Harrison Neurology in Clinical Medicine Second Edition

SECTION III Diseases of the Central Nervous System582 In most patients, the weakness remains restricted to Clinical Features facial, upper extremity, and distal lower extremity muscles. In 20% of patients, weakness progresses to involve the Oculopharyngeal muscular dystrophy has a late onset; it pelvic girdle muscles, and severe functional impairment usually presents in the fourth to sixth decade with ptosis and possible wheelchair dependency result. and/or dysphagia.The extraocular muscle impairment is Characteristically, patients with FSH dystrophy do not less prominent in the early phase but may be severe have involvement of other organ systems, although labile later. The swallowing problem may become debilitating hypertension is common, and there is an increased inci- and result in pooling of secretions and repeated episodes dence of nerve deafness. Coats’ disease, a disorder consist- of aspiration. Mild weakness of the neck and extremities ing of telangiectasia, exudation, and retinal detachment, also occurs. also occurs. Laboratory Features Laboratory Features The serum CK level may be two to three times normal. The serum CK level may be normal or mildly elevated. Myopathic EMG findings are typical. On biopsy, muscle EMG usually indicates a myopathic pattern. The muscle fibers are found to contain rimmed vacuoles, which by biopsy shows nonspecific features of a myopathy.A promi- electron microscopy are shown to contain membranous nent inflammatory infiltrate, which is often multifocal in whorls, accumulation of glycogen, and other nonspecific distribution, is present in some biopsy samples.The cause debris related to lysosomes. A distinct feature of ocu- or significance of this finding is unknown. lopharyngeal dystrophy is the presence of tubular fila- ments, 8.5 nm in diameter, in muscle cell nuclei. An autosomal dominant inheritance pattern with almost complete penetrance has been established, but Oculopharyngeal dystrophy has an autosomal domi- each family member should be examined for the pres- nant inheritance pattern with complete penetrance. The ence of the disease, since ~30% of those affected are incidence is high in French-Canadians and in Spanish- unaware of involvement. FSH dystrophy is caused by American families of the southwestern United States. deletions of tandem 3.3-kb repeats at 4q35.The deletion Large kindreds of Italian and of eastern European Jewish reduces the number of repeats to a fragment of <35 kb descent have been reported. The molecular defect in in most patients.This mutation may result in an overex- oculopharyngeal muscular dystrophy is a subtle expan- pression of upstream genes and a loss of DNA binding sion of a modest polyalanine repeat tract in a poly-RNA of a multiprotein complex mediating transcriptional binding protein (PABP2) in muscle. repression of 4q35 genes. The mutation permits carrier detection and prenatal diagnosis. Most sporadic cases Treatment: represent new mutations. OCULOPHARYNGEAL DYSTROPHY Dysphagia can cause inanition, making oculopharyngeal Treatment: muscular dystrophy a potentially life-threatening disease. FACIOSCAPULOHUMERAL Cricopharyngeal myotomy may improve swallowing, MUSCULAR DYSTROPHY although it does not prevent aspiration. Eyelid crutches can improve vision when ptosis obstructs vision; candi- No specific treatment is available; ankle-foot orthoses dates for ptosis surgery must be carefully selected—those are helpful for footdrop. Scapular stabilization proce- with severe facial weakness are not suitable. dures improve scapular winging but may not improve function. DISTAL MYOPATHIES OCULOPHARYNGEAL DYSTROPHY A group of muscle diseases, the distal myopathies, are notable for their preferential distal distribution of This form of muscular dystrophy represents one of several muscle weakness in contrast to most muscle conditions disorders characterized by progressive external ophthal- associated with proximal weakness. The major distal moplegia, which consists of slowly progressive ptosis and myopathies are summarized in Table 43-9. limitation of eye movements with sparing of pupillary reactions for light and accommodation. Patients usually Clinical Features do not complain of diplopia, in contrast to patients having conditions with a more acute onset of ocular muscle Welander, Udd, and Markesbery-Griggs distal myopathies are weakness (e.g., myasthenia gravis). all late-onset, dominantly inherited disorders of distal limb

TABLE 43-9 583 DISTAL MYOPATHIES DISEASE CLINICAL FEATURES LABORATORY FEATURES INHERITANCE/ CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases Welander distal LOCUS OR GENE Onset in fifth decade Serum CK 2–3 × normal myopathy Weakness begins in hands EMG myopathic AD Slow progression with spread to NCS normal Chromosome 2p13 Tibial muscular distal lower extremities Muscle biopsy shows dystrophic features dystrophy (Udd) Lifespan normal AD Onset 4th to 8th decade Serum CK 2–4 × normal Titin Markesbery- Distal lower extremity weakness EMG myopathic Griggs distal (tibial distribution) NCS normal AD myopathy Upper extremities usually normal Muscle biopsy shows dystrophic features Z-band alternatively spliced Laing distal Lifespan normal Titin absent in M-line of muscle PDX motif-containing myopathy Onset 4th to 8th decade Serum CK is usually mildly elevated protein (ZASP) Distal lower extremity weakness EMG reveals irritative myopathy AD Nonaka distal (tibial distribution) with progression Muscle biopsies demonstrate rimmed vac- Myosin heavy chain 7 myopathy (auto- to distal arms and proximal muscles uoles and features of myofibrillar myopathy somal recessive Onset childhood to 3d decade Serum CK is normal or slightly elevated ARGNE gene: UDP- hereditary inclu- Distal lower extremity weakness Muscle biopsies do not show rimmed N-acetylglucosamine sion body (tibial distribution) and neck flexors vacuoles 2-epimerase/ myopathy) affected early Large deposits of myosin heavy chain N-acetylmannosamine Miyoshi are seen in type 1 muscle fibers kinase myopathy Onset 2d to 3d decade Serum CK 3–10 × normal Allelic to hereditary inclu- Lower extremity distal weakness EMG myopathic sion body myopathy Myofibrillar Mild distal upper limb weakness NCS normal AR myopathies may be present early Dystrophic features on muscle biopsy Allelic to LGMD2B (see Progression to other muscles sparing plus rimmed vacuoles and 15- to 19-nm Table 43-7) quadriceps filaments within vacuoles Dysferlin Ambulation may be lost in 10–15 years Onset 2d to 3d decade Serum CK 20–100 × normal Genetically heterogeneous Lower extremity weakness in posterior EMG myopathic AD: compartment muscles NCS normal Myotilin (also known as Progression leads to weakness in Muscle biopsy shows nonspecific LGMD 1A) other muscle groups dystrophic features often with prominent ZASP (see Markesbery- Ambulation lost after 10–15 years in inflammatory cell infiltration; no rimmed Griggs distal myopathy) about one-third of cases vacuoles Filamin-C Onset from early childhood to late Serum CKs can be normal or moderately Desmin adult life elevated Alpha B crystallin Weakness may be distal, proximal, EMG is myopathic and often associated AR: or generalized with myopathic discharges Desmin Cardiomyopathy and respiratory Muscle biopsy demonstrates abnormal Selenoprotein N1 involvement is not uncommon accumulation of desmin and other pro- teins, rimmed vacuoles, and myofibrillar degeneration Note: CK, creatine kinase; AD, autosomal dominant; AR, autosomal recessive; EMG, electromyography; NCS, nerve conduction studies. muscles, usually beginning after 40 years of age.Welander or twenties. Nonaka myopathy entails anterior tibial weak- distal myopathy preferentially involves the wrist and fin- ness, whereas Miyoshi myopathy is unique in that gastroc- ger extensors, whereas the others are associated with nemius muscles are preferentially affected at onset. Finally, anterior tibial weakness leading to progressive footdrop. the myofibrillar myopathies (MFM) are a clinically and genet- Laing distal myopathy is also a dominantly inherited dis- ically heterogeneous group of disorders that can be associ- order heralded by tibial weakness; however, it is distin- ated with prominent distal weakness; they can be inherited guished by onset in childhood or early adult life. Nonaka in an autosomal dominant or recessive pattern. distal myopathy and Miyoshi myopathy are distinguished by autosomal recessive inheritance and onset in the late teens Confounding these clinical features is the observation that proximal muscles can be affected as each of these

SECTION III Diseases of the Central Nervous System584 disorders progresses (less so for Welander disease than the with stair climbing, running, and getting up from the others). In contrast to many other inherited muscle dis- floor. On examination, there is mild facial, neck-flexor, eases, the distal myopathies are for the most part limited and proximal-extremity muscle weakness. Legs are more to skeletal muscle. affected than arms. Skeletal abnormalities include con- genital hip dislocation, scoliosis, and pes cavus; clubbed Laboratory Features feet also occur. Most cases are nonprogressive, but excep- tions are well documented. Susceptibility to malignant Serum CK level is particularly helpful in diagnosing hyperthermia must be considered as a potential risk Miyoshi myopathy since it is very elevated. In the other factor for patients with central core disease. conditions serum CK is only slightly increased. EMGs are myopathic. In the myofibrillar myopathies (MFM), The serum CK level is usually normal. Needle EMG myotonic or pseudomyotonic discharges are common. demonstrates a myopathic pattern. Muscle biopsy shows Muscle biopsy shows nonspecific dystrophic features and, fibers with single or multiple central or eccentric discrete with the exception of Laing and Nonaka distal myopathies, zones (cores) devoid of oxidative enzymes. Cores occur often shows rimmed vacuoles. MFM is associated with preferentially in type 1 fibers and represent poorly aligned the accumulation of dense inclusions, as well as amorphous sarcomeres associated with Z disk streaming. material best seen on Gomori trichrome and myofibrillar disruption on electron microscopy. Immune staining some- Autosomal dominant inheritance is characteristic; times demonstrates accumulation of desmin and other sporadic cases also occur. The disease is caused by point proteins in MFM, large deposits of myosin heavy chain in mutations of the ryanodine receptor gene on chromo- the subsarcolemmal region of type 1 muscle fibers in Laing some 19q, encoding the calcium-release channel of the myopathy, and reduced or absent dysferlin in Miyoshi sarcoplasmic reticulum of skeletal muscle; mutations of myopathy. this gene also account for some cases of inherited malig- nant hyperthermia. Malignant hyperthermia is an allelic The affected genes and their gene products are listed condition; C-terminal mutations of the RYR1 gene pre- in Table 43-9. The gene for Welander disease awaits dispose to this complication. identification. Specific treatment is not required, but establishing a Treatment: diagnosis of central core disease is extremely important DISTAL MYOPATHIES because these patients have a known predisposition to malignant hyperthermia during anesthesia. Occupational therapy is offered for loss of hand function; ankle-foot orthoses can support distal lower limb mus- NEMALINE MYOPATHY cles. The MFMs can be associated with cardiomyopathy (congestive heart failure or arrhythmias) and respiratory The term nemaline refers to the distinctive presence in failure that may require medical management. muscle fibers of rods or threadlike structures (Greek nema, “thread”). Nemaline myopathy is clinically hetero- CONGENITAL MYOPATHIES geneous. A severe neonatal form presents with hypotonia and feeding and respiratory difficulties, leading to early These rare disorders are distinguished from muscular dys- death. Nemaline myopathy usually presents in infancy or trophies by the presence of specific histochemical and struc- childhood with delayed motor milestones.The course is tural abnormalities in muscle.Although primarily disorders nonprogressive or slowly progressive.The physical appear- of infancy or childhood, three forms that may present in ance is striking because of the long, narrow facies, high- adulthood are described here: central core disease, nemaline arched palate, and open-mouthed appearance due to a (rod) myopathy, and centronuclear (myotubular) myopathy. prognathous jaw. Other skeletal abnormalities include Other types, such as minicore myopathy (multi-minicore pectus excavatum, kyphoscoliosis, pes cavus, and clubfoot disease), fingerprint body myopathy, and sarcotubular deformities. Facial and generalized muscle weakness, myopathy, are not discussed. including respiratory muscle weakness, is common. An adult-onset disorder with progressive proximal weakness CENTRAL CORE DISEASE may be seen. Myocardial involvement is occasionally pre- sent in both the childhood and adult-onset forms. The Patients with central core disease may have decreased serum CK level is usually normal or slightly elevated.The fetal movements and breech presentation. Hypotonia EMG demonstrates a myopathic pattern. Muscle biopsy and delay in motor milestones, particularly in walking, shows clusters of small rods (nemaline bodies), which occur are common. Later in childhood, patients develop problems preferentially, but not exclusively, in the sarcoplasm of type 1 muscle fibers. Occasionally, the rods are also appar- ent in myonuclei.The muscle often shows type 1 muscle fiber predominance. Rods originate from the Z disk mate- rial of the muscle fiber.

Five genes have been associated with nemaline myopa- late infancy–early childhood disorder is probably autosomal 585CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases thy. All code for thin filament–associated proteins, suggest- recessive, and for the late childhood–adult form is probably ing disturbed assembly or interplay of these structures as a autosomal dominant. No specific treatment is available. pivotal mechanism. Mutations of the nebulin (NEB) gene Some of the autosomal dominant late-onset cases, which account for most cases, including both severe neonatal and are allelic to a form of CMT2, are associated with muta- early childhood forms, inherited as autosomal recessive tions in the gene that encodes dynamin-2. disorders. Neonatal and childhood cases, inherited as pre- dominantly autosomal dominant disorders, are caused by DISORDERS OF MUSCLE mutations of the skeletal muscle α-actinin (ACTA1) gene. ENERGY METABOLISM In milder forms of the disease with autosomal dominant inheritance, mutations have been identified in both the There are two principal sources of energy for skeletal slow α-tropomyosin (TPM3) and β-tropomyosin (TPM2) muscle—fatty acids and glucose. Abnormalities in either genes accounting for <3% of cases. Muscle troponin T glucose or lipid utilization can be associated with dis- (TNNT1) gene mutations appear to be limited to the tinct clinical presentations that can range from an acute, Amish population in North America. No specific treat- painful syndrome with rhabdomyolysis and myoglobinuria ment is available. to a chronic, progressive muscle weakness simulating mus- cular dystrophy. CENTRONUCLEAR (MYOTUBULAR) MYOPATHY GLYCOGEN STORAGE AND GLYCOLYTIC DEFECTS Three distinct variants of centronuclear myopathy occur.A neonatal form, also known as myotubular myopathy, presents Disorders of Glycogen Storage Causing with severe hypotonia and weakness at birth. The late Progressive Weakness infancy–early childhood form presents with delayed motor milestones. Later, difficulty with running and stair climb- α-Glucosidase, or Acid Maltase, Deficiency ing becomes apparent. A marfanoid, slender body habitus, (Pompe’s Disease) long narrow face, and high-arched palate are typical. Sco- Three clinical forms of α-glucosidase, or acid maltase, liosis and clubbed feet may be present. Most patients deficiency (type II glycogenosis) can be distinguished. The exhibit progressive weakness, some requiring wheelchairs. infantile form is the most common, with onset of symp- Progressive external ophthalmoplegia with ptosis and toms in the first 3 months of life. Infants develop severe varying degrees of extraocular muscle impairment are muscle weakness, cardiomegaly, hepatomegaly, and respi- characteristic of both the neonatal and the late-infantile ratory insufficiency. Glycogen accumulation in motor forms. A third variant, the late childhood–adult form, has neurons of the spinal cord and brainstem contributes to an onset in the second or third decade. Patients have full muscle weakness. Death usually occurs by 1 year of age. extraocular muscle movements and rarely exhibit ptosis. In the childhood form, the picture resembles muscular There is mild, slowly progressive limb weakness that may dystrophy. Delayed motor milestones result from proximal be distally predominant [some of these patients have been limb muscle weakness and involvement of respiratory classified as having Charcot-Marie-Tooth disease type 2 muscles. The heart may be involved, but the liver and (CMT2); Chap. 40]. brain are unaffected. The adult form usually begins in the third or fourth decade but can present as late as the Normal or slightly elevated CK levels occur in each of seventh decade. Respiratory failure and diaphragmatic the forms. Nerve conduction studies may reveal reduced weakness are often initial manifestations, heralding pro- amplitudes of distal compound muscle action potentials, gressive proximal muscle weakness. The heart and liver in particular in adult-onset cases that resemble CMT2. are not involved. EMG studies often give distinctive results, showing posi- tive sharp waves and fibrillation potentials, complex and The serum CK level is 2 to 10 times normal in infantile repetitive discharges, and rarely myotonic discharges. or childhood-onset Pompe disease but can be normal in Muscle biopsy specimens in longitudinal section demon- adult-onset cases. EMG examination demonstrates a strate rows of central nuclei, often surrounded by a halo. myopathic pattern, but other features are especially dis- In transverse sections, central nuclei are found in 25–80% tinctive, including myotonic discharges, trains of fibrilla- of muscle fibers. tion and positive waves, and complex repetitive discharges. EMG discharges are very prominent in the lumbosacral A gene for the neonatal form of centronuclear myopathy paraspinal muscles.The muscle biopsy in infants typically has been localized to Xq28; this gene encodes myotubu- reveals vacuoles containing glycogen and the lysosomal larin, a protein tyrosine phosphatase. Missense, frameshift, enzyme acid phosphatase. Electron microscopy reveals and splice-site mutations predict loss of myotubularin func- membrane-bound and free tissue glycogen. However, mus- tion in affected individuals. Carrier identification and pre- cle biopsies in late-onset Pompe’s disease may demonstrate natal diagnosis are possible.The inheritance pattern for the

SECTION III Diseases of the Central Nervous System586 only nonspecific abnormalities. Enzyme analysis of dried (switching to utilization of fatty acids). Varying degrees blood spots is a new and sensitive technique to screen of hemolytic anemia accompany deficiencies of both for Pompe’s disease. A definitive diagnosis is established phosphofructokinase (mild) and phosphoglycerate kinase by enzyme assay in muscle or cultured fibroblasts or by (severe). In phosphoglycerate kinase deficiency, the usual genetic testing. clinical presentation is a seizure disorder associated with Acid maltase deficiency is inherited as an autosomal mental retardation; exercise intolerance is an infrequent recessive disorder caused by mutations of the α-glucosidase manifestation. gene. Recently, replacement therapy with IV recombinant human α-glucosidase has been shown to be beneficial in In all of these conditions, the serum CK levels fluctu- infantile-onset Pompe disease and was approved by the ate widely and may be elevated even during symptom- U.S. Food and Drug Administration (FDA).The efficacy free periods. CK levels >100 times normal are expected, in later-onset cases is under study. Clinical benefits in accompanying myoglobinuria. All patients with suspected the infantile disease include reduced heart size, improved glycolytic defects leading to exercise intolerance should muscle function, reduced need for ventilatory support, undergo a forearm exercise test. An impaired rise in and longer life. venous lactate is highly indicative of a glycolytic defect. In lactate dehydrogenase deficiency, venous levels of lactate Other Glycogen Storage Diseases do not increase, but pyruvate rises to normal. A definitive with Progressive Weakness diagnosis of glycolytic disease is made by muscle biopsy In debranching enzyme deficiency (type III glycogenosis), a slowly and subsequent enzyme analysis or by genetic testing. progressive form of muscle weakness can develop after puberty. Rarely, myoglobinuria may be seen. Patients are Myophosphorylase deficiency, phosphofructokinase defi- usually diagnosed in infancy, however, because of hypo- ciency, and phosphoglycerate mutase deficiency are inher- tonia and delayed motor milestones, hepatomegaly, growth ited as autosomal recessive disorders. Phosphoglycerate retardation, and hypoglycemia. Branching enzyme deficiency kinase deficiency is X-linked recessive. Mutations can be (type IV glycogenosis) is a rare and fatal glycogen storage found in the respective genes encoding the abnormal disease characterized by failure to thrive and hepatomegaly. proteins in each of these disorders. Hypotonia and muscle wasting may be present, but the skeletal muscle manifestations are minor compared to Training may enhance exercise tolerance, perhaps by liver failure. increasing perfusion to muscle. Dietary intake of free glucose or fructose prior to activity may improve function Disorders of Glycolysis Causing but care must be taken to avoid obesity from ingesting Exercise Intolerance too many calories. Several glycolytic defects are associated with recurrent LIPID AS AN ENERGY SOURCE myoglobinuria: myophosphorylase deficiency (type V glycogeno- AND ASSOCIATED DEFECTS sis), phosphofructokinase deficiency (type VII glycogenosis), phosphoglycerate kinase deficiency (type IX glycogenosis), phos- Lipid is an important muscle energy source during rest and phoglycerate mutase deficiency (type X glycogenosis), lactate during prolonged, submaximal exercise. Fatty acids are dehydrogenase deficiency (glycogenosis type XI), and beta-enolase derived from circulating very low density lipoprotein deficiency. Myophosphorylase deficiency, also known as (VLDL) in the blood or from triglycerides stored in muscle McArdle’s disease, is by far the most common of the gly- fibers. Oxidation of fatty acids occurs in the mitochondria. colytic defects associated with exercise intolerance. These To enter the mitochondria, a fatty acid must first be con- glycolytic defects result in a common failure to support verted to an “activated fatty acid,” acyl-CoA.The acyl-CoA energy production at the initiation of exercise, although must be linked with carnitine by the enzyme carnitine the exact site of energy failure remains controversial. palmitoyltransferase (CPT) I for transport into the mito- chondria. CPT I is present on the inner side of the outer Clinical muscle manifestations in these conditions usu- mitochondrial membrane. Carnitine is removed by CPT ally begin in adolescence. Symptoms are precipitated by II, an enzyme attached to the inside of the inner mito- brief bursts of high-intensity exercise, such as running or chondrial membrane, allowing transport of acyl-CoA into lifting heavy objects.A history of myalgia and muscle stiff- the mitochondrial matrix for β-oxidation. ness usually precedes the intensely painful muscle contrac- tures, which may be followed by myoglobinuria. Acute Carnitine Palmitoyltransferase Deficiency renal failure accompanies significant pigmenturia. CPT II deficiency is the most common recognizable cause Certain features help distinguish some enzyme defects. of recurrent myoglobinuria, more common than the gly- In McArdle’s disease exercise tolerance can be enhanced by colytic defects. Onset is usually in the teenage years or a slow induction phase (warm-up) or brief periods of rest, early twenties. Muscle pain and myoglobinuria typically allowing for the start of the “second-wind” phenomenon 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 equivalents.The latter are transported through the respi- 587 CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases between attacks. In contrast to disorders caused by defects ratory chain in the process known as oxidative phosphory- in glycolysis, in which muscle cramps follow short, intense lation. The energy generated by the oxidation-reduction bursts of exercise, the muscle pain in CPT II deficiency reactions of the respiratory chain is stored in an electro- does not occur until the limits of utilization have been chemical gradient coupled to ATP synthesis. exceeded and muscle breakdown has already begun. Episodes of rhabdomyolysis may produce severe weak- A novel feature of mitochondria is their genetic com- ness. In young children and newborns, CPT II deficiency position. Each mitochondrion possesses a DNA genome can present with a very severe clinical picture including that is distinct from that of the nuclear DNA. Human hypoketotic hypoglycemia, cardiomyopathy, liver failure, mitochondrial DNA (mtDNA) consists of a double-strand, and sudden death. circular molecule comprising 16,569 base pairs. It codes for 22 transfer RNAs, 2 ribosomal RNAs, and 13 polypep- Serum CK levels and EMG findings are both usually tides of the respiratory chain enzymes. The genetics of normal between episodes. A normal rise of venous lactate mitochondrial diseases differ from the genetics of chro- during forearm exercise distinguishes this condition from mosomal disorders.The DNA of mitochondria is directly glycolytic defects, especially myophosphorylase deficiency. inherited from the cytoplasm of the gametes, mainly from Muscle biopsy does not show lipid accumulation and is the oocyte. The sperm contributes very little of its mito- usually normal between attacks. The diagnosis requires chondria to the offspring at the time of fertilization.Thus, direct measurement of muscle CPT or genetic testing. mitochondrial genes are derived almost exclusively from the mother, accounting for maternal inheritance of some CPT II deficiency is much more common in men than mitochondrial disorders. women (5:1); nevertheless, all evidence indicates autoso- mal recessive inheritance. A mutation in the gene for CPT Patients with mitochondrial disorders have clinical man- II (chromosome 1p36) causes the disease in some individ- ifestations that fall into three groups: chronic progressive uals.Attempts to improve exercise tolerance with frequent external ophthalmoplegia (CPEO), skeletal muscle–CNS meals and a low-fat, high-carbohydrate diet, or by substi- syndromes, and pure myopathy simulating muscular dystro- tuting medium-chain triglycerides in the diet, have not phy or metabolic myopathy. proven to be beneficial. PROGRESSIVE EXTERNAL Myoadenylate Deaminase Deficiency OPHTHALMOPLEGIA SYNDROMES WITH RAGGED RED FIBERS The muscle enzyme myoadenylate deaminase converts adenosine 5′-monophosphate (5′-AMP) to inosine The single most common sign of a mitochondrial myopa- monophosphate (IMP) with liberation of ammonia. thy is CPEO, occurring in >50% of all mitochondrial Myoadenylate deaminase may play a role in regulating myopathies. Varying degrees of ptosis and weakness of adenosine triphosphate (ATP) levels in muscles. Most extraocular muscles are seen, usually in the absence of individuals with myoadenylate deaminase deficiency have diplopia, a point of distinction from disorders with fluc- no symptoms. There have been a few reports of patients tuating eye weakness (e.g., myasthenia gravis). with this disorder who have exercise-exacerbated myal- gia and myoglobinuria. Many questions have been raised KEARNS-SAYRE SYNDROME (KSS) about the clinical effects of myoadenylate deaminase deficiency, and, specifically, its relationship to exertional KSS is a widespread multiorgan system disorder with a myalgia and fatigability, but there is no consensus. defined triad of clinical findings: onset <20 years, CPEO, and pigmentary retinopathy plus one or more of the fol- MITOCHONDRIAL MYOPATHIES lowing features: complete heart block, cerebrospinal fluid (CSF) protein >1.0 g/L (100 mg/dL), or cerebellar ataxia. In 1972, Olson and colleagues recognized that muscle Some patients with CPEO and ragged red fibers may fibers with significant numbers of abnormal mitochondria not fulfill all of the criteria for KSS. The cardiac disease could be highlighted with the modified trichrome stain; includes syncopal attacks and cardiac arrest related to the the term ragged red fibers was coined. By electron microscopy, abnormalities in the cardiac conduction system: prolonged the mitochondria in ragged red fibers are enlarged and intraventricular conduction time, bundle branch block, often bizarrely shaped and have crystalline inclusions. and complete atrioventricular block. Death attributed to Since that seminal observation, the understanding of these heart block occurs in ~20% of the patients.Varying degrees disorders of muscle and other tissues has expanded. of progressive limb muscle weakness and easy fatigability affect activities of daily living. Endocrine abnormalities Mitochondria play a key role in energy production. are common, including gonadal dysfunction in both sexes Oxidation of the major nutrients derived from carbohy- with delayed puberty, short stature, and infertility. Diabetes drate, fat, and protein leads to the generation of reducing mellitus is a cardinal sign of mitochondrial disorders and

SECTION III Diseases of the Central Nervous System588 is estimated to occur in 13% of KSS patients. Other less inner mitochondrial channel through which ADP enters common endocrine disorders include thyroid disease, and ATP leaves the mitochondrial matrix. In the chro- hyperaldosteronism, Addison’s disease, and hypoparathy- mosome 10q–related disorder, mutations of the gene roidism. Both mental retardation and dementia are com- C10orf2 are found. Its gene product, twinkle, co-localizes mon accompaniments to this disorder. Serum CK levels with the mtDNA and is named for its punctate, starlike are normal or slightly elevated. Serum lactate and pyru- staining properties. The function of twinkle is presumed vate levels may be elevated. EMG is myopathic. Nerve to be critical for lifetime maintenance of mitochondrial conduction studies may be abnormal related to an associ- integrity. In the cases mapped to chromosome 15q, a ated neuropathy. Muscle biopsies reveal ragged red fibers, mutation affects the gene encoding mtDNA polymerase highlighted in oxidative enzyme stains, many showing (POLG), an enzyme important in mtDNA replication. defects in cytochrome oxidase. By electron microscopy Autosomal recessive PEO has also been described with there are increased numbers of mitochondria that often mutations in the POLG gene. Point mutations have been appear enlarged and contain paracrystalline inclusions. identified within various mitochondrial tRNA (Leu, KSS is a sporadic disorder.The disease is caused by sin- Ile, Asn, Trp) genes in families with maternal inheri- gle mtDNA deletions presumed to arise spontaneously in tance of PEO. the ovum or zygote. The most common deletion, occur- ring in about one-third of patients, removes 4977 bp of Exercise may improve function but will depend on contiguous mtDNA. Monitoring for cardiac conduction the patients’ ability to participate. defects is critical. Prophylactic pacemaker implantation is indicated when ECGs demonstrate a bifascicular block. In AUTOSOMAL RECESSIVE CARDIOMYOPATHY KSS no benefit has been shown for supplementary thera- AND OPHTHALMOPLEGIA (ARCO) pies, including multivitamins or coenzyme Q10. Of all the proposed options, exercise might be the most applica- ARCO is a rare mitochondrial disorder clinically impor- ble but must be approached cautiously because of defects tant because of an associated life-threatening cardiomy- in the cardiac conduction system. opathy. CPEO is the initial manifestation, occurring between ages 8 and 10. Exercise intolerance and fatigue PROGRESSIVE EXTERNAL follow the early symptoms, accompanied by palpitations OPHTHALMOPLEGIA (PEO) and chest pain. Examination reveals extraocular muscle weakness, ptosis, facial weakness, reduced muscle bulk, This condition is caused by nuclear DNA mutations and limb weakness, greater in proximal muscles. A dilated affecting mtDNA copy number and integrity and is thus cardiomyopathy is typical, and some patients have con- inherited in a Mendelian fashion. Onset is usually after duction system involvement. Death from congestive heart puberty. Fatigue, exercise intolerance, and complaints of failure occurs as early as 13 years of age. Serum lactate is muscle weakness are typical. Some patients notice swal- normal at rest but increases with mild exercise. Serum CK lowing problems. The neurologic examination confirms is increased two- to fourfold. EMG is normal or myo- the ptosis and ophthalmoplegia, usually asymmetric in pathic. Muscle biopsy demonstrates typical ragged red distribution. A sensorineural hearing loss may be encoun- fibers. Multiple mtDNA deletions are seen on Southern tered. Mild facial, neck flexor, and proximal weakness are blots of muscle. Echocardiograms show reduced ejection typical. Rarely, respiratory muscles may be progressively fraction. Conduction block is seen on ECGs. The disease affected and may be the direct cause of death. Serum is inherited as an autosomal recessive disorder. The gene CK is normal or mildly elevated. The resting lactate has not been identified. Heart failure may require ortho- level is normal or slightly elevated but may rise exces- topic cardiac transplantation. Cardiac pacemakers are sively after exercise. CSF protein is normal.The EMG is appropriate for patients with heart block. myopathic, and nerve conduction studies are usually normal. Ragged red fibers are prominently displayed in MTDNA SKELETAL MUSCLE–CENTRAL the muscle biopsy. Southern blots of muscle reveal a NERVOUS SYSTEM SYNDROMES normal mtDNA band at 16.6 kb and several additional mtDNA deletion bands with genomes varying from 0.5 Myoclonic Epilepsy with Ragged to 10 kb. Red Fibers (MERRF) This autosomal dominant form of CPEO has been The onset of MERRF is variable, ranging from late child- linked to loci on three chromosomes: 4q35, 10q24, and hood to middle adult life. Characteristic features include 15q22-26. In the chromosome 4q–related form of disease, myoclonic epilepsy, cerebellar ataxia, and progressive mus- mutations of the gene encoding the heart and skeletal cle weakness.The seizure disorder is an integral part of the muscle–specific isoform of the adenine nucleotide disease and may be the initial symptom. Cerebellar ataxia translocator 1 (ANT1) gene are found. This highly precedes or accompanies epilepsy. It is slowly progressive abundant mitochondrial protein forms a homodimeric and generalized. The third major feature of the disease is

muscle weakness in a limb-girdle distribution. Other more reported in mtDNA polypeptide-coding genes. Two 589 CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases variable features include dementia, peripheral neuropathy, mutations were found in the ND5 subunit of complex I optic atrophy, hearing loss, and diabetes mellitus. of the respiratory chain. A missense mutation has been reported at mtDNA position 9957 in the gene for sub- Serum CK levels are normal or slightly increased.The unit III of cytochrome C oxidase. No specific treatment serum lactate may be elevated. EMG is myopathic, and is available. Supportive treatment is essential for the stroke- in some patients nerve conduction studies show a neu- like episodes, seizures, and endocrinopathies. ropathy. The electroencephalogram is abnormal, corrob- orating clinical findings of epilepsy. Typical ragged red PURE MYOPATHY SYNDROMES fibers are seen on muscle biopsy. MERRF is caused by maternally inherited point mutations of mitochondrial Muscle weakness and fatigue can be the predominant tRNA genes.The most common mutation found in 80% manifestations of mtDNA mutations.When the condition of MERRF patients is an A to G substitution at nucleotide affects exclusively muscle (pure myopathy), the disorder 8344 of tRNA lysine (A8344G tRNAlys). Other tRNAlys becomes difficult to recognize. Occasionally, mitochondr- mutations include base-pair substitutions T8356C and ial myopathies can present with recurrent myoglobinuria G8363A. Only supportive treatment is possible, with without fixed weakness and thus resemble a glycogen special attention to epilepsy. storage disorder or CPT deficiency. Mitochondrial Myopathy, Encephalopathy, Mitochondrial DNA Depletion Myopathy Lactic Acidosis, and Stroke-Like Episodes (MELAS) This disorder, clinically indistinguishable from muscular dystrophy, usually presents in the neonatal period with MELAS is the most common mitochondrial encephalomy- weakness, hypotonia, and delayed motor milestones. opathy. The term stroke-like is appropriate because the Some cases are rapidly fatal, with death <2 years of age.A cerebral lesions do not conform to a strictly vascular dis- milder form affects patients at a slightly later age. These tribution.The age of onset in the majority of patients is patients have slowly evolving proximal muscle weakness <20 years. Seizures, usually partial motor or generalized, simulating Duchenne muscular dystrophy. In some, seizures are common and may represent the first clearly recog- and cardiomyopathy may be present. Serum CK can reach nizable sign of disease.The cerebral insults that resemble levels of 20 to 30 times normal. Resting lactate varies from strokes cause hemiparesis, hemianopia, and cortical blind- normal to mildly elevated. The EMG is myopathic, and ness. A presumptive stroke occurring <40 years should ragged red fibers are seen on muscle biopsy. The place this mitochondrial encephalomyopathy high in the mtDNA depletion syndrome is inherited as an autosomal differential diagnosis. Associated conditions include hearing recessive condition. Mutations have been identified in loss, diabetes mellitus, hypothalamic pituitary dysfunction the TK2 gene on chromosome 16q22 encoding thymi- causing growth hormone deficiency, hypothyroidism, and dine kinase-2. The affected gene controls the supply of absence of secondary sexual characteristics. In its full deoxyribonucleotides used for the synthesis of mtDNA. expression MELAS leads to dementia, a bedridden state, No specific treatment is available. Supportive care fol- and a fatal outcome. Serum lactic acid is typically ele- lows the approaches outlined for muscular dystrophy. vated. The CSF protein is also increased but is usually ≤1.0 g/L (100 mg/dL). Muscle biopsies show ragged red DISORDERS OF MUSCLE fibers. Neuroimaging demonstrates basal ganglia calcifi- MEMBRANE EXCITABILITY cation in a high percentage of cases. Focal lesions that mimic infarction are present predominantly in the occipi- Muscle membrane excitability is affected in a group of tal and parietal lobes. Strict vascular territories are not disorders referred to as channelopathies. The heart may respected, and cerebral angiography fails to demonstrate also be involved, resulting in life-threatening complica- lesions of the major cerebral blood vessels. tions (Table 43-10). MELAS is caused by maternally inherited point muta- CALCIUM CHANNEL DISORDERS tions of mitochondrial tRNA genes. Most of the tRNA OF MUSCLE mutations are lethal, accounting for the paucity of multi- generation families with this syndrome.The A3243G point Hypokalemic Periodic Paralysis (HypoKPP) mutation in tRNALeu(UUR) is the most common, occur- ring in ~80% of MELAS cases. About 10% of MELAS Onset occurs at adolescence. Men are more often affected patients have other mutations of the tRNALeu(UUR) gene because of decreased penetrance in women. Episodic including 3252G, 3256T, 3271C, and 3291C. Other tRNA weakness with onset >25 years of age is almost never due gene mutations have also been reported in MELAS to periodic paralyses with the exception of thyrotoxic including G583A tRNAPhe, G1642A tRNAVal, G4332A periodic paralysis (see later). Attacks are often provoked tRNAGlu, and T8316C tRNALys. Mutations have also been

590 TABLE 43-10 CLINICAL FEATURES OF PERIODIC PARALYSIS AND NONDYSTROPHIC MYOTONIAS CALCIUM CHANNEL SODIUM CHANNEL POTASSIUM CHANNEL FEATURE HYPOKALEMIC PP HYPERKALEMIC PP PARAMYOTONIA CONGENITA ANDERSON’S SYNDROMEb Mode of inheritance AD AD AD AD Age of onset Adolescence Early childhood Early childhood Early childhood Myotoniaa No Yes Yes No Episodic weakness Yes Yes Yes Yes Frequency of attacks Daily to yearly May be 2–3/d With cold, usually rare Daily to yearly of weakness 2–12 h From 1–2 h to >1 d 2–24 h 2–24 h Duration of attacks Decreased Increased or normal Usually normal Variable of weakness Serum K+ level during No change Increased myotonia, Increased myotonia No change attacks of weakness then weakness No change Effect of K+ loading Increased myotonia Increased myotonia, Yes then weakness SECTION III Diseases of the Central Nervous System Effect of muscle No change Yes Yes cooling Yes Fixed weakness aMay be paradoxical in paramyotonia congenita. bDysmorphic features and cardiac arrhythmias are distinguishing features (see text). Note: AD, autosomal dominant; PP, periodic paralysis. by meals high in carbohydrates or sodium and may voltage-sensitive, skeletal muscle calcium channel gene, accompany rest following prolonged exercise. Weakness CALCL1A3 (Fig. 43-8). Approximately 10% of cases usually affects proximal limb muscles more than distal. are HypoKPP type 2, arising from mutations in the Ocular and bulbar muscles are less likely to be affected. voltage-sensitive sodium channel gene (SCN4A). Respiratory muscles are usually spared but when they are involved, the condition may prove fatal.Weakness may take Treatment: as long as 24 h to resolve. Life-threatening cardiac arrhyth- HYPOKALEMIC PERIODIC PARALYSIS mias related to hypokalemia may occur during attacks. As a late complication, patients commonly develop severe, The acute paralysis improves after the administration of disabling proximal lower extremity weakness. potassium. Muscle strength and ECG should be moni- tored. Oral KCl (0.2–0.4 mmol/kg) should be given every Attacks of thyrotoxic periodic paralysis resemble those of 30 min. Only rarely is IV therapy necessary (e.g., when primary HypoKPP. Despite a higher incidence of thyrotoxi- swallowing problems or vomiting is present). Adminis- cosis in women, men, particularly those of Asian descent, tration of potassium in a glucose solution should be are more likely to manifest this complication.Attacks abate avoided because it may further reduce serum potassium with treatment of the underlying thyroid condition. levels. Mannitol is the preferred vehicle for administra- tion of IV potassium. The long-term goal of therapy is to A low serum potassium level during an attack, exclud- avoid attacks. This may reduce late-onset, fixed weak- ing secondary causes, establishes the diagnosis. Interattack ness. Patients should be made aware of the importance muscle biopsies show the presence of single or multiple of a low-carbohydrate, low-sodium diet and conse- centrally placed vacuoles or tubular aggregates. Provoca- quences of intense exercise. Prophylactic administration tive tests with glucose and insulin to establish a diagnosis of acetazolamide (125–1000 mg/d in divided doses) are usually not necessary and are potentially hazardous. reduces or may abolish attacks in HypoKPP type 1. Para- doxically the potassium is lowered, but this is offset by In the midst of an attack of weakness, motor conduc- the beneficial effect of metabolic acidosis. If attacks per- tion studies may demonstrate reduced amplitudes, whereas sist on acetazolamide, oral KCl should be added. Some EMG may show electrical silence in severely weak mus- patients require treatment with triamterine (25–100 mg/d) cles. In between attacks, the EMG and nerve conduction or spironolactone (25–100 mg/d). However, in patients studies are normal, with the exception that myopathic with HypoKPP type 2, attacks of weakness can be exac- motor unit action potentials may be seen in patients with erbated with acetazolamide. fixed weakness. HypoKPP is caused by mutations in either of two genes. HypoKPP type 1, the most common form, is inherited as an autosomal dominant disorder with incom- plete penetrance. These patients have mutations in the

Sodium channel α subunit III IV variant of this disorder, the predominant symptom is 591 I II Outside myotonia without weakness (potassium-aggravated myoto- nia). The symptoms are aggravated by cold, and myoto- 1 2345 6 Inside nia makes the muscles stiff and painful.This disorder can NH13 COO2 be confused with paramyotonia congenita, myotonia congenita, and proximal myotonic myopathy (DM2). HyperKPP PC PAM IV III HG Potassium may be slightly elevated but may also be nor- Calcium channel α subunit mal during an attack. As in HypoKPP, nerve conduction I II R Outside studies in HyperKPP muscle may demonstrate reduced H motor amplitudes and the EMG may be silent in very weak muscles. In between attacks of weakness, the con- R duction studies are normal. The EMG will often demon- strate myotonic discharges during and between attacks. NH13 Δ Inside CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases Chloride channel COO2 The muscle biopsy shows vacuoles that are smaller, Outside less numerous, and more peripheral compared to the 2 hypokalemic form or tubular aggregates. Provocative tests by administration of potassium can induce weakness but 1 3 456 7 8 9 1112 are usually not necessary to establish the diagnosis. Hyper- NH13 KPP and potassium-aggravated myotonia are inherited as Δ Inside autosomal dominant disorders. Mutations of the voltage- COO2 gated sodium channel SCN4A gene (Fig. 43-8) cause these 10 13 conditions. For patients with frequent attacks, acetazo- lamide (125–1000 mg/d) is helpful.We have found mexile- Δ tine to be helpful in patients with significant myotonia. Myotonia Congenita Myotonia Congenita ADR (murine) Paramyotonia Congenita Dominant Recessive insertion In paramyotonia congenita (PC) the attacks of weakness Myotonic goat adrmto (murine) are cold-induced or occur spontaneously and are mild. Ala Pro stop Myotonia is a prominent feature but worsens with muscle activity (paradoxical myotonia).This is in contrast to clas- FIGURE 43-8 sic myotonia in which exercise alleviates the condition. The sodium and calcium channels are depicted here as con- Attacks of weakness are seldom severe enough to require taining four homologous domains, each with six membrane- emergency room treatment. Over time patients develop spanning segments. The fourth segment of each domain bears interattack weakness as they do in other forms of periodic positive charges and acts as the “voltage sensor” for the chan- paralysis. PC is usually associated with normokalemia or nel. The association of the four domains is thought to form a hyperkalemia. pore through which ions pass. Sodium channel mutations are shown along with the phenotype that they confer. HyperKPP, Serum CK is usually mildly elevated. Routine sensory hyperkalemic periodic paralysis; PC, paramyotonia congenita; and motor nerve conduction studies are normal. Cooling PAM, potassium-aggravated myotonia. See text for details. of the muscle often dramatically reduces the amplitude of the compound muscle action potentials. EMG reveals dif- The chloride channel is envisioned to have ten membrane- fuse myotonic potentials in PC. Upon local cooling of the spanning domains. The positions of mutations causing muscle the myotonic discharges disappear as the patient dominantly and recessively inherited myotonia congenita are becomes unable to activate motor unit action potentials. indicated, along with mutations that cause this disease in mice and goats. PC is inherited as an autosomal dominant condition; voltage-gated sodium channel mutations (Fig. 43-8) are SODIUM CHANNEL DISORDERS responsible and thus this disorder is allelic with Hyper- OF MUSCLE KPP and potassium-aggravated myotonia. Patients with PC seldom seek treatment during attacks. Oral adminis- Hyperkalemic Periodic Paralysis (HyperKPP) tration of glucose or other carbohydrates hastens recovery. Since interattack weakness may develop after repeated The term hyperkalemic is misleading since patients are episodes, prophylactic treatment is usually indicated. often normokalemic during attacks. The fact that attacks Thiazide diuretics (e.g., chlorothiazide, 250–1000 mg/d) are precipitated by potassium administration best defines and mexiletine (slowly increase dose from 450 mg/d) the disease. The onset is in the first decade. Attacks are are reported to be helpful. Patients should be advised to brief and mild, usually lasting 30 min to 4 h. Weakness increase carbohydrates in their diet. affects proximal muscles, sparing bulbar muscles. Attacks are precipitated by rest following exercise and fasting. In a

SECTION III Diseases of the Central Nervous System592 POTASSIUM CHANNEL DISORDERS atrophy rather than destruction of muscle fibers. Nearly all endocrine myopathies respond to treatment. Andersen-Tawil Syndrome THYROID DISORDERS This rare disease is characterized by episodic weakness, cardiac arrhythmias, and dysmorphic features (short stature, Abnormalities of thyroid function can cause a wide array scoliosis, clinodactyly, hypertelorism, small or prominent of muscle disorders. These conditions relate to the impor- low set ears, micrognathia, and broad forehead). The tant role of thyroid hormones in regulating the metabolism cardiac arrhythmias are potentially serious and life threat- of carbohydrates and lipids as well as the rate of protein ening.They include long QT, ventricular ectopy, bidirec- synthesis and enzyme production. Thyroid hormones also tional ventricular arrhythmias, and tachycardia. For many stimulate calorigenesis in muscle, increase muscle demand years the classification of this disorder was uncertain because for vitamins, and enhance muscle sensitivity to circulating episodes of weakness are associated with elevated, nor- catecholamines. mal, or reduced levels of potassium during an attack. In addition, the potassium levels differ among kindreds Hypothyroidism but are consistent within a family. Inheritance is autoso- mal dominant, with incomplete penetrance and variable Patients with hypothyroidism have frequent muscle com- expressivity. The disease is caused by mutations of the plaints, and proximal muscle weakness occurs in about inwardly rectifying potassium channel (Kir 2.1) gene. one-third of them. Muscle cramps, pain, and stiffness are The treatment is similar to that for other forms of peri- common. Some patients have enlarged muscles. Features odic paralysis and must include cardiac monitoring. The of slow muscle contraction and relaxation occur in 25% episodes of weakness may differ between patients because of patients; the relaxation phase of muscle stretch reflexes of potassium variability.Acetazolamide decreases the attack is characteristically prolonged and best observed at the frequency and severity. ankle or biceps brachii reflexes. The serum CK level is often elevated (up to 10 times normal), even when there CHLORIDE CHANNEL DISORDERS is minimal clinical evidence of muscle disease. EMG is typically normal. The cause of muscle enlargement has Two forms of this disorder, autosomal dominant (Thomsen’s not been determined, and muscle biopsy shows no dis- disease) and autosomal recessive (Becker’s disease) are related tinctive morphologic abnormalities. to the same gene abnormality. Symptoms are noted in infancy and early childhood. The severity lessens in the Hyperthyroidism third to fourth decade. Myotonia is worsened by cold and improved by activity. The gait may appear slow and Patients who are thyrotoxic commonly have proximal mus- labored at first but improves with walking. In Thomsen’s cle weakness and atrophy on examination, but they rarely disease muscle strength is normal, but in Becker’s, which is complain of myopathic symptoms. Activity of deep tendon usually more severe, there may be muscle weakness. Mus- reflexes may be enhanced. Bulbar, respiratory, and even cle hypertrophy is usually present. Myotonic discharges are esophageal muscles may occasionally be affected, causing prominently displayed by EMG recordings. dysphagia, dysphonia, and aspiration.When bulbar involve- ment occurs, it is usually accompanied by chronic proximal Serum CK is normal or mildly elevated. The muscle limb weakness, but occasionally it presents in the absence biopsy shows hypertrophied fibers.The disease is inherited of generalized thyrotoxic myopathy. Fasciculations may be as dominant or recessive and is caused by mutations of the apparent and, when coupled with increased muscle stretch chloride channel gene (Fig. 43-8). Many patients will not reflexes, may lead to an erroneous diagnosis of amyotrophic require treatment and learn that the symptoms improve lateral sclerosis. Other neuromuscular disorders occur with activity. Medications that can be used to decrease in association with hyperthyroidism, including acquired myotonia include quinine, phenytoin, and mexiletine. hypokalemic periodic paralysis, myasthenia gravis, and a progressive ocular myopathy associated with proptosis ENDOCRINE AND METABOLIC (Graves’ ophthalmopathy). Serum CK levels are not elevated MYOPATHIES in thyrotoxic myopathy, the EMG is normal, and muscle histology usually shows only atrophy of muscle fibers. Many endocrine disorders cause weakness. Muscle fatigue is more common than true weakness. The cause of PARATHYROID DISORDERS weakness in these disorders is not well defined. It is not even clear that weakness results from disease of muscle Hyperparathyroidism as opposed to another part of the motor unit, since the serum CK level is often normal (except in hypothy- Muscle weakness is an integral part of primary and sec- roidism) and the muscle histology is characterized by ondary hyperparathyroidism. Proximal muscle weakness, muscle wasting, and brisk muscle stretch reflexes are the

main features of this endocrinopathy. Some patients a neuropathy affecting the proximal major nerve trunks 593 CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases develop neck extensor weakness (part of the dropped head and lumbosacral plexus. More appropriate terms for this syndrome). Serum CK levels are usually normal or slightly disorder include diabetic proximal neuropathy and lum- elevated. Serum parathyroid hormone levels are elevated. bosacral radiculoplexus neuropathy. Serum calcium and phosphorus levels show no correlation with the clinical neuromuscular manifestations. Muscle The only notable myopathy of diabetes mellitus is biopsies show only varying degrees of atrophy without ischemic infarction of leg muscles, usually involving one muscle fiber degeneration. of the thigh muscles but on occasion affecting the distal leg. This condition occurs in patients with poorly con- Hypoparathyroidism trolled diabetes and presents with abrupt onset of pain, tenderness, and edema of one thigh. The area of muscle An overt myopathy due to hypocalcemia rarely occurs. infarction is hard and indurated.The muscles most often Neuromuscular symptoms are usually related to localized affected include the vastus lateralis, thigh adductors, or generalized tetany. Serum CK levels may be increased and biceps femoris. CT or MRI can demonstrate focal secondary to muscle damage from sustained tetany. abnormalities in the affected muscle. Diagnosis by imaging Hyporeflexia or areflexia is usually present and contrasts is preferable to muscle biopsy, if possible, as hemorrhage with the hyperreflexia in hyperparathyroidism. into the biopsy site can occur. ADRENAL DISORDERS VITAMIN DEFICIENCY Conditions associated with glucocorticoid excess cause a Vitamin D deficiency due to either decreased intake, myopathy; in fact, steroid myopathy is the most commonly decreased absorption, or impaired vitamin D metabolism diagnosed endocrine muscle disease. Glucocorticoid excess, (as occurs in renal disease) may lead to chronic muscle either endogenous or exogenous (see Drug-Induced weakness. Pain reflects the underlying bone disease (osteo- Myopathies, below), produces various degrees of proxi- malacia).Vitamin E deficiency may result from malabsorp- mal limb weakness. Muscle wasting may be striking. A tion. Clinical manifestations include ataxic neuropathy cushingoid appearance usually accompanies clinical signs due to loss of proprioception and myopathy with proxi- of myopathy. Histologic sections demonstrate muscle fiber mal weakness. Progressive external ophthalmoplegia is a atrophy, preferentially affecting type 2b fibers, rather than distinctive finding. It has not been established that defi- degeneration or necrosis of muscle fibers. Adrenal insuf- ciency of other vitamins causes a myopathy. ficiency commonly causes muscle fatigue.The degree of weakness may be difficult to assess but is typically mild. MYOPATHIES OF SYSTEMIC ILLNESS In primary hyperaldosteronism (Conn’s syndrome), neuro- muscular complications are due to potassium depletion. Systemic illnesses such as chronic respiratory, cardiac, or The clinical picture is one of persistent muscle weakness. hepatic failure are frequently associated with severe Long-standing hyperaldosteronism may lead to proximal muscle wasting and complaints of weakness. Fatigue is limb weakness and wasting. Serum CK levels may be usually a more significant problem than weakness, which elevated, and a muscle biopsy may demonstrate degener- is typically mild. ating fibers, some with vacuoles.These changes relate to hypokalemia and are not a direct effect of aldosterone Myopathy may be a manifestation of chronic renal on skeletal muscle. failure, independent of the better known uremic polyneu- ropathy.Abnormalities of calcium and phosphorus home- PITUITARY DISORDERS ostasis and bone metabolism in chronic renal failure result from a reduction in 1,25-dihydroxyvitamin D, Patients with acromegaly usually have mild proximal weak- leading to decreased intestinal absorption of calcium. ness without muscle atrophy. Muscles often appear enlarged Hypocalcemia, further accentuated by hyperphosphatemia but exhibit decreased force generation. The duration of due to decreased renal phosphate clearance, leads to sec- acromegaly, rather than the serum growth hormone levels, ondary hyperparathyroidism. Renal osteodystrophy results correlates with the degree of myopathy. from the compensatory hyperparathyroidism, which leads to osteomalacia from reduced calcium availability DIABETES MELLITUS and to osteitis fibrosa from the parathyroid hormone excess. The clinical picture of the myopathy of chronic Neuromuscular complications of diabetes mellitus are most renal failure is identical to that of primary hyperparathy- often related to neuropathy, with cranial and peripheral roidism and osteomalacia.There is proximal limb weakness nerve palsies or distal sensorimotor polyneuropathy. Diabetic with bone pain. amyotrophy is a clumsy term since the condition represents Gangrenous calcification represents a separate, rare, and sometimes fatal complication of chronic renal failure. In

SECTION III Diseases of the Central Nervous System594 this condition, widespread arterial calcification occurs and of muscle necrosis are seen, and in severe reactions rhab- results in ischemia. Extensive skin necrosis may occur, domyolysis and myoglobinuria occur. Concomitant use along with painful myopathy and even myoglobinuria. of statins with fibrates and cyclosporine is more likely to cause adverse reactions than use of one agent alone. A DRUG-INDUCED MYOPATHIES polymorphism has been identified which increases the risk of statin-induced myopathy. Elevated serum CK is an Drug-induced myopathies are relatively uncommon in important indication of toxicity. Muscle weakness is clinical practice with the exception of those caused by the accompanied by a myopathic EMG, and muscle necrosis cholesterol-lowering agents and glucocorticoids. Others is observed by muscle biopsy. Severe myalgias, muscle impact practice to a lesser degree but are important to weakness, significant elevations in serum CK (> three consider in specific situations. Table 43-11 provides a times baseline), and myoglobinuria are indications for comprehensive list of drug-induced myopathies with their stopping the drug. Patients usually improve with drug distinguishing features. cessation, although this may take several weeks. Rare cases continue to progress after the offending agent is MYOPATHY FROM LIPID-LOWERING discontinued. It is possible that in such cases the statin AGENTS may have triggered an immune-mediated necrotizing myopathy, as these individuals may respond to glucocor- All classes of lipid-lowering agents have been implicated ticoid therapy. in muscle toxicity including fibrates (clofibrate, gemfi- brozil), HMG-CoA reductase inhibitors (referred to as GLUCOCORTICOID-RELATED MYOPATHIES statins), niacin (nicotinic acid), and ezetimibe. Myalgia, malaise, and muscle tenderness are the most common Glucocorticoid myopathy occurs with chronic treatment manifestations. Muscle pain may be related to exercise. or as “acute quadriplegic” myopathy secondary to high- Patients may exhibit proximal weakness.Varying degrees dose, IV glucocorticoids. Chronic administration produces TABLE 43-11 MAJOR TOXIC REACTION DRUG-INDUCED MYOPATHIES Drugs belonging to all three of the major classes of lipid- lowering agents can produce a spectrum of toxicity: asymp- DRUGS tomatic serum creatine kinase elevation, myalgias, exercised- induced pain, rhabdomyolysis, and myoglobinuria. Lipid-lowering agents Fibric acid derivatives Acute, high-dose glucocorticoid treatment can cause acute HMG-CoA reductase inhibitors quadriplegic myopathy. These high doses of steroids are often Niacin (nicotinic acid) combined with nondepolarizing neuromuscular blocking agents but the weakness can occur without their use. Chronic steroid Glucocorticoids administration produces predominantly proximal weakness. Acute quadriplegic myopathy can occur with or without Nondepolarizing neuromuscular concomitant glucocorticoids. blocking agents Mitochondrial myopathy with ragged red fibers. All drugs in this group can lead to widespread muscle Zidovudine breakdown, rhabdomyolysis, and myoglobinuria. Drugs of abuse Local injections cause muscle necrosis, skin induration, and limb contractures. Alcohol Amphetamines Use of this drug may cause polymyositis and myasthenia gravis. Cocaine Heroin All amphophilic drugs have the potential to produce painless, Phencyclidine proximal weakness associated with autophagic vacuoles in Meperidine the muscle biopsy. Autoimmune toxic myopathy D-Penicillamine This drug produces painless, proximal weakness especially Amphophilic cationic drugs in the setting of renal failure. Muscle biopsy shows autophagic Amiodarone vacuoles. Chloroquine Hydroxychloroquine Antimicrotubular drugs Colchicine

proximal weakness accompanied by cushingoid manifes- to be drug-related, the medication should be stopped or 595 CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases tations, which can be quite debilitating; the chronic use the dosage reduced. of prednisone at a daily dose of ≥30 mg/d is most often associated with toxicity. Patients taking fluorinated gluco- DRUGS OF ABUSE AND corticoids (triamcinolone, betamethasone, dexamethasone) RELATED MYOPATHIES appear to be at especially high risk for myopathy. Patients receiving high-dose, IV glucocorticoids for status asth- Myotoxicity is a potential consequence of addiction to maticus, chronic obstructive pulmonary disease, or other alcohol and illicit drugs. Ethanol is one of the most indications may develop severe generalized weakness. commonly abused substances with potential to damage Involvement of the diaphragm and intercostal muscles muscle. Other potential toxins include cocaine, heroin, causes respiratory failure and requires ventilatory support. and amphetamines.The most deleterious reactions occur In this setting, the use of glucocorticoids in combination from overdosing leading to coma and seizures, causing with nondepolarizing neuromuscular blocking agents to rhabdomyolysis, myoglobinuria, and renal failure. Direct further decrease airway resistance is particularly likely to toxicity can occur from cocaine, heroin, and ampheta- lead to this complication. In chronic steroid myopathy mines causing muscle breakdown and varying degrees of the serum CK is usually normal. Serum potassium may weakness. The effects of alcohol are more controversial. be low. The muscle biopsy in chronic cases shows pref- Direct muscle damage is less certain, since toxicity usu- erential type 2 muscle fiber atrophy; this is not reflected ally occurs in the setting of poor nutrition and possible in the EMG, which is usually normal. In acute cases contributing factors such as hypokalemia and hypophos- with quadriplegic myopathy the muscle biopsy is abnormal, phatemia. Alcoholics are also prone to neuropathy and a showing a distinctive loss of thick filaments (myosin) by variety of CNS disorders (Chap. 50). electron microscopy. By light microscopy there is focal loss of ATPase staining in central or paracentral areas of Focal myopathies from self-administration of meperi- the muscle fiber. Calpain stains show diffusely reactive dine, heroin, and pentazocine can cause pain, swelling, atrophic fibers.Withdrawal of glucocorticoids will improve muscle necrosis, and hemorrhage.The cause is multifactor- the chronic myopathy. In acute quadriplegic myopathy, ial; needle trauma, direct toxicity of the drug or vehicle, recovery is slow. Patients require supportive care and and infection may all play a role.When severe, there may rehabilitation. be overlying skin induration and contractures with replacement of muscle by connective tissue. Elevated serum MYOPATHY OF NONDEPOLARIZING CK and myopathic EMG are characteristic of these reac- NEUROMUSCULAR BLOCKING AGENTS tions.The muscle biopsy shows widespread or focal areas of necrosis. In conditions leading to rhabdomyolysis, Patients may receive nondepolarizing neuromuscular patients need adequate hydration to reduce serum myo- blocking agents because of life-threatening airway resis- globin and protect renal function. In all of these condi- tance. Acute quadriplegic myopathy may result, with or tions, counseling is essential to limit drug abuse. without glucocorticoid use. The clinical features are identical to acute quadriplegic myopathy secondary to DRUG-INDUCED AUTOIMMUNE glucocorticoids. MYOPATHIES DRUG-INDUCED MITOCHONDRIAL The most consistent drug-related inflammatory or MYOPATHY antibody-mediated myopathy is caused by D-penicillamine. This drug chelates copper and is used in the treatment of Zidovudine, used in the treatment of HIV infection, is a Wilson’s disease. It is also used to treat other disorders thymidine analogue that inhibits viral replication by inter- including scleroderma, rheumatoid arthritis, and primary rupting reverse transcriptase. Myopathy is a well-established biliary cirrhosis. Adverse events include drug-induced complication of this agent. Patients present with myalgias, polymyositis, indistinguishable from the spontaneous muscle weakness, and atrophy affecting the thigh and calf disease. The incidence of this inflammatory muscle dis- muscles.The complication occurs in about 17% of patients ease is about 1%. Myasthenia gravis is also induced by treated with doses of 1200 mg/d for 6 months. The d-penicillamine, with a higher incidence estimated at introduction of protease inhibitors for treatment of HIV 7%. These disorders resolve with drug withdrawal, infection has led to lower doses of zidovudine therapy although immunosuppressive therapy may be warranted and a decreased incidence of myopathy. Serum CK is in severe cases. elevated and EMG is myopathic. Muscle biopsy shows ragged red fibers with minimal inflammation; the lack of Scattered reports of other drugs causing an inflamma- inflammation serves to distinguish zidovudine toxicity tory myopathy are rare and include a heterogeneous group from HIV-related myopathy. If the myopathy is thought of agents: cimetidine, phenytoin, procainamide, and propylthiouracil. In most cases, a cause-and-effect relation- ship is uncertain. A complication of interest was related

SECTION III Diseases of the Central Nervous System596 to L-tryptophan. In 1989 an epidemic of eosinophilia- GLOVER L, BROWN RH Jr: Dysferlin in membrane trafficking and myalgia syndrome (EMS) in the United States was caused patch repair.Traffic 8:785, 2007 by a contaminant in the product from one manufacturer. The product was withdrawn, and incidence of EMS GODFREY C et al: Fukutin mutations in steroid-responsive limb girdle diminished abruptly following this action. muscular dystrophy.Ann Neurol 60:603, 2006 OTHER DRUG-INDUCED MYOPATHIES GROH WJ et al: Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med 358:2688, 2008 Certain drugs produce painless, largely proximal, muscle weakness. These drugs include the amphophilic cationic GUGLIERI M et al: Limb-girdle muscular dystrophies. Curr Opin Neurol drugs (amiodarone, chloroquine, hydroxychloroquine) and 21:576, 2008 antimicrotubular drugs (colchicine) (Table 43-11). Muscle biopsy can be useful in the identification of toxicity since LUECK JD et al: Chloride channelopathy in myotonic dystrophy autophagic vacuoles are prominent pathologic features of resulting from loss of post-transcriptional regulation for CLCN1. these toxins. Am J Physiol Cell Physiol 292:C1291, 2007 FURTHER READINGS MENDELL JR et al:The congenital muscular dystrophies: Recent advances and molecular insights. Pediatr Devel Path 9:427, 2006 BRAIS B: Oculopharyngeal muscular dystrophy: a polyalanine myopathy. Curr Neurol Neurosci Rep 9:76, 2009 MEOLA G et al: Diagnosis and new treatment in muscle channelopathies. J Neurol Neurosurg Psychiatry 80:360, 2009 DALAKAS MC:Toxic and drug-induced myopathies. J Neurol Neurosurg Psychiatry 80:832, 2009 RANUM LPW, COOPER TA: RNA-mediated neuromuscular disorders. Ann Rev Neurosci 29:259, 2006 DAVIES KE, NOWAK KJ: Molecular mechanisms of muscular dystrophies: Old and new players. Nat Rev Mol Cell Biol 7:762, 2006 RODINO-KLAPAC LR et al: Gene therapy for Duchenne muscular dystrophy: Expectations and challenges. Arch Neurol 64:1236, DIMAURO S, DAVIDZON G: Mitochondrial DNA and disease. Ann 2007 Med 37:222, 2005 SAMPAOLESI M et al: Mesangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature 444:574, 2006 THE SEARCH COLLABORATIVE GROUP: SLCO1B1 variants and statin-induced myopathy—A genomewide study. N Engl J Med 359:789, 2008 VAN DE MAAREL SM et al: Facioscapuloperoneal muscular dystrophy. Biochim Biophys Acta 189:697, 2007 WELCH E et al: PTC124 targets genetic disorders caused by nonsense mutations. Nature 447:87, 2007

CHAPTER 44 POLYMYOSITIS, DERMATOMYOSITIS, AND INCLUSION BODY MYOSITIS Marinos C. Dalakas Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 Specific Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 Associated Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . 599 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608 The inflammatory myopathies represent the largest muscles are spared, even in advanced, untreated cases; if group of acquired and potentially treatable causes of these muscles are affected, the diagnosis of inflammatory skeletal muscle weakness. They are classified into three myopathy should be questioned. Facial muscles are unaf- major groups: polymyositis (PM), dermatomyositis fected in PM and DM, but mild facial muscle weakness (DM), and inclusion body myositis (IBM). is common in patients with IBM. In all forms of inflam- matory myopathy, pharyngeal and neck-flexor muscles CLINICAL FEATURES are often involved, causing dysphagia or difficulty in holding up the head (head drop). In advanced and rarely The prevalence of the inflammatory myopathies is esti- in acute cases, respiratory muscles may also be affected. mated at 1 in 100,000. PM as a stand-alone entity is a Severe weakness, if untreated, is almost always associated rare disease affecting adults. DM affects both children with muscle wasting. Sensation remains normal. The and adults and women more often than men. IBM is tendon reflexes are preserved but may be absent in three times more frequent in men than in women, more severely weakened or atrophied muscles, especially in common in whites than blacks, and is most likely to IBM where atrophy of the quadriceps and the distal affect persons >50 years of age. muscles is common. Myalgia and muscle tenderness may occur in a small number of patients, usually early These disorders present as progressive and symmetric in the disease, and particularly in DM associated with muscle weakness except for IBM, which can have an connective tissue disorders. Weakness in PM and DM asymmetric pattern. Patients usually report increasing progresses subacutely over a period of weeks or months difficulty with everyday tasks requiring the use of proxi- and rarely acutely; by contrast, IBM progresses very mal muscles, such as getting up from a chair, climbing slowly, over years, simulating a late-life muscular dystro- steps, stepping onto a curb, lifting objects, or combing phy (Chap. 43) or slowly progressive motor neuron dis- hair. Fine-motor movements that depend on the order (Chap. 27). strength of distal muscles, such as buttoning a shirt, sewing, knitting, or writing, are affected only late in the SPECIFIC FEATURES course of PM and DM, but fairly early in IBM. Falling is common in IBM because of early involvement of the (Table 44-1) quadriceps muscle with buckling of the knees. Ocular 597

598 TABLE 44-1 FEATURES ASSOCIATED WITH INFLAMMATORY MYOPATHIES CHARACTERISTIC POLYMYOSITIS DERMATOMYOSITIS INCLUSION BODY MYOSITIS >18 years >50 years Age at onset No Adulthood and childhood Yes, in some cases Familial association Yes No Yes Extramuscular manifestations Yes Associated conditions Yesa Yes, in up to 20% of casesa Connective tissue diseases Scleroderma and mixed Frequent connective tissue disease Infrequent Systemic autoimmune (overlap syndromes) diseasesb No Infrequent No Malignancy Yesc Yesc Yes Yes, in up to 15% of cases No Viruses Yes Unproven No Drugsd Yes, rarely Parasites and bacteriae No SECTION III Diseases of the Central Nervous System aSystemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, mixed connective tissue disease. bCrohn’s disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult celiac disease, chronic graft-versus-host disease, discoid lupus, ankylos- ing spondylitis, Behçet’s syndrome, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimoto’s disease, granulomatous diseases, agammaglobulinemia, monoclonal gammopathy, hypereosinophilic syndrome, Lyme disease, Kawasaki disease, autoimmune throm- bocytopenia, hypergammaglobulinemic purpura, hereditary complement deficiency, IgA deficiency. cHIV (human immunodeficiency virus) and HTLV-I (human T cell lymphotropic virus type I). dDrugs include penicillamine (dermatomyositis and polymyositis), zidovudine (polymyositis), and contaminated tryptophan (dermatomyositis-like illness). Other myotoxic drugs may cause myopathy but not an inflammatory myopathy (see text for details). eParasites (protozoa, cestodes, nematodes), tropical and bacterial myositis (pyomyositis). Polymyositis violaceous scaly eruption (Gottron’s sign). The erythema- tous rash can also occur on other body surfaces, including The actual onset of PM is often not easily determined, the knees, elbows, malleoli, neck and anterior chest (often and patients typically delay seeking medical advice for in a V sign), or back and shoulders (shawl sign), and may several months. This is in contrast to DM, in which the worsen after sun exposure. In some patients the rash is rash facilitates early recognition (see later). PM mimics pruritic, especially on the scalp, chest, and back. Dilated many other myopathies and is a diagnosis of exclusion. capillary loops at the base of the fingernails are also char- It is a subacute inflammatory myopathy affecting adults, acteristic. The cuticles may be irregular, thickened, and dis- and rarely children, who do not have any of the follow- torted, and the lateral and palmar areas of the fingers may ing: rash, involvement of the extraocular and facial mus- become rough and cracked, with irregular, “dirty” hori- cles, family history of a neuromuscular disease, history of zontal lines, resembling mechanic’s hands.The weakness can exposure to myotoxic drugs or toxins, endocrinopathy, be mild, moderate, or severe enough to lead to quadri- neurogenic disease, muscular dystrophy, biochemical paresis. At times, the muscle strength appears normal, muscle disorder (deficiency of a muscle enzyme), or hence the term dermatomyositis sine myositis. When muscle IBM as excluded by muscle biopsy analysis (see later). As biopsy is performed in such cases, however, significant an isolated entity, PM is a rare (and overdiagnosed) dis- perivascular and perimysial inflammation is often seen. order; more commonly, PM occurs in association with a systemic autoimmune or connective tissue disease, or DM usually occurs alone but may overlap with scle- with a known viral or bacterial infection. Drugs, espe- roderma and mixed connective tissue disease. Fasciitis cially d-penicillamine or zidovudine (AZT), may also and thickening of the skin, similar to that seen in produce an inflammatory myopathy similar to PM. chronic cases of DM, have occurred in patients with the eosinophilia-myalgia syndrome associated with the inges- Dermatomyositis tion of contaminated l-tryptophan. DM is a distinctive entity identified by a characteristic rash Inclusion Body Myositis accompanying, or more often preceding, muscle weakness. The rash may consist of a blue-purple discoloration on the In patients ≥50 years, IBM is the most common of the upper eyelids with edema, a flat red rash on the face and inflammatory myopathies. It is often misdiagnosed as PM upper trunk, and erythema of the knuckles with a raised and is suspected only later when a patient with presumed PM does not respond to therapy. Weakness and atrophy

of the distal muscles, especially foot extensors and deep itself or from hypertension associated with long- 599 CHAPTER 44 Polymyositis, Dermatomyositis, and Inclusion Body Myositis finger flexors, occur in almost all cases of IBM and may term use of glucocorticoids. be a clue to early diagnosis. Some patients present with 5. Pulmonary dysfunction, due to weakness of the tho- falls because their knees collapse due to early quadriceps racic muscles, interstitial lung disease, or drug- weakness. Others present with weakness in the small induced pneumonitis (e.g., from methotrexate), muscles of the hands, especially finger flexors, and com- which may cause dyspnea, nonproductive cough, plain of inability to hold objects such as golf clubs or and aspiration pneumonia. Interstitial lung disease perform tasks such as turning keys or tying knots. On may precede myopathy or occur early in the disease occasion, the weakness and accompanying atrophy can and develops in up to 10% of patients with PM or be asymmetric and selectively involve the quadriceps, DM, most of whom have antibodies to t-RNA syn- iliopsoas, triceps, biceps, and finger flexors, resembling a thetases, as described below. lower motor neuron disease. Dysphagia is common, 6. Subcutaneous calcifications, in DM, sometimes extrud- occurring in up to 60% of IBM patients, and may lead to ing on the skin and causing ulcerations and episodes of choking. Sensory examination is generally infections. normal; some patients have mildly diminished vibratory 7. Arthralgias, synovitis, or deforming arthropathy with sensation at the ankles that presumably is age-related.The subluxation in the interphalangeal joints can occur pattern of distal weakness, which superficially resembles in some patients with DM and PM who have Jo-1 motor neuron or peripheral nerve disease, results from antibodies (see later). the myopathic process affecting distal muscles selectively. Disease progression is slow but steady, and most patients Association with Malignancies require an assistive device such as cane, walker, or wheel- chair within several years of onset. Although all the inflammatory myopathies can have a chance association with malignant lesions, especially in In at least 20% of cases, IBM is associated with systemic older age groups, the incidence of malignant conditions autoimmune or connective tissue diseases. Familial aggre- appears to be specifically increased only in patients with gation of typical IBM may occur; such cases have been DM and not in those with PM or IBM.The most com- designated as familial inflammatory IBM.This disorder is dis- mon tumors associated with DM are ovarian cancer, tinct from hereditary inclusion body myopathy (h-IBM), breast cancer, melanoma, colon cancer, and non- which describes a heterogeneous group of recessive, and Hodgkin lymphoma. The extent of the search that less frequently dominant, inherited syndromes; the h-IBMs should be conducted for an occult neoplasm in adults are noninflammatory myopathies. A subset of h-IBM that with DM depends on the clinical circumstances.Tumors spares the quadriceps muscles has emerged as a distinct in these patients are usually uncovered by abnormal entity. This disorder, originally described in Iranian Jews findings in the medical history and physical examination and now seen in many ethnic groups, is linked to chromo- and not through an extensive blind search. The weight some 9p1 and results from mutations in the UDP- of evidence argues against performing expensive, inva- N-acetylglucosamine 2-epimerase/N-acetylmannosamine sive, and nondirected tumor searches. A complete annual kinase (GNE) gene. physical examination with pelvic, breast (mammogram, if indicated), and rectal examinations (with colonoscopy ASSOCIATED CLINICAL FINDINGS according to age and family history); urinalysis; com- plete blood count; blood chemistry tests; and a chest Extramuscular Manifestations film should suffice in most cases. In Asians, nasopharyn- geal cancer is common, and a careful examination of These may be present to a varying degree in patients ears, nose, and throat is indicated. with PM or DM, and include: Overlap Syndromes 1. Systemic symptoms, such as fever, malaise, weight loss, arthralgia, and Raynaud’s phenomenon, especially These describe the association of inflammatory myopathies when inflammatory myopathy is associated with a with connective tissue diseases. A well-characterized over- connective tissue disorder. lap syndrome occurs in patients with DM who also have manifestations of systemic sclerosis or mixed connective tis- 2. Joint contractures, mostly in DM and especially in sue disease, such as sclerotic thickening of the dermis, con- children. tractures, esophageal hypomotility, microangiopathy, and calcium deposits (Table 44-1). By contrast, signs of rheuma- 3. Dysphagia and gastrointestinal symptoms, due to toid arthritis, systemic lupus erythematosus, or Sjögren’s involvement of oropharyngeal striated muscles and syndrome are very rare in patients with DM. Patients with upper esophagus, especially in DM and IBM. the overlap syndrome of DM and systemic sclerosis may 4. Cardiac disturbances, including atrioventricular con- duction defects, tachyarrhythmias, dilated cardiomy- opathy, a low ejection fraction, and congestive heart failure, may rarely occur, either from the disease

SECTION III Diseases of the Central Nervous System600 have a specific antinuclear antibody, the anti-PM/Scl, hypoperfusion that is prominent in the periphery of the directed against a nucleolar-protein complex. muscle fascicles. PATHOGENESIS By contrast, in PM and IBM a mechanism of T cell–mediated cytotoxicity is likely. CD8 T cells, along An autoimmune etiology of the inflammatory myopathies with macrophages, initially surround and eventually is indirectly supported by an association with other auto- invade and destroy healthy, nonnecrotic muscle fibers immune or connective tissue diseases; the presence of various that aberrantly express class I MHC molecules. MHC-I autoantibodies; an association with specific major histo- expression, absent from the sarcolemma of normal mus- compatibility complex (MHC) genes; demonstration of T cle fibers, is probably induced by cytokines secreted by cell–mediated myocytotoxicity or complement-mediated activated T cells and macrophages. The CD8/MHC-I microangiopathy; and a response to immunotherapy. complex is characteristic of PM and IBM; its detection can aid in confirming the histologic diagnosis of PM, as Autoantibodies and Immunogenetics discussed below.The cytotoxic CD8 T cells contain per- forin and granzyme granules directed towards the sur- Various autoantibodies against nuclear antigens (antinu- face of the muscle fibers and capable of inducing clear antibodies) and cytoplasmic antigens are found in myonecrosis. Analysis of T cell receptor molecules up to 20% of patients with inflammatory myopathies. expressed by the infiltrating CD8 cells have revealed The antibodies to cytoplasmic antigens are directed clonal expansion and conserved sequences in the anti- against ribonucleoproteins involved in protein synthesis gen-binding region, both suggesting an antigen-driven (anti-synthetases) or translational transport (anti-signal- T cell response. Whether the putative antigens are recognition particles). The antibody directed against endogenous (e.g., muscle) or exogenous (e.g., viral) the histidyl-transfer RNA synthetase, called anti-Jo-1, sequences is unknown.Viruses have not been identified accounts for 75% of all the anti-synthetases and is clini- within the muscle fibers. Co-stimulatory molecules and cally useful because up to 80% of patients with anti-Jo-1 their counterreceptors, which are fundamental for T cell antibodies have interstitial lung disease. Some patients activation and antigen recognition, are strongly upregu- with the anti-Jo-1 antibody also have Raynaud’s phe- lated in PM and IBM. Key molecules involved in T nomenon, nonerosive arthritis, and the MHC molecules cell–mediated cytotoxicity are depicted in Fig. 44-2. DR3 and DRw52. DR3 haplotypes (molecular designa- tion DRB1∗0301, DQB1∗0201) occur in up to 75% of The Role of Nonimmune Factors in IBM patients with PM and IBM, whereas in juvenile DM there is an increased frequency of DQA1∗0501. In IBM, the presence of β-amyloid deposits within vac- uolated muscle fibers and abnormal mitochondria with Immunopathologic Mechanisms cytochrome oxidase–negative fibers suggest that, in addition to the autoimmune component, there is also a In DM, humoral immune mechanisms are implicated, degenerative process. Similar to Alzheimer’s disease, the resulting in a microangiopathy and muscle ischemia amyloid deposits in IBM are immunoreactive against (Fig. 44-1). Endomysial inflammatory infiltrates are amyloid precursor protein (APP), chymotrypsin, composed of B cells located in proximity to CD4 T cells, apolipoprotein E, and phosphorylated tau, but it is dendritic cells, and macrophages; there is a relative unclear whether these deposits are directly pathogenic absence of lymphocytic invasion of nonnecrotic muscle or represent secondary phenomena.The same is true for fibers. Activation of the complement C5b-9 membra- the mitochondrial abnormalities, which may also be sec- nolytic attack complex is thought to be a critical early ondary to the effects of aging or a bystander effect of event that triggers release of proinflammatory cytokines upregulated cytokines. Expression of cytokines and and chemokines, induces expression of vascular cell upregulation of MHC class I by the muscle fibers may adhesion molecule (VCAM) 1 and intracellular adhesion cause an endoplasmic reticulum stress response resulting molecule (ICAM) 1 on endothelial cells, and facilitates in intracellular accumulation of misfolded glycoproteins migration of activated lymphoid cells to the perimysial and activation of nuclear factor κB (NFκB), leading to and endomysial spaces. Necrosis of the endothelial cells, further cytokine activation. reduced numbers of endomysial capillaries, ischemia, and muscle-fiber destruction resembling microinfarcts occur. Association with Viral Infections and the Role The remaining capillaries often have dilated lumens in of Retroviruses response to the ischemic process. Larger intramuscular blood vessels may also be affected in the same pattern. Several viruses, including coxsackieviruses, influenza, Residual perifascicular atrophy reflects the endofascicular paramyxoviruses, mumps, cytomegalovirus, and Epstein- Barr virus, have been indirectly associated with myositis.

Molecular mimicry, 601 tumors, viruses? C1 C3 C3a Macrophage C4 B cell Chemokines C2 Cytokines C3b B C3 MAC T cell T cell D LFA-1 VLA-4 Mac-1 ICAM-1 VCAM-1 ICAM-1 MAC B cell C3bNEO T cell Cytokines NO, TNF-α STAT-1, Chemokines, CHAPTER 44 Polymyositis, Dermatomyositis, and Inclusion Body Myositis Cathepsin, TGF-β FIGURE 44-1 B cells, CD4 T cells, and macrophages traffic from the circu- Immunopathogenesis of dermatomyositis. Activation of lation to the muscle. Endothelial expression of vascular cell complement, possibly by autoantibodies (Y), against adhesion molecule (VCAM) and intercellular adhesion mole- endothelial cells and formation of C3 via the classic or alter- cule (ICAM) is induced by cytokines released by the native pathway. Activated C3 leads to formation of C3b, mononuclear cells. Integrins, specifically very late activation C3bNEO, and membrane attack complexes (MAC), which antigen (VLA)-4 and leukocyte function-associated antigen are deposited in and around the endothelial cell wall of the (LFA)-1, bind VCAM and ICAM and promote T cell and endomysial capillaries. Deposition of MAC leads to destruc- macrophage infiltration of muscle through the endothelial tion of capillaries, ischemia, or microinfarcts most prominent cell wall. in the periphery of the fascicles, and perifascicular atrophy. For the coxsackieviruses, an autoimmune myositis trig- disease course. Retroviral antigens have been detected gered by molecular mimicry has been proposed because only in occasional endomysial macrophages and not of structural homology between histidyl-transfer RNA within the muscle fibers themselves, suggesting that per- synthetase that is the target of the Jo-1 antibody (see ear- sistent infection and viral replication within the muscle lier) and genomic RNA of an animal picornavirus, the does not occur. Histologic findings are identical to encephalomyocarditis virus. Sensitive polymerase chain retroviral-negative PM or IBM. The infiltrating T cells reaction (PCR) studies, however, have repeatedly failed to in the muscle are clonally driven and a number of them confirm the presence of such viruses in muscle biopsies. are retroviral-specific. This disorder should be distin- guished from a toxic myopathy related to long-term The best evidence of a viral connection in PM and therapy with AZT, characterized by fatigue, myalgia, IBM is with the retroviruses. Some individuals infected mild muscle weakness, and mild elevation of creatine with HIV or with human T cell lymphotropic virus I kinase (CK). AZT-induced myopathy, which generally (HTLV-I) develop PM or IBM; a similar disorder has improves when the drug is discontinued, is a mitochon- been described in nonhuman primates infected with the drial disorder characterized histologically by “ragged- simian immunodeficiency virus. The inflammatory red” fibers. AZT inhibits γ-DNA polymerase, an enzyme myopathy may occur as the initial manifestation of a found solely in the mitochondrial matrix. retroviral infection, or myositis may develop later in the

602 Antigen Macrophage Systemic immune compartment Co-stimulation MHC Clonal expansion Infection? TCR CD8 CD8 Chemokines Integrins VCAM-1 (MCP-1, Mig, IP-10) LFA-4 CD8 MMPs CD8 Cytokines IFN-γ TNF-α MMP-9 IL-1, 2 LFA-1 CD28 CTLA-4 TCR BB1 ICAM-1 MMP-9 IFN-γ MHC-I MMP-2 TFN-α SECTION III Diseases of the Central Nervous System IL-1, 2 Perforin Ag Calnexin Necrosis (virus, muscle MHC-I peptide) TAP β2m Endoplasmic reticulum FIGURE 44-2 of T cells and their attachment to the muscle surface. Muscle Cell-mediated mechanisms of muscle damage in fiber necrosis occurs via perforin granules released by the polymyositis (PM) and inclusion body myositis (IBM). autoaggressive T cells. A direct myocytotoxic effect exerted Antigen-specific CD8 cells are expanded in the periphery, by the cytokines interferon (IFN) γ, interleukin (IL) 1, or tumor cross the endothelial barrier, and bind directly to muscle fibers necrosis factor (TNF) α may also play a role. Death of the mus- via T cell receptor (TCR) molecules that recognize aberrantly cle fiber is mediated by necrosis. MHC class I molecules con- expressed MHC-I. Engagement of co-stimulatory molecules sist of a heavy chain and a light chain [β2 microglobulin (β2m)] (BB1 and ICOSL) with their ligands (CD28, CTLA-4, and ICOS) complexed with an antigenic peptide that is transported into along with ICAM-1/LFA-1, stabilize the CD8–muscle fiber the endoplasmic reticulum by TAP proteins. interaction. Metalloproteinases (MMP) facilitate the migration DIFFERENTIAL DIAGNOSIS rarely present after the age of 30. It may be difficult, even with a muscle biopsy, to distinguish chronic PM The clinical picture of the typical skin rash and proximal from a rapidly advancing muscular dystrophy. This is or diffuse muscle weakness has few causes other than particularly true of facioscapulohumeral muscular dys- DM. However, proximal muscle weakness without skin trophy, dysferlin myopathy, and the dystrophinopathies involvement can be due to many conditions other than where inflammatory cell infiltration is often found early PM or IBM. in the disease. Such doubtful cases should always be given an adequate trial of glucocorticoid therapy and Subacute or Chronic Progressive undergo genetic testing to exclude muscular dystrophy. Muscle Weakness Identification of the MHC/CD8 lesion by muscle biopsy is helpful to identify cases of PM. Some meta- This may be due to denervating conditions such as the bolic myopathies, including glycogen storage disease due spinal muscular atrophies or amyotrophic lateral sclerosis to myophosphorylase or acid maltase deficiency, lipid (Chap. 27). In addition to the muscle weakness, upper storage myopathies due to carnitine deficiency, and motor neuron signs in the latter and signs of denerva- mitochondrial diseases produce weakness that is often tion detected by electromyography (EMG) aid in the associated with other characteristic clinical signs; diag- diagnosis. The muscular dystrophies (Chap. 43) may be nosis rests upon histochemical and biochemical studies additional considerations; however, these disorders usu- of the muscle biopsy. The endocrine myopathies such as ally develop over years rather than weeks or months and

those due to hypercorticosteroidism, hyper- and syndrome, contaminated l-tryptophan) or with muta- 603 CHAPTER 44 Polymyositis, Dermatomyositis, and Inclusion Body Myositis hypothyroidism, and hyper- and hypoparathyroidism tions in the calpain gene. A distinct subset of myofasciitis require the appropriate laboratory investigations for is characterized by pronounced infiltration of the con- diagnosis. Muscle wasting in patients with an underlying nective tissue around the muscle by sheets of periodic neoplasm may be due to disuse, cachexia, or rarely to a acid–Schiff-positive macrophages and occasional CD8 T paraneoplastic neuromyopathy (Chap. 39). cells (macrophagic myofasciitis). Such histologic involve- ment is focal and limited to sites of previous vaccina- Diseases of the neuromuscular junction, including tions, which may have been administered months or myasthenia gravis or the Lambert-Eaton myasthenic years earlier. This disorder, which to date has not been syndrome, cause fatiguing weakness that also affects ocu- observed outside of France, has been linked to an alu- lar and other cranial muscles (Chap. 42). Repetitive minum-containing substrate in vaccines. Most patients nerve stimulation and single-fiber EMG studies aid in respond to glucocorticoid therapy, and the overall prog- diagnosis. nosis seems favorable. Acute Muscle Weakness Necrotizing Myositis This may be caused by an acute neuropathy such as This is an increasingly recognized entity that has distinct Guillain-Barré syndrome (Chap. 41), transverse myelitis features, even though it is often labeled as PM. It pre- (Chap. 30), a neurotoxin, or a neurotropic viral infection sents often in the fall or winter as an acute or subacute such as poliomyelitis or West Nile virus (Chap. 35).When onset of symmetric muscle weakness; CK is typically acute weakness is associated with painful muscle cramps, extremely high. The weakness can be severe. Coexisting rhabdomyolysis, and myoglobinuria, it may be due to a interstitial lung disease and cardiomyopathy may be pre- viral infection or a metabolic disorder such as myophos- sent. The disorder may develop after a viral infection or phorylase deficiency or carnitine palmitoyltransferase in association with cancer. Some patients have antibod- deficiency (Chap. 43). Several animal parasites, including ies against signal recognition particle (SRP).The muscle protozoa (toxoplasma, trypanosoma), cestodes (cysticerci), biopsy demonstrates necrotic fibers infiltrated by and nematodes (trichinae), may produce a focal or diffuse macrophages but only rare, if any,T cell infiltrates. Muscle inflammatory myopathy known as parasitic polymyositis. MHC-I expression is only slightly and focally upregu- Staphylococcus aureus, Yersinia, Streptococcus, or anaerobic lated. The capillaries may be swollen with hyalinization, bacteria may produce a suppurative myositis, known as thickening of the capillary wall, and deposition of com- tropical polymyositis, or pyomyositis. Pyomyositis, previously plement. Some patients respond to immunotherapy, but rare in the west, is now occasionally seen in AIDS others are resistant. patients. Other bacteria, such as Borrelia burgdorferi (Lyme disease) and Legionella pneumophila (Legionnaire’s disease) Drug-Induced Myopathies may infrequently cause myositis. D-Penicillamine and procainamide may produce a true Patients with periodic paralysis experience recurrent myositis resembling PM, and a DM-like illness had episodes of acute muscle weakness without pain, always been associated with the contaminated preparations of beginning in childhood. Chronic alcoholics may develop l-tryptophan. As noted above, AZT causes a mitochon- painful myopathy with myoglobinuria after a bout of drial myopathy. Other drugs may elicit a toxic nonin- heavy drinking. Acute painless muscle weakness with flammatory myopathy that is histologically different myoglobinuria may occur with prolonged hypokalemia, from DM, PM, or IBM. These include cholesterol- or hypophosphatemia and hypomagnesemia, usually in lowering agents such as clofibrate, lovastatin, simvas- chronic alcoholics or in patients on nasogastric suction tatin, or pravastatin, especially when combined with receiving parenteral hyperalimentation. cyclosporine or gemfibrozil. Rhabdomyolysis and myo- globinuria have been rarely associated with ampho- Myofasciitis tericin B, ε-aminocaproic acid, fenfluramine, heroin, and phencyclidine.The use of amiodarone, chloroquine, This distinctive inflammatory disorder affecting muscle colchicine, carbimazole, emetine, etretinate, ipecac and fascia presents as diffuse myalgias, skin induration, syrup, chronic laxative or licorice use resulting in fatigue, and mild muscle weakness; mild elevations of hypokalemia, and glucocorticoids or growth hormone serum CK are usually present. The most common form administration have also been associated with myo- is eosinophilic myofasciitis characterized by peripheral pathic muscle weakness. Some neuromuscular blocking blood eosinophilia and eosinophilic infiltrates in the agents such as pancuronium, in combination with gluco- endomysial tissue. In some patients, the eosinophilic corticoids, may cause an acute critical illness myopathy. A myositis/fasciitis occurs in the context of parasitic infec- careful drug history is essential for diagnosis of these tions, vasculitis, mixed connective tissue disease, hypere- osinophilic syndrome, or toxic exposures (e.g., toxic oil

SECTION III Diseases of the Central Nervous System604 drug-induced myopathies, which do not require biopsy is usually normal or nonspecific. Many such immunosuppressive therapy. patients show some response to nonsteroidal anti- inflammatory agents or glucocorticoids, though most “Weakness” Due to Muscle Pain continue to have indolent complaints. An indolent fasci- and Muscle Tenderness itis in the setting of an ill-defined connective tissue dis- order may be present, and these patients should not be A number of conditions including polymyalgia rheumatica labeled as having a psychosomatic disorder. Chronic and arthritic disorders of adjacent joints may enter into fatigue syndrome, which may follow a viral infection, can the differential diagnosis of inflammatory myopathy, present with debilitating fatigue, fever, sore throat, even though they do not cause myositis. The muscle painful lymphadenopathy, myalgia, arthralgia, sleep dis- biopsy is either normal or discloses type II muscle fiber order, and headache (Chap. 47). These patients do not atrophy. Patients with fibrositis and fibromyalgia complain have muscle weakness, and the muscle biopsy is normal. of focal or diffuse muscle tenderness, fatigue, and aching, which is sometimes poorly differentiated from joint DIAGNOSIS pain. Some patients, however, have muscle tenderness, painful muscles on movement, and signs suggestive of a The clinically suspected diagnosis of PM, DM, or IBM collagen vascular disorder, such as an increased erythro- is confirmed by examining the serum muscle enzymes, cyte sedimentation rate, C-reactive protein, antinuclear EMG findings, and muscle biopsy (Table 44-2). antibody, or rheumatoid factor, along with modest ele- vation of the serum CK and aldolase. They demonstrate The most sensitive enzyme is CK, which in active a “give-way” pattern of weakness with difficulty sustain- disease can be elevated as much as 50-fold. Although the ing effort but not true muscle weakness. The muscle CK level usually parallels disease activity, it can be nor- mal in some patients with active IBM or DM, especially TABLE 44-2 CRITERIA FOR DIAGNOSIS OF INFLAMMATORY MYOPATHIES POLYMYOSITIS CRITERION DEFINITE PROBABLE DERMATOMYOSITIS INCLUSION BODY Yes Yes MYOSITIS Myopathic muscle weaknessa Yesb Yes; slow onset, early involvement Electromyographic Myopathic Myopathic Myopathic of distal muscles, findings Elevated (up to frequent falls Elevated (up to Elevated (up to 50-fold) or normal Myopathic with Muscle enzymes 50-fold) 50-fold) Perifascicular, perimysial, mixed potentials “Primary” inflammation Ubiquitous MCH-I or perivascular infiltrates, Elevated (up to Muscle biopsy with the CD8/MHC-I expression but perifascicular atrophy 10-fold) or normal findingsc complex and no minimal inflammation Primary inflammation vacuoles and no vacuolesd Presentf with CD8/MHC-I complex; vacuolated Rash or calcinosis Absent Absent fibers with β-amyloid deposits; cytochrome oxygenase–negative fibers; signs of chronic myopathye Absent aMyopathic muscle weakness, affecting proximal muscles more than distal ones and sparing eye and facial muscles, is characterized by a suba- cute onset (weeks to months) and rapid progression in patients who have no family history of neuromuscular disease, no endocrinopathy, no exposure to myotoxic drugs or toxins, and no biochemical muscle disease (excluded on the basis of muscle-biopsy findings). bIn some cases with the typical rash, the muscle strength is seemingly normal (dermatomyositis sine myositis); these patients often have new onset of easy fatigue and reduced endurance. Careful muscle testing may reveal mild muscle weakness. cSee text for details. dAn adequate trial of prednisone or other immunosuppressive drugs is warranted in probable cases. If, in retrospect, the disease is unresponsive to therapy, another muscle biopsy should be considered to exclude other diseases or possible evolution in inclusion body myositis. eIf the muscle biopsy does not contain vacuolated fibers but shows chronic myopathy with hypertrophic fibers, primary inflammation with the CD8/MHC-I complex and cytochrome oxygenase–negative fibers, the diagnosis is probable inclusion body myositis. fIf rash is absent but muscle biopsy findings are characteristic of dermatomyositis, the diagnosis is probable DM.

605 FIGURE 44-3 FIGURE 44-4 CHAPTER 44 Polymyositis, Dermatomyositis, and Inclusion Body Myositis Cross section of a muscle biopsy from a patient with Cross section of a muscle biopsy from a patient with der- polymyositis demonstrates scattered inflammatory foci with matomyositis demonstrates atrophy of the fibers at the lymphocytes invading or surrounding muscle fibers. Note periphery of the fascicle (perifascicular atrophy). lack of chronic myopathic features (increased connective tis- sue, atrophic or hypertrophic fibers) as seen in inclusion ubiquitously expressed on the sarcolemma, even in body myositis. fibers not invaded by CD8+ cells. The CD8/MHC-I lesion is now fundamental for confirming or establishing when associated with a connective tissue disease. The the diagnosis and to exclude disorders with secondary, CK is always elevated in patients with active PM. Along nonspecific, inflammation. When the disease is chronic, with the CK, the serum glutamic-oxaloacetic and gluta- connective tissue is increased and may react positively mate pyruvate transaminases, lactate dehydrogenase, and with alkaline phosphatase. aldolase may be elevated. In DM the endomysial inflammation is predominantly Needle EMG shows myopathic potentials character- perivascular or in the interfascicular septae and around, ized by short-duration, low-amplitude polyphasic units rather than within, the muscle fascicles (Fig. 44-4). The on voluntary activation and increased spontaneous activ- intramuscular blood vessels show endothelial hyperplasia ity with fibrillations, complex repetitive discharges, and with tubuloreticular profiles, fibrin thrombi, and oblitera- positive sharp waves. Mixed potentials (polyphasic units tion of capillaries. The muscle fibers undergo necrosis, of short and long duration) indicating a chronic process degeneration, and phagocytosis, often in groups involv- and muscle fiber regeneration are often present in IBM. ing a portion of a muscle fasciculus in a wedge-like These EMG findings are not diagnostic of an inflamma- shape or at the periphery of the fascicle, due to microin- tory myopathy but are useful to identify the presence of farcts within the muscle. This results in perifascicular active or chronic myopathy and to exclude neurogenic atrophy, characterized by 2–10 layers of atrophic fibers at disorders. the periphery of the fascicles.The presence of perifascic- ular atrophy is diagnostic of DM, even in the absence of MRI is not routinely used for the diagnosis of PM, inflammation. DM, or IBM. However, it may guide the location of the muscle biopsy in certain clinical settings. In IBM (Fig. 44-5), there is endomysial inflammation with T cells invading MHC-I-expressing nonvacuolated Muscle biopsy is the definitive test for establishing the muscle fibers; basophilic granular deposits distributed diagnosis of inflammatory myopathy and for excluding around the edge of slitlike vacuoles (rimmed vacuoles); other neuromuscular diseases. Inflammation is the histo- loss of fibers, replaced by fat and connective tissue, logic hallmark for these diseases; however, additional fea- hypertrophic fibers, and angulated or round fibers; tures are characteristic of each subtype (Figs. 44-3, 44-4, eosinophilic cytoplasmic inclusions; abnormal mito- and 44-5). chondria characterized by the presence of ragged-red fibers or cytochrome oxidase–negative fibers; amyloid In PM the inflammation is primary, a term used to deposits within or next to the vacuoles; and filamentous indicate that T cell infiltrates, located primarily within inclusions seen by electron microscopy in the vicinity of the muscle fascicles (endomysially), surround individ- the rimmed vacuoles. ual, healthy muscle fibers and result in phagocytosis and necrosis (Fig. 44-3). The MHC-I molecule is

606 SECTION III Diseases of the Central Nervous System FIGURE 44-5 amyloid visualized with crystal violet (B), cytochrome oxi- Cross sections of a muscle biopsy from a patient with dase-negative fibers, indicative of mitochondrial dysfunction inclusion body myositis demonstrate the typical features of (C), and ubiquitous MHC-I expression at the periphery of all vacuoles with lymphocytic infiltrates surrounding nonvacuo- fibers (D). lated or necrotic fibers (A), tiny endomysial deposits of Treatment: 1. Glucocorticoids. Oral prednisone is the initial treat- INFLAMMATORY MYOPATHIES ment of choice; the effectiveness and side effects of this therapy determine the future need for stronger The goal of therapy is to improve muscle strength, immunosuppressive drugs. High-dose prednisone, at thereby improving function in activities of daily living, least 1 mg/kg per day, is initiated as early in the and ameliorate the extramuscular manifestations (rash, disease as possible. After 3–4 weeks, prednisone is dysphagia, dyspnea, fever). When strength improves, the tapered slowly over a period of 10 weeks to 1 mg/kg serum CK falls concurrently; however, the reverse is not every other day. If there is evidence of efficacy and no always true. Unfortunately, there is a common tendency serious side effects, the dosage is then further to “chase” or treat the CK level instead of the muscle reduced by 5 or 10 mg every 3–4 weeks until the low- weakness, a practice that has led to prolonged and est possible dose that controls the disease is reached. unnecessary use of immunosuppressive drugs and erro- The efficacy of prednisone is determined by an neous assessment of their efficacy. It is prudent to dis- objective increase in muscle strength and activities continue these drugs if, after an adequate trial, there is of daily living, which almost always occurs by the no objective improvement in muscle strength whether third month of therapy. A feeling of increased energy or not CK levels are reduced. Agents used in the treat- or a reduction of the CK level without a concomitant ment of PM and DM include:

increase in muscle strength is not a reliable sign of 3. Immunomodulation. In a controlled trial of patients 607 improvement. If prednisone provides no objective with refractory DM, intravenous immunoglobulin benefit after ~3 months of high-dose therapy, the (IVIg) improved not only strength and rash but also CHAPTER 44 Polymyositis, Dermatomyositis, and Inclusion Body Myositis disease is probably unresponsive to the drug and the underlying immunopathology. The benefit is tapering should be accelerated while the next-in-line often short-lived (≤8 weeks); repeated infusions every immunosuppressive drug is started. Although con- 6–8 weeks are generally required to maintain trolled trials have not been performed, almost all improvement. A dose of 2 g/kg divided over 2–5 days patients with true PM or DM respond to glucocorti- per course is recommended. Uncontrolled observa- coids to some degree and for some period of time; in tions suggest that IVIg may also be beneficial for general, DM responds better than PM. patients with PM. Neither plasmapheresis nor leuka- pheresis appears to be effective in PM and DM. The long-term use of prednisone may cause increased weakness associated with a normal or The following sequential empirical approach to the unchanged CK level; this effect is referred to as steroid treatment of PM and DM is suggested: Step 1: high-dose myopathy. In a patient who previously responded to prednisone; Step 2: azathioprine, mycophenolate, or high doses of prednisone, the development of new methotrexate for steroid-sparing effect; Step 3: IVIg; weakness may be related to steroid myopathy or to Step 4: a trial, with guarded optimism, of one of the fol- disease activity that either will respond to a higher lowing agents, chosen according to the patient’s age, dose of glucocorticoids or has become glucocorti- degree of disability, tolerance, experience with the drug, coid-resistant. In uncertain cases, the prednisone and general health: rituximab, cyclosporine, cyclophos- dosage can be steadily increased or decreased as phamide, or tacrolimus. Patients with interstitial lung desired: the cause of the weakness is usually evident disease may benefit from aggressive treatment with in 2–8 weeks. cyclophosphamide or tacrolimus. 2. Other immunosuppressive drugs. Approximately 75% of patients ultimately require additional treatment. A patient with presumed PM who has not responded This occurs when a patient fails to respond ade- to any form of immunotherapy most likely has IBM quately to glucocorticoids after a 3-month trial, the or another disease, usually a metabolic myopathy, a patient becomes glucocorticoid-resistant, glucocorti- muscular dystrophy, a drug-induced myopathy, or an coid-related side effects appear, attempts to lower endocrinopathy. In these cases, a repeat muscle biopsy the prednisone dose repeatedly result in a new and a renewed search for another cause of the myopa- relapse, or rapidly progressive disease with evolving thy is indicated. severe weakness and respiratory failure develops. Calcinosis, a manifestation of DM, is difficult to treat; The following drugs are commonly used but have however, new calcium deposits may be prevented if the never been tested in controlled studies: (1) Azathio- primary disease responds to the available therapies. prine is well tolerated, has few side effects, and Bisphosphonates, aluminum hydroxide, probenecid, appears to be as effective for long-term therapy as colchicine, low doses of warfarin, calcium blockers, and other drugs. The dose is up to 3 mg/kg daily. (2) surgical excision have all been tried without success. Methotrexate has a faster onset of action than aza- thioprine. It is given orally starting at 7.5 mg weekly IBM is generally resistant to immunosuppressive ther- for the first 3 weeks (2.5 mg every 12 h for 3 doses), apies. Prednisone together with azathioprine or with gradual dose escalation by 2.5 mg per week to methotrexate is often tried for a few months in newly a total of 25 mg weekly. A rare side effect is diagnosed patients, although results are generally disap- methotrexate pneumonitis, which can be difficult to pointing. Because occasional patients may feel subjec- distinguish from the interstitial lung disease of the tively weaker after these drugs are discontinued, some primary myopathy associated with Jo-1 antibodies clinicians prefer to maintain some patients on low-dose, (described above). (3) Mycophenolate mofetil also has every-other-day prednisone or weekly methotrexate in a faster onset of action than azathioprine. At doses an effort to slow disease progression, even though there up to 2.5 mg/d, it is well tolerated and appears is no objective evidence or controlled study to support promising for long-term use. (4) Monoclonal anti- this practice. In two controlled studies of IVIg in IBM, mini- CD20 (rituximab) has been shown in a small uncon- mal benefit in up to 30% of patients was found; the trolled series to benefit patients with DM. (5) strength gains, however, were not of sufficient magnitude Cyclosporine has inconsistent and mild benefit. (6) to justify its routine use. Another trial of IVIg combined Cyclophosphamide (0.5–1 g IV monthly for 6 months) with prednisone was ineffective. Nonetheless, many has limited success and significant toxicity. (7) experts believe that a 2- to 3-month trial with IVIg may be Tacrolimus (formerly known as FK506) has been reasonable for selected patients with IBM who experi- effective in some difficult cases of PM. ence rapid progression of muscle weakness or choking episodes due to worsening dysphagia.

608 PROGNOSIS FURTHER READINGS The 5-year survival rate for treated patients with PM AMATO AA, BAROHN RJ: Evaluation and treatment of inflammatory and DM is ~95% and the 10-year survival 84%; death is myopathies. J Neurol Neurosurg Psychiatry 80:1060, 2009 usually due to pulmonary, cardiac, or other systemic complications. Patients severely affected at presentation ASKANAS V et al: Inclusion-body myositis: Clinical and pathologic or treated after long delays, those with severe dysphagia aspects, and basic research potentially relevant to treatment. or respiratory difficulties, older patients, and those with Neurology 24:66(Suppl 1), 2006 associated cancer have a worse prognosis. DM responds more favorably to therapy than PM and thus has a better DALAKAS MC: Signaling pathways and immunobiology of inflamma- prognosis. Most patients improve with therapy, and tory myopathies. Nat Clin Pract Rheumatol 2:219, 2006 many make a full functional recovery, which is often sustained with maintenance therapy. Up to 30% may be ENGEL AG, HOHLFELD R: The polymyositis and dermatomyositis left with some residual muscle weakness. Relapses may syndromes, in Myology, 3d ed, AG Engel, C Franzini-Armstrong occur at any time. (eds). New York, McGraw-Hill, 2004, pp 1321–1366 IBM has the least favorable prognosis of the inflamma- GREENBERG SA: Inflammatory myopathies: Evaluation and manage- tory myopathies. Most patients will require the use of an ment. Semin Neurol 28:241, 2008 assistive device such as a cane, walker, or wheelchair within 5–10 years of onset. In general, the older the age of onset KARPATI G, O’FERRALL EK: Sporadic inclusion body myositis: path- in IBM, the more rapidly progressive is the course. ogenic considerations.Ann Neurol 65:7, 2009 MIKOL J, ENGEL AG: Inclusion body myositis, in: Myology, 3d ed, AG Engel, C Franzini-Armstrong (eds). New York, McGraw-Hill, 2004, pp 1367–1388 SECTION III Diseases of the Central Nervous System

CHAPTER 45 SPECIAL ISSUES IN INPATIENT NEUROLOGIC CONSULTATION Scott Andrew Josephson I Martin A. Samuels I Consultations Regarding Central Nervous Magnesium Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . 614 System Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 I Consultations Regarding Peripheral Nervous Hyperperfusion States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 System Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614 Post-Cardiac Bypass Brain Injury . . . . . . . . . . . . . . . . . . . . . 611 Entrapment Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . 614 Post-Solid Organ Transplant Brain Injury . . . . . . . . . . . . . . . . 612 I Radial Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614 I Common Neurologic Complications of Electrolyte I Ulnar Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614 I Peroneal Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614 Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612 Proximal Femoral Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . 615 Hypernatremia and Hyperosmolality . . . . . . . . . . . . . . . . . . . 612 I Lateral Femoral Cutaneous Nerve . . . . . . . . . . . . . . . . . . . . . 615 Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 Obstetric Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616 Hypokalemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616 Hyperkalemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 Calcium Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 Inpatient neurologic consultations usually involve ques- should allow for clinical recovery if superimposed hemor- tions about specific disease processes or prognostication rhage or infarction has not occurred. after various cerebral injuries. Common reasons for neu- rologic consultation include stroke (Chap. 21), seizures The brain’s autoregulatory capability successfully (Chap. 20), altered mental status (Chap. 13), headache maintains a fairly stable cerebral blood flow in adults (Chap. 6), and management of coma and other critical despite alterations in systemic mean arterial pressure conditions (Chaps. 14 and 22). This chapter focuses on (MAP) ranging from 50–150 mm Hg. In patients with additional common reasons for consultation that are not chronic hypertension, this cerebral autoregulation curve addressed elsewhere in the text. is shifted, resulting in autoregulation working over a much higher range of pressures (e.g., 70–175 mmHg). CONSULTATIONS REGARDING CENTRAL In these hypertensive patients, cerebral blood flow is NERVOUS SYSTEM DYSFUNCTION kept steady at higher MAP, but a rapid lowering of pressure can more easily lead to ischemia on the lower HYPERPERFUSION STATES end of the autoregulatory curve. This autoregulatory phenomenon is achieved through both myogenic and A group of neurologic disorders shares the common fea- neurogenic influences causing small arterioles to con- ture of hyperperfusion playing a key role in pathogenesis. tract and dilate. When the systemic blood pressure These seemingly diverse syndromes include hypertensive exceeds the limits of this mechanism, breakthrough of encephalopathy, eclampsia, post-carotid endarterectomy autoregulation occurs, resulting in hyperperfusion via syndrome, and toxicity from calcineurin-inhibitor med- increased cerebral blood flow, capillary leakage into the ications. Modern imaging techniques and experimental interstitium, and resulting edema.The predilection of all models suggest that vasogenic edema is usually the pri- of the hyperperfusion disorders to affect the posterior mary process leading to neurologic dysfunction; therefore rather than anterior portions of the brain may be due prompt recognition and management of this condition to a lower threshold for autoregulatory breakthrough in the posterior circulation. 609

SECTION III Diseases of the Central Nervous System610 TABLE 45-1 FIGURE 45-1 Axial fluid-attenuated inversion recovery (FLAIR) MRI of SOME COMMON ETIOLOGIES OF HYPERPERFUSION the brain in a patient taking cyclosporine after liver trans- SYNDROME plantation who presented with seizures, headache, and corti- cal blindness. Increased signal is seen bilaterally in the Disorders in which increased capillary pressure dominates occipital lobes predominantly involving the white matter, con- the pathophysiology sistent with a hyperperfusion state secondary to calcineurin- Hypertensive encephalopathy, including secondary inhibitor exposure. causes such as renovascular hypertension, pheochromocytoma, cocaine use, etc. reveal a systemic blood pressure that is increased above Post-carotid endarterectomy syndrome baseline. It appears as if the rapidity of rise rather than Preeclampsia/eclampsia the absolute value of pressure is the most important risk High-altitude cerebral edema factor. Disorders in which endothelial dysfunction dominates the The diagnosis in all of these conditions is clinical. pathophysiology The symptoms of these disorders are common and Calcineurin-inhibitor toxicity nonspecific, so a long differential diagnosis should be Chemotherapeutic agent toxicity (e.g., cytarabine, entertained, including consideration of other causes of azathioprine, 5-fluorouracil, cisplatin, methotrexate) confusion, focal deficits, headache, and seizures. MRI Glucocorticoids has improved the ability of clinicians to diagnose hyper- Erythropoietin perfusion syndromes, although cases have been reported HELLP syndrome (hemolysis, elevated liver enzyme with normal imaging. Patients classically exhibit the levels, low platelet count) high T2 signal of edema primarily in the posterior Thrombotic thrombocytopenic purpura (TTP) occipital lobes, not respecting any single vascular terri- Hemolytic uremic syndrome (HUS) tory (Fig. 45-1). Diffusion-weighted images are typically Systemic lupus erythematosus (SLE) normal, emphasizing the vasogenic rather than cytotoxic Wegener’s granulomatosis nature of this edema. Imaging with CT is less sensitive but may show a pattern of patchy hypodensity in the Although elevated or relatively elevated blood pressure involved territory. Previously this classic radiographic is common in many of these disorders, some hyperperfu- appearance had been termed reversible posterior leukoen- sion states such as calcineurin-inhibitor toxicity occur cephalopathy (RPLE). However, this term has fallen out of with no apparent pressure rise. In these cases, vasogenic favor because none of its elements are completely accu- edema is likely due primarily to dysfunction of the capil- rate: the radiographic and clinical changes are not always lary endothelium itself, leading to breakdown of the reversible, the territory involved is not uniquely poste- blood-brain barrier. It is useful to separate disorders of rior, and gray matter may be affected as well, rather than hyperperfusion into those caused primarily by increased purely white matter as the word “leukoencephalopathy” pressure and those due mostly to endothelial dysfunction intimates. Other ancillary studies such as cerebrospinal from a toxic or autoimmune etiology (Table 45-1). In fluid (CSF) analysis often yield nonspecific results. It reality, both of these pathophysiologic processes are likely should be noted that many of the substances that have playing some role in each of these disorders. been implicated, such as cyclosporine, can cause this syndrome even at low doses or after years of treatment. The clinical presentation of the hyperperfusion syn- Therefore, normal serum levels of these medications do dromes is similar, with prominent headaches, seizures, or not exclude them as inciting agents. focal 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 mul- tiple 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 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 in the ipsilateral newly reperfused hemisphere. In conditions where increased cerebral blood flow plays a role, exami- nation of the inpatient vital signs record will usually

In cases of hyperperfusion syndromes, treatment should 611CHAPTER 45 Special Issues in Inpatient Neurologic Consultation commence urgently once the diagnosis is considered. Hypertension plays a key role commonly, and judicious FIGURE 45-2 lowering of the blood pressure with IV agents such as Coronal fluid-attenuated inversion recovery (FLAIR) MRI labetolol or nicardipine is advised along with continuous of the brain in a patient presenting with altered mental cardiac and blood pressure monitoring, often through an status after an episode of hypotension during coronary arterial line. It is reasonable to lower mean arterial pres- artery bypass grafting (CABG). Increased signal is seen in the sure by ~20% initially, as further lowering of the pressure border zones bilaterally between the middle cerebral artery may cause secondary ischemia as pressure drops below the and anterior cerebral artery territories. Diffusion-weighted lower range of the patient’s autoregulatory capability. In MRI sequences demonstrated restricted diffusion in these cases where there is an identified cause of the syndrome, same locations, suggesting acute infarction. these etiologies should be treated promptly, including discontinuation of offending substances such as calcineurin cerebral circulation. Cross-clamping of the aorta, manipu- inhibitors in toxic processes, treatment of immune-mediated lation of the heart, extracorporeal circulation techniques disorders such as thrombotic thrombocytopenic purpura (“bypass”), arrhythmias such as atrial fibrillation, and (TTP), and prompt delivery of the fetus in eclampsia. introduction of air through suctioning have all been Seizures must be identified and controlled, often neces- implicated as potential sources of emboli. Histologic stud- sitating continuous EEG monitoring. Anticonvulsants are ies indicate that literally millions of tiny emboli may be effective, but in the special case of eclampsia, there is good released, even using modern surgical techniques. evidence to support the use of magnesium sulfate for seizure control. This shower of microemboli results in a number of clinical syndromes. Occasionally, a single large embolus POST-CARDIAC BYPASS BRAIN INJURY leads to an isolated large-vessel stroke that presents with obvious clinical focal deficits. More commonly, the Central nervous system (CNS) injuries following open emboli released are multiple and smaller.When there is a heart or coronary artery bypass grafting (CABG) surgery high burden of these small emboli, an acute encephalopa- are common and include acute encephalopathy, stroke, and thy can occur postoperatively, presenting as either a a chronic syndrome of cognitive impairment, which is hyperactive or hypoactive confusional state, the latter of now increasingly recognized. Hypoperfusion and embolic which is frequently and incorrectly ascribed to depres- disease are frequently involved in the pathogenesis of sion.When the burden of microemboli is lower, no acute these syndromes, although multiple mechanisms may be syndrome is recognized, but the patient may suffer a involved in these critically ill patients who are at risk for chronic cognitive deficit. Cardiac surgery can be viewed, various metabolic and polypharmaceutical complications. like delirium, as a “stress test for the brain.” Some patients with a low cerebral reserve due to underlying cerebrovas- The frequency of hypoxic injury secondary to inade- cular disease or an early neurodegenerative process will quate blood flow intraoperatively has been markedly develop a chronic, cognitive deficit, whereas others with decreased by the use of modern surgical and anesthetic higher reserves may remain asymptomatic despite a simi- techniques. Despite these advances, some patients still lar dose of microemboli. In this manner, cardiac surgery experience neurologic complications from cerebral may serve to unmask the early manifestations of disorders hypoperfusion or may suffer focal ischemia from tight such as vascular dementia and Alzheimer’s disease. carotid or focal intracranial stenoses in the setting of regional hypoperfusion. Postoperative infarcts in the bor- Since modern techniques have successfully mini- der zones between vascular territories commonly are mized hypoperfusion complications during these surg- blamed on systemic hypotension although some have eries, much attention is now focused on reducing this suggested that these infarcts can also result from embolic inevitable shower of microemboli. Off-pump CABG disease (Fig. 45-2). surgeries have the advantages of reducing length of stay and perioperative complications; however, some recent Embolic disease is likely the predominant mecha- nism of cerebral injury during cardiac surgery as evi- denced by diffusion-weighted MRI and intraoperative transcranial Doppler studies. It should be noted that some of the emboli that are found histologically in these patients are too small to be detected by standard imaging sequences; therefore, a negative MRI after surgery does not exclude the diagnosis of emboli-related complica- tions.Thrombus in the heart itself as well as atheromas in the aortic arch can become dislodged during cardiac surgeries, releasing a shower of particulate matter into the

SECTION III Diseases of the Central Nervous System612 data suggest that off-pump CABG does not preserve providing yet another mechanism for stroke. Imaging cognitive function compared with on-pump CABG. Fil- with CT or MRI with diffusion is advised when cere- ters placed in the aortic arch may have some promise in brovascular complications are suspected to confirm the capturing these emboli, although convincing evidence is diagnosis and to exclude intracerebral hemorrhage, which currently lacking. Development of successful endovascu- most often occurs in the setting of coagulopathy sec- lar operative approaches may provide a reasonable alter- ondary to liver failure or after cardiac bypass procedures. native to conventional CABG procedures, especially for patients at high risk of developing cognitive dysfunction Because patients with solid organ transplants are chron- after surgery due to advanced age, previous stroke, or ically immunosuppressed, infections are a common con- severe atheromatous disease of the carotid arteries or cern. In any transplant patient with new CNS signs or aortic arch. symptoms such as seizure, confusion, or focal deficit, the diagnosis of a nervous system infection should be consid- POST-SOLID ORGAN TRANSPLANT ered and evaluated through imaging (usually MRI) and BRAIN INJURY possibly lumbar puncture. The most common pathogens responsible for CNS infections in these patients vary based Patients who have undergone solid organ transplantation on time since transplant. In the first month posttransplant, are at risk for neurologic injury in the postoperative common pathogens include the usual bacterial organisms period and for the months to years thereafter. Neuro- associated with surgical procedures and indwelling logic consultants should view these patients as a special catheters. Starting in the second month posttransplant, population at risk for both unique neurologic complica- opportunistic infections of the CNS become more com- tions as well as for the usual disorders found in any criti- mon, including Nocardia and Toxoplasma species as well as cally ill inpatient. fungal infections such as aspergillosis.Viral infections that can affect the brain of the immunosuppressed patient, such Immunosuppressive medications are administered in as herpes simplex virus, cytomegalovirus, and varicella, also high doses to patients after solid organ transplant, and become more common after the first month posttrans- many of these compounds have well-described neuro- plant. After 6 months posttransplant, immunosuppressed logic complications. In patients with headache, seizures, patients still remain at risk for these opportunistic bacter- or focal neurologic deficits taking calcineurin inhibitors, ial, fungal, and viral infections but can also suffer late CNS the diagnosis of hyperperfusion syndrome should be infectious complications such as progressive multifocal considered, as discussed above.This neurotoxicity occurs leukoencephalopathy (PML) associated with JC virus and mainly with cyclosporine and tacrolimus and can pre- Epstein-Barr virus–driven clonal expansions of B cells sent even in the setting of normal serum drug levels. resulting in CNS lymphoma. Treatment primarily involves lowering the drug dosage or discontinuing the drug. A related newer agent, COMMON NEUROLOGIC sirolimus, has very few recorded cases of neurotoxicity COMPLICATIONS OF and may be a reasonable alternative for some patients. ELECTROLYTE DISTURBANCES Other examples of immunosuppressive medications and their neurologic complications include OKT3-associated A wide variety of neurologic conditions can result from akinetic mutism and the leukoencephalopathy seen with abnormalities in serum electrolytes, and consideration of methotrexate, especially when it is administered intrathe- electrolyte disturbances should be part of any inpatient cally or with concurrent radiotherapy. In any solid organ neurologic consultation. transplant patient with neurologic complaints, a careful examination of the medication list is required to search HYPERNATREMIA AND HYPEROSMOLALITY for these possible drug effects. The normal range of serum osmolality is around Cerebrovascular complications of solid organ transplant 275–295 mOsm/kg, but neurologic manifestations are are often first recognized in the immediate postoperative usually seen only at levels >325 mOsm/kg. Hyperosmo- period. Border zone territory infarctions can occur, espe- lality is usually due to hypernatremia, hyperglycemia, cially in the setting of systemic hypotension during car- azotemia, or the addition of extrinsic osmoles such as diac transplant surgery. Embolic infarctions classically mannitol, which is commonly used in critically ill neuro- complicate cardiac transplantation, but all solid organ logic patients. Hyperosmolality itself can lead to a gener- transplant procedures place patients at risk for systemic alized encephalopathy that is nonspecific and without emboli. When cerebral embolization accompanies renal focal findings; however, an underlying lesion such as a or liver transplantation surgery, a careful search for right- mass can become symptomatic under the metabolic stress to-left shunting should include evaluation of the heart of a hyperosmolar state, producing focal signs. Some with agitated saline echocardiography, as well as looking patients with hyperosmolality from severe hyperglycemia for intrapulmonary shunting. Renal and some cardiac transplant patients often have advanced atherosclerosis,

can present, for unclear reasons, with generalized seizures or congestive heart failure. Finally, in hypovolemic hypotonic 613CHAPTER 45 Special Issues in Inpatient Neurologic Consultation unilateral movement disorders, which usually respond to hyponatremia, volume is replaced with isotonic saline lowering of the serum glucose.The treatment of all forms of while underlying conditions of the kidneys, adrenals, and hyperosmolality involves calculation of apparent water losses gastrointestinal tract are addressed. and slow replacement so that the serum sodium declines no faster than 2 mmol/L (2 meq/L) per hour. One neurologic cause of hypovolemic hypotonic hyponatremia is the cerebral salt-wasting syndrome that Hypernatremia leads to the loss of intracellular water, accompanies subarachnoid hemorrhage and, less com- leading to cell shrinkage. In the cells of the brain, solutes monly, other cerebral processes such as meningitis or such as glutamine and urea are generated under these stroke. In these cases, the degree of renal sodium excre- conditions in order to minimize this shrinkage. Despite tion can be remarkable, and large amounts of saline, this corrective mechanism, when hypernatremia is hypertonic saline, or oral sodium may need to be given severe [serum sodium >160 mmol/L (>160 meq/L)] or in a judicious fashion in order to avoid complications occurs rapidly, cellular metabolic processes fail and from cerebral edema. encephalopathy will result. There are many etiologies of hypernatremia including, most commonly, renal and HYPOKALEMIA extrarenal losses of water. Causes of neurologic relevance include central diabetes insipidus, where hyperosmolality Hypokalemia, defined as a serum potassium level is accompanied by submaximal urinary concentration <3.5 mmol/L (<3.5 meq/L), occurs either because of due to inadequate release of antidiuretic hormone excessive potassium losses (from the kidneys or gut) or (ADH) from the posterior pituitary, resulting often from due to an abnormal potassium distribution between the pituitary injury in the setting of surgery, hemorrhage, intracellular and extracellular spaces. At very low levels infiltrative processes, or cerebral herniation. (<1.5 mmol/L), hypokalemia may be life threatening due to the risk of cardiac arrhythmia and may present HYPONATREMIA neurologically with severe muscle weakness and paraly- sis. Hypokalemic periodic paralysis is a rare disorder Hyponatremia is commonly defined as a serum sodium caused by excessive intracellular potassium uptake in the <135 mmol/L (<135 meq/L). Neurologic symptoms setting of a calcium or sodium channel mutation. Treat- occur at different levels of low sodium, depending not ment of hypokalemia is dependent on the etiology but only on the absolute value but also on the rate of fall. In usually includes replacement of potassium through oral patients with hyponatremia that develops over hours, or IV routes as well as correcting the cause of potassium life-threatening seizures and cerebral edema may occur at balance problems (e.g., eliminating β2-adrenergic agonist values as high as 125 mmol/L. In contrast, some patients medications). with more chronic hyponatremia that has slowly devel- oped over months to years may be asymptomatic even HYPERKALEMIA with serum levels <110 mmol/L. Correction of hypona- tremia, especially when chronic, must take place slowly Hyperkalemia is defined as a serum potassium level in order to avoid additional neurologic complications. >5.5 mmol/L (>5.5 meq/L) and can neurologically Cells in the brain swell in hypotonic hyponatremic states present as muscle weakness with or without paresthesias. but may compensate over time by excreting solute into Hyperkalemia becomes life threatening when it produces the extracellular space, leading to restoration of cell vol- electrocardiographic abnormalities such as peaked T ume when water follows the solute out of the cells. If waves or a widened QRS complex. In these cases, prompt treatment of hyponatremia results in a rapid rise in serum treatment is essential and consists of strategies that protect sodium, cells in the brain may quickly shrink, leading the heart against arrhythmias (calcium gluconate adminis- to osmotic demyelination, a process that previously tration), promote potassium redistribution into cells (with was thought to be limited exclusively to the brainstem glucose, insulin, and β2-agonist medications), and increase (central pontine myelinolysis; see Fig. 22-6), but now has potassium removal (through sodium polystyrene sul- been described elsewhere in the CNS. fonate, loop diuretics, or hemodialysis). Treatment of hyponatremia is dependent on the cause. CALCIUM DISTURBANCES Hypertonic hyponatremia treatment focuses on the underlying condition, such as hyperglycemia. Isovolemic Hypercalcemia usually occurs in the setting of either hyponatremia (syndrome of inappropriate antidiuretic hyperparathyroidism or systemic malignancy. Neurologic hormone, SIADH) is managed with water restriction or manifestations include encephalopathy as well as muscle administration of ADH antagonists. The management of weakness due to reduced neuromuscular excitability. choice for patients with hypervolemic hypotonic hypona- Seizures can occur but are more common in states of tremia is free-water restriction and treatment of the under- low calcium. lying edematous disorder, such as nephrotic syndrome or

SECTION III Diseases of the Central Nervous System614 Hypocalcemia in adults often follows surgical treat- brachioradialis, and supinator muscles in addition to wrist ment of the thyroid or parathyroid. Seizures and altered drop. A more common site of compression occurs in the mental status dominate the neurologic picture and usu- spiral groove of the upper arm in the setting of a humerus ally resolve with calcium repletion. Tetany is due to fracture or from sleeping with the arm draped over a spontaneous, repetitive action potentials in peripheral bench or chair (“Saturday night palsy”). Sparing of the nerves and remains the classic sign of symptomatic triceps is the rule when the nerve is injured in this loca- hypocalcemia. tion. Because extensors of the upper extremity are injured preferentially in radial nerve injury, these lesions may be MAGNESIUM DISTURBANCES mistaken for the pyramidal distribution of weakness that accompanies upper motor neuron lesions from brain or Disorders of magnesium are difficult to correlate with spinal cord processes. serum levels because a very small amount of total-body magnesium is located in the extracellular space. Hypo- ULNAR NEUROPATHY magnesemia presents neurologically with seizures, tremor, and myoclonus. When intractable seizures occur Compression of the ulnar nerve is the second most in the setting of hypomagnesemia, only administration common entrapment neuropathy after carpal tunnel of magnesium will lead to resolution. High levels of syndrome. The most frequent site of compression is at magnesium, in contrast, lead to CNS depression. Hyper- the elbow where the nerve passes superficially in the magnesemia usually occurs only in the setting of renal ulnar groove. Symptoms usually begin with tingling in failure and can lead to confusion and muscular paralysis the ulnar distribution, including the fourth and fifth when severe. digits of the hand (Fig. 45-3B). Sensory symptoms may be worsened by elbow flexion due to increased pressure CONSULTATIONS REGARDING on the nerve, hence the tendency of patients to com- PERIPHERAL NERVOUS SYSTEM plain of increasing paresthesias at night when the arm is DYSFUNCTION flexed at the elbow during sleep. Motor dysfunction can be disabling and involves most of the intrinsic hand ENTRAPMENT NEUROPATHIES muscles, limiting dexterity and strength of grasp and pinch. Etiologies of ulnar entrapment include trauma to Polyneuropathy is a common cause of outpatient neuro- the nerve (hitting the “funny bone”), malpositioning logic consultation (Chap. 40). In the inpatient setting, during anesthesia for surgical procedures, and chronic however, mononeuropathies are more frequent, especially arthritis of the elbow. When a perioperative ulnar nerve the entrapment neuropathies that complicate many surgical injury is considered, stretch injury or trauma to the procedures and medical conditions. Median neuropathy lower trunk of the brachial plexus should be entertained at the wrist (carpal tunnel syndrome) is the most frequent as well since its symptoms can mimic those of an ulnar entrapment neuropathy by far, but it is rarely a cause neuropathy. If the clinical examination is equivocal, elec- for inpatient consultation. Mechanisms for perioperative trodiagnostic studies can definitively distinguish between mononeuropathy include traction, compression, and plexus and ulnar nerve lesions a few weeks after the ischemia of the nerve. Imaging with MR neurography injury. Conservative methods of treatment are often the may allow these causes to be distinguished definitively. In first step, but a variety of surgical approaches may be all cases of mononeuropathy, the diagnosis can be made effective, including anterior ulnar nerve transposition through the clinical examination and then confirmed and release of the flexor carpi ulnaris aponeurosis. with electrodiagnostic studies in the subacute period, if necessary. Treatment consists mainly of avoidance of PERONEAL NEUROPATHY repetitive trauma but may also include surgical approaches to relieve pressure on the nerve. The peroneal nerve winds around the head of the fibula in the leg below the lateral aspect of the knee, and its RADIAL NEUROPATHY superficial location at this site makes it vulnerable to trauma. Patients present with weakness of foot dorsiflex- Radial nerve injury classically presents with weakness of ion (“foot drop”) as well as with weakness in eversion extension of the wrist and fingers (“wrist drop”) with but not inversion at the ankle. Sparing of inversion, or without more proximal weakness of extensor muscles which is a function of muscles innervated by the tibial of the upper extremity, depending on the site of injury. nerve, helps to distinguish peroneal neuropathies from L5 Sensory loss is in the distribution of the radial nerve, radiculopathies. Sensory loss involves the lateral aspect of which includes the dorsum of the hand (Fig. 45-3A). the leg as well as the dorsum of the foot (Fig. 45-3C). Compression at the level of the axilla, e.g., resulting Fractures of the fibular head may be responsible for from use of crutches, includes weakness of the triceps,

Radial nerve Ulnar nerve Peroneal nerve 615 Sensory distribution of the radial nerve Sensory distribution of Deep peroneal the peroneal nerve nerve Lateral cutaneous nerve of arm Sensory distribution of the ulnar nerve Lateral cutaneous nerve of calf Posterior cutaneous nerve of arm Superficial peroneal nerve Posterior cutaneous nerve of forearm Superficial branch A B C Sensory distribution Anterior femoral Lateral femoral of the femoral nerve cutaneous nerve cutaneous nerve Medial femoral CHAPTER 45 Special Issues in Inpatient Neurologic Consultation cutaneous nerve Saphenous nerve DE B. Ulnar nerve. C. Peroneal nerve. D. Femoral nerve. E. Lat- eral femoral cutaneous nerve. FIGURE 45-3 Sensory distribution of peripheral nerves commonly affected by entrapment neuropathies. A. Radial nerve. peroneal neuropathies, but in the perioperative setting these conditions. Bleeding into the pelvis resulting in poorly applied braces exerting pressure on the nerve hematoma can occur spontaneously, following trauma, or while the patient is unconscious are more often responsi- after intrapelvic surgeries such as renal transplantation. In ble. Tight-fitting stockings or casts of the upper leg can intoxicated or comatose patients, stretch injuries to the also cause a peroneal neuropathy, and thin individuals femoral nerve are seen following prolonged, extreme hip and those with recent weight loss are at increased risk. flexion or extension. Rarely, attempts at femoral vein or arterial puncture can be complicated by injury to this PROXIMAL FEMORAL NEUROPATHY nerve. Lesions of the proximal femoral nerve are relatively LATERAL FEMORAL CUTANEOUS uncommon but may present dramatically with weakness NERVE of hip flexion, quadriceps atrophy, weakness of knee extension (often manifesting with leg-buckling falls), and The symptoms of lateral femoral cutaneous nerve an absent patellar reflex. Adduction of the thigh is spared entrapment, commonly known as “meralgia paresthetica,” as these muscles are supplied by the obturator nerve, include sensory loss, pain, and dysesthesia in part of the thereby distinguishing a femoral neuropathy from a more area supplied by the nerve (Fig. 45-3E). There is no proximal lumbosacral plexus lesion. The sensory loss motor component to the nerve, and therefore weakness found is in the distribution of the femoral nerve sensory is not a part of this syndrome. Symptoms often are branches on the anterior part of the thigh (Fig. 45-3D). worsened by standing or walking. Compression of the Compressive lesions from retroperitoneal hematomas or nerve occurs where it enters the leg near the inguinal masses are common, and a CT of the pelvis should be ligament, usually in the setting of tight-fitting belts, obtained in all cases of femoral neuropathy to exclude

SECTION III Diseases of the Central Nervous System616 pants, corsets, or recent weight gain, including that of lithotomy positioning. The latter presents with medial pregnancy. The differential diagnosis of these symptoms thigh pain that may be accompanied by weakness of thigh includes hip problems such as trochanteric bursitis. adduction.There is also a clear association between preg- nancy and an increased frequency of idiopathic facial OBSTETRIC NEUROPATHIES palsy (Bell’s palsy). Pregnancy and delivery place women at special risk for a FURTHER READINGS variety of nerve injuries. Radiculopathy due to a herni- ated lumbar disc is not common during pregnancy, but BARYYNSKI WS: Posterior reversible encephalopathy syndrome, part 1: compressive injuries of the lumbosacral plexus do occur fundamental imaging and clinical features. AJNR 29:1036, 2008 secondary to either the fetal head passing through the pelvis or the use of forceps during delivery. These plexus JILLAPALLI D, SHEFNER JM: Electrodiagnosis in common mononeu- injuries are more frequent with cephalopelvic dispropor- ropathies and plexopathies. Semin Neurol 25:196, 2005 tion and often present with a painless unilateral foot drop which must be distinguished from a peroneal neuropathy KARNAD DR, GUNTUPALLI KK: Neurologic disorders in pregnancy. caused by pressure on the nerve while in lithotomy Crit Care Med 33:S362, 2005 position during delivery. Other compressive mononeu- ropathies of pregnancy include meralgia paresthetica, KUMAR S et al: Central pontine myelinolysis, an update. Neurol Res carpal tunnel syndrome, femoral neuropathy when the 28:360, 2006 thigh is abducted severely in an effort to facilitate delivery of the fetal shoulder, and obturator neuropathy during SELNES OA et al: Cognition 6 years after surgical or medical therapy for coronary artery disease.Ann Neurol 63:581, 2008 SENZOLO M et al: Neurologic complications after solid organ trans- plantation.Transpl Int 22:269, 2009 VAN DIJK D et al: Cognitive and cardiac outcomes 5 years after off- pump vs. on-pump coronary artery bypass graft surgery. JAMA 297;701, 2007

CHAPTER 46 ATLAS OF NEUROIMAGING Andre Furtado I William P. Dillon FIGURE 46-1 Limbic encephalitis (Chap. 39) Coronal (A, B), axial FLAIR (C, D), and axial T2-weighted (E ) MR images demonstrate abnormal high signal involving the bilateral mesial temporal lobes (arrowheads) including the hippocampi (left greater than right) without significant mass effect (arrows). There was no enhancement on post-gadolinium images (not shown). 617

SECTION III Diseases of the Central Nervous System618 FIGURE 46-1 (Continued) FIGURE 46-2 Axial T1-weighted MR images post-gadolinium (B, C) demon- CNS tuberculosis (Chap. 35) strate ring enhancement of the lesions (arrows) and additional Axial T2-weighted MRI (A) demonstrates multiple lesions lesions in the subarachnoid space (arrowheads). (arrows) with peripheral high signal and central low signal, located predominantly in the cortex and subcortical white matter, as well as in the basal ganglia.

619 FIGURE 46-2 (Continued) Sagittal T1-weighted MR image post-gadolinium of the cervi- CHAPTER 46 Atlas of Neuroimaging Sagittal T2-weighted MR image of the cervical spine (D) cal spine (E ) demonstrates enhancement of the lesion in the demonstrates a hypointense lesion in the subarachnoid space subarachnoid space at the level of T5 (arrow). at the level of T5 (arrow). FIGURE 46-3 and in a wedge-shaped distribution in the right parietal lobe Neurosyphilis (Chap. 35) (arrows). Case I Axial T2-weighted MR images (A, B) demonstrate well-defined areas of abnormal high signal in the basal ganglia bilaterally

SECTION III Diseases of the Central Nervous System620 FIGURE 46-3 (Continued) Axial (C, D) T1-weighted images post-gadiolinium. Coronal (E, F ) T1-weighted images post-gadolinium demonstrate irregular ring enhancement of the lesions (arrows).

621CHAPTER 46 Atlas of Neuroimaging FIGURE 46-4 Neurosyphilis (Chap. 35) Case II Axial T2-weighted MRI (A) demonstrates a dural-based, peripherally hyperintense and centrally hypointense lesion located lateral to the left frontal lobe (arrows). Axial (B) and coronal (C) T1-weighted MR images post- gadolinium demonstrate peripheral enhancement of the lesion (arrows).

SECTION III Diseases of the Central Nervous System622 FIGURE 46-5 Histoplasmosis of the pons Axial FLAIR (A) and T2- weighted (B) MR images demonstrate a low signal mass in the right pons (arrows) with surrounding vasogenic edema. Axial T1-weighted MR image post-gadolinium (C) demon- strates ring enhancement of the lesion in the right pons (arrows). Of note, there was no evidence of restricted diffusion (not shown).

623CHAPTER 46 Atlas of Neuroimaging FIGURE 46-6 Coccidiomycosis meningitis (Chap. 36) Axial post-contrast CT (A) and axial (B) and coronal (C) T1-weighted MR images post-gadolinium demonstrate enhancement of the perimesencephalic cisterns (arrows), as well as the sylvian and interhemispheric fissures.

624 SECTION III Diseases of the Central Nervous System FIGURE 46-7 ADC map (D, E) demonstrates restricted diffusion of water Candidiasis in a newborn Axial T2-weighted MR image (A) molecules in the lesions (arrowheads). demonstrates multiple punctate foci of low signal diffusely distributed in the brain parenchyma (arrowheads). Axial T1-weighted MR images post-gadolinium (B, C) demon- strate marked enhancement of the lesions (arrowheads).

625 CHAPTER 46 Atlas of Neuroimaging FIGURE 46-8 Axial T2-weighted MR images (C, D) demonstrate intrinsic low CNS aspergillosis (Chap. 36) signal in the lesions (arrows), suggesting the presence of Axial FLAIR MR images (A, B) demonstrate multiple areas of blood products. Some of the lesions also show vasogenic abnormal high signal in the basal ganglia as well as cortex edema. and subcortical white matter (arrows). There is also abnormal high signal in the subarachnoid space adjacent to the lesions (arrowhead) that can correspond to blood or high protein content.

SECTION III Diseases of the Central Nervous System626 FIGURE 46-8 (Continued) Coronal (E ) and axial (F ) T1-weighted MR images post- gadolinium demonstrate peripheral enhancement of the lesions (arrows). FIGURE 46-9 B. T1-weighted image pre-gadolinium demonstrates enhance- Invasive sinonasal aspergillosis Axial T2-weighted MR image ment of lesion (arrow). (A) demonstrates an irregularly shaped low signal lesion involving the left orbital apex (arrow).

627CHAPTER 46 Atlas of Neuroimaging FIGURE 46-9 (Continued) C. T1-weighted image post-gadolinium demonstrates enhance- ment of lesion (arrow). FIGURE 46-10 Behçet’s disease Axial FLAIR MRI demonstrates abnormal high signal involving the anterior pons (arrow); following gadolinium administration, the lesion was nonenhancing (not shown). Brainstem lesions are typical of Behçet’s disease, caused primarily by vasculitis and in some cases demyelinat- ing lesions.

SECTION III Diseases of the Central Nervous System628 FIGURE 46-11 Neurosarcoid Case I Axial (A) and coronal (B) T1-weighted images post-gadolinium with fat suppression demonstrate a homogeneously enhancing well circumscribed mass centered in the left Meckel’s cave (arrows). FIGURE 46-12 Neurosarcoid Case II Axial (A, B) and sagittal (C) T1-weighted images post-gadolinium with fat suppression demonstrate a homogeneously enhanc- ing mass involving the hypothalamus and the pituitary stalk (arrows).

629CHAPTER 46 Atlas of Neuroimaging FIGURE 46-13 Neurosarcoid Case III Axial FLAIR images (A–E) demonstrate abnormal high signal and slight expansion in the midbrain, dorsal pons, and pineal region (arrows) without significant mass effect.

SECTION III Diseases of the Central Nervous System630 FIGURE 46-13 (Continued) Sagittal T1-weighted images post-gadolinium (F) with fat suppression demonstrate abnormal enhancement in the mid- brain, dorsal pons, and pineal region (arrows). FIGURE 46-14 internal capsule and globus pallidus, bilateral cerebral pedun- Neurosarcoid cles, bilateral gyrus rectus, right frontal lobe periventricular Case IV white matter, and patchy areas in bilateral temporal lobes. Axial T2-weighted images (A–D) demonstrate numerous areas of abnormal hyperintensity involving the corpus callosum, left

631CHAPTER 46 Atlas of Neuroimaging FIGURE 46-14 (Continued) T1-weighted images post-gadolinium (E–H) demonstrate abnormal enhancement of those areas with high T2 signal. (Continued )