Approach to the patient with Myopathy By Michael May, 2007
Outline • Basics • Clinical manifestations • Diagnostic approach • Individual myopathies • Approach to the patient
Skeletal muscle • Composed of muscle fibers that contract when stimulated by a motor neuron • Skeletal muscle: covered by connective tissue sheath( epimysium) : composed of many columns( fascicles) • Fascicles: surrounded by perimysium :composed of many muscle fibers • Muscle fibers: covered by cell membrane ( sarcolemma) and surrounded by endomysium. :anatomic and physiologic unit . Two types : 1. Type - I / slow twitch/ red fibers : richer in oxidative but poorer in glycolytic enzymes. 2. Type- II/ fast twitch/ white fibers :richer in glycolytic but poorer in oxidative enzymes. : composed of nuclei, cytoplasm ( sarcoplasm), myofibrils, ribosomes, mitochondria, stored fat, many enzymes, glycogen, myoglobin.
Cont,d • Myofibril : longitudinally oriented interdigitating filaments of contractile proteins ( Actin, Myosin) & regulatory proteins ( Troponin, tropomyosine, nebuline). : Thick filaments: composed of protein, Myosin. : Thin filaments: composed of protein , Actin. : enveloped by a membranous net ( sarcoplasmic reticulum) • Motor unit : each somatic motor neuron together with all of the muscle fibers it innervates. : each neuron innervates muscle fibers of one type only. : Neuromuscular junction( NMJ) : junction of the terminal of the motor neuron with the muscle fiber. : Motor end plate: specialized region of the sarcolemma of the muscle fiber at the NMJ.
Cont,dMotor unit courtesy : Prof. Janzer
Cont,d • Muscle contraction: sliding of thin filaments over and b/n thick filaments by the action of numerous cross bridges that extend out from the myosine toward the actin. • : muscle fiber stimulation by motor neuron → ca+2 moves from its store site in the sarcoplasmic reticulum to the sarcoplasm→ attaches to troponine → conformational change that moves the troponin complex and its attached tropomyosine out of the way so that cross bridges can attach to actin→ sliding of filaments and thus muscle tension and shortening. ▪ Energy source : fatty acids , glycogen and blood glucose, aminoacids : skeletal muscles generate ATP through anaerobic and aerobic respirations and phosphate groups donated by creatine phosphate. ATP : serves as the immediate source of energy for 1. movement of cross bridges for muscle contraction 2. pumping of ca+2 in to the sarcoplasmic reticulum for muscle relaxation.
Cont,d • Mitochondria : plays key role in energy production • Anaerobic respiration : major source of energy during exercise Glucose → Lactic acid + ATP • Aerobic respiration : lipids – important sources of energy during rest & during prolonged submaximal exercise VLDL Triglycerides → fatty acids → activated fatty acids/ acyl-coA/ ↓ CPT-I linked with carnitine ↓ mitochondria ↓ CPT-II ATP ← Beta oxidation ← acyl-coA + carnitine
Myopathy • Defn. : disorders with structural changes or functional impairment of a muscle; unrelated to any disorder of innervation or NMJ. • Classification : 1. Acquired 2. Hereditary/ genetic : mutations or deletions of genes coding for parts of a muscle ( filament proteins, mitochondrial enzymes, sarcoplasmic reticulum, specialized channels for entry of ca+2 , Na+2, Cl- , K+1 transverse tubules, sarcolemma ) : affect structure or biochemical processes which convert chemical energy derived from cell metabolism in to mechanical energy in a controlled manner.
Causes • Inflammatory • Metabolic • Toxic • Congenital /inherited • Endocrinopathies • Chanellopathies • Muscular dystrophies
Clinical presentation • Muscle weakness • Fatigue • Muscle pain( myalgia), cramps and stiffness • Muscle contracture • myoglobinuria • Myotonia • Muscle enlargement and atrophy • Manifestations of specific illnesses
Muscle weakness • Symptoms: Proximal – difficulty in combing hair, getting up from a chair, climbing stairs, getting up from a squatting position. :Distal – difficulty buttoning, writing, knitting. • Types: Intermittent ( periodic)- proximal > distal ( limb- girdle pattern ) - HypoKPP, HyperKPP, paramyotonia congenita - metabolic energy deficiencies of glycolysis - abnormalities in fatty acid metabolism - myasthenia gravis: NCS~ repetitive nerve stimulation decremental response : Persistent ( fixed) - most muscle disorders - limb - girdle pattern /face spared/ is common - some patterns are restricted to certain diseases.
Inability to maintain or sustain a force fatigue • Pathologic fatiguability -Disorders of neuromuscular transmission, disorders altering energy metabolism ( glycolysis, lipid metabolism), disorders in mitochondrial energy production - Chronic myopathies - Accompanied by abnormal clinical or laboratory findings • Asthenia - a type of fatigue caused by excess tirdeness or lack of energy - a tendency to avoid physical activities - complaints of daytime sleepiness - necessity for frequent naps - difficulty concentrating on activities such as reading - feelings of overwhelming stress & depression
Muscle pain (myalgia), cramps, and stiffness- not a feature of most primary muscle diseases • Cramp: painful, involuntary, localized, muscle contraction with a visible or palpable hardening of the muscle. : often occur in neurogenic disorders/ motor neuron diseases, radiculopathies, polyneuropathies/ : common in patients with Duchenne MD : firing of MUAPs at a rate of 40-60 Hz, with abrupt onset & cessation • Myalgia: localized or generalized and may be accompanied by tenderness & swelling. :should be differentiated from myofascial pain syndromes • Fibromyalgia▪polymyalgia rheumatica - have specific trigger points - in patients > 50yrs of age - easy fatiguability - stiffness & pain in the shoulders, - sleep disturbances lower back, hips, and thighs - serum CK & ESR are normal - ESR elevated - CK, EMG & muscle biopsy are N
Cont,d stiffness • Uncommon • Joint inflammation • Hyperexcitable motor nerves( spinal cord, peripheral nerves) contracture • Muscle unable to relax after after an active muscle contraction • EMG shows complete electrical silence ( firing of motor neurons in a cramp) • Uncommon in most muscle diseases • Fixed contracture occurs early in patients with Emery- Dreifuss MD & Bethlem myopathy.
Cont,d myoglobinuria ▪ dark or dark- brown urine Myotonia • prolonged muscle contraction followed by slow muscle relaxation • voluntary contraction, mechanical stimulation ( percussion myotonia) • DM, myotonia congenita, paramyotonia congenita Muscle enlargement and atrophy • Size of muscle is usually not affected. • Enlarged cuff muscles are typical Duchenne & Becker MDs. • Can also result from infiltration by sarcoid granulomas , amyloid deposits, bacterial and parasitic infections, and focal myositis.
Laboratory evaluation • Diagnose myopathy • Serum enzymes - ALT, AST, LDH, Aldolase : found in both skeletal muscle & liver : elevated GGT helps to establish a liver origin. - CK ( CKMM) :preferred enzyme to measure in the evaluation of myopathies. • Electrodiagnostic studies - NCS, Repetitive nerve stimulation : help to differentiate myopathies from neuropathies & NMJ disorders. - EMG : diagnose myopathy, helps also to choose an appropriately affected muscle for biopsy. - Myopathic EMG: low amplitude, short duration & polyphasic MUPs - inflammatory myopathies : increased spontaneous activity, irritability on needle placement. - myotonic discharges : sustained run of positive sharp waves : sustained run of negative spikes
Lab. Cont,d • Diagnose specific types of myopathies • Forearm exercise test - place a small indwelling catheter in to an antecubital vein & obtain baseline blood sample for lactic acid and ammonia. - the fore arm muscles are exercised by asking the patient to vigorously squeeze a sphygmomanometer bulb for 1 min. -blood is then obtained at intervals of 1,2,4,6 & 10 min. for comparison with the baseline. Both rise with exercise. - Glycolytic defects : lactic acid rise is absent or below normal while rise in ammonia will reach control values. - myoadenylate deaminase deficiency: selective failure to increase ammonia.
Lab. Cont,d • DNA analysis - for definite diagnosis of certain muscle disorders associated with gene defects ( deletions or mutations ). • Muscle biopsy - safe diagnostic procedure in establishing the final diagnosis of suspected myopathy. - different techniques of microscopic evaluation ( histochemistry, immunohistochemistry with a battery of antibodies, electron microscopy) - site :muscle selected for biopsy should have mild to moderate muscle weakness. : not performed on a muscle that has been injured by a previous trauma, injections, EMG needles( within 4-6 weeks after EMG ) - common muscles used for biopsy : proximal – Biceps, Triceps, Quadriceps : Distal – Extensor carpi radialis, Anterior tibialis
Approach to the patient • Emergency: manage acute life threatening complications Respiratory insufficiency : mechanical ventilator Dysphagia : endotracheal intubation Rhabdomyolysis : hydration, diuresis Heart block : pace maker insertion HypoKPP : iv. Or oral potassium replacement • Non-emergency : identify a disorder as a myopathy : identify a specific etiology for the myopathy • History - symptoms : muscle weakness, presence or absence of sensory complaints , acuity of symptom onset - family history of muscle weakness, frontal baldness - personal history of autoimmune disease , endocrinopathy, renal insufficiency, alcoholism - Previous history of severe weakness, particularly any that occurred after exercise, exposure to cold temperatures, eating high CHO diets
Approach cont,d - history of medication use • Physical examination - objective weakness - fever ( polymyositis ) - muscle tenderness - muscle mass : atrophy is a very late sign - skin examination : Gottron’s papule, heliotrope rash - level of consciousness : usually normal - sensory perception : normal - DTR : usually normal : may be absent or diminished in HypoKPP • Laboratory tests : CBC, ESR, CK isoenzymes, electrolytes, U/A serum myoglobin, RFT, TFT Definitive diagnosis : EMG, Genetic testing, ANA, Muscle enzymes, muscle biopsy
Muscular dystrophies • Group of inherited disorders characterized by progressive degeneration of groups of muscles, sometimes with involvement of the heart muscle or conducting tissue, and other parts of the nervous system. • Classified based on the age at onset, distribution of affected muscles and pattern of inheritance. Duchenne muscular dystrophy • Inheritance- X- linked recessive disorder • Defective gene- Dystrophin • Onset- usually b/n 3-5yrs age • C/F – progressive weakness of the girdle muscles - difficulty running , jumping, hopping, unable to get up from the floor (Gower’s maneuver) - toe walking is associated with lordotic posture - contractures( hip, knee, elbow, wrist) with chest deformities →severe pulmonary infections → death at age 16-18yrs
Cont,d Others : cardiomyopathy , mental retardation • Lab. – Serum CK : elevated 20-100x normal - EMG : myopathic features - Muscle biopsy: muscle fibers of varying size as well as small groups of necrotic and regenerating fibers. : deficiency of dystrophin seen on western blot analysis & immunohistochemical staining. - DNA analysis : mutation of gene that encodes dystrophin • Treatment : prednisolone 0.75mg/kg/day increases muscle strength & slows the progression of disease for up to 3 yrs.
Becker muscular dystrophy • Inheritance – X- linked recessive disorder • Defective gene – dystrophin • Onset- experience difficulty b/n 5- 15yrs of age • C/F – proximal muscles especially of lower extremities are prominently involved. - hypertrophy of muscles , particularly the calves, is an early & prominent finding. - cardiomyopathy may occur , MR is less common • Lab. – CK : elevated - EMG : myopathic - muscle biopsy : similar to DMD : reduced amount or abnormality of dystrophin( Dx) - DNA analysis : deletions or duplications( Dx) • Treatment – supportive • Survival : survive in to the 4th to 5th decade
Limb- girdle muscular dystrophy/ LGMD / • Inheritance : Autosomal dominant/ recessive • Defective gene : several genes • M:F – 1:1 • Onset – late 1st to 4th decade • C/F – progressive weakness of pelvic & shoulder girdle muscles - diaphragmatic weakness & cardiomyopathy may also occur - intellectual function is intact • Treatment - supportive
Emery- Dreifuss muscular dystrophy/EDMD/ • Inheritance- X-linked recessive/ Autosomal dominant • Defective gene : Emerin/ Lamins A/C • Onset – early childhood & teenage years • C/F – prominent and early contractures ( elbows, neck) often preceding muscle weakness. - muscle weakness is in a limb- girdle distribution - dilated cardiomyopathy may occur and may result in sudden death, arrhythmia, & conduction defects. ▪ Lab. - CK : 2-10x ed - EMG : Myopathic - Biopsy : non-specific dystrophic features • Treatment - supportive : Ambulatory aid : manage cardiomyopathy & arrhythmia
Fascioscapulohumeral /FSH/ muscular dystrophy • Inheritance: AD • Onset : childhood or young adulthood • Defective gene: deletion, distal 4q • C/F- facial weakness: initial manifestation - weakness of shoulder girdle muscles : weak arm elevation : scapular winging - weak wrist extension > wrist flexion - foot drop : weakness of anterior compartment muscles of the legs - weakness of the pelvic girdle muscles : 20% - other organ ( rarely) : labile HTN, nerve deafness • Lab. – CK : N or elevated - EMG: myopathic pattern - biopsy: non-specific features of myopathy • Treatment – no specific treatment is available - ankle foot orthoses may help for foot drops - scapular stabilization procedures may improve scapular winging
Oculopharyngeal dystrophy • Inheritance: AD with complete penetrance • Defective gene: expansion, poly-A-RNA binding protein • Onset – usually late onset ( 4th – 5th decade ) • C/F – progressive external ophthalmoplegia ( slowly progressive ptosis, limitation of eye movements with sparing of pupillary rxns. - dysphagia : can be life threatening : may result in repeated episodes of aspiration - mild weakness of the neck and extremities • Lab. – EMG: myopathic features - CK : 2-3x N - biopsy : distinct features – presence of tubular filaments in muscle cell nuclei. • Treatment- Dysphagia : cricopharyngeal myotomy may improve swallowing - Ptosis : eyelid crutches may improve vision
Distal myopathies • Notable for their preferential distal distribution of muscle weakness in contrast to most muscle conditions associated with proximal weakness • Four types : mode of inheritance, age of onset, pattern of weakness 1. Welander DM : AD 2. Tibial MD : AD - late onset, usually after age 40; start in the hands 3. Nonanka DM: AR 4. Miyoshi myopathy : AR - early onset in late teens or twenties; start in the lower limbs • Lab. – CK : only slightly elevated except in Miyoshi myopathy - Biopsy : non- specific dystrophic changes - EMG : myopathic • Treatment – occupational therapy for loss of hand function - Ankle - foot orthoses to support distal lower limbs
Myotonic dystrophy/ DM / • Inheritance : AD • Defective gene: two types with distinct molecular genetic defects -DM1 : expansion CTG repeat - DM2 ( proximal myotonic myopathy – PROMM ): CCTG repeat • C/F – myotonia : usually appears by age 5 yrs - Hatchet- faced appearance: temporalis , masseter , facial muscle atrophy & weakness - frontal baldness in men - foot drop : ankle dorsiflexor weakness - weakness of wrist extensors , finger extensors, & intrinsic hand muscles - early involvement of neck muscle flexors, sternocleidomastoids - dysarthritic speech, nasal voice, swallowing problems due to palatal , pharyngeal, and tongue involvement - respiratory insufficiency : diaphragm & intercostal muscle involvement - cardiac disturbances : conduction block with sudden death : CHF from cor pulmonale 2ry to respiratory failure
Cont,d Hatchet-faced appearance
Cont,d • - other system manifestations : intellectual impairment, hypersomnia, cataract, gonadal atrophy, insulin resistance, reduced esophageal & colonic motility • Lab. – Dx ; usually based on clinical findings - CK : N or mildly elevated - EMG : evidence of myotonia - Biopsy : atrophy which selectively involves type – 1 fibers in 50% • Treatment – treat myotonia : membrane stabilizing agents : phenytoin is preferred - pacemaker for advanced conduction block - molded ankle foot - orthoses help prevent foot drop in patients with distal lower extremity weakness.
Congenital myopathy • Rare disorders distinguished from muscular dystrophies by the presence of specific histochemical & structural abnormalities in muscle fibers. • Onset : infancy or childhood • Three types: pattern of inheritance & type of structural abnormality in muscle fibers -central core disease : AD - Nemaline (rod ) myopathy: AD - Myotubular( centronuclear ) myopathy : AD , XR • C/F - progressive muscle weakness ( proximal> distal, legs> arms) & limpness, hypotonia & delayed milestones /walking/ - skeletal deformities (kyphoscoliosis, club foot, hip dislocation) • Lab. - CK: usually N or slightly elevated - EMG : myopathic/ mostly/; positive sharp waves, myotonic discharges - Biopsy : features specific to each type • Treatment – no specific treatment
Disorders of muscle membrane excitability/chanellopathies/ • Inherited abnormalities (mutations) of the Na+, Ca+2, K+, Cl- ion channels in striated skeletal muscles. • C/F- various syndromes of familial periodic paralysis affecting proximal muscles more than distal, mostly sparing ocular , bulbar and respiratory muscles. : long term repeated attacks may result in fixed proximal weakness. - myotonia : paradoxic in PC (aggravated by exercise ) :HyperKPP ( K+ -aggravated myotonia) , few cases of HypoKPP • Inheritance – AD except few sporadic cases • Recognized by their : clinical characteristics : provocation by exercise, eating , cold exposure, and associated changes : serum potassium concentration during an attack
HypoKPP Attacks may stay for as long as 24hrs Precipitated by rest following exercise, meals high in CHO, Na+ Biopsy shows single or multiple centrally placed vacuoles Rx of acute paralysis - K+ supplementation (oral or IV ) Prevention of recurrent attacks -low CHO, Na+ diet -avoid intense exercise -K+ -sparing diuretics -Acetazolamide 125-1000mg/day HyperKPP Attacks are brief and mild (30’- 4hrs) Precipitated by rest following exercise, fasting and K+ administration Biopsy shows vacuoles that are smaller, less numerous & more peripheral compared to HypoKPP Rx of acute paralysis - not important Prevention of recurrent attacks -increase CHO in diet -K+ - losing diuretics -Acetazolamide 125 – 1000mg/day Cont,d
Mitochondrial myopathies • Mitochondria plays a key role in energy production • Inherited disorders of the oxidative pathways of the respiratory chain. • Onset : most in childhood or early adulthood • Lab. - CK : usually N or slightly ed - Serum lactate : usually ed - EMG : myopathic - NCS : neuropathic features in some with peripheral neuropathy - Biopsy :modified trichrome stain - ‘ragged red fiber ‘ appearance :electron microscopy - muscle fibers with significant numbers of abnormal mitochondria • Structures affected: skeletal muscles, CNS, endocrine glands, heart • Course : progressive & downhill • Treatment : supportive - exercise - pace maker insertion for heart block - treat epilepsy - treat endocrinopathies
Cont,d…Ragged red fiber appearance • courtesy : Prof. Janzer
Clinical manifestations fall in to three groups 1. progressive external ophthalmoplegia ( CPEO ): > 50%, characterized by ptosis & extra ocular muscle weakness in the absence of diplopia KSS, AD- CPEO, ARCO 2. skeletal muscle- CNS syndromes : MERRF, MELAS 3. pure myopathy simulating muscular dystrophy Kearns sayre syndrome ( SSS ) - sporadic, non-inherited disorder, single deletions of mtDNA -Triads : CPEO : pigmentary retinopathy : heart block &/or cerebellar ataxia, &/or CSF protein>100mg/dl others: short stature ,dementia, MR, sensory neural hearing loss, diabetes, hypothyroidism, gonadal dysfunction in both sexes. -Course – most die in their 4th or 5th decade
Cont,d Myoclonic Epilepsy with Ragged Red Fibers/ MERRF/ • Point mutation of mitochondrial transfer RNA • C/F - myoclonic epilepsy: integral part & may be the initial symptom - cerebellar ataxia : progressive, both trunks & the limbs - progressive muscle weakness : limb- girdle distribution • others: dementia, optic atrophy, peripheral neuropathy, hearing loss , Diabetes • Rx- supportive with special attention to epilepsy
Cont,d Mitochondrial myopathy, Encephalopathy, Lactic acidosis, Stroke-like episodes / MELAS / • Most common encephalomyopathy • Maternally inherited point mutations of mtRNA gene • C/F - partial or generalized seizures : could be the 1st sign - stroke- like Sxs- hemiparesis, hemianopia, cortical blindness - serum lactic acid : typically ed • others : dementia, hearing loss, hypothyroidism, diabetes, hypothalamic- pituitary dysfunction • Neuroimaging : basal ganglia calcifications in high percentage of cases • Treatment – supportive , fatal outcome
Cont,d Pure myopathy syndrome • C/F – muscle weakness and fatigue which makes differentiation from muscular dystrophies difficult. • Onset - usually neonatal, occasionally at a later age - weakness, hypotonia, delayed milestones & death before age 2 yrs • Treatment – supportive care similar to muscular dystrophies • t
Disorders of muscle energy metabolism • Abnormalities in either glucose or lipid utilization • Presentation : acute painful syndromes with rhabdomyolysis & myoglobinuria :chronic progressive muscle weakness simulating dystrophies
Cont,d • Disorders of glycogen storage causing progressive muscle weakness • C/F – usually present during infancy - severe muscle weakness, delayed milestones,, cardiomegally, hepatomegally, respiratory insufficiency - death usually occurs by 1 yr of age • Three types: 1. Debranching enzyme deficiency 2. Branching enzyme deficiency 3. Acid maltase deficiency – commoner, AR inheritance -can present during adulthood ( heart & liver not involved) -respiratory failure & diaphragmatic weakness are often initial manifestations, heralding progressive proximal weakness Dx- membrane bound & free tissue glycogen on electron microscopy - definitive diagnosis through enzyme determination in muscle Rx. – recombinant enzyme replacement may improve muscle weakness & prolong life.
Disorders of glycolysis causing exercise intolerance • Defects in genes encoding the abnormal proteins. • Effects: failure to support energy production at the initiation of exercise • Onset : adolescence • C/F – painful muscle contractures followed by myoglobinuria - Sxs are precipitated by brief bursts of high intensity exercise such as running or lifting heavy objects • 5 types : Myophosphorylase deficiency ( McArdle’s disease ) - most common , AR inheritance • Lab.- CK : >100x elevated accompanying myoglobinuria - U/A : myoglobinuria - Fore arm exercise test : impaired rise in venous lactate • Definitive diagnosis : muscle biopsy • Treatment : exercise tolerance can be enhanced by training / warm-up or brief periods of rest / : training allows start of ‘2nd wind’ phenomenon / switching to utilization of fatty acids/
Disorders of lipid metabolism • Oxidation of fatty acids occurs through a multi-step process • Carnitine deficiency • Primary: AD • Secondary : ↓ed synthesis/cirrhosis/, insufficient intake /parentral nutrition/, excessive loss/renal dialysis/ • Onset: childhood • C/F- progressive generalized proximal muscle weakness - severe cardiomyopathy may occur • Lab. – CK : mildly or markedly ed - Biopsy : striking lipid accumulation • Treatment : not satisfactory : supplementation, steroid may help some