by muscle biopsy and subsequent enzyme analysis or by genetic testing. Myophosphorylase deficiency, phosphofructokinase deficiency, and phosphoglycerate mutase deficiency are inherited as autosomal recessive disorders. Phosphoglycerate kinase deficiency is X-linked recessive. Mutations can be found in the respective genes encoding the abnormal proteins in each of these disorders.


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InternalMed_Harrison. Training may enhance exercise tolerance, perhaps by increasing perfusion to muscle. Dietary intake of free glucose or fructose prior to activity may improve function but care must be taken to avoid obesity from ingesting too many calories.


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InternalMed_Harrison. Lipid is an important muscle energy source during rest and during prolonged, submaximal exercise. Fatty acids are derived from circulating very-low-density lipoprotein (VLDL) in the blood or from triglycerides stored in muscle fibers. Oxidation of fatty acids occurs in the mitochondria. To enter the mitochondria, a fatty acid must first be converted to an “activated fatty acid,” acyl-CoA. The acyl-CoA must be linked with carnitine by the enzyme carnitine palmitoyltransferase (CPT) I for transport into the mitochondria. CPT I is present on the inner side of the outer mitochondrial membrane. Carnitine is removed by CPT II, an enzyme attached to the inside of the inner mitochondrial membrane, allowing transport of acyl-CoA into the mitochondrial matrix for β-oxidation.


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InternalMed_Harrison. Carnitine Palmitoyltransferase Deficiency CPT II deficiency is the most common recognizable cause of recurrent myoglobinuria, more common than the glycolytic defects. Onset is usually in the teenage years or early twenties. Muscle pain and myoglobinuria typically occur after prolonged exercise but can also be precipitated by fasting or infections; up to 20% of patients do not exhibit myoglobinuria, however. Strength is normal between attacks. In contrast to disorders caused by defects in glycolysis, in which muscle cramps follow short, intense bursts of exercise, the muscle pain in CPT II deficiency does not occur until the limits of utilization have been exceeded and muscle breakdown has already begun. Episodes of rhabdomyolysis may produce severe weakness. In young children and newborns, CPT II deficiency can present with a very severe clinical picture including hypoketotic hypoglycemia, cardiomyopathy, liver failure, and sudden death.


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InternalMed_Harrison. Serum CK levels and EMG findings are both usually normal between episodes. A normal rise of venous lactate during forearm exercise distinguishes this condition from glycolytic defects, especially myophosphorylase deficiency. Muscle biopsy does not show lipid accumulation and is usually normal between attacks. The diagnosis requires direct measurement of muscle CPT or genetic testing. CPT II deficiency is much more common in men than women (5:1); nevertheless, all evidence indicates autosomal recessive inheritance. A mutation in the gene for CPT II (chromosome 1p36) causes the disease in some individuals. Attempts to improve exercise tolerance with frequent meals and a low-fat, high-carbohydrate diet, or by substituting medium-chain triglycerides in the diet, have not proven to be beneficial.


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InternalMed_Harrison. Myoadenylate Deaminase Deficiency The muscle enzyme myoadenylate deaminase converts adenosine-5′-monophosphate (5′-AMP) to inosine monophosphate (IMP) with liberation of ammonia. Myoadenylate deaminase may play a role in regulating adenosine triphosphate (ATP) levels in muscles. Most individuals with myoadenylate deaminase deficiency have no symptoms. There have been a few reports of patients with this disorder who have exercise-exacerbated myalgia and myoglobinuria. Many questions have been raised about the clinical effects of myoadenylate deaminase deficiency, and, specifically, its relationship to exertional myalgia and fatigability, but there is no consensus.


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InternalMed_Harrison. In 1972, Olson and colleagues recognized that muscle fibers with significant numbers of abnormal mitochondria could be highlighted with the modified trichrome stain; the term ragged red fibers was coined. By electron microscopy, the mitochondria in ragged red fibers are enlarged and often bizarrely shaped and have crystalline inclusions. Since that seminal observation, the understanding of these disorders of muscle and other tissues has expanded (Chap. 82). Mitochondria play a key role in energy production. Oxidation of the major nutrients derived from carbohydrate, fat, and protein leads to the generation of reducing equivalents. The latter are transported through the respiratory chain in the process known as oxidative phosphorylation. The energy generated by the oxidation-reduction reactions of the respiratory chain is stored in an electrochemical gradient coupled to ATP synthesis.


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InternalMed_Harrison. A novel feature of mitochondria is their genetic composition. Each mitochondrion possesses a DNA genome that is distinct from that of the nuclear DNA. Human mitochondrial DNA (mtDNA) consists of a double-strand, circular molecule comprising 16,569 base pairs. It codes for 22 transfer RNAs, 2 ribosomal RNAs, and 13 polypeptides 462e-15 of the respiratory chain enzymes. The genetics of mitochondrial diseases differ from the genetics of chromosomal disorders. The DNA of mitochondria is directly inherited from the cytoplasm of the gametes, mainly from the oocyte. The sperm contributes very little of its mitochondria to the offspring at the time of fertilization. Thus, mitochondrial genes are derived almost exclusively from the mother, accounting for maternal inheritance of some mitochondrial disorders.


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InternalMed_Harrison. Patients with mitochondrial myopathies have clinical manifestations that usually fall into three groups: chronic progressive external ophthalmoplegia (CPEO), skeletal muscle–CNS syndromes, and pure myopathy simulating muscular dystrophy or metabolic myopathy. The single most common sign of a mitochondrial myopathy is CPEO, occurring in >50% of all mitochondrial myopathies. Varying degrees of ptosis and weakness of extraocular muscles are seen, usually in the absence of diplopia, a point of distinction from disorders with fluctuating eye weakness (e.g., myasthenia gravis).


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InternalMed_Harrison. KSS is a widespread multiorgan system disorder with a defined triad of clinical findings: onset before age 20, CPEO, and pigmentary retinopathy, plus one or more of the following features: complete heart block, cerebrospinal fluid (CSF) protein >1 g/L (100 mg/dL), or cerebellar ataxia. Some patients with CPEO and ragged red fibers may not fulfill all of the criteria for KSS. The cardiac disease includes syncopal attacks and cardiac arrest related to the abnormalities in the cardiac conduction system: prolonged intraventricular conduction time, bundle branch block, and complete atrioventricular block. Death attributed to heart block occurs in ~20% of the patients. Varying degrees of progressive limb muscle weakness and easy fatigability affect activities of daily living. Endocrine abnormalities are common, including gonadal dysfunction in both sexes with delayed puberty, short stature, and infertility. Diabetes mellitus is a cardinal sign of mitochondrial disorders and is estimated to


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InternalMed_Harrison. are common, including gonadal dysfunction in both sexes with delayed puberty, short stature, and infertility. Diabetes mellitus is a cardinal sign of mitochondrial disorders and is estimated to occur in 13% of KSS patients. Other less common endocrine disorders include thyroid disease, hyperaldosteronism, Addison’s disease, and hypoparathyroidism. Both mental retardation and dementia are common accompaniments to this disorder. Serum CK levels are normal or slightly elevated. Serum lactate and pyruvate levels may be elevated. EMG is myopathic. Nerve conduction studies may be abnormal related to an associated neuropathy. Muscle biopsies reveal ragged red fibers, highlighted in oxidative enzyme stains, many showing defects in cytochrome oxidase. By electron microscopy, there are increased numbers of mitochondria that often appear enlarged and contain paracrystalline inclusions.


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InternalMed_Harrison. KSS is a sporadic disorder. The disease is caused by single mtDNA deletions presumed to arise spontaneously in the ovum or zygote. The most common deletion, occurring in about one-third of patients, removes 4977 bp of contiguous mtDNA. Monitoring for cardiac conduction defects is critical. Prophylactic pacemaker implantation is indicated when ECGs demonstrate a bifascicular block. In KSS, no benefit has been shown for supplementary therapies, including multivitamins or coenzyme Q10. Of all the proposed options, exercise might be the most applicable but must be approached cautiously because of defects in the cardiac conduction system.


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InternalMed_Harrison. This condition is caused by nuclear DNA mutations affecting mtDNA copy number and integrity and is thus inherited in a Mendelian fashion. Onset is usually after puberty. Fatigue, exercise intolerance, and complaints of muscle weakness are typical. Some patients notice swallowing problems. The neurologic examination confirms the ptosis and ophthalmoplegia, usually asymmetric in distribution. A sensorineural hearing loss may be encountered. Mild facial, neck flexor, and proximal weakness are typical. Rarely, respiratory muscles may be progressively affected and may be the direct cause of death. Serum CK is normal or mildly elevated. The resting lactate level is normal or slightly elevated but may rise excessively after exercise. CSF protein is normal. The EMG is myopathic, and nerve conduction studies are usually normal. Ragged red fibers are prominently displayed in the muscle biopsy. Southern blots of muscle reveal a normal mtDNA band at 16.6 kb and several additional mtDNA deletion


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InternalMed_Harrison. studies are usually normal. Ragged red fibers are prominently displayed in the muscle biopsy. Southern blots of muscle reveal a normal mtDNA band at 16.6 kb and several additional mtDNA deletion bands with genomes varying from 0.5 to 10 kb.


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InternalMed_Harrison. This autosomal dominant form of CPEO has been linked to loci on three chromosomes: 4q35, 10q24, and 15q22–26. In the chromosome 4q-related form of disease, mutations of the gene encoding the heart and skeletal muscle–specific isoform of the adenine nucleotide translocator 1 (ANT1) gene are found. This highly abundant mitochondrial protein forms a homodimeric inner mitochondrial channel through which adenosine diphosphate (ADP) enters and ATP leaves the mitochondrial matrix. In the chromosome 10q–related disorder, mutations of the gene C10orf2 are found. Its gene product, twinkle, co-localizes with the mtDNA and is named for its punctate, starlike staining properties. The function of twinkle is presumed to be critical for lifetime maintenance of mitochondrial integrity. In the cases mapped to chromosome 15q, a mutation affects the gene encoding mtDNA polymerase (POLG), an enzyme important in mtDNA replication. Autosomal recessive PEO has also been described with mutations in the POLG


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InternalMed_Harrison. to chromosome 15q, a mutation affects the gene encoding mtDNA polymerase (POLG), an enzyme important in mtDNA replication. Autosomal recessive PEO has also been described with mutations in the POLG gene. Point mutations have been identified within various mitochondrial tRNA (Leu, Ile, Asn, Trp) genes in families with maternal inheritance of PEO.


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InternalMed_Harrison. Exercise may improve function but will depend on the patient’s ability to participate. MITOCHONDRIAL DNA SKELETAL MUSCLE–CENTRAL NERVOUS SYSTEM SYNDROMES Myoclonic Epilepsy with Ragged Red Fibers (MERRF) The onset of MERRF is variable, ranging from late childhood to middle adult life. Characteristic features include myoclonic epilepsy, cerebellar ataxia, and progressive muscle weakness. The seizure disorder is an integral part of the disease and may be the initial symptom. Cerebellar ataxia precedes or accompanies epilepsy. It is slowly progressive and generalized. The third major feature of the disease is muscle weakness in a limb-girdle distribution. Other more variable features include dementia, peripheral neuropathy, optic atrophy, hearing loss, and diabetes mellitus.


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InternalMed_Harrison. Serum CK levels are normal or slightly increased. The serum lactate may be elevated. EMG is myopathic, and in some patients nerve conduction studies show a neuropathy. The electroencephalogram is abnormal, corroborating clinical findings of epilepsy. Typical ragged red fibers are seen on muscle biopsy. MERRF is caused by maternally inherited point mutations of mitochondrial tRNA genes. The most common mutation found in 80% of MERRF patients is an A to G substitution at nucleotide 8344 of tRNA lysine (A8344G tRNAlys). Other tRNAlys mutations include base-pair substitutions T8356C and G8363A. Only supportive treatment is possible, with special attention to epilepsy.


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InternalMed_Harrison. Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike Episodes (MELAS) MELAS is the most common mitochondrial encephalomyopathy. The term strokelike is appropriate because the cerebral lesions do not conform to a strictly vascular distribution. The onset in the majority of patients is before age 20. Seizures, usually partial motor or generalized, are common and may represent the first clearly recognizable sign of disease. The cerebral insults that resemble strokes cause hemiparesis, hemianopia, and cortical blindness. A presumptive stroke occurring before age 40 should place this mitochondrial encephalomyopathy high in the differential diagnosis. Associated conditions include hearing loss, diabetes mellitus, hypothalamic pituitary dysfunction causing growth hormone deficiency, hypothyroidism, and absence of secondary sexual characteristics. In its full expression, MELAS leads to dementia, a bedridden state, and a fatal outcome. Serum lactic acid is typically


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InternalMed_Harrison. deficiency, hypothyroidism, and absence of secondary sexual characteristics. In its full expression, MELAS leads to dementia, a bedridden state, and a fatal outcome. Serum lactic acid is typically elevated. The CSF protein is also increased but is usually ≤1 g/L (100 mg/dL). Muscle biopsies show ragged red fibers. Neuroimaging demonstrates basal ganglia calcification in a high percentage of cases. Focal lesions that mimic infarction are present predominantly in the occipital and parietal lobes. Strict vascular territories are not respected, and cerebral angiography fails to demonstrate lesions of the major cerebral blood vessels.


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InternalMed_Harrison. MELAS is caused by maternally inherited point mutations of mitochondrial tRNA genes. Most of the tRNA mutations are lethal, accounting for the paucity of multigeneration families with this syndrome. The A3243G point mutation in tRNALeu(UUR) is the most common, occurring in ~80% of MELAS cases. About 10% of MELAS patients have other mutations of the tRNALeu(UUR) gene, including 3252G, 3256T, 3271C, and 3291C. Other tRNA gene mutations have also been reported in MELAS, including G583A tRNAPhe, G1642A tRNAVal, G4332A tRNAGlu, and T8316C tRNALys. Mutations have also been reported in mtDNA polypeptide-coding genes. Two mutations were found in the ND5 subunit of complex I of the respiratory chain. A missense mutation has been reported at mtDNA position 9957 in the gene for subunit III of cytochrome C oxidase. No specific treatment is available. Supportive treatment is essential for the strokelike episodes, seizures, and endocrinopathies.


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InternalMed_Harrison. Muscle weakness and fatigue can be the predominant manifestations of mtDNA mutations. When the condition affects exclusively muscle (pure myopathy), the disorder becomes difficult to recognize. Occasionally, mitochondrial myopathies can present with recurrent myoglobinuria without fixed weakness and thus resemble a glycogen storage disorder or CPT deficiency.


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InternalMed_Harrison. Mitochondrial DNA Depletion Syndromes Mitochondrial DNA depletion syndrome (MDS) is a heterogeneous group of disorders that are inherited in an autosomal recessive fashion and can present in infancy or adults. MDS can be caused by mutations in genes (TK2, DGUOK, RRM2B, TYMP, SUCLA1, and SUCLA2) that lead to depletion of pools of mitochondrial deoxyribonucleotide (dNTP) pools necessary for mtDNA replication The other major cause of MDS is a set of mutations in genes essential for mtDNA replication (e.g., POLG1 and C10orf2). The clinical phenotypes associated with MDS vary. Patients may develop a severe encephalopathy (e.g., Leigh’s syndrome), PEO, an isolated myopathy, myo-neuro-gastrointestinal-encephalopathy (MNGIE), and a sensory neuropathy with ataxia. Muscle membrane excitability is affected in a group of disorders referred to as channelopathies. The heart may also be involved, resulting in life-threatening complications (Table 462e-10).


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InternalMed_Harrison. CALCIUM CHANNEL DISORDERS OF MUSCLE Hypokalemic Periodic Paralysis (HypoKPP) Onset occurs at adolescence. Men are more often affected because of decreased penetrance in women. Episodic weakness with onset after age 25 is almost never due to periodic paralyses, with the exception of thyrotoxic periodic paralysis (see below). Attacks are often provoked by meals high in carbohydrates or sodium and may accompany rest following prolonged exercise. Weakness usually affects proximal limb muscles more than distal. Ocular and bulbar muscles are less likely to be affected. Respiratory muscles are usually spared, but when they are involved, the condition may prove fatal. Weakness may take as long as 24 h to resolve. Life-threatening cardiac arrhythmias related to hypokalemia may occur during attacks. As a late complication, patients commonly develop severe, disabling proximal lower extremity weakness.


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InternalMed_Harrison. Attacks of thyrotoxic periodic paralysis resemble those of primary HypoKPP. Despite a higher incidence of thyrotoxicosis in women, men, particularly those of Asian descent, are more likely to manifest this complication. Attacks abate with treatment of the underlying thyroid condition. A low serum potassium level during an attack, excluding secondary causes, establishes the diagnosis. Interattack muscle biopsies show the presence of single or multiple centrally placed vacuoles or tubular aggregates. Provocative tests with glucose and insulin to establish a diagnosis are usually not necessary and are potentially hazardous.


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InternalMed_Harrison. type 1, the most common form, is inherited as an autosomal dominant disorder with incomplete penetrance. These patients have mutations in the voltage-sensitive, skeletal muscle calcium channel gene, CALCL1A3 (Fig. 462e-8). Approximately 10% of cases are HypoKPP type 2, arising from mutations in the voltage-sensitive sodium channel gene (SCN4A). In either instance, the mutations lead to an abnormal gating pore current that predisposes the muscle cell to depolarize when potassium levels are low. It is also now recognized that some cases of thyrotoxic HypoKPP are caused by genetic variants in a potassium channel (Kir 2.6), whose expression is regulated by thyroid hormone. The chloride channel is envisioned to have 10 membrane-spanning domains. The positions of mutations causing dominantly and recessively inherited myotonia congenita are indicated, along with mutations that cause this disease in mice and goats.


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InternalMed_Harrison. The acute paralysis improves after the administration of potassium. Muscle strength and ECG should be monitored. Oral KCl (0.2–0.4 mmol/kg) should be given every 30 min. Only rarely is IV therapy necessary (e.g., when swallowing problems or vomiting is present). Administration of potassium in a glucose solution should be avoided because it may further reduce serum potassium levels. Mannitol is the preferred vehicle for administration of IV potassium. The long-term goal of therapy is to avoid attacks. This may reduce late-onset, fixed weakness. Patients should be made aware of the importance of a low-carbohydrate, low-sodium diet and consequences of intense exercise. Prophylactic administration of acetazolamide (125–1000 mg/d in divided doses) reduces or may abolish attacks in HypoKPP type 1. Paradoxically the potassium is lowered, but this is offset by the beneficial effect of metabolic acidosis. If attacks persist on acetazolamide, oral KCl should be added. Some patients require


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InternalMed_Harrison. type 1. Paradoxically the potassium is lowered, but this is offset by the beneficial effect of metabolic acidosis. If attacks persist on acetazolamide, oral KCl should be added. Some patients require treatment with triamterene (25–100 mg/d) or spironolactone (25–100 mg/d). However, in patients with HypoKPP type 2, attacks of weakness can be exacerbated with acetazolamide.


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InternalMed_Harrison. SODIUM CHANNEL DISORDERS OF MUSCLE Hyperkalemic Periodic Paralysis (HyperKPP) The term hyperkalemic is misleading because patients are often normokalemic during attacks. FIgURE 462e-8 The sodium and calcium channels are depicted here as containing four homologous domains, each with six membrane-spanning segments. The fourth segment of each domain bears positive charges and acts as the “voltage sensor” for the channel. The association of the four domains is thought to form a pore through which ions pass. Sodium channel mutations are shown along with the phenotype that they confer. HyperKPP, hyperkalemic periodic paralysis; PC, paramyotonia congenita; PAM, potassium-aggravated myotonia. See text for details.


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InternalMed_Harrison. The fact that attacks are precipitated by potassium administration best defines the disease. The onset is in the first decade; males and females are affected equally. Attacks are brief and mild, usually lasting 30 min to 4 ho. Weakness affects proximal muscles, sparing bulbar muscles. Attacks are precipitated by rest following exercise and fasting. In a variant of this disorder, the predominant symptom is myotonia without weakness (potassium-aggravated myotonia). The symptoms are aggravated by cold, and myotonia makes the muscles stiff and painful. This disorder can be confused with paramyotonia congenita, myotonia congenita, and proximal myotonic myopathy (DM2).


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InternalMed_Harrison. Potassium may be slightly elevated but may also be normal during an attack. As in HypoKPP, nerve conduction studies in HyperKPP muscle may demonstrate reduced motor amplitudes and the EMG may be silent in very weak muscles. In between attacks of weakness, the conduction studies are normal. The EMG will often demonstrate myotonic discharges during and between attacks. The muscle biopsy shows vacuoles that are smaller, less numerous, and more peripheral compared to the hypokalemic form or tubular aggregates. Provocative tests by administration of potassium can induce weakness but are usually not necessary to establish the diagnosis. HyperKPP and potassium-aggravated myotonia are inherited as autosomal dominant disorders. Mutations of the voltage-gated sodium channel SCN4A gene (Fig. 462e-8) cause these conditions. For patients with frequent attacks, acetazolamide (125–1000 mg/d) is helpful. We have found mexiletine to be helpful in patients with significant myotonia.


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InternalMed_Harrison. Paramyotonia Congenita In paramyotonia congenita (PC), the attacks of weakness are cold-induced or occur spontaneously and are mild. Myotonia is a prominent feature but worsens with muscle activity (paradoxical myotonia). This is in contrast to classic myotonia in which exercise alleviates the condition. Attacks of weakness are seldom severe enough to require emergency room treatment. Over time patients develop interattack weakness as they do in other forms of periodic paralysis. PC is usually associated with normokalemia or hyperkalemia. Serum CK is usually mildly elevated. Routine sensory and motor nerve conduction studies are normal. Short exercise test may be abnormal however, and cooling of the muscle often dramatically reduces the amplitude of the compound muscle action potentials. EMG reveals diffuse myotonic potentials in PC. Upon local cooling of the muscle, the myotonic discharges disappear as the patient becomes unable to activate MUAPs.


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InternalMed_Harrison. PC is inherited as an autosomal dominant condition; voltage-gated sodium channel mutations (Fig. 462e-8) are responsible, and thus this disorder is allelic with HyperKPP and potassium-aggravated myotonia. Patients with PC seldom seek treatment during attacks. Oral administration of glucose or other carbohydrates hastens recovery. Because interattack weakness may develop after repeated episodes, prophylactic treatment is usually indicated. Thiazide diuretics (e.g., chlorothiazide, 250–1000 mg/d) and mexiletine (slowly increase dose from 450 mg/d) are reported to be helpful. Patients should be advised to increase carbohydrates in their diet.


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InternalMed_Harrison. POTASSIUM CHANNEL DISORDERS Andersen-Tawil Syndrome This rare disease is characterized by episodic weakness, cardiac arrhythmias, and dysmorphic features (short stature, scoliosis, clinodactyly, hypertelorism, small or prominent low-set ears, micrognathia, and broad forehead). The cardiac arrhythmias are potentially serious and life threatening. They include long QT, ventricular ectopy, bidirectional ventricular arrhythmias, and tachycardia. For many years, the classification of this disorder was uncertain because episodes of weakness are associated with elevated, normal, or reduced levels of potassium during an attack. In addition, the potassium levels differ among kindreds but are consistent within a family. Inheritance is autosomal dominant, with incomplete penetrance and variable expressivity. The disease is caused by mutations of the inwardly rectifying potassium channel (Kir 2.1) gene that heighten muscle cell excitability. The treatment is similar to that for other forms of


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InternalMed_Harrison. The disease is caused by mutations of the inwardly rectifying potassium channel (Kir 2.1) gene that heighten muscle cell excitability. The treatment is similar to that for other forms of periodic paralysis and must include cardiac monitoring. The episodes of weakness may differ between patients because of potassium variability. Acetazolamide may decrease the attack frequency and severity.


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InternalMed_Harrison. Two forms of this disorder, autosomal dominant (Thomsen’s disease) and autosomal recessive (Becker disease), are related to the same gene abnormality. Symptoms are noted in infancy and early childhood. The severity lessens in the third to fourth decade. Myotonia is worsened by cold and improved by activity. The gait may appear slow and labored at first but improves with walking. In Thomsen’s disease, muscle strength is normal, but in Becker disease, which is usually more severe, there may be muscle weakness. Muscle hypertrophy is usually present. Myotonic discharges are prominently displayed by EMG recordings.


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InternalMed_Harrison. Serum CK is normal or mildly elevated. The muscle biopsy shows hypertrophied fibers. The disease is inherited as dominant or recessive and is caused by mutations of the chloride channel gene (Fig. 462e-8) that increase muscle cell excitability. Many patients will not require treatment and learn that the symptoms improve with activity. Medications that can be used to decrease myotonia include quinine, phenytoin, and mexiletine. Many endocrine disorders cause weakness. Muscle fatigue is more common than true weakness. The cause of weakness in these disorders is not well defined. It is not even clear that weakness results from disease of muscle as opposed to another part of the motor unit, since the serum CK level is often normal (except in hypothyroidism) and the muscle histology is characterized by atrophy rather than destruction of muscle fibers. Nearly all endocrine myopathies respond to treatment.


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InternalMed_Harrison. (See also Chap. 405) Abnormalities of thyroid function can cause a wide array of muscle disorders. These conditions relate to the important role of thyroid hormones in regulating the metabolism of carbohydrates and lipids as well as the rate of protein synthesis and enzyme production. Thyroid hormones also stimulate calorigenesis in muscle, increase muscle demand for vitamins, and enhance muscle sensitivity to circulating catecholamines.


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InternalMed_Harrison. Hypothyroidism Patients with hypothyroidism have frequent muscle complaints, and proximal muscle weakness occurs in about one-third of them. Muscle cramps, pain, and stiffness are common. Some patients have enlarged muscles. Features of slow muscle contraction and relaxation occur in 25% of patients; the relaxation phase of muscle stretch reflexes is characteristically prolonged and best observed at the ankle or biceps brachii reflexes. The serum CK level is often elevated (up to 10 times normal), even when there is minimal clinical evidence of muscle disease. EMG is typically normal. The cause of muscle enlargement has not been determined, and muscle biopsy shows no distinctive morphologic abnormalities.


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InternalMed_Harrison. Hyperthyroidism Patients who are thyrotoxic commonly have proximal muscle weakness and atrophy on examination, but they rarely complain of myopathic symptoms. Activity of deep tendon reflexes may be enhanced. Bulbar, respiratory, and even esophageal muscles may occasionally be affected, causing dysphagia, dysphonia, and aspiration. When bulbar involvement occurs, it is usually accompanied by chronic proximal limb weakness, but occasionally it presents in the absence of generalized thyrotoxic myopathy. Fasciculations may be apparent and, when coupled with increased muscle stretch reflexes, may lead to an erroneous diagnosis of amyotrophic lateral sclerosis. A form hypokalemic periodic paralysis can occur in patients who are thyrotoxic. Recently, mutations in the KCNJ18 gene that encodes for the inwardly rectifying potassium channel, Kir 2.6, have been discovered in up to a third of cases. Other neuromuscular disorders that occur in association with hyperthyroidism include myasthenia


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InternalMed_Harrison. for the inwardly rectifying potassium channel, Kir 2.6, have been discovered in up to a third of cases. Other neuromuscular disorders that occur in association with hyperthyroidism include myasthenia gravis (Chap.


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InternalMed_Harrison. 461) and a progressive ocular myopathy associated with proptosis (Graves’ ophthalmopathy). Serum CK levels are not elevated in thyrotoxic myopathy, the EMG is normal, and muscle histology usually shows only atrophy of muscle fibers. (See also Chap. 424) Hyperparathyroidism Muscle weakness is an integral part of primary and secondary hyperparathyroidism. Proximal muscle weakness, muscle wasting, and brisk muscle stretch reflexes are the main features of this endocrinopathy. Some patients develop neck extensor weakness (part of the dropped head syndrome). Serum CK levels are usually normal or slightly elevated. Serum parathyroid hormone levels are elevated. Serum calcium and phosphorus levels show no correlation with the clinical neuromuscular manifestations. Muscle biopsies show only varying degrees of atrophy without muscle fiber degeneration.


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InternalMed_Harrison. Hypoparathyroidism An overt myopathy due to hypocalcemia rarely occurs. Neuromuscular symptoms are usually related to localized or generalized tetany. Serum CK levels may be increased secondary to muscle damage from sustained tetany. Hyporeflexia or areflexia is usually present and contrasts with the hyperreflexia in hyperparathyroidism.


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InternalMed_Harrison. (See also Chap. 406) Conditions associated with glucocorticoid excess cause a myopathy; in fact, steroid myopathy is the most commonly diagnosed endocrine muscle disease. Glucocorticoid excess, either endogenous or exogenous (see “Drug-Induced Myopathies,” below), produces various degrees of proximal limb weakness. Muscle wasting may be striking. A cushingoid appearance usually accompanies clinical signs of myopathy. Histologic sections demonstrate muscle fiber atrophy, preferentially affecting type 2b fibers, rather than degeneration or necrosis of muscle fibers. Adrenal insufficiency commonly causes muscle fatigue. The degree of weakness may be difficult to assess but is typically mild. In primary hyperaldosteronism (Conn’s syndrome), neuromuscular complications are due to potassium depletion. The clinical picture is one of persistent muscle weakness. Long-standing hyperaldosteronism may lead to proximal limb weakness and wasting. Serum CK levels may be elevated, and a muscle biopsy


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InternalMed_Harrison. The clinical picture is one of persistent muscle weakness. Long-standing hyperaldosteronism may lead to proximal limb weakness and wasting. Serum CK levels may be elevated, and a muscle biopsy may demonstrate degenerating fibers, some with vacuoles. These changes relate to hypokalemia and are not a direct effect of aldosterone on skeletal muscle.


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InternalMed_Harrison. (See also Chap. 403) Patients with acromegaly usually have mild proximal weakness without muscle atrophy. Muscles often appear enlarged but exhibit decreased force generation. The duration of acromegaly, rather than the serum growth hormone levels, correlates with the degree of myopathy. (See also Chap. 417) Neuromuscular complications of diabetes mellitus are most often related to neuropathy, with cranial and peripheral nerve palsies or distal sensorimotor polyneuropathy. Diabetic amyotrophy is a clumsy term because the condition represents a neuropathy affecting the proximal major nerve trunks and lumbosacral plexus. More appropriate terms for this disorder include diabetic proximal neuropathy and lumbosacral radiculoplexus neuropathy.


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InternalMed_Harrison. The only notable myopathy of diabetes mellitus is ischemic infarction of leg muscles, usually involving one of the thigh muscles but on occasion affecting the distal leg. This condition occurs in patients with poorly controlled diabetes and presents with abrupt onset of pain, tenderness, and edema of one thigh. The area of muscle infarction is hard and indurated. The muscles most often affected include the vastus lateralis, thigh adductors, and biceps femoris. Computed tomography (CT) or MRI can demonstrate focal abnormalities in the affected muscle. Diagnosis by imaging is preferable to muscle biopsy, if possible, as hemorrhage into the biopsy site can occur.


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InternalMed_Harrison. Vitamin D deficiency (Chap. 96e) due to decreased intake, decreased absorption, or impaired vitamin D metabolism (as occurs in renal disease) may lead to chronic muscle weakness. Pain reflects the underlying bone disease (osteomalacia). Vitamin E deficiency may result from malabsorption. Clinical manifestations include ataxic neuropathy due to loss of proprioception and myopathy with proximal weakness. Progressive external ophthalmoplegia is a distinctive finding. It has not 462e-19 been established that deficiency of other vitamins causes a myopathy. Systemic illnesses such as chronic respiratory, cardiac, or hepatic failure are frequently associated with severe muscle wasting and complaints of weakness. Fatigue is usually a more significant problem than weakness, which is typically mild.


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InternalMed_Harrison. Myopathy may be a manifestation of chronic renal failure (CRF), independent of the better known uremic polyneuropathy. Abnormalities of calcium and phosphorus homeostasis and bone metabolism in chronic renal failure result from a reduction in 1,25-dihydroxyvitamin D, leading to decreased intestinal absorption of calcium. Hypocalcemia, further accentuated by hyperphosphatemia due to decreased renal phosphate clearance, leads to secondary hyperparathyroidism. Renal osteodystrophy results from the compensatory hyperparathyroidism, which leads to osteomalacia from reduced calcium availability and to osteitis fibrosa from the parathyroid hormone excess. The clinical picture of the myopathy of CRF is identical to that of primary hyperparathyroidism and osteomalacia. There is proximal limb weakness with bone pain.


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InternalMed_Harrison. Gangrenous calcification represents a separate, rare, and sometimes fatal complication of CRF. In this condition, widespread arterial calcification occurs and results in ischemia. Extensive skin necrosis may occur, along with painful myopathy and even myoglobinuria. Drug-induced myopathies are relatively uncommon in clinical practice with the exception of those caused by the cholesterol-lowering agents and glucocorticoids. Others impact practice to a lesser degree but are important to consider in specific situations. Table 462e-11 provides a comprehensive list of drug-induced myopathies with their distinguishing features.


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InternalMed_Harrison. All classes of lipid-lowering agents have been implicated in muscle toxicity, including fibrates (clofibrate, gemfibrozil), HMG-CoA reductase inhibitors (referred to as statins), niacin (nicotinic acid), and ezetimibe. Myalgia, malaise, and muscle tenderness are the most common manifestations. Muscle pain may be related to exercise. Patients may exhibit proximal weakness. Varying degrees of muscle necrosis are seen, and in severe reactions rhabdomyolysis and myoglobinuria occur. Concomitant use of statins with fibrates and cyclosporine is more likely to cause adverse reactions than use of one agent alone. Elevated serum CK is an important indication of toxicity. Muscle weakness is accompanied by a myopathic EMG, and muscle necrosis is observed by muscle biopsy. Severe myalgias, muscle weakness, significant elevations in serum CK (>three times baseline), and myoglobinuria are indications for stopping the drug. Patients usually improve with drug cessation, although this may take several


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InternalMed_Harrison. significant elevations in serum CK (>three times baseline), and myoglobinuria are indications for stopping the drug. Patients usually improve with drug cessation, although this may take several weeks. Rare cases continue to progress after the offending agent is discontinued. It is possible that in such cases the statin may have triggered an immune-mediated necrotizing myopathy, as these individuals require aggressive immunotherapy (e.g., prednisone and sometimes other agents) to improve and often relapse when these therapies are discontinued. Interestingly, antibodies directed against the 100-kDa HMG-CoA reductase receptor on muscle fibers have been identified in many of these cases.


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InternalMed_Harrison. Glucocorticoid myopathy occurs with chronic treatment or as “acute quadriplegic” myopathy secondary to high-dose IV glucocorticoid use. Chronic administration produces proximal weakness accompanied by cushingoid manifestations, which can be quite debilitating; the chronic use of prednisone at a daily dose of ≥30 mg/d is most often associated with toxicity. Patients taking fluorinated glucocorticoids (triamcinolone, betamethasone, dexamethasone) appear to be at especially high risk for myopathy. In chronic steroid myopathy, the serum CK is Lipid-lowering agents Drugs belonging to all three of the major classes of lipid-lowering agents Fibric acid derivatives can produce a spectrum of toxicity: HMG-CoA reductase inhibitors asymptomatic serum creatine kinase Niacin (nicotinic acid) elevation, myalgias, exercise-induced pain, rhabdomyolysis, and myoglobinuria.


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InternalMed_Harrison. Niacin (nicotinic acid) elevation, myalgias, exercise-induced pain, rhabdomyolysis, and myoglobinuria. Glucocorticoids Acute, high-dose glucocorticoid treatment can cause acute quadriplegic myopathy. These high doses of steroids are often combined with nondepolarizing neuromuscular blocking agents but the weakness can occur without their use. Chronic steroid administration produces predominantly proximal weakness. Nondepolarizing neuromuscular Acute quadriplegic myopathy can blocking agents occur with or without concomitant glucocorticoids. Zidovudine Mitochondrial myopathy with ragged red fibers Drugs of abuse All drugs in this group can lead to widespread muscle breakdown, rhab- Alcohol domyolysis, and myoglobinuria. necrosis, skin induration, and limb Heroin contractures. Autoimmune toxic myopathy Use of this drug may cause polymyositis and myasthenia gravis. Amphophilic cationic drugs All amphophilic drugs have the potential to produce painless,


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InternalMed_Harrison. Autoimmune toxic myopathy Use of this drug may cause polymyositis and myasthenia gravis. Amphophilic cationic drugs All amphophilic drugs have the potential to produce painless, Amiodarone proximal weakness associated with Chloroquine autophagic vacuoles in the muscle Hydroxychloroquine biopsy. Antimicrotubular drugs This drug produces painless, proximal weakness especially in the setting of Colchicine renal failure. Muscle biopsy shows autophagic vacuoles. usually normal. Serum potassium may be low. The muscle biopsy in chronic cases shows preferential type 2 muscle fiber atrophy; this is not reflected in the EMG, which is usually normal.


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InternalMed_Harrison. Patients receiving high-dose IV glucocorticoids for status asthmaticus, chronic obstructive pulmonary disease, organ transplantation, or other indications may develop severe generalized weakness (critical illness myopathy). This myopathy, also known as acute quadriplegic myopathy, can also occur in the setting of sepsis. Involvement of the diaphragm and intercostal muscles causes respiratory failure and requires ventilatory support. In these settings, the use of glucocorticoids in combination with nondepolarizing neuromuscular blocking agents potentiates this complication. In critical illness myopathy, the muscle biopsy is abnormal, showing a distinctive loss of thick filaments (myosin) by electron microscopy. By light microscopy, there is focal loss of ATPase staining in central or paracentral areas of the muscle fiber. Calpain stains show diffusely reactive atrophic fibers. Withdrawal of glucocorticoids will improve the chronic myopathy. In acute quadriplegic myopathy, recovery is


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InternalMed_Harrison. areas of the muscle fiber. Calpain stains show diffusely reactive atrophic fibers. Withdrawal of glucocorticoids will improve the chronic myopathy. In acute quadriplegic myopathy, recovery is slow. Patients require supportive care and rehabilitation.


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InternalMed_Harrison. Zidovudine, used in the treatment of HIV infection, is a thymidine analogue that inhibits viral replication by interrupting reverse transcriptase. Myopathy is a well-established complication of this agent. Patients present with myalgias, muscle weakness, and atrophy affecting the thigh and calf muscles. The complication occurs in about 17% of patients treated with doses of 1200 mg/d for 6 months. The introduction of protease inhibitors for treatment of HIV infection has led to lower doses of zidovudine therapy and a decreased incidence of myopathy. Serum CK is elevated and EMG is myopathic. Muscle biopsy shows ragged red fibers with minimal inflammation; the lack of inflammation serves to distinguish zidovudine toxicity from HIV-related myopathy. If the myopathy is thought to be drug related, the medication should be stopped or the dosage reduced.


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InternalMed_Harrison. Myotoxicity is a potential consequence of addiction to alcohol and illicit drugs. Ethanol is one of the most commonly abused substances with potential to damage muscle. Other potential toxins include cocaine, heroin, and amphetamines. The most deleterious reactions occur from overdosing leading to coma and seizures, causing rhabdomyolysis, myoglobinuria, and renal failure. Direct toxicity can occur from cocaine, heroin, and amphetamines causing muscle breakdown and varying degrees of weakness. The effects of alcohol are more controversial. Direct muscle damage is less certain, since toxicity usually occurs in the setting of poor nutrition and possible contributing factors such as hypokalemia and hypophosphatemia. Alcoholics are also prone to neuropathy (Chap. 467).


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InternalMed_Harrison. Focal myopathies from self-administration of meperidine, heroin, and pentazocine can cause pain, swelling, muscle necrosis, and hemorrhage. The cause is multifactorial; needle trauma, direct toxicity of the drug or vehicle, and infection may all play a role. When severe, there may be overlying skin induration and contractures with replacement of muscle by connective tissue. Elevated serum CK and myopathic EMG are characteristic of these reactions. The muscle biopsy shows widespread or focal areas of necrosis. In conditions leading to rhabdomyolysis, patients need adequate hydration to reduce serum myoglobin and protect renal function. In all of these conditions, counseling is essential to limit drug abuse.


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InternalMed_Harrison. As mentioned previously, an autoimmune necrotizing myopathy associated with autoantibodies directed against HMG-CoA rarely occurs in the setting of statin use. An inflammatory myopathy also may occur with d-penicillamine, sometimes used in the treatment of Wilson’s disease scleroderma, rheumatoid arthritis, and primary biliary cirrhosis. The incidence of this inflammatory muscle disease is about 1%. Myasthenia gravis is also induced by d-penicillamine, with a higher incidence estimated at 7%. These disorders resolve with drug withdrawal, although immunosuppressive therapy may be warranted in severe cases.


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InternalMed_Harrison. Scattered reports of other drugs causing an inflammatory myopathy are rare and include a heterogeneous group of agents: cimetidine, phenytoin, procainamide, and propylthiouracil. In most cases, a causeand-effect relationship is uncertain. A complication of interest was related to l-tryptophan. In 1989 an epidemic of eosinophilia-myalgia syndrome (EMS) in the United States was caused by a contaminant in the product from one manufacturer. The product was withdrawn, and incidence of EMS diminished abruptly following this action. Certain drugs produce painless, largely proximal, muscle weakness. These drugs include the amphophilic cationic drugs (amiodarone, chloroquine, hydroxychloroquine) and antimicrotubular drugs (colchicine) (Table 462e-11). Muscle biopsy can be useful in the identification of toxicity because autophagic vacuoles are prominent pathologic features of these toxins.


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InternalMed_Harrison. Special Issues in Inpatient Neurologic Consultation S. Andrew Josephson, Martin A. Samuels Inpatient neurologic consultations usually involve questions regard-ing specific disease processes or prognostication after various cerebral 463e injuries. Common reasons for neurologic consultation include stroke (Chap. 446), seizures (Chap. 445), altered mental status (Chap. 34), headache (Chap. 21), and management of coma and other neurocritical care conditions (Chaps. 328 and 330). This chapter focuses on additional common reasons for consultation that are not addressed elsewhere in the text.


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InternalMed_Harrison. A group of neurologic disorders shares the common feature of hyper-perfusion, probably related to endothelial dysfunction, playing a key role in pathogenesis. These seemingly diverse syndromes include hypertensive encephalopathy, eclampsia, postcarotid endarterectomy syndrome, and toxicity from calcineurin-inhibitor and other medications. Modern imaging techniques and experimental models suggest that vasogenic edema is typically the primary process leading to neurologic dysfunction; therefore, prompt recognition and management of this condition should allow for clinical recovery as long as superimposed hemorrhage or infarction has not occurred.


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InternalMed_Harrison. The brain’s autoregulatory capability successfully maintains a fairly stable cerebral blood flow in adults despite alterations in systemic mean arterial pressure (MAP) ranging from 50 to 150 mmHg (Chap. 330). In patients with chronic hypertension, this cerebral autoregulation curve is shifted, resulting in autoregulation working over a much higher range of pressures (e.g., 70–175 mmHg). In these hypertensive patients, cerebral blood flow is kept steady at higher MAP, but a rapid lowering of pressure can lead to ischemia on the lower end of the autoregulatory curve, even at values typically thought of as normotensive. This autoregulatory phenomenon is achieved through both myogenic and neurogenic influences causing small arterioles to contract and dilate. When the systemic blood pressure exceeds the limits of this mechanism, breakthrough of autoregulation occurs, resulting in hyperperfusion via increased cerebral blood flow, capillary leakage into the interstitium, and resulting edema.


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InternalMed_Harrison. the limits of this mechanism, breakthrough of autoregulation occurs, resulting in hyperperfusion via increased cerebral blood flow, capillary leakage into the interstitium, and resulting edema. The predilection of all of the hyperperfusion disorders to affect the posterior rather than anterior portions of the brain may be due to a lower threshold for autoregulatory breakthrough in the posterior circulation or a vasculopathy that is more common in these blood vessels.


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InternalMed_Harrison. Although elevated or relatively elevated blood pressure is common in many of these disorders, some hyperperfusion states such as calcineurin-inhibitor toxicity occur with no apparent pressure rise. In these cases, vasogenic edema is likely due primarily to dysfunction of the capillary endothelium itself, leading to breakdown of the blood-brain barrier. It is useful to separate disorders of hyperperfusion into those caused primarily by increased pressure and those due mostly to endothelial dysfunction from a toxic or autoimmune etiology (Table 463e-1). In reality, both of these pathophysiologic processes likely play some role in each of these disorders.


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InternalMed_Harrison. The clinical presentation of all of the hyperperfusion syndromes is similar with prominent headaches, seizures, or focal neurologic deficits. Headaches have no specific characteristics, range from mild to severe, and may be accompanied by alterations in consciousness ranging from confusion to coma. Seizures may be present, and these can be of multiple types depending on the severity and location of the edema. Nonconvulsive seizures have been described in hyperperfusion states; therefore, a low threshold for obtaining an electroencephalogram (EEG) in these patients should be maintained. The typical focal deficit Some CommoN etIoLogIeS of hyperperfuSIoN SyNdrome Disorders in which increased capillary pressure dominates the pathophysiology Hypertensive encephalopathy, including secondary causes such as reno vascular hypertension, pheochromocytoma, cocaine use, etc. Disorders in which endothelial dysfunction dominates the pathophysiology


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InternalMed_Harrison. Disorders in which endothelial dysfunction dominates the pathophysiology Chemotherapeutic agent toxicity (e.g., cytarabine, azathioprine, 5-fluoro uracil, cisplatin, methotrexate, tumor necrosis factor α antagonists) HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet Granulomatosis with polyangiitis (Wegener’s) in hyperperfusion states is cortical visual loss, given the tendency of the process to involve the occipital lobes. However, any focal deficit can occur depending on the area affected, as evidenced by patients who, after carotid endarterectomy, exhibit neurologic dysfunction referable to the ipsilateral newly reperfused hemisphere. In conditions where increased cerebral blood flow plays a role, examination of the inpatient vital signs record will usually reveal a systemic blood pressure that is increased above the patient’s baseline. It appears as if the rapidity of rise, rather than the absolute value of pressure, is the most important risk factor.


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InternalMed_Harrison. The diagnosis in all of these conditions is clinical. The symptoms of these disorders are common and nonspecific, so a long differential diagnosis should be entertained, including consideration of other causes of confusion, focal neurologic deficits, headache, and seizures. Magnetic resonance imaging (MRI) has improved the ability of clinicians to diagnose hyperperfusion syndromes, although cases have been reported with normal imaging. Patients classically exhibit the high T2 signal of edema primarily in the posterior occipital lobes, not respecting any single vascular territory (Fig. 463e-1). Diffusion-weighted images are typically normal, emphasizing the vasogenic rather than cytotoxic nature of this edema. Imaging with computed tomography (CT) is less sensitive but may show a pattern of patchy hypodensity in the involved territory. Previously this classic radiographic appearance had been termed reversible posterior leukoencephalopathy (RPLE). However, this term has fallen out of


InternalMed_Harrison

InternalMed_Harrison. of patchy hypodensity in the involved territory. Previously this classic radiographic appearance had been termed reversible posterior leukoencephalopathy (RPLE). However, this term has fallen out of favor because none of its elements are completely accurate. The radiographic and clinical changes are not always reversible; the territory involved is not uniquely posterior; and gray matter may be affected as well, rather than purely white matter as the term “leukoencephalopathy” intimates. The now more commonly used radiologic term posterior reversible encephalopathy syndrome (PRES) suffers from many of these same limitations. Vessel imaging may demonstrate narrowing of the cerebral vasculature, especially in the posterior circulation; whether this noninflammatory vasculopathy is a primary cause of the edema or occurs as a secondary phenomenon remains unclear. Other ancillary studies such as cerebrospinal fluid (CSF) analysis often yield nonspecific results. It should be noted that many


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InternalMed_Harrison. of the edema or occurs as a secondary phenomenon remains unclear. Other ancillary studies such as cerebrospinal fluid (CSF) analysis often yield nonspecific results. It should be noted that many of the substances that have been implicated, such as cyclosporine, can cause this syndrome even at low doses or after years of treatment. Therefore, normal serum levels of these medications do not exclude them as inciting agents.