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MUSCLE DISEASES.pdf

This document provides information on muscle diseases and myopathies. It discusses the classification, diagnosis, clinical features, histopathology, and genetics of various muscle disorders. Some key points include: - Muscle diseases can be hereditary or acquired and affect skeletal muscle structure or function. Around 1/1000 people have a primary muscle disease. - Diagnosis involves confirming a myogenic syndrome, determining the etiology through various tests, and ruling out neurogenic or other causes. - Muscle is composed of fascicles of muscle fibers which contain myofibrils and other structures. There are different types of muscle fibers. - Histopathology can identify features of muscle disease like fiber atrophy, necrosis, regeneration

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MUSCLE DISEASES
1- Disorders in which there is a structural or functional abnormality of skeletal muscle 2- About 50000 people / 60 million in the UK have a primary muscle disease ( hereditary or acquired )( ~ 1/1000 ) 3- Many more have muscle symptoms related to drugs or systemic diseases 4- Some of these conditions are treatable Introduction Rosette Jabbour, MD 2
DIAGNOSIS 1st STEP: confirm the MYOGENIC SYNDROME differentiate from ▪ a neurogenic syndrome: - peripheral nerve disease - motor neuron disease (neuronopathy, anterior horn) ▪ myasthenic syndrome (neuromuscular junction) based on clinical findings, labs, neurophysiology 2nd STEP: look for the ETIOLOGY clinical findings ( personal and family history, physical findings ) complete laboratory work-up tests for metabolic diseases neurophysiology testing MRI of the muscles muscle biopsy genetic testing Rosette Jabbour, MD 3
myofibril MUSCLE STRUCTURE 1- A muscle fiber is made of a large number of myofibrils 2- Several muscle fibers are arranged in fascicles endomysium 3- several fascicles form a muscle epimysium perimysium endomysium Rosette Jabbour, MD 4
nucleus mitochondria myofibrils Basal lamina Sarcoplasmic membrane Sarcoplasmic reticulum sarcoplasm MUSCLE FIBER Rosette Jabbour, MD 5
Transversal Section Longitudinal section Rosette Jabbour, MD 6
SECTION OF NORMAL MUSCLE Section of normal adult muscle stained With hematoxylin and eosin. Muscle fibers Are uniform in size and stain pink with eosin. Their nuclei stain blue with hematoxylin Section of normal adult muscle stained With Gomori trichrome stain. Muscle fibers are stained greenish blue And nuclei are dark red Rosette Jabbour, MD 7
Type I: red fibers (myoglobin) slow contraction tonic activity not easily tired rich in mitochondria Aerobic metabolism (oxydation of glucose: succinodehydrogenase, cytochrome c oxidase) Type II: white fibers ( A,B) rapid contraction phasic activity easily tired Anaerobic metabolism (glycolysis, ATPase, phosphorylase) DIFFERENT TYPES OF FIBERS Rosette Jabbour, MD 8
DISTRIBUTION OF HISTOCHEMICAL FIBER TYPES IN NORMAL MUSCLE ( TYPE I, 2A, 2B ). ATPase stain pH 4.6 ( glycolytic enzyme activity ) Rosette Jabbour, MD 9
2A 1 2B 1 NORMAL DISTRIBUTION OF OXIDATIVE ENZYME ACTIVITY IN NORMAL MUSCLE FIBERS. TYPE I FIBERS CONTAIN MORE MITOCHONDRIA THAN TYPE 2 FIBERS, AND STAIN DARKER. Cytochrome c oxidase stain Rosette Jabbour, MD 10
TYPE 2 MUSCLE FIBER ATROPHY ( darker staining ) ATPase stain pH 9.4 Rosette Jabbour, MD 11
MUSCLE FIBERS IN DENERVATION ATROPHY LARGE GROUPS OF ATROPHIC FIBERS OF ALL HISTOCHEMICAL TYPES. ATPase stain pH 4.6 Rosette Jabbour, MD 12
SITE OF THE MUSCLE LESION Muscle channel: sodium, potassium, chloride ( modification of the action potential ) Muscle structure: proteins in the membrane and sarcoplasm ( modification of the structure and trophicity of the fibers ) or the interstitial tissue ( secondary alteration of the myofibrils ) Muscle metabolism: source of energy: glycogen, lipids, mitochohondria ( modification of the function of the fibers ) Neuromuscular junction: postsynaptic acetylcholine receptors ( alteration of the neuromuscular transmission ) Rosette Jabbour, MD 13
DEPOLARIZATION REPOLARIZATION AFTER POTENTIALS Rosette Jabbour, MD 14
Sarcoplasmic membrane Extracellular Matrix collagen actine dystrophin α β sarcoglycans sarcoplasm dystroglycans dysferlin laminin syntrophins sarcospan STRUCTURAL PROTEINS Rosette Jabbour, MD 15
CLASSIFCATION OF MYOPATHIES HEREDITARY MUSCULAR DYSTROPHIES without myotonia Duchenne and Becker muscular dystrophy ( DMD / BMD ) Emery - Dreifus muscular dystrophy Limb girdle muscular dystrophy ( LGMD ) Facioscapulohumeral dystrophy ( FSMD ) Oculopharyngeal muscular dystrophy MUSCULAR DYSTROPHIES with myotonia Myotonic dystrophy (classic form ) DM1 ( steinert ) Proximal myotonic dystrophy ( DM2 ) CHANNELOPATHIES Myotonia congenita Hyperkalemic periodic paralysis Hypokalemic periodic paralysis METABOLIC MYOPATHIES Glycogen storage diseases Lipid storage diseases Mitochondrial myopathies CONGENITAL MYOPATHIES Congenital muscular dystrophies Congenital myopathies (nemaline, myotubular, central core ) Malignant hyperthermia Rosette Jabbour, MD 16
CLASSIFICATION OF MYOPATHIES ACQUIRED Inflammatory myopathies ( PM-DM ) Inclusion body myopathies ( IBM ) Endocrine myopathies Myopathies associated with systemic disease (critical illness, trichinosis, amyloidosis..) Drug induced myopathies / toxic Rosette Jabbour, MD 17
CLINICAL FINDINGS IN MYOPATHY NEGATIVE 1- weakness 2- muscle atrophy 3- exercise intolerance and fatigue POSITIVE 1- myalgias 2- cramps 3- myotonia 4- stiffness 5- muscle hypertrophy 6- myoglobinuria 7- contractures 8- tendon reflexes Rosette Jabbour, MD 18
WEAKNESS 1- PROXIMAL MUSCLE WEAKNESS Difficulty climbing stairs, arising from a chair, brushing hair, lifting objects overhead 2- DISTAL MUSCLE WEAKNESS Difficulty opening jars, turning a key, tripping 3- CRANIAL MUSCLE WEAKNESS dysphagia, dysarthria, diplopia (rare), ptosis, difficulty whistling, blowing up balloons, using a straw, sleeping with eyes open Rosette Jabbour, MD 19
FUNCTIONNAL ASSESSMENT OF WEAKNESS Rosette Jabbour, MD 20
GOWER’S SIGN Rosette Jabbour, MD 21
MUSCLE ATROPHY AND HYPERTROPHY Atrophy with time without fasciculations Hypertrophy, true: in MYOTONIA CONGENITA due to repetitive activity Hypertrophy, pseudo: in DMD, BMD, some LGMD, due to connective tissue proliferation MYALGIAS, CRAMPS AND EXERCISE INTOLERANCE Constant in most of inflammatory myopathies (myalgias) Frequent in drug-induced and hypothyroidism (myalgias, cramps) in electrolytes disturbances (cramps) Episodic, after or during exercises in metabolic and mitochondrial myopathies (myalgias and cramps) Rosette Jabbour, MD 22
PSEUDOHYPERTROPHY TRUE HYPERTROPHY Rosette Jabbour, MD 23
MYOTONIA Muscle stiffness and difficulty in muscle relaxation due to repetitive depolarization of the muscle membrane Active and passive Worsening with rest and cold, improving with exercise: myotonia congenita Exacerbation with exercise and cold: paramyotonia congenita Some drugs exacerbate myotonia: β-blockers Rosette Jabbour, MD 24
REFLEXES AND CONTRACTURES DTR : - preserved in pure myopathy - may be lost when there is advanced wasting - lost if there is a myopathy + neuropathy Contractures : - early in Emery- Dreifus and some LGMD - late in most myopathies: fixed contractures Rosette Jabbour, MD 25
MYOGLOBINURIA Discoloration of urine: brown-black ( like cola ), due to liberation of myoglobin from the muscle Causes : - Excessive exercise - Inflammatory myopathies - Viral/Bacterial infection - Metabolic myopathies: - Drugs and toxins glycogen: Mc Ardle - Neuroleptic malignant syndrome lipid: CPT deficiency - Heat stroke - LGMD 2C-F - Malignant hyperthermia - Prolonged fever - Prolonged immobilization - Metabolic disturbances Rosette Jabbour, MD 26
NON MYOPATHIC FEATURES CNS, eyes ( retina ), GI, liver, endocrine, kidneys, blood, skin Cardiac: arrhythmias, heart failure Respiratory: due to diaphragm and respiratory muscle involvement Rosette Jabbour, MD 27 Muscular dystrophy Congenital myopathies Inflammatory myopathies
CARDIAC COMPLICATIONS Rosette Jabbour, MD 28 Arrythmia CHF Congestive
LABORATORY WORK-UP MUSCLE ENZYMES Rosette Jabbour, MD 29 CK LEV ELS
DIFFERENTIAL DIAGNOSIS OF CK ELEVATION HIGH CK WITH WEAKNESS HIGH CK WITHOUT WEAKNESS Rosette Jabbour, MD 30
MAGNITUDE OF CK ELEVATION Rosette Jabbour, MD 31
DRUGS-ASSOCIATED HIGH CK Rosette Jabbour, MD 32
CLASSIFCATION OF MYOPATHIES HEREDITARY MUSCULAR DYSTROPHIES without myotonia Duchenne and Becker muscular dystrophy Emery - Dreifus muscular dystrophy Limb girdle muscular dystrophy Facioscapulohumeral dystrophy Oculopharyngeal muscular dystrophy Rosette Jabbour, MD 33
DUCHENNE MUSCULAR DYSTROPHY ■ Incidence: 1/3000-4000 male births. X – linked . ■ Near total loss of dystrophin  structural protein bound to the sarcolemma providing structural integrity to the muscle membrane  Abnormal dystrophin gene located on chromosome Xp21  female carriers or spontaneous mutations ■ Clinical features:  new born: normal – high CK  babies: slight delay in walking( 18 months )  3-5 yrs: progressive weakness, proximal more than distal, pelvic girdle more than scapular  12-15 yrs: wheelchair  20-25 yrs: respiratory and cardiac complications Other musculoskeletal:  calf hypertrophy  heel cord shortening  hyperlordosis and kyphoscoliosis Extra-muscular:  cardiomyopathy with arrhythmias and congestive heart failure  gastro paresis and pseudo obstruction Rosette Jabbour, MD 34
■ Laboratory features: 1- CK markedly elevated ( 50-100X ) 2- EMG: abnormal polyphasic MUP normal NCV 3- Histopathology: a- muscle fibers degeneration and regeneration ( variation in size ) b- increased connective tissue c- marked reduction of dystrophin on immunostaining and on western blot analysis ■Treatment: 1- steroids - creatine 2- supportive therapy- bracing- surgery DUCHENNE MUSCULAR DYSTROPHY Rosette Jabbour, MD 35
DMD Rosette Jabbour, MD 36
DMD- HE stain: cluster of necrotic and regenerating fibers Rosette Jabbour, MD 37
Dystrophin immunostaining Rosette Jabbour, MD 38
BECKER MUSCULAR DYSTROPHY Incidence: 1/20000 male births. X – linked Abnormal dystrophin ( reduced amount and abnormal function ) Phenotype similar to that of DMD, but delayed expression Severity variable, usually mild Life expectancy reduced but significantly longer than DMD Rosette Jabbour, MD 39
BECKER MUSCULAR DYSTROPHY HE stain: chronic myopathic changes: variation of fiber Sizes, endomysial fibrosis, internal nuclei. Rosette Jabbour, MD 40
EMERY- DREIFUS MUSCULAR DYSTROPHY X – linked Much less severe weakness ( humero – peroneal ) Contractures ( Achilles tendons, elbows, posterior cervical muscles ) Cardiomyopathy with conduction defects: stroke and arrhythmias Abnormal structural protein of the nuclear membrane: Emerine Mutation in a gene located on chromosome Xq28 Rosette Jabbour, MD 41
LIMB GIRDLE MUSCULAR DYSTROPHY Incidence: 6-7/100000 births Autosomal recessive: LGMD-2 A, B, C,… Autosomal dominant : LGMD-1 A, B, C... ( less common ) Spontaneous mutations on different chromosomes 5, 1, 3, 6, 7… Abnormal structural proteins of the membrane and the cytoplasm of the muscular fiber: Sarcoglycans (α, β, γ..), dysferlin, merosin,.. Dystrophin is normal Clinical features not specific: early scapular, or early pelvic early onset, rapid progression late onset, slow progression Differential with other myopathies: inflammatory, metabolic,.. or neurogenic ( SMA ) Rosette Jabbour, MD 42
LGMD Rosette Jabbour, MD 43
Rosette Jabbour, MD 44
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY Incidence: 4/million Autosomal dominant with variable degree of penetrance of clinical findings within families Gene not yet isolated. Could be present on the chromosome 4q35 Clinical features: age of onset variable: 5 to 45 years facial muscles are affected the earlier ( incomplete eye closure ) scapular winging weakness of biceps and triceps weakness of tibialis anterior: foot drop pelvic girdle later: hyperlordosis Normal life span Rosette Jabbour, MD 45
OCULOPHARYNGEAL MUSCULAR DYSTROPHY Autosomal dominant Mutations on the chromosome 14q11 Clinical features:  in fourth to six decades  bilateral ptosis  difficulty in swallowing 1/4  extra ocular muscles affected 1/2 ( usually without diplopia)  mild weakness of the neck and proximal limbs (sometimes) Slow progression and normal life span CK normal or mildly elevated Rosette Jabbour, MD 46
CLASSIFCATION OF MYOPATHIES HEREDITARY MUSCULAR DYSTROPHIES without myotonia Duchenne and Becker muscular dystrophy Emery - Dreifus muscular dystrophy Limb girdle muscular dystrophy Facioscapulohumeral dystrophy Oculopharyngeal muscular dystrophy MUSCULAR DYSTROPHIES with myotonia Myotonic dystrophy (classic form )( DM1) ( STEINERT disease ) Proximal myotonic dystrophy ( DM2 ) Rosette Jabbour, MD 47
MUSCULAR DYSTROPHIES with MYOTONIA MYOTONIC DYSTROPHY ( classic form) STEINERT DISEASE Incidence: 1/8000. most frequent dystrophy in adults Autosomal dominant Chromosome 19q13.2- increased number of repetition of CTG coding the myotonin protein kinase Clinical features:  myotonia  weakness and atrophy: - limbs: distal lower part of the forearm, intrinsic muscles of the hands, peroneal muscles. - head: ptosis, wasting of temporalis and masseter muscles orbicularis oris (eversion of the lower lip), sternocleidomastoid, tongue, pharyngeal and laryngeal muscles, abnormal voice Rosette Jabbour, MD 48
MYOTONIC DYSTROPHY Extra muscular manifestations:  Frontal balding  Sub scapular cataract  Atrophy of testicles, impotence with high FSH and preserved sexual characters  Cardiac conduction defects (long PR – AV block )  Dysphagia and chronic pseudo obstruction  Hypoventilation (diaphragm, intercostal muscles) decreased central drive with sleep apnea  Cognitive impairment, mental retardation Life span reduced Rosette Jabbour, MD 49
MYOTONIC DYSTROPHY Rosette Jabbour, MD 50
STEINERT- Gomori trichrome stain: increase in the number of fibers containing Internal nuclei Rosette Jabbour, MD 51
MYOTONIC DYSTROPHY Rosette Jabbour, MD 52
CLASSIFCATION OF MYOPATHIES HEREDITARY MUSCULAR DYSTROPHIES without myotonia Duchenne and Becker muscular dystrophy Emery - Dreifus muscular dystrophy Limb girdle muscular dystrophy Facioscapulohumeral dystrophy Oculopharyngeal muscular dystrophy MUSCULAR DYSTROPHIES with myotonia Myotonic dystrophy (classic form ) STEINERT CHANNELOPATHIES Myotonia congenita Hyperkalemic periodic paralysis Hypokalemic periodic paralysis Paramyotonia congenita Central core disease Anderson - Tawil syndrome Rosette Jabbour, MD 53
MYOTONIA CONGENITA Mutation of CLCN1 (chloride channel gene) on chromosome 7q35 Autosomal dominant: Thomsen Autosomal recessive: Becker Clinical features:  Myotonia: improving by repetition of movements (warm up phenomenon)  Muscle hypertrophy: athletic, herculean appearance  Muscle stiffness  No weakness Recessive :  Myotonia worse  Proximal weakness Life span normal Lab: CK normal or slightly elevated EMG: myotonic discharges Rosette Jabbour, MD 54
Rosette Jabbour, MD 55
HYPOKALEMIC PERIODIC PARALYSIS Age at onset: puberty Duration of episodes: hours- days Weakness: episodic, possibly permanent later in life Myotonia: absent Precipitants: cold, rest after exercise, carbohydrate loading Alleviating factors: potassium loading, exercise Inheritance, gene mutation: AD, CACNL1A, SCN4A, 17q23 Remark: always look for hyperthyroidism Age at onset: infancy-early childhood Duration of episodes: minutes-hours Weakness: episodic, possibly permanent later in life Myotonia: possibly ( between episodes of weakness) EMG (+) Precipitants: potassium loading, cold, fasting, rest after exercise Alleviating factors: carbohydrate loading, exercise Inheritance, gene mutation: AD, SCN4A, 17q23 HYPERKALEMIC PERIODIC PARALYSIS Rosette Jabbour, MD 56
CLASSIFCATION OF MYOPATHIES HEREDITARY MUSCULAR DYSTROPHIES without myotonia Duchenne and Becker muscular dystrophy Emery - Dreifus muscular dystrophy Limb girdle muscular dystrophy Facioscapulohumeral dystrophy Oculopharyngeal muscular dystrophy MUSCULAR DYSTROPHIES with myotonia Myotonic dystrophy (classic form ) STEINERT CHANNELOPATHIES Myotonia congenita Hyperkalemic periodic paralysis Hypokalemic periodic paralysis METABOLIC MYOPATHIES Glycogen storage diseases Lipid storage diseases Mitochondrial myopathies Rosette Jabbour, MD 57
GLYCOGEN STORAGE DISEASES ► Glycogen storage disease type II: Acid maltase deficiency: 1- Autosomal recessive ( 17q23-25 ) 2- Lysosomal enzyme(α-glycosidase: conversion of glycogen to glucose) 3- Severe infantile form: Pompe’s disease cardiomyopathy, hepatomegaly, hypotonia, feeding and respiratory weakness 4- Less virulent juvenile or adult type = Limb girdles ► Glycogen storage disease type V: Mc Ardle disease 1- Autosomal recessive 2- Muscular phosphorylase 3- Cramps, stiffness pain on exertion, myoglobinuria Rosette Jabbour, MD 58
Vacuoles, subsarcolemma, containing PAS (+) material ( glycogen ) Rosette Jabbour, MD 59
EM: accumulation of glycogen in the sub sarcolemma Rosette Jabbour, MD 60
LIPID STORAGE DISEASES CPT1 and CPT2 ( carnitine- palmityl transferase ) deficiency: Enzymes required for the active transport of long chain fatty acids into mitochondria For β-oxidation which is a process of aerobic energy production converting these FA To acetyl –CoA which then used to generate ATP Episodic exercise-induced myalgia, myoglobinuria and weakness Myalgias occur after exercise, or during prolonged exercices and fasting ( glcogen storage diseases: during exercises ) Myalgias without cramps and myoglobinuria Muscle biopsy may show lipid accumulation CK normal between attacks Rosette Jabbour, MD 61
Gomori trichrome stain: vacuoles containing lipids Rosette Jabbour, MD 62
Red oil stain: vacuoles filled with lipids ( red material ) Rosette Jabbour, MD 63
EM: lipid droplets Rosette Jabbour, MD 64
MITOCHONDRIAL MYOPATHIES Multisystem diseases, sometimes confined to muscle (brain, liver, kidneys) Autosomal recessive, dominant or X-linked DNA mutations responsible for enzyme deficiency, or structural abnormalities CLINICAL MANIFESTATIONS : - non specific: mild weakness, episodic weakness with acidosis, precipitated by infection, alcohol or exercise. Myalgia, exercise-induced cramps, rhabdomyolysis, myoglobinuria. - specific presentations: Chronic progressive external ophtalmoplegia Kearns-Sayre syndrome: ptosis, ophtalmoplegia, pigmentary retinopathy, with heart block or high protein in CSF, or cerebellar ataxia - other presentations: MELAS: mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes MERRF: myoclonic epilepsy with ragged red fibers Leber’s hereditary optic neuropathy Leigh’s syndrome LAB: CK normal, high lactate on aerobic exercise muscle biopsy with immunostaining and electron microscopy genetic testing in blood, urine and muscle. Rosette Jabbour, MD 65
Ragged-red fibers with increased sub sarcolemmal red staining membranous material ( accumulation of mitochondria ) Gomori trichrome stain Rosette Jabbour, MD 66
EM: collections of abnormal mitochondria containing abnormal inclusions Rosette Jabbour, MD 67
Cytochrome oxidase negative fibers ( cytochrome c oxidase stain ) Rosette Jabbour, MD 68
CONGENITAL MYOPATHIES Myopathic disorders presenting preferentially at birth But not exclusively CONGENITAL MUSCULAR DYSTROPHIES 1- Hypotonia + arthrogryposis +abnormal myelination ( mental retardation) 2- Some are related to deficit in merosine ( membrane of the muscle fiber ) OTHER CONGENITAL MYOPATHIES 1- Less severe 2- Neonatal onset or delayed 3- Specific : • Nemaline myopathy • Myotubular myopathy • Central core disease Rosette Jabbour, MD 69
Rosette Jabbour, MD 70
MALIGNANT HYPERTHERMIA Incidence: 1/7000-1/50000 anesthetics given 50% had previous anesthesia without clinically manifesting the disorder Autosomal dominant. at least 6 different genes identified Mutations in RyR1(ryanodine receptors) on chromosome 19q13 Activation of mutant receptors causes calcium release from sarcoplasmic reticulum stores, leading to excessive muscle contraction, overproduction of heat, fever and rhabdomyolysis. Precipitated by depolarizing muscle relaxants( succinylcholine ), and halogenated inhalation anesthetic agents ( isoflurane ) Other conditions that predispose: myotonia congenita, periodic paralysis, myotonic dystrophy, Duchenne and Becker dystrophies, mitochondrial disorders, CPT deficiency. Clinical manifestations: severe muscle rigidity, myoglobinuria fever, tachycardia, arrhythmias Testing: genetic susceptibility test (fresh muscle sample with halothane or caffeine) Rosette Jabbour, MD 71
CLASSIFICATION OF MYOPATHIES ACQUIRED Inflammatory myopathies ( PM-DM ) Inclusion body myositis Endocrine myopathies Myopathies associated with systemic disease (critical illness, trichinosis, amyloidosis..) Drug induced myopathies / toxic Rosette Jabbour, MD 72
INFLAMMATORY MYOPATHIES GENERAL REMARKS: Characterized by: muscle weakness, high CK, inflammation on biopsy 3 major groups: ► Idiopathic inflammatory myopathies ( of unknown etiology ) ■ Dermatomyositis (the most common in childhood and adulthood) ■ Polymyositis (rare, overdiagnosed, many turn out to be IBM, or DM with minimal rash, or muscular dystrophy with inflammation) ■ Inclusion body myositis( most common in patients older than 50 yrs) ► Myositis associated with connective tissue disease (SLE, Sjogren, RA, ..) ► Myositis due to infection (virus, HIV, trichinosis,..) PAYHOPHYSIOLOGY: DM: humoral mediated microangiopathy of the skin and muscle. Weakness is related to ischemia/infarction of muscles PM: cell mediated autoimmune attack against specific antigen in muscle fibers IBM: unclear cell mediated like PM inflammation secondary to a degenerative myopathy ? (poor response to immunosuppression) Rosette Jabbour, MD 73
CLINICAL FEATURES: DM: 1- acute or insidious onset of proximal greater than distal 2- skin rash: heliotrope, forehead and malar regions, chest and neck, extensor surface of extremities and joints 3- other organs: interstitial lung disease(10-20%), myocarditis, GI bleeding, arthritis. 4- increased risk of malignancy PM: 1- same as DM 2- with no rash IBM: 1- Insidious onset of proximal and distal weakness 2- early involvement of wrist and fingers flexors with relative sparing of deltoids, and of quadriceps and ankle dorsiflexion 3- weakness is often asymmetric 4- cranial muscles spared except for dysphagia, sometimes 5- no increased risk of malignancy Rosette Jabbour, MD 74
IBM Rosette Jabbour, MD 75
LABORATORY FEATURES: DM/PM: 1-CK can be normal early or when onset is insidious more commonly high ( more than 10X ) 2-CK not a good indicator of disease activity 3-ANA positive when underlying CTD 4-Anti-jo-1 positive when ILD IBM: 1-CK normal or mildly elevated ( less than 10X ) 2-Autoantibodies uncommon and non significant ELECTRODIAGNOSTIC FEATURES: 1-Increased spontaneous activities ( fibrillation potentials, positive sharp waves ) 2-MUP: small amplitude, short duration, polyphasic with earl recruitment . Rosette Jabbour, MD 76
HISTOLOGIC FEATURES: DM: a- infiltration by inflammatory mononuclear cells of the perimysium and the perivascular space b- perifascicular atrophy c- immune complex deposition on small blood vessels d- no endomysial inflammation and no invasion of non necrotic fibers PM: a- infiltration by inflammatory mononuclear cells of the endomysium and invasion of non necrotic muscle fibers IBM: a- infiltration by inflammatory mononuclear cells of the endomysium and and invasion of non necrotic fibers b- presence of rimmed vacuoles in the muscle fibers c- mitochondrial abnormalities d- EM: 15-21 nm tubulofilamants in the cytoplasm of vacuolated fibers, and less commonly in nuclei e- 20-30% will not demonstrate all these findings leading to erroneous diagnosis of PM ( importance of the clinical pattern ) Rosette Jabbour, MD 77
DM- HE stain: inflammatory infiltrates in the perimysium - perivascular Rosette Jabbour, MD 78
DM- HE stain: perifascicular atrophy Rosette Jabbour, MD 79
PM- HE stain: inflammatory infiltrates present at several endomysial sites Rosette Jabbour, MD 80
PM- HE stain: focal invasion of a non-necrotic fiber by inflammatory cells Rosette Jabbour, MD 81
IBM- Gomori trichrome stain: inflammatory cells focally invade a non-necrotic muscle fiber Rosette Jabbour, MD 82
IBM- Gomori trichrome stain: muscle fibers with rimmed vacuoles Rosette Jabbour, MD 83
IBM- EM: filamentous inclusions near an autophagic vacuole containing degenerating membranous material with myeloid figures Rosette Jabbour, MD 84
IBM- EM: intranuclear filamentous inclusions Rosette Jabbour, MD 85
ENDOCRINE MYOPATHIES Important role of the endocrine system in controlling the structure and the function of the muscle. 1- HYPERTHYROIDISM 2- HYPOTHYROIDISM 3- HYPERCORTICISM 4- HYPOCORTICISM Signs are not specific Proximal weakness of variable intensity Muscular atrophy, cramps, slow relaxation Periodic paralysis Rosette Jabbour, MD 86
DRUGS INDUCING MYOPATHIES Rosette Jabbour, MD 87
DRUG-INDUCED- Necrotizing myopathy Rosette Jabbour, MD 88
SPECIFIC TREATMENT FOR MUSCLE DISEASE Rosette Jabbour, MD 89
SPECIFIC TREATMENT FOR MUSCLE DISEASE conditions Specific treatment Rosette Jabbour, MD 90

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MUSCLE DISEASES.pdf

  • 1.
  • 2.
    1- Disorders inwhich there is a structural or functional abnormality of skeletal muscle 2- About 50000 people / 60 million in the UK have a primary muscle disease ( hereditary or acquired )( ~ 1/1000 ) 3- Many more have muscle symptoms related to drugs or systemic diseases 4- Some of these conditions are treatable Introduction Rosette Jabbour, MD 2
  • 3.
    DIAGNOSIS 1st STEP: confirmthe MYOGENIC SYNDROME differentiate from ▪ a neurogenic syndrome: - peripheral nerve disease - motor neuron disease (neuronopathy, anterior horn) ▪ myasthenic syndrome (neuromuscular junction) based on clinical findings, labs, neurophysiology 2nd STEP: look for the ETIOLOGY clinical findings ( personal and family history, physical findings ) complete laboratory work-up tests for metabolic diseases neurophysiology testing MRI of the muscles muscle biopsy genetic testing Rosette Jabbour, MD 3
  • 4.
    myofibril MUSCLE STRUCTURE 1- Amuscle fiber is made of a large number of myofibrils 2- Several muscle fibers are arranged in fascicles endomysium 3- several fascicles form a muscle epimysium perimysium endomysium Rosette Jabbour, MD 4
  • 5.
  • 6.
  • 7.
    SECTION OF NORMALMUSCLE Section of normal adult muscle stained With hematoxylin and eosin. Muscle fibers Are uniform in size and stain pink with eosin. Their nuclei stain blue with hematoxylin Section of normal adult muscle stained With Gomori trichrome stain. Muscle fibers are stained greenish blue And nuclei are dark red Rosette Jabbour, MD 7
  • 8.
    Type I: redfibers (myoglobin) slow contraction tonic activity not easily tired rich in mitochondria Aerobic metabolism (oxydation of glucose: succinodehydrogenase, cytochrome c oxidase) Type II: white fibers ( A,B) rapid contraction phasic activity easily tired Anaerobic metabolism (glycolysis, ATPase, phosphorylase) DIFFERENT TYPES OF FIBERS Rosette Jabbour, MD 8
  • 9.
    DISTRIBUTION OF HISTOCHEMICALFIBER TYPES IN NORMAL MUSCLE ( TYPE I, 2A, 2B ). ATPase stain pH 4.6 ( glycolytic enzyme activity ) Rosette Jabbour, MD 9
  • 10.
    2A 1 2B 1 NORMAL DISTRIBUTION OFOXIDATIVE ENZYME ACTIVITY IN NORMAL MUSCLE FIBERS. TYPE I FIBERS CONTAIN MORE MITOCHONDRIA THAN TYPE 2 FIBERS, AND STAIN DARKER. Cytochrome c oxidase stain Rosette Jabbour, MD 10
  • 11.
    TYPE 2 MUSCLEFIBER ATROPHY ( darker staining ) ATPase stain pH 9.4 Rosette Jabbour, MD 11
  • 12.
    MUSCLE FIBERS INDENERVATION ATROPHY LARGE GROUPS OF ATROPHIC FIBERS OF ALL HISTOCHEMICAL TYPES. ATPase stain pH 4.6 Rosette Jabbour, MD 12
  • 13.
    SITE OF THEMUSCLE LESION Muscle channel: sodium, potassium, chloride ( modification of the action potential ) Muscle structure: proteins in the membrane and sarcoplasm ( modification of the structure and trophicity of the fibers ) or the interstitial tissue ( secondary alteration of the myofibrils ) Muscle metabolism: source of energy: glycogen, lipids, mitochohondria ( modification of the function of the fibers ) Neuromuscular junction: postsynaptic acetylcholine receptors ( alteration of the neuromuscular transmission ) Rosette Jabbour, MD 13
  • 14.
  • 15.
  • 16.
    CLASSIFCATION OF MYOPATHIES HEREDITARY MUSCULARDYSTROPHIES without myotonia Duchenne and Becker muscular dystrophy ( DMD / BMD ) Emery - Dreifus muscular dystrophy Limb girdle muscular dystrophy ( LGMD ) Facioscapulohumeral dystrophy ( FSMD ) Oculopharyngeal muscular dystrophy MUSCULAR DYSTROPHIES with myotonia Myotonic dystrophy (classic form ) DM1 ( steinert ) Proximal myotonic dystrophy ( DM2 ) CHANNELOPATHIES Myotonia congenita Hyperkalemic periodic paralysis Hypokalemic periodic paralysis METABOLIC MYOPATHIES Glycogen storage diseases Lipid storage diseases Mitochondrial myopathies CONGENITAL MYOPATHIES Congenital muscular dystrophies Congenital myopathies (nemaline, myotubular, central core ) Malignant hyperthermia Rosette Jabbour, MD 16
  • 17.
    CLASSIFICATION OF MYOPATHIES ACQUIRED Inflammatorymyopathies ( PM-DM ) Inclusion body myopathies ( IBM ) Endocrine myopathies Myopathies associated with systemic disease (critical illness, trichinosis, amyloidosis..) Drug induced myopathies / toxic Rosette Jabbour, MD 17
  • 18.
    CLINICAL FINDINGS INMYOPATHY NEGATIVE 1- weakness 2- muscle atrophy 3- exercise intolerance and fatigue POSITIVE 1- myalgias 2- cramps 3- myotonia 4- stiffness 5- muscle hypertrophy 6- myoglobinuria 7- contractures 8- tendon reflexes Rosette Jabbour, MD 18
  • 19.
    WEAKNESS 1- PROXIMAL MUSCLEWEAKNESS Difficulty climbing stairs, arising from a chair, brushing hair, lifting objects overhead 2- DISTAL MUSCLE WEAKNESS Difficulty opening jars, turning a key, tripping 3- CRANIAL MUSCLE WEAKNESS dysphagia, dysarthria, diplopia (rare), ptosis, difficulty whistling, blowing up balloons, using a straw, sleeping with eyes open Rosette Jabbour, MD 19
  • 20.
    FUNCTIONNAL ASSESSMENT OFWEAKNESS Rosette Jabbour, MD 20
  • 21.
  • 22.
    MUSCLE ATROPHY ANDHYPERTROPHY Atrophy with time without fasciculations Hypertrophy, true: in MYOTONIA CONGENITA due to repetitive activity Hypertrophy, pseudo: in DMD, BMD, some LGMD, due to connective tissue proliferation MYALGIAS, CRAMPS AND EXERCISE INTOLERANCE Constant in most of inflammatory myopathies (myalgias) Frequent in drug-induced and hypothyroidism (myalgias, cramps) in electrolytes disturbances (cramps) Episodic, after or during exercises in metabolic and mitochondrial myopathies (myalgias and cramps) Rosette Jabbour, MD 22
  • 23.
  • 24.
    MYOTONIA Muscle stiffness anddifficulty in muscle relaxation due to repetitive depolarization of the muscle membrane Active and passive Worsening with rest and cold, improving with exercise: myotonia congenita Exacerbation with exercise and cold: paramyotonia congenita Some drugs exacerbate myotonia: β-blockers Rosette Jabbour, MD 24
  • 25.
    REFLEXES AND CONTRACTURES DTR: - preserved in pure myopathy - may be lost when there is advanced wasting - lost if there is a myopathy + neuropathy Contractures : - early in Emery- Dreifus and some LGMD - late in most myopathies: fixed contractures Rosette Jabbour, MD 25
  • 26.
    MYOGLOBINURIA Discoloration of urine: brown-black( like cola ), due to liberation of myoglobin from the muscle Causes : - Excessive exercise - Inflammatory myopathies - Viral/Bacterial infection - Metabolic myopathies: - Drugs and toxins glycogen: Mc Ardle - Neuroleptic malignant syndrome lipid: CPT deficiency - Heat stroke - LGMD 2C-F - Malignant hyperthermia - Prolonged fever - Prolonged immobilization - Metabolic disturbances Rosette Jabbour, MD 26
  • 27.
    NON MYOPATHIC FEATURES CNS,eyes ( retina ), GI, liver, endocrine, kidneys, blood, skin Cardiac: arrhythmias, heart failure Respiratory: due to diaphragm and respiratory muscle involvement Rosette Jabbour, MD 27 Muscular dystrophy Congenital myopathies Inflammatory myopathies
  • 28.
    CARDIAC COMPLICATIONS Rosette Jabbour,MD 28 Arrythmia CHF Congestive
  • 29.
    LABORATORY WORK-UP MUSCLEENZYMES Rosette Jabbour, MD 29 CK LEV ELS
  • 30.
    DIFFERENTIAL DIAGNOSIS OFCK ELEVATION HIGH CK WITH WEAKNESS HIGH CK WITHOUT WEAKNESS Rosette Jabbour, MD 30
  • 31.
  • 32.
  • 33.
    CLASSIFCATION OF MYOPATHIES HEREDITARY MUSCULARDYSTROPHIES without myotonia Duchenne and Becker muscular dystrophy Emery - Dreifus muscular dystrophy Limb girdle muscular dystrophy Facioscapulohumeral dystrophy Oculopharyngeal muscular dystrophy Rosette Jabbour, MD 33
  • 34.
    DUCHENNE MUSCULAR DYSTROPHY ■Incidence: 1/3000-4000 male births. X – linked . ■ Near total loss of dystrophin  structural protein bound to the sarcolemma providing structural integrity to the muscle membrane  Abnormal dystrophin gene located on chromosome Xp21  female carriers or spontaneous mutations ■ Clinical features:  new born: normal – high CK  babies: slight delay in walking( 18 months )  3-5 yrs: progressive weakness, proximal more than distal, pelvic girdle more than scapular  12-15 yrs: wheelchair  20-25 yrs: respiratory and cardiac complications Other musculoskeletal:  calf hypertrophy  heel cord shortening  hyperlordosis and kyphoscoliosis Extra-muscular:  cardiomyopathy with arrhythmias and congestive heart failure  gastro paresis and pseudo obstruction Rosette Jabbour, MD 34
  • 35.
    ■ Laboratory features: 1-CK markedly elevated ( 50-100X ) 2- EMG: abnormal polyphasic MUP normal NCV 3- Histopathology: a- muscle fibers degeneration and regeneration ( variation in size ) b- increased connective tissue c- marked reduction of dystrophin on immunostaining and on western blot analysis ■Treatment: 1- steroids - creatine 2- supportive therapy- bracing- surgery DUCHENNE MUSCULAR DYSTROPHY Rosette Jabbour, MD 35
  • 36.
  • 37.
    DMD- HE stain:cluster of necrotic and regenerating fibers Rosette Jabbour, MD 37
  • 38.
  • 39.
    BECKER MUSCULAR DYSTROPHY Incidence:1/20000 male births. X – linked Abnormal dystrophin ( reduced amount and abnormal function ) Phenotype similar to that of DMD, but delayed expression Severity variable, usually mild Life expectancy reduced but significantly longer than DMD Rosette Jabbour, MD 39
  • 40.
    BECKER MUSCULAR DYSTROPHY HEstain: chronic myopathic changes: variation of fiber Sizes, endomysial fibrosis, internal nuclei. Rosette Jabbour, MD 40
  • 41.
    EMERY- DREIFUS MUSCULARDYSTROPHY X – linked Much less severe weakness ( humero – peroneal ) Contractures ( Achilles tendons, elbows, posterior cervical muscles ) Cardiomyopathy with conduction defects: stroke and arrhythmias Abnormal structural protein of the nuclear membrane: Emerine Mutation in a gene located on chromosome Xq28 Rosette Jabbour, MD 41
  • 42.
    LIMB GIRDLE MUSCULARDYSTROPHY Incidence: 6-7/100000 births Autosomal recessive: LGMD-2 A, B, C,… Autosomal dominant : LGMD-1 A, B, C... ( less common ) Spontaneous mutations on different chromosomes 5, 1, 3, 6, 7… Abnormal structural proteins of the membrane and the cytoplasm of the muscular fiber: Sarcoglycans (α, β, γ..), dysferlin, merosin,.. Dystrophin is normal Clinical features not specific: early scapular, or early pelvic early onset, rapid progression late onset, slow progression Differential with other myopathies: inflammatory, metabolic,.. or neurogenic ( SMA ) Rosette Jabbour, MD 42
  • 43.
  • 44.
  • 45.
    FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY Incidence:4/million Autosomal dominant with variable degree of penetrance of clinical findings within families Gene not yet isolated. Could be present on the chromosome 4q35 Clinical features: age of onset variable: 5 to 45 years facial muscles are affected the earlier ( incomplete eye closure ) scapular winging weakness of biceps and triceps weakness of tibialis anterior: foot drop pelvic girdle later: hyperlordosis Normal life span Rosette Jabbour, MD 45
  • 46.
    OCULOPHARYNGEAL MUSCULAR DYSTROPHY Autosomaldominant Mutations on the chromosome 14q11 Clinical features:  in fourth to six decades  bilateral ptosis  difficulty in swallowing 1/4  extra ocular muscles affected 1/2 ( usually without diplopia)  mild weakness of the neck and proximal limbs (sometimes) Slow progression and normal life span CK normal or mildly elevated Rosette Jabbour, MD 46
  • 47.
    CLASSIFCATION OF MYOPATHIES HEREDITARY MUSCULARDYSTROPHIES without myotonia Duchenne and Becker muscular dystrophy Emery - Dreifus muscular dystrophy Limb girdle muscular dystrophy Facioscapulohumeral dystrophy Oculopharyngeal muscular dystrophy MUSCULAR DYSTROPHIES with myotonia Myotonic dystrophy (classic form )( DM1) ( STEINERT disease ) Proximal myotonic dystrophy ( DM2 ) Rosette Jabbour, MD 47
  • 48.
    MUSCULAR DYSTROPHIES withMYOTONIA MYOTONIC DYSTROPHY ( classic form) STEINERT DISEASE Incidence: 1/8000. most frequent dystrophy in adults Autosomal dominant Chromosome 19q13.2- increased number of repetition of CTG coding the myotonin protein kinase Clinical features:  myotonia  weakness and atrophy: - limbs: distal lower part of the forearm, intrinsic muscles of the hands, peroneal muscles. - head: ptosis, wasting of temporalis and masseter muscles orbicularis oris (eversion of the lower lip), sternocleidomastoid, tongue, pharyngeal and laryngeal muscles, abnormal voice Rosette Jabbour, MD 48
  • 49.
    MYOTONIC DYSTROPHY Extra muscularmanifestations:  Frontal balding  Sub scapular cataract  Atrophy of testicles, impotence with high FSH and preserved sexual characters  Cardiac conduction defects (long PR – AV block )  Dysphagia and chronic pseudo obstruction  Hypoventilation (diaphragm, intercostal muscles) decreased central drive with sleep apnea  Cognitive impairment, mental retardation Life span reduced Rosette Jabbour, MD 49
  • 50.
  • 51.
    STEINERT- Gomori trichromestain: increase in the number of fibers containing Internal nuclei Rosette Jabbour, MD 51
  • 52.
  • 53.
    CLASSIFCATION OF MYOPATHIES HEREDITARY MUSCULARDYSTROPHIES without myotonia Duchenne and Becker muscular dystrophy Emery - Dreifus muscular dystrophy Limb girdle muscular dystrophy Facioscapulohumeral dystrophy Oculopharyngeal muscular dystrophy MUSCULAR DYSTROPHIES with myotonia Myotonic dystrophy (classic form ) STEINERT CHANNELOPATHIES Myotonia congenita Hyperkalemic periodic paralysis Hypokalemic periodic paralysis Paramyotonia congenita Central core disease Anderson - Tawil syndrome Rosette Jabbour, MD 53
  • 54.
    MYOTONIA CONGENITA Mutation ofCLCN1 (chloride channel gene) on chromosome 7q35 Autosomal dominant: Thomsen Autosomal recessive: Becker Clinical features:  Myotonia: improving by repetition of movements (warm up phenomenon)  Muscle hypertrophy: athletic, herculean appearance  Muscle stiffness  No weakness Recessive :  Myotonia worse  Proximal weakness Life span normal Lab: CK normal or slightly elevated EMG: myotonic discharges Rosette Jabbour, MD 54
  • 55.
  • 56.
    HYPOKALEMIC PERIODIC PARALYSIS Age atonset: puberty Duration of episodes: hours- days Weakness: episodic, possibly permanent later in life Myotonia: absent Precipitants: cold, rest after exercise, carbohydrate loading Alleviating factors: potassium loading, exercise Inheritance, gene mutation: AD, CACNL1A, SCN4A, 17q23 Remark: always look for hyperthyroidism Age at onset: infancy-early childhood Duration of episodes: minutes-hours Weakness: episodic, possibly permanent later in life Myotonia: possibly ( between episodes of weakness) EMG (+) Precipitants: potassium loading, cold, fasting, rest after exercise Alleviating factors: carbohydrate loading, exercise Inheritance, gene mutation: AD, SCN4A, 17q23 HYPERKALEMIC PERIODIC PARALYSIS Rosette Jabbour, MD 56
  • 57.
    CLASSIFCATION OF MYOPATHIES HEREDITARY MUSCULARDYSTROPHIES without myotonia Duchenne and Becker muscular dystrophy Emery - Dreifus muscular dystrophy Limb girdle muscular dystrophy Facioscapulohumeral dystrophy Oculopharyngeal muscular dystrophy MUSCULAR DYSTROPHIES with myotonia Myotonic dystrophy (classic form ) STEINERT CHANNELOPATHIES Myotonia congenita Hyperkalemic periodic paralysis Hypokalemic periodic paralysis METABOLIC MYOPATHIES Glycogen storage diseases Lipid storage diseases Mitochondrial myopathies Rosette Jabbour, MD 57
  • 58.
    GLYCOGEN STORAGE DISEASES ►Glycogen storage disease type II: Acid maltase deficiency: 1- Autosomal recessive ( 17q23-25 ) 2- Lysosomal enzyme(α-glycosidase: conversion of glycogen to glucose) 3- Severe infantile form: Pompe’s disease cardiomyopathy, hepatomegaly, hypotonia, feeding and respiratory weakness 4- Less virulent juvenile or adult type = Limb girdles ► Glycogen storage disease type V: Mc Ardle disease 1- Autosomal recessive 2- Muscular phosphorylase 3- Cramps, stiffness pain on exertion, myoglobinuria Rosette Jabbour, MD 58
  • 59.
    Vacuoles, subsarcolemma, containingPAS (+) material ( glycogen ) Rosette Jabbour, MD 59
  • 60.
    EM: accumulation ofglycogen in the sub sarcolemma Rosette Jabbour, MD 60
  • 61.
    LIPID STORAGE DISEASES CPT1and CPT2 ( carnitine- palmityl transferase ) deficiency: Enzymes required for the active transport of long chain fatty acids into mitochondria For β-oxidation which is a process of aerobic energy production converting these FA To acetyl –CoA which then used to generate ATP Episodic exercise-induced myalgia, myoglobinuria and weakness Myalgias occur after exercise, or during prolonged exercices and fasting ( glcogen storage diseases: during exercises ) Myalgias without cramps and myoglobinuria Muscle biopsy may show lipid accumulation CK normal between attacks Rosette Jabbour, MD 61
  • 62.
    Gomori trichrome stain:vacuoles containing lipids Rosette Jabbour, MD 62
  • 63.
    Red oil stain:vacuoles filled with lipids ( red material ) Rosette Jabbour, MD 63
  • 64.
  • 65.
    MITOCHONDRIAL MYOPATHIES Multisystem diseases,sometimes confined to muscle (brain, liver, kidneys) Autosomal recessive, dominant or X-linked DNA mutations responsible for enzyme deficiency, or structural abnormalities CLINICAL MANIFESTATIONS : - non specific: mild weakness, episodic weakness with acidosis, precipitated by infection, alcohol or exercise. Myalgia, exercise-induced cramps, rhabdomyolysis, myoglobinuria. - specific presentations: Chronic progressive external ophtalmoplegia Kearns-Sayre syndrome: ptosis, ophtalmoplegia, pigmentary retinopathy, with heart block or high protein in CSF, or cerebellar ataxia - other presentations: MELAS: mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes MERRF: myoclonic epilepsy with ragged red fibers Leber’s hereditary optic neuropathy Leigh’s syndrome LAB: CK normal, high lactate on aerobic exercise muscle biopsy with immunostaining and electron microscopy genetic testing in blood, urine and muscle. Rosette Jabbour, MD 65
  • 66.
    Ragged-red fibers withincreased sub sarcolemmal red staining membranous material ( accumulation of mitochondria ) Gomori trichrome stain Rosette Jabbour, MD 66
  • 67.
    EM: collections ofabnormal mitochondria containing abnormal inclusions Rosette Jabbour, MD 67
  • 68.
    Cytochrome oxidase negativefibers ( cytochrome c oxidase stain ) Rosette Jabbour, MD 68
  • 69.
    CONGENITAL MYOPATHIES Myopathic disorderspresenting preferentially at birth But not exclusively CONGENITAL MUSCULAR DYSTROPHIES 1- Hypotonia + arthrogryposis +abnormal myelination ( mental retardation) 2- Some are related to deficit in merosine ( membrane of the muscle fiber ) OTHER CONGENITAL MYOPATHIES 1- Less severe 2- Neonatal onset or delayed 3- Specific : • Nemaline myopathy • Myotubular myopathy • Central core disease Rosette Jabbour, MD 69
  • 70.
  • 71.
    MALIGNANT HYPERTHERMIA Incidence: 1/7000-1/50000anesthetics given 50% had previous anesthesia without clinically manifesting the disorder Autosomal dominant. at least 6 different genes identified Mutations in RyR1(ryanodine receptors) on chromosome 19q13 Activation of mutant receptors causes calcium release from sarcoplasmic reticulum stores, leading to excessive muscle contraction, overproduction of heat, fever and rhabdomyolysis. Precipitated by depolarizing muscle relaxants( succinylcholine ), and halogenated inhalation anesthetic agents ( isoflurane ) Other conditions that predispose: myotonia congenita, periodic paralysis, myotonic dystrophy, Duchenne and Becker dystrophies, mitochondrial disorders, CPT deficiency. Clinical manifestations: severe muscle rigidity, myoglobinuria fever, tachycardia, arrhythmias Testing: genetic susceptibility test (fresh muscle sample with halothane or caffeine) Rosette Jabbour, MD 71
  • 72.
    CLASSIFICATION OF MYOPATHIES ACQUIRED Inflammatorymyopathies ( PM-DM ) Inclusion body myositis Endocrine myopathies Myopathies associated with systemic disease (critical illness, trichinosis, amyloidosis..) Drug induced myopathies / toxic Rosette Jabbour, MD 72
  • 73.
    INFLAMMATORY MYOPATHIES GENERAL REMARKS: Characterizedby: muscle weakness, high CK, inflammation on biopsy 3 major groups: ► Idiopathic inflammatory myopathies ( of unknown etiology ) ■ Dermatomyositis (the most common in childhood and adulthood) ■ Polymyositis (rare, overdiagnosed, many turn out to be IBM, or DM with minimal rash, or muscular dystrophy with inflammation) ■ Inclusion body myositis( most common in patients older than 50 yrs) ► Myositis associated with connective tissue disease (SLE, Sjogren, RA, ..) ► Myositis due to infection (virus, HIV, trichinosis,..) PAYHOPHYSIOLOGY: DM: humoral mediated microangiopathy of the skin and muscle. Weakness is related to ischemia/infarction of muscles PM: cell mediated autoimmune attack against specific antigen in muscle fibers IBM: unclear cell mediated like PM inflammation secondary to a degenerative myopathy ? (poor response to immunosuppression) Rosette Jabbour, MD 73
  • 74.
    CLINICAL FEATURES: DM: 1- acuteor insidious onset of proximal greater than distal 2- skin rash: heliotrope, forehead and malar regions, chest and neck, extensor surface of extremities and joints 3- other organs: interstitial lung disease(10-20%), myocarditis, GI bleeding, arthritis. 4- increased risk of malignancy PM: 1- same as DM 2- with no rash IBM: 1- Insidious onset of proximal and distal weakness 2- early involvement of wrist and fingers flexors with relative sparing of deltoids, and of quadriceps and ankle dorsiflexion 3- weakness is often asymmetric 4- cranial muscles spared except for dysphagia, sometimes 5- no increased risk of malignancy Rosette Jabbour, MD 74
  • 75.
  • 76.
    LABORATORY FEATURES: DM/PM: 1-CK canbe normal early or when onset is insidious more commonly high ( more than 10X ) 2-CK not a good indicator of disease activity 3-ANA positive when underlying CTD 4-Anti-jo-1 positive when ILD IBM: 1-CK normal or mildly elevated ( less than 10X ) 2-Autoantibodies uncommon and non significant ELECTRODIAGNOSTIC FEATURES: 1-Increased spontaneous activities ( fibrillation potentials, positive sharp waves ) 2-MUP: small amplitude, short duration, polyphasic with earl recruitment . Rosette Jabbour, MD 76
  • 77.
    HISTOLOGIC FEATURES: DM: a-infiltration by inflammatory mononuclear cells of the perimysium and the perivascular space b- perifascicular atrophy c- immune complex deposition on small blood vessels d- no endomysial inflammation and no invasion of non necrotic fibers PM: a- infiltration by inflammatory mononuclear cells of the endomysium and invasion of non necrotic muscle fibers IBM: a- infiltration by inflammatory mononuclear cells of the endomysium and and invasion of non necrotic fibers b- presence of rimmed vacuoles in the muscle fibers c- mitochondrial abnormalities d- EM: 15-21 nm tubulofilamants in the cytoplasm of vacuolated fibers, and less commonly in nuclei e- 20-30% will not demonstrate all these findings leading to erroneous diagnosis of PM ( importance of the clinical pattern ) Rosette Jabbour, MD 77
  • 78.
    DM- HE stain:inflammatory infiltrates in the perimysium - perivascular Rosette Jabbour, MD 78
  • 79.
    DM- HE stain:perifascicular atrophy Rosette Jabbour, MD 79
  • 80.
    PM- HE stain:inflammatory infiltrates present at several endomysial sites Rosette Jabbour, MD 80
  • 81.
    PM- HE stain:focal invasion of a non-necrotic fiber by inflammatory cells Rosette Jabbour, MD 81
  • 82.
    IBM- Gomori trichromestain: inflammatory cells focally invade a non-necrotic muscle fiber Rosette Jabbour, MD 82
  • 83.
    IBM- Gomori trichromestain: muscle fibers with rimmed vacuoles Rosette Jabbour, MD 83
  • 84.
    IBM- EM: filamentousinclusions near an autophagic vacuole containing degenerating membranous material with myeloid figures Rosette Jabbour, MD 84
  • 85.
    IBM- EM: intranuclearfilamentous inclusions Rosette Jabbour, MD 85
  • 86.
    ENDOCRINE MYOPATHIES Important roleof the endocrine system in controlling the structure and the function of the muscle. 1- HYPERTHYROIDISM 2- HYPOTHYROIDISM 3- HYPERCORTICISM 4- HYPOCORTICISM Signs are not specific Proximal weakness of variable intensity Muscular atrophy, cramps, slow relaxation Periodic paralysis Rosette Jabbour, MD 86
  • 87.
  • 88.
  • 89.
    SPECIFIC TREATMENT FORMUSCLE DISEASE Rosette Jabbour, MD 89
  • 90.
    SPECIFIC TREATMENT FORMUSCLE DISEASE conditions Specific treatment Rosette Jabbour, MD 90