Table 14.7 Causes of myoglobinuria Excessive physical stress Metabolic myopathies (cf. Table 14.6) Myotonias Myositis Infection (viral, bacterial) Muscular dystrophy Ischemic necrosis of muscle Mechanical trauma, crushing injury, burn, status epilepticus Medications and toxicsubstances(alco- hol, gasoline v apors, anesthetic gases, succinylcholine, illicit drugs, hypnotics, neuroleptics, clofibrate, statins, snake venom , insecticides, etc.) Malignant hyperthermia (see above) Malignant neuroleptic syndrome Electrolyte disturbances (hypokalemia, hypophosphatemia [785]) component. The responsible genetic defects are locatedonchromosomes 19q13.1 and 17q11.2-24. The defect at the former locus causes faulty expres- sion of the ryanodine receptor of the calcium channels of the sarcoplasmic reticulum. A defect at the same locus is the genetic basis of central core myopathy, a disorder that predispo- ses to malignant hyperthermia. This explains whypatientswith certain kinds of myopathy are at elevated risk of malignant hyperthermia. Clinical Features Most patients are asymptomatic until they undergo general anesthesia and, while anesthetized, develop an unex- pected and potentially lethal hyper- metabolic disorder of muscle. Halo- genat ed inhalational anesthetics, such as halothane, and depolarizing muscle relaxants, such as succinyl- choline, are among the morecom- mon precipitating agents. The hallmarks of this syndrome are difficult intubation, tachycardia, ar- rhythmia, possible cardiac arrest, hy- perventilation, muscle rigidity, and, above all, extreme hyperthermia. The syndrome is similar in some respects to ma lignant neu roleptic syndrome (p. 307). Identification of Persons at Risk The best indicator of risk is a positive personal or famil y history of similar events. Uncomplicated general anes- thesia in the past unfortunately does not mean that malignant hyperther- mia cannot occur during a subse- quent operation under general anes- thesia. As mentioned above, certain types of myopathy, including the dystrophinopathies (p. 866) and cen- tral core myopathy (p. 899), are asso- ciated with an elevated risk of malig- nant hyperthermia. In persons at risk, the serum creatine kinase concentra- tion is often mildly elevated. Treatment In the acute stage, dantrolene (2.5 mg/kg) is rapidly infused. If there is no improvement in 45 minutes, an additional dose of 7.5 mg/kg is given. 894 14 Myopathies Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Mitochondrial Encephalomyopathies (235, 467, 575b, 575c, 676, 807) Overview: The diseases in this clinically heterogeneous group are all due to structural, biochemical, or geneti c abnormalities of the mitochondria. Mitochondrial diseases affect all organ systems of the body. We discuss them here in the chapter on myopathy because myopathy and encephalopathy are often among their more prominent manifestations. Mitochondria are intracel lular organ- elles. Carbohydrates, fat, and protein are broken down intheliver and other organs into pyruvate, fatty ac- ids, and amino acids that can be Table 14.8 Biochemical classification of the mitochondrial myopathies and ence- phalomyopathies Transport disorders: Carnitine deficiency Carnitine palmitoyltransferase deficiency Substrate utilization defects: Pyruvate dehydrogenase deficiency Pyruvate ca rboxylase deficiency -oxidation defects Defects of the Krebs cycle: Fumarase deficiency Aconitase deficiency Defects inwhichoxidative phosphorylation is uncoupled: Luft syndrome Defects of the respiratory chain: Complex I deficiency* Complex II deficiency Complex III deficiency* Complex IV deficiency* Complex V deficiency* Combined defects of complexes I–V* *EncodedbymtRNA. transported into the mitochondria, where they are used to generate ATP. Like the metabolic myopathies, the mitochondrial myopathies, too, can be classified according to their under- lying biochemical defects (Ta- ble 14.8). Some of the defects listed here have been documented in no more than a few case reports but share genetic and clinical features with the other, more common ones. Genetics In addition to the DNA contained in the nucleus of each cell (nuclear DNA, nDNA ), each mitochondrion contains multiple copies of its own mitochon- drial DNA (mtDNA). Mitochondrial DNA encodes 22 transfer RNA mole- cules, two ribosomal RNA molecules, and most of the enzymes of the respi- ratory chain. NuclearDNAisinherited autosomally according to the familiar mendelian rules. Mitochondrial DNA, in contrast, is transmitted indepen- dently of the nuclear genome, di- rectly in themitochondria of the sperm cell and oocyte that join to form the zygote. The oocyte contains far more mitochondria than the sperm cell, a s it is much larger, and thus contributes the overwhelming majority of mitochondria to the zy- gote. It follows that the inheritance Mitochondrial Encephalomyopathies 895 Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Table 14.9 Clinical manifestations of mitochondrial diseases Organ Manifestation Muscle Myopathy with ragged red fibers Progressive external ophthalmoplegia Exercise intolerance Nervous system Myoclonus and generalized seizures Stroke in younger individuals Ataxia Dementia Polyneuropathy Deafness Optic neuropathy Migraine Basal ganglionic calcification (Fahr syndrome) Dystonia Elevated CSF protein Eye Retinitis pigmentosa Cataract Heart Cardiomyopathy Conduction abnormalities Gastrointestinal system Intestinal pseudo-obstruction Diarrhea Endocrine system Short stature Diabetes Goiter Hypogonadism Skin Multiple lipomas Ichthyosis pattern of mitochondrial diseases is nearly exclusively maternal. Further characteristics of mitochon- drial DNA include a high incidence of mutation, and heteroplasmia –i.e., the coexistence, within a single cell, of both normal and mutated mtDNA. In the normal case, of course, there is homoplasmia, as the cell contains nothing but normal (unmutated) mtDNA. When mutated mtDNA is present, the relative proportions of normal and mutated mtDNA deter- mine the clinical phenotype. Disease is clinically evident only when the percentage of mutated mtDNA ex- ceeds a certain threshold.Inpersons harboring mutated mtDNA, the pro- portions of normal and mutated mtDNA typically vary from organ to organ, and also change over the course of the individual’s life and with every cell division. It follows that the mitochondrial genotype 896 14 Myopathies Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. changes over the years, and there may not be any overt disease until the threshold value for mutated mtDNA is crossed (if it is ever crossed). Mitochondrial diseases due to mtDNA mutations are much more common than those due to nDNA mutations. Clinical Features (236a) Mitochondrial disorders may display apredilection for a particular organ. Generally, however, multiple organs are affected to differing degrees. The manifestations of mitochondrial dis- orders in different organ systems are listed in Table14.9. Mitochondrial Disease Syndromes Carnitine deficiency and carnitine palmitoyltransferase deficiency are two types of mitochondrial disorder that are autosomally inherited – i.e., based on a defect in nuclear DNA. The disorders of the pyruvate dehydroge- nase complex and of the Krebs cycle are also of this type. Disorders of the pyruvate dehydroge- nase complex. These disorders cause lactic acidosis and progressive cere- bral dysfunction. In the more severe forms, the abnormality is already ap- parent immediately after birth. Forms of intermediate sever ity are charac- terized by episodic lactic acidosis and progressive encephalopathy, or by Leigh syndrome (p. 296). The mild phenotype manifests itself in episodic ataxia in childhood and adolescence. Disorders of the Krebs cycle. These include fumarase deficiency, which manifests itself in early childhood with progressive encephalopathy, and aconitase deficiency, which causes exercise intolerance and my- oglobinuria. Disorders of the respiratory chain. These disorders all display a mito- chondrialinheritance pattern (with one exception). Most of them cause myopathy with ragged red fibers, though not always as the most promi- nent manifestation. The individual disorders are brieflydiscussed in the following paragraphs. Progressive external ophthalmople- gia with ragged red fibers (2 35, 467, 724). This syndrome consists of a combination of bilateral ptosis, limi- tation of ocular motility, a usually mild, generalized myopathy, and ragg ed red fibers on muscle biopsy . The latter are created by the accumu- lation of mit ochondria in muscle fi- bers, which are stained red by the Go- mori stain. The disorder progresses inexorably over the years. Further clinical and laboratory evidence of a mitochondrial disorder may be pre- sent. Progressive external ophthal- moplegia is found as a familial syn- drome with a maternal or autosomal dominant inheritance pattern, and as acomponent of Kearns-Sayre syn- drome. Kearns-Sayre syndrome (KSS). KSS is caused by a single deletion mutation in mtDNA in patientswithanegative family history. Its cardinal manifesta- tions are progressive external oph- thalmoplegia, mitochondrial myopa- thy with ragged red fibers, retinal pigment degeneration (retinitis pig- mentosa), and intracardiac conduc- tion disturbances. Further clinical manifestations (Table 14.9)mayalso be present in varying combinations. The disease appears before age 20 and confers a risk ofsuddencardiac death. Mitochondrial Encephalomyopathies 897 Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. MELAS syndrome (mitochondrial my- opathy, encephalopathy, lactic acido- sis, and stroke-like episodes) (746). This syndrome usually makes its ap- pearance in childhood with TIAs, ce- rebral infarction, and episodic vomit- ing. Lactic acidosis is present. In the full-fledged syndrome, patients be- come demented and die before the age of 20. Myoclonic and generalized epileptic seizures occur as well. In such cases, only DNA analysis can es- tablish the differential diagnosis be- tween MELAS and MERRF syndrome. MERRF syndrome (myoclonus epi- lepsy with ragged red fibers) (993). Phenomenologically, this syndrome consists of myoclonic and generalized epileptic seizures, myopathy and weakness of the limb muscles, mental retardat ion or dement ia, ataxia, and hearing loss, and usually lactic acido- sis. Ophthalmoplegia is not part of the syndrome. There may, however, be ce- rebral calcifications, short stature, neuropathy, and other mitochondrial manifestations. The clinical course is highly variable; some patients die before reaching adulthood, while oth- ers live a full normal life span with no more than mild myopathy. NARP syndrome (neuropathy, at axia, and retinitis pigmentosa) (427). A point mutation of mtDNA causes NARP syndrome, which is character- ized by proximal muscle weakness, sensory neuropathy, developmental disturbances, ataxia, epileptic sei- zures, dementia, and retinitis pig- mentosa. Some patients suffering from Leigh syndrome (p. 296) have the samemutation. COX (cytochrome c oxidase ) defi- ciency. This disorder is clinically manifested by fatal infantile myo- pathy, benign infantile myopathy, or Leigh syndrome. Aside from myo- pathy, it can also cause encephalo- pathy and renal tubular defects of a type designated separately as Debr ´e- de Toni-Fanconi syndrome. MNGIE syndrome (myoneurogastro- intestinal encephalopathy) (940). This syndrome consists of myopathy, neuropathy, encephalopathy, and gastrointestinal manifestations (in- testinal pseudo-obstruction, chronic diarrhea). Ophthalmoplegia with pto- sisisusually also present, along with further mitochondrial manifesta- tions. LHON syndrome (Leber’s hereditary optic neuropathy) (p. 630) (466). Pa- tients with this syndrome suffer from loss of visual acuity and optic nerve atrophy, whichusually arises acutely or subacutely and then progresses, first in one eye and then in the other as well. Further manifestations may include ataxia, polyneuropathy, intra- cardiac conduction abnormalities, or ragg ed red fi bers onmuscle biopsy. DAD syndrome(deafnessand diabe- tes syndrome). Deafness in the early years of life, diabet es mellitus, and of- ten also migraine-like headaches characterize this syndrome. Luft syndrome (mitochondrial hyper- metabolism). This disorder consists of euthyroid hypermetabolism with progressive muscle weakness, hypo- tonia, and heat intolerance. Succinate dehydrogenase deficiency. This is the only respiratory chain dis- order that is purely nDNA dependent and inheritedinanautosomalre- 898 14 Myopathies Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. cessive pattern. It becomes evident in childhood and is characterized by ex- ercise intolerance with d yspnea, pal- pitations, and rhabdomyolysis. Diagnostic Evaluation and Ancillary Tests If there is clinical suspicion of a mito- chondrial my opath y, this can be fol- lowed up with the following tests: in the serum,theconcentrations of py- ruvate, lactate, and al anine are often elevated, and the creatine kinase con- centration is normal or mildly ele- vated. In the ischemia test (p. 890), the lactate concentration may rise disproportionately. In the CSF,the protein concentration may be ele- vated. The EMG is normal or displays myopathic changes. The sensory and motor nerve conduction velocities may be mildly slowed. Intracardiac con- duction abnormalities are found mainly in Kearns-Sayre syndrome. CT may reveal calcifications in the basal ganglia and cerebellar nuclei, while MRI shows nonspecific signal abnor- malities in the basal ganglia, cerebel- lum, and cerebral white matter (cf. Fahr syndrome, p. 299). The keys to diagnosis are muscle bi- opsy and DNA analysis.Musclebiopsy may be pathognomonic if a modified trichromatic stain reveals the pres- ence of ragged red fibers. Mito chon- drial abnormalities are visible by electron microscopy. DNA analysis may reveal (for example) deletions or point mutations in mitochondrial DNA. Treatment There is no etiological treatment for any of the mitochondrial disor- ders. They progress inexorably as the patient ages. The possibilities for treatment are l imited to symp- tomatic measures, such as eyelid surgery for ptosis. Congenital Myopathies Overview: By definition, congenital myopathies are present at birth, progress little or not at all, and are characterized by specific morphological abnormalities visible on muscle biopsy. They are thus distinct from progressive neuro- muscular diseases such as dystrophies, spinal muscular atrophies, and oth- ers. They are presumed to b e due to specific genetic defects, though the underlying defect has only been identified in a few of them to date. In their description of central core myopathy, Shy and Magee define d a congenital myopathy as one that is present at birth and does not progress (874). In this particular disorder, there was also a well-defined mor- phologic abnormality (i.e., the central cores). Today, the term “congenital myopathy” refers to any of an etiolog- ically heterogeneous group of myopa- thies that are present at birth, may or may not be hereditary, are histologi- cally well-defined, and progress little or not at all (Table 14.10). Congenital Myopathies 899 Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Table 14.10 Congenital myopathies Well-recognized forms Central core myopathy Nemaline (rod) myopathy Centronuclear myopathy Multicore myopathy Fingerprint body myopathy Sarcotubular myopathy Hyaline body myopathy (= myopathy with disintegration of myofibrils in type I fibers) Inadequately character- ized or questionable congenital forms Myopathy with congenital fiber type disproportion Congenital hypotonia with type I fiber predominance X-linked myotubular myopathy Fingerprint body myopathy Reducing body myopathy Cytoplasmic body myopathy Myopathy with tubular aggregates Zebra body myopathy Trilaminar fiber myopathy Spheroid body myopathy Genetics Most congenital myopathies are of autosomal dominant or X-linked re- cessive inheritance (myotubular my- opathy, centronuclear myopathy). Sporadic cases are also found, and, for some of these disorders, the pattern of inheritance is not yet clearly de- fined. In central core myopathy, the gene defect lies on chromosome 19q13.1, while in X-linked hereditary centronuclear myopathy it is on chro- mosome Xq28 (524). Clinical Features In infancy,patientsmanifest “myoto- nia congenita” (floppy infant, Oppen- heim disease). Motor development and learning to walk are almost al- ways delayed. In chi ldhood and adult- hood, there is mainly proximal weak- ness affecting the lower and, to a lesser extent, the upper limbs. These children often use the Gowers ma- neuver to stand up – i.e., they climb up their own legs with their arms and hands. Occasionally,theextraocular and facialmuscles are also involved. The face and head are usually narrow and high (dolichocephaly) and the palatal vault is high (Gothic palate). Deformities such aspectusexcava- tum, scoliosis, hip dysplasia, pes ca- vus, pes planus, and clubfoot are common. The intrinsic muscle re- flexes can be eithernormalordimin- ished. The disease progresses little, if at all; progression and premature death from myopathy occur only in excep- tional cases. Cardiomyopathy is a rare component of the syndrome. Some types of congenital myopathy are as- sociated with mental retardation (e.g., fingerprint body myopathy). Ancillary Tests The serum creatine kinase concentra- tion is usually normal or only mildly elevated. The EMG gene rallyshows myopathic changes. Muscle biopsy re- veals specific structural abnormali- 900 14 Myopathies Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Table 14.11 Differential diagnosis of con- genital m yopathy Spinal muscular atrophy Congenital muscular dystrophy Congenital myotonic dystrophy and other congenital myot onias Congenital myasthenic syndromes Glycogenoses, particularly types II, III, and IV (cf. Table 2.72) Carnitine deficiency Mitochondrialmyopathies Congenital polyneuropathies ties in the muscle fibers, establishing the diagnosis. Examples are the cen- tral cores of central core disease, the rods of nemaline myopathy, and rows of central nuclei in centronuclear my- opathy. Differential Diagnosis The differential diagnosis may be dif- ficult, particularly in infants. The im- portant entities tobeconsideredare listed in Table14.11. Treatment No etiologic treatment is available to date fo r the congen ital myopa- thies. Their treatment is thus lim- ited to symptomatic measures such as physical therapy and corrective orthopedic procedures. Precise di- agnosis of these syndromes is nonetheless justified and impor- tant, as they must be clinically dif- ferentiated from entities such as muscular dystrophies, spinal mus- cular atrophies, neuropathies and others that may beatleastpartly treatable. The diagnosis of a con- genital myopathy also p rovides the basis for prognostication and ge- netic counseling. Myositis (203, 401) Overview: The term “myositis”refers to an inflammation of muscle of any cause (ster- ile or infectious). A classification of the myositides based on their histori- cal, clinical, histologic, electromyographic, and serologic features, such as that found in Table 14.12,isuseful for clinical purposes. Autoimmune and infectious myositides are the twomaincategories.Inflammation of muscle can also result from any type of muscle damage – e.g., muscular dystro- phies; inflammation of this type should not be confused with primary myositis. Myositis 901 Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Table 14.12 Inflammatory myopathies (myositides) Autoimmune inflamma- tory disorders mainly affecting muscle Dermatomyositis and polymyositis in adults Dermatomyositis and polymyositis in children Dermatomyositis and polymyositis accompanying malignancy Inclusion body myositis Autoimmune inflamma- tory disordersaffecting muscle as well as other organ systems Scleroderma (progressive systemic sclerosis) Sjögren syndrome Systemic lupus erythematosus Rheumatoid arthritis (=primary chronic polyarthritis) Mixedcollagenosis (mixed connective tissue disease, Sharp syndrome) Polyarteritis nodosa Beh¸cet’s disease Other noninfectious myositides Giant-cell myositis Diffuse fasciitis with eosinophilia Eosinophilic polymyositis Polymyalgia rheumatica Sarcoidosis Myositis in Crohn’s disease Myositis ossificans Myosclerosis Infectious myositides Viral Bacterial Borrelial Fungal Protozoal Helminthic Polymyositis and Dermatomyositis (117, 203,401) Overview: These are generalized, usually symmetric, more or less rapidly progressive inflammatory diseases of muscle. Inflammation of the skin is additionally present in dermatomyositis. Epidemiology Poly- and dermatomyositis are rare diseases with an incidence of 5–10 cases per million persons per year. The age-specific incidence of derma- tomyosit is has two peaks, one before puberty and another around age 40. Polymyositis appears almost exclu- sively afterage35andaffectsmore women thanmen.Inbothdisorders, the family history is usually negative. 902 14 Myopathies Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. [...]... tylcholine into the synaptic cleft functions Ach-R-Ab Antibody against acetylcholine normally, but, because there are fewer rereceptors ceptors, the end plate potential that is genCa-C-Ab Antibody against calcium chanerated is insufficient to initiate an action nels of the nerve terminal potential In the Lambert-Eaton myas- Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms... Ancillary Tests The serum creatine kinase concentration is markedly elevated (1 0- fold or more above normal) It becomes normal again only in long-standing, “burnt-out” myositis The erythrocyte sedimentation rate and C-reactive protein concentration are usually elevated as well, and protein electropho- Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license... (neuromuscular synapse) The action potential arriving at the nerve terminal causes acetylcholine packets Axon with nerve terminal Vesicles containing ACh ACh Acetylcholine receptor Normal Acetylcholinesterase Ca-C-Ab ACh-R-Ab Myasthenia gravis Lambert–Eaton myasthenic syndrome Fig 14.9 Neuromuscular junction in the normal state, in myasthenia gravis, and in the Lambert-Eaton myasthenic syndrome In myasthenia... myopathy in alcoholics A further probable clinical entity is hypokalemic myopathy in alcoholics ( 810) Painless weakness arises and progresses rapidly (days) There is no swelling or myoglobinuria The weakness is accompanied by hypokalemia and responds to potassium adminis- Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license Disorders of Neuromuscular... management, 2nd ed Oxford: Blackwell Science, 2001 Weir B Subarachnoid hemorrhage: causes and cures Oxford: Oxford University Press, 1999 Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license Appendix Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license 928 Appendix Scales for the Assessment of Neurologic... elevated risk, as are those who take steroids in combination with substances causing neuromuscular blockade (cf myopathy with myosin deficiency in muscle fibers, p 911) A dosage of 10 mg of pred- Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license 908 14 Myopathies nisone daily, however, can suffice to produce steroid myopathy The serum creatine kinase... gasoline vapor are at risk for rhabdomyolysis (29) Toluene causes marked hypokalemia and hypophosphatemia, both of which promote rhabdomyolysis (pp 910 ff.) Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license 910 14 Myopathies Antilipemic Drugs Drugs such as clofibrate, lovastatin, simvastatin, gemfibrozil, and niacin cause structural damage in muscle,... be released: acetylcholine-containing vesicles previously stored in the nerve terminal fuse with its membrane, liberating their contents into the synaptic cleft Acetylcholine molecules then bind to the acetylcholine receptors of the postsynaptic membrane, whereupon the cation channels in the receptors transiently open, generating an end-plate potential If the summed end-plate potential from all of the... In particular, the serum should be tested for antibodies against striated muscle, thyroid hormone, antithyroid antibodies, antinuclear antibodies, rheumatoid factor, and vitamin B12 and glucose concentrations Baseline Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license 918 14 Myopathies pulmonary function testing should also be performed as part. .. have shown promising results of mono- or combination therapy with this drug in myasthenia gravis The usual dose is 2 g/day It should not, however, be given in combination with azathioprine (risk of severe leukopenia) Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license Disorders of Neuromuscular Transmission 921 Short-acting immunotherapy (38, 216) . concentra- tion is markedly elevated (1 0- fold or more above normal). It becomes nor- mal again only i n long-standing, “burnt-out” myositis. The erythrocyte sedimentation rate and C-reactive protein. myopa- thies that are present at birth, may or may not be hereditary, are histologi- cally well-defined, and progress little or not at all (Table 14 .10) . Congenital Myopathies 899 Mumenthaler, Neurology. s often require immunosup- pressive therapy in addition to ste- roids, particularly in order to av oid the complications of long-term ste- roid use. Prednisone is recom- mended at a dose of 1–1.5