Presentation on theme: "Approach to the patient with Myopathy"— Presentation transcript:
1Approach to the patient with Myopathy By MichaelMay, 2007
2Outline Basics Clinical manifestations Diagnostic approach Individual myopathiesApproach to the patient
3Skeletal muscleComposed of muscle fibers that contract when stimulated by a motor neuronSkeletal muscle: covered by connective tissue sheath( epimysium): composed of many columns( fascicles)Fascicles: surrounded by perimysium:composed of many muscle fibersMuscle 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.
5Cont,dMyofibril : 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.
7Cont,dMuscle 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 for1. movement of cross bridges for muscle contraction2. pumping of ca+2 in to the sarcoplasmic reticulum for musclerelaxation.
8Cont,d Mitochondria : plays key role in energy production Anaerobic respiration : major source of energy during exerciseGlucose → Lactic acid + ATPAerobic respiration : lipids – important sources of energy during rest & during prolonged submaximal exerciseVLDLTriglycerides → fatty acids → activated fatty acids/ acyl-coA/↓ CPT-Ilinked with carnitine↓mitochondria↓ CPT-IIATP ← Beta oxidation ← acyl-coA + carnitine
9MyopathyDefn. : disorders with structural changes or functional impairment of a muscle; unrelated to any disorder of innervation or NMJ.Classification :1. Acquired2. 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 transverse tubules, sarcolemma ): affect structure or biochemical processes which convert chemical energy derived from cell metabolism in to mechanical energy in a controlled manner.
15fatigue Inability to maintain or sustain a force 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 findingsAsthenia- 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
16TABLE 367-1 Observations on Examination That Disclose Muscle Weakness Functional ImpairmentMuscle WeaknessInability to forcibly close eyesUpper facial musclesImpaired puckerLower facial musclesInability to raise head from prone positionNeck extensor musclesInability to raise head from supine positionNeck flexor musclesInability to raise arms above headProximal arm muscles (may be only scapular stabilizing muscles)Inability to walk without hyperextending knee (backkneeing or genu recurvatum)Knee extensor musclesInability to walk with heels touching the floor (toe walking)Shortening of the Achilles tendonInability to lift foot while walking (steppage gait or footdrop)Anterior compartment of legInability to walk without a waddling gaitHip musclesInability to get up from the floor without climbing up the extremities (Gowers' sign)Inability to get up from a chair without using arms
18Muscle 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 Hz, with abrupt onset & cessationMyalgia: localized or generalized and may be accompanied by tenderness & swelling.:should be differentiated from myofascial pain syndromesFibromyalgia ▪ 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
19Cont,d stiffness Uncommon Joint inflammation Hyperexcitable motor nerves( spinal cord, peripheral nerves)contractureMuscle unable to relax after after an active muscle contractionEMG shows complete electrical silence ( firing of motor neurons in a cramp)Uncommon in most muscle diseasesFixed contracture occurs early in patients with Emery- Dreifuss MD & Bethlem myopathy.
20Cont,d myoglobinuria ▪ dark or dark- brown urine Myotonia prolonged muscle contraction followed by slow muscle relaxationvoluntary contraction, mechanical stimulation ( percussion myotonia)DM, myotonia congenita, paramyotonia congenitaMuscle enlargement and atrophySize 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.
21Laboratory evaluation Diagnose myopathySerum 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
22Lab. 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.
23Lab. Cont,dDNA 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
24Approach to the patient Emergency: manage acute life threatening complicationsRespiratory insufficiency : mechanical ventilatorDysphagia : endotracheal intubationRhabdomyolysis : hydration, diuresisHeart block : pace maker insertionHypoKPP : iv. Or oral potassium replacementNon-emergency : identify a disorder as a myopathy: identify a specific etiology for the myopathyHistory- 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
25Approach 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 HypoKPPLaboratory tests : CBC, ESR, CK isoenzymes, electrolytes, U/Aserum myoglobin, RFT, TFTDefinitive diagnosis : EMG, Genetic testing, ANA, Muscle enzymes, muscle biopsy
26Muscular dystrophies Duchenne muscular dystrophy 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 dystrophyInheritance- X- linked recessive disorderDefective gene- DystrophinOnset- usually b/n 3-5yrs ageC/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
27Cont,d Others : cardiomyopathy , mental retardation Lab. – Serum CK : elevated x 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 dystrophinTreatment : prednisolone 0.75mg/kg/day increases muscle strength & slows the progression of disease for up to 3 yrs.
28Becker muscular dystrophy Inheritance – X- linked recessive disorderDefective gene – dystrophinOnset- experience difficulty b/n 5- 15yrs of ageC/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 commonLab. – CK : elevated- EMG : myopathic- muscle biopsy : similar to DMD: reduced amount or abnormality of dystrophin( Dx)- DNA analysis : deletions or duplications( Dx)Treatment – supportiveSurvival : survive in to the 4th to 5th decade
29Limb- girdle muscular dystrophy/ LGMD / Inheritance : Autosomal dominant/ recessiveDefective gene : several genesM:F – 1:1Onset – late 1st to 4th decadeC/F – progressive weakness of pelvic & shoulder girdle muscles- diaphragmatic weakness & cardiomyopathy may also occur- intellectual function is intactTreatment - supportive
30Emery- Dreifuss muscular dystrophy/EDMD/ Inheritance- X-linked recessive/ Autosomal dominantDefective gene : Emerin/ Lamins A/COnset – early childhood & teenage yearsC/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 featuresTreatment - supportive : Ambulatory aid: manage cardiomyopathy & arrhythmia
31Fascioscapulohumeral /FSH/ muscular dystrophy Inheritance: ADOnset : childhood or young adulthoodDefective gene: deletion, distal 4qC/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 deafnessLab. – CK : N or elevated- EMG: myopathic pattern- biopsy: non-specific features of myopathyTreatment – no specific treatment is available- ankle foot orthoses may help for foot drops- scapular stabilization procedures may improve scapular winging
32Oculopharyngeal dystrophy Inheritance: AD with complete penetranceDefective gene: expansion, poly-A-RNA binding proteinOnset – 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 extremitiesLab. – EMG: myopathic features- CK : 2-3x N- biopsy : distinct features – presence of tubular filaments in musclecell nuclei.Treatment- Dysphagia : cricopharyngeal myotomy may improve swallowing- Ptosis : eyelid crutches may improve vision
33Distal myopathiesNotable for their preferential distal distribution of muscle weakness in contrast to most muscle conditions associated with proximal weaknessFour types : mode of inheritance, age of onset, pattern of weakness1. Welander DM : AD2. Tibial MD : AD- late onset, usually after age 40; start in the hands3. Nonanka DM: AR4. Miyoshi myopathy : AR- early onset in late teens or twenties; start in the lower limbsLab. – CK : only slightly elevated except in Miyoshi myopathy- Biopsy : non- specific dystrophic changes- EMG : myopathicTreatment – occupational therapy for loss of hand function- Ankle - foot orthoses to support distal lower limbs
34Myotonic dystrophy/ DM / Inheritance : ADDefective gene: two types with distinct molecular genetic defects-DM1 : expansion CTG repeat- DM2 ( proximal myotonic myopathy – PROMM ): CCTG repeatC/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
36Cont,d- other system manifestations : intellectual impairment, hypersomnia, cataract, gonadal atrophy, insulin resistance, reduced esophageal & colonic motilityLab. – 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.
37Congenital myopathyRare disorders distinguished from muscular dystrophies by the presence of specific histochemical & structural abnormalities in muscle fibers.Onset : infancy or childhoodThree types: pattern of inheritance & type of structural abnormality in muscle fibers-central core disease : AD- Nemaline (rod ) myopathy: AD- Myotubular( centronuclear ) myopathy : AD , XRC/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 typeTreatment – no specific treatment
38Disorders 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 HypoKPPInheritance – AD except few sporadic casesRecognized by their : clinical characteristics: provocation by exercise, eating , cold exposure, and associated changes: serum potassium concentration during an attack
40Cont,d HypoKPP HyperKPP Attacks are brief and mild (30’- 4hrs) Attacks may stay for as long as 24hrsPrecipitated by rest following exercise,meals high in CHO, Na+Biopsy shows single or multiple centrally placed vacuolesRx of acute paralysis- K+ supplementation (oral or IV )Prevention of recurrent attacks-low CHO, Na+ diet-avoid intense exercise-K+ -sparing diuretics-Acetazolamide mg/dayHyperKPPAttacks are brief and mild (30’- 4hrs)Precipitated by rest following exercise, fasting and K+ administrationBiopsy shows vacuoles that are smaller, less numerous & more peripheral compared to HypoKPPRx of acute paralysis- not importantPrevention of recurrent attacks-increase CHO in diet-K+ - losing diuretics-Acetazolamide 125 – 1000mg/day
41Mitochondrial myopathies Mitochondria plays a key role in energy productionInherited disorders of the oxidative pathways of the respiratory chain.Onset : most in childhood or early adulthoodLab. - 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 mitochondriaStructures affected: skeletal muscles, CNS, endocrine glands, heartCourse : progressive & downhillTreatment : supportive - exercise- pace maker insertion for heart block- treat epilepsy- treat endocrinopathies
42Cont,d… Ragged red fiber appearance courtesy : Prof. Janzer
43Clinical manifestations fall in to three groups 1. progressive external ophthalmoplegia ( CPEO ): > 50%, characterized by ptosis & extra ocular muscle weakness in the absence of diplopiaKSS, AD- CPEO, ARCO2. skeletal muscle- CNS syndromes : MERRF, MELAS3. pure myopathy simulating muscular dystrophyKearns sayre syndrome ( SSS )- sporadic, non-inherited disorder, single deletions of mtDNA-Triads : CPEO: pigmentary retinopathy: heart block &/or cerebellar ataxia, &/or CSF protein>100mg/dlothers: short stature ,dementia, MR, sensory neural hearing loss, diabetes, hypothyroidism, gonadal dysfunction in both sexes.-Course – most die in their 4th or 5th decade
44Cont,d Myoclonic Epilepsy with Ragged Red Fibers/ MERRF/ Point mutation of mitochondrial transfer RNAC/F - myoclonic epilepsy: integral part & may be the initial symptom- cerebellar ataxia : progressive, both trunks & the limbs- progressive muscle weakness : limb- girdle distributionothers: dementia, optic atrophy, peripheral neuropathy, hearing loss , DiabetesRx- supportive with special attention to epilepsy
45Cont,dMitochondrial myopathy, Encephalopathy, Lactic acidosis, Stroke-like episodes / MELAS /Most common encephalomyopathyMaternally inherited point mutations of mtRNA geneC/F - partial or generalized seizures : could be the 1st sign- stroke- like Sxs- hemiparesis, hemianopia, cortical blindness- serum lactic acid : typically edothers : dementia, hearing loss, hypothyroidism, diabetes, hypothalamic pituitary dysfunctionNeuroimaging : basal ganglia calcifications in high percentage of casesTreatment – supportive , fatal outcome
46Cont,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 yrsTreatment – supportive care similar to muscular dystrophiest
47Disorders of muscle energy metabolism Abnormalities in either glucose or lipid utilizationPresentation: acute painful syndromes with rhabdomyolysis & myoglobinuria:chronic progressive muscle weakness simulating dystrophies
48Cont,dDisorders of glycogen storage causing progressive muscle weaknessC/F – usually present during infancy- severe muscle weakness, delayed milestones,, cardiomegally, hepatomegally, respiratory insufficiency- death usually occurs by 1 yr of ageThree types: 1. Debranching enzyme deficiency2. Branching enzyme deficiency3. 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 weaknessDx- membrane bound & free tissue glycogen on electron microscopy- definitive diagnosis through enzyme determination in muscleRx. – recombinant enzyme replacement may improve muscle weakness & prolong life.
49Disorders of glycolysis causing exercise intolerance Defects in genes encoding the abnormal proteins.Effects: failure to support energy production at the initiation of exerciseOnset : adolescenceC/F – painful muscle contractures followed by myoglobinuria- Sxs are precipitated by brief bursts of high intensity exercise such as running or lifting heavy objects5 types : Myophosphorylase deficiency ( McArdle’s disease )- most common , AR inheritanceLab.- CK : >100x elevated accompanying myoglobinuria- U/A : myoglobinuria- Fore arm exercise test : impaired rise in venous lactateDefinitive diagnosis : muscle biopsyTreatment : 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/
50Disorders of lipid metabolism Oxidation of fatty acids occurs through a multi-step processCarnitine deficiencyPrimary: ADSecondary : ↓ed synthesis/cirrhosis/, insufficient intake /parentral nutrition/, excessive loss/renal dialysis/Onset: childhoodC/F- progressive generalized proximal muscle weakness- severe cardiomyopathy may occurLab. – CK : mildly or markedly ed- Biopsy : striking lipid accumulationTreatment : not satisfactory: supplementation, steroid may help some
51Carnitine palmitoyltransferase deficiency Most common cause of recurrent myoglobinuriaCause : CPT-II deficiencyInheritance : AR ; but commoner in men / 5:1 /Onset – teenage years or early childhoodC/F – muscle pain & myoglobinuria : following prolonged exercise, some times following fasting: doesn’t occur until the limits of utilization have been exceeded & muscle breakdown has already begun unlike glycolytic defects- strength is normal in b/n attacks unlike carnitine deficiency.Lab.- CK, EMG usually N b/n attacks- forearm exercise test : normal rise of venous lactate- muscle biopsy : usually NDx.- direct measurement of muscle CPT-IIRx.- frequent meals /low fat, high CHO/ may prolong exercise tolerance
52Endocrine and metabolic myopathies Many cause weaknessFatigue is more common than weaknessCause : not well defined: ? Disease of muscle or ? another part of the motor unit- CK : usually N , except in hypothyriodism- muscle histology : atrophy rather than destruction of the muscle fibersRx- nearly all respond to treatment
53Thyroid disorders Hypothyroidism -muscle weakness with muscle cramps, pain & stiffness in 1/3rd- prolonged relaxation phase of muscle stretch reflexes-Hoffman’s syndrome: muscle enlargement ( unknown cause), &weakness with muscle stiffness-CK- usually >10x ed-Biopsy : normalHyperthyroidism-proximal weakness with atrophy-sometimes bulbar, respiratory & esophageal muscle involvement: dysphagia, dysphonia, aspiration-muscle stretch reflexes are often brisk-CK: usually N-Biopsy : atrophy of fibersOthers:- thyrotoxic periodic paralysis- Grave’s ophthalmopathy :progressive ophthalmopathy, with proptosis
54Cont,d Hyperparathyoidism -proximal muscle weakness, muscle wasting, brisk stretch reflexes-CK : usually N-Biopsy : varying degrees of atrophyHypoparathyoidism- Hypocalcemia resulting in sustained tetany & muscle damage- Hypo- or areflexia- CK : may be edDiabetes mellitus- myopathy is uncommon- rarely ischemic infarction of the thigh muscles- abrupt onset of pain, tenderness, & edema of one thigh- hard & indurated area on palpationDx- imaging / CT, MRI /-focal abnormality in muscleVitamin deficiency- myopathy is rare- proximal muscle weakness- CPEO- Vit. D , Vit. E deficiency
55Adrenal disorders Cushing’s disease Adrenal insufficiency - Steroid excess causes various degrees of muscle weakness- proximal limb muscle weakness- striking muscle atrophy- Associated cushingoid appearance- CK: Usually N-Biopsy : atrophy of fibers▪ Acromegally- Mild proximal muscle weakness without muscle atrophyAdrenal insufficiency- mild weakness with prominent fatigueConn’s syndrome- due to persistent hypokalemia- Persistent muscle weakness- muscle wasting if long standing- CK : may be elevated- Biopsy : degenerating fibers
56Toxic myopathies Direct toxicity : common : muscle breakdown, rhabdomyolysis & myoglobinuria may occurEx.- lipid lowering agents, glucocorticoids - commonDrug induced autoimmune myopathyEx. – D-penicillamine : features similar to polymyositisLipid lowering agentsall classesSx - proximal weakness- myalgia, malaise, muscle tenderness- severe rxns : rhabdomyolysis & myoglobinuriaLab.- CK: elevated- EMG : myopathic- Biopsy : muscle necrosisRx – cessation of drugs
57cont,d Glucocorticoid related Flourinated steroids ( triamcinolone, dexamethasone, bethametasone)Chronic use of steroids ( prednisolone > 30mg/day )Respiratory muscles could be involvedPresentation1. Chronic : proximal muscle weakness associated with cushingoid appearance: Lab. - CK , EMG are usually N- Biopsy – preferential atrophy of type – II muscle fibers: Rx – drug withdrawal2. Acute : associated with high dose iv. glucocorticoid use ( severe asthma, COPD): acute quadriplegia: Biopsy – distinctive loss of thin filaments by electron microscopy: Rx- drug withdrawal, supportive care, rehabilitation- recovery is slow
58Cont,d Zidovudine / AZT / related myopathy Mitochondrial myopathy Occurs in 17% of patients treated with doses of 1200mg/day for 6 months.Sx.- myalgias, muscle weakness & atrophy affecting the thigh & cuff musclesLab.- CK : elevated- EMG : myopathic- Biopsy : ragged red fibers with minimal inflammationHIV- related myopathy : marked inflammationRx – reduce dose or withdraw drug
59Inflammatory myopathies Largest group of acquired & potentially treatable causes of skeletal muscle weaknessPrevalence : 1 in 100,000Types : - Polymyositis ( PM )- Dermatomyositis ( DM )- Inclusion body myositis ( IBM )Pathogenesis : Autoimmune diseases- Humeral ( autoantibodies ) : DM- nuclear antigens ( ANAs )- cytoplasmic antigens * Anti-jo-1 antibody- T - cell mediated myotoxicity ( CD8 cells) : PM, IBMResults – complement mediated microangiopathy & muscle ischemia →necrosis , degeneration & phagocytosis of fibers- direct injury to fibers → necrosis & phagocytosisTriggering agent - ? Endogenous antigens- ? Exogenous Ags. : viruses / HIV, CMV, EBV, Coxackie …/
60Cont,d C/F – progressive , often symmetrical proximal muscle weakness - early distal muscle weakness in IBM- quadriceps atrophy with repeated falling : common in IBM- dysphagia & head drop : pharyngeal & neck flexor muscles are often involved- ocular muscles are spared- facial muscles often not involved : mild weakness common in IBM- myalgia & muscle tenderness : rarely- respiratory muscle weakness : rare- muscle wasting : untreated & long standing diseaseDisease progression- sub acute / weeks – months/ : DM, PM- chronic / years / : IBM
63Cont,d Associated malignancies : specific to DM, increased incidence - ovarian ca, breast ca, melanoma, colonic ca, NHLOverlap syndromes : diseases found in association with inflammatory M.- CTD : systemic sclerosis, RA, SLE, Sjogren’s syndrome- ILD : 80% 0f patients with Anti-jo-1 abs. have ILDDx.- CK : elevated as much as 50 fold- Needle EMG : myopathic potentials: increased spontaneous activity with fibrillations, complex repetitive discharges, & positive sharp waves: mixed potentials - IBM indicating chronic process- Biopsy : definitive diagnosis: inflammation – histologic hallmark: features characteristic to each type
64PM DM IBM Age at onset >18yrs Adulthood, childhood >50yrs sex M=FF>MM>FWeaknessproximalProximal, early distalinvolvementFamilial associationNoYes, in some cases /familial inflammatory myopathies /Response to treatmentgoodbetterpoorCTDsyesYes, in up to 20%malignacyyes, in up to 15% of casesRashAbsentPresentBiopsy“primary” inflammation with the CD8/MHC-I complex & vacuolesPerifascicular, perymysial, or privascular infiltrates, perifascicular atrophyPrimary inflammation with CD8/MHC-I complex; vacuolated fibers with b-amyloid deposits , cytochrome oxygenase-negative fibers ; signs of chronic myopathy
65Cont,dTreatmentGoal : improve muscle strength, thereby improving function in activities of daily living, and ameliorate the extramuscular manifestations( rash, dysphagia, dyspnea, fever)Response : clinical improvement: CK might remain elevatedStep- 1 : high- dose prednisolone- 1mg/kg/day : taper gradually based on the response until the lowest possible dose that controls the disease is reachedStep- 2 : immunosuppressive drugs : if a patient fails to respond adequatelyto glucocorticoids after a 3 month trial.Azathioprine – 3mg/kg/dayMethotrexate – 7.5mg weekly with gradual dose escalationCyclophosphamide – 0.5mg-1mg IV. Monthly for 6 monthsChlorambucilCyclosporine
66Cont,d Step- 3 : Immunomodulation - IVIg : short lived & repeated infusions are requiredPrognosis : treatment- 5yr. Survival : 95% for PM, DM- 10yr. Survival : 84%- poor : severe illness, long duration, older age, associated cancersevere dysphagia or respiratory difficulties: IBM
67References Harrison’s principles of internal medicine, 16th ed. Human physiology, stuart IRA Fox, 7th ed.Internet : E- medicine