Myopathy refers to primary skeletal muscle dysfunction, which can manifest through various symptoms including muscle wasting, pain, and involuntary contractions. This document categorizes myopathies into several types, emphasizing inflammatory myopathies as the largest group, detailing their pathogenesis, clinical features, diagnostic processes, and treatment options. The document outlines the importance of proper diagnosis through muscle biopsy and electromyography, highlighting that conditions like polymyositis and dermatomyositis often respond well to treatment, while inclusion body myositis poses a more challenging prognosis.

1. myopathiesDR.PRAVEENNAGULA

2. UNVERRICHTERNST LEBERECHT WAGNERETIENNE JULES MAREYHARVEY CUSHING

3. Basic muscle anatomy.physiology

5. INTRODUCTIONMYOPATHY means primary skeletal muscle dysfunction.WASTING--- related to muscle MYALGIA– muscle painFIBRILLATIONS - when muscle fibers lose contact with their innervating axon producing a spontaneous action potential, "fibrillation potential" that results in the muscle fiber's contraction. not visible under the skin and are detectable through needle electromyography (EMG) and ultrasound.-pathologicalFASCICULATIONS – visible spontaneuos contractions. SPASM/CRAMP – sudden PAINFUL involuntary contraction of muscleTONE – continuous and partial contraction of the muscles AT REST.resting muscle tensionCLONUS –series of involuntary muscle contractions.MYOKYMIA – INVOLUNTARY ,groups of fasciculations –continuous undualtions of muscle.

6. NERVOUS SYSTEM EXAMINATIONIn motor unit points in favour of myopathy:

7. Muscle appearance – wasting ,atrophy (neurogenic)

8. ABSENT fasciculations (+Denervation)

9. Tenderness on palpation

10. Tone –normal ,decreased in advanced cases.

11. Distribution of weakness –proximal,distal (distal myopathies)

12. Pronator drift test

13. Tendon reflexes – normal /hypoactive in adv.cases

14. Babinski sign negative

15. SENSORY system is normal.

16. GAIT – lordosis on stance,increased on toe walking

17. Waddling gait – b/l pelvic girdle weakness

18. Genurecurvatum –quadriceps weakness.TYPE OF WEAKNESS

19. APPROACH OF A PATIENT WITH INTERMITTENT WEAKNESS

20. Approach to a patient with PERSISTENT WEAKNESS

21. Based on other complaints

22. EMG –assess the function of type I fibersnormal in steroid,disuse atrophy

23. CLASSIFICATION1.INFLAMMATORY /INFECTIOUS MYOPATHIES

24. 2.CONGENITAL DISTAL MYOPATHIES

25. 3.DISORDERS OF MUSCLE MEMBRANE EXCITABILITY

26. 4.DRUG INDUCED/TOXIN INDUCED MYOPATHY

27. 5.METABOLIC MYOPATHY

28. 6.ENDOCRINE MYOPATHY

29. 7.CRITICAL ILLNESS MYOPATHY

30. 8.MITOCHONDRIAL MYOPATHIES

31. 9.MUSCULAR DYSTROPHIES.

32. 10.MISCELLANEOUSINFLAMMATORY MYOPATIHESLargest group of acquired and potentially treatable causes of skeletal muscle weakness .POLYMYOSITIS (PM)DERMATOMYOSITIS (DM)INCLUSION BODY MYOSITIS (IBM)1 :1,00,000 PM – as alone is a rare disease affecting ADULTS.DM – affects both children,adults W>MIBM – M:F –3:1 ,caucasians,>50yrs.

33. PATHOGENESISAutoimmune etiology - assosciation with other autoimmune CTD ,various Auto Ab, MHC ,T CELL myotoxicity,complement, response to immunotherapy.

34. AUTOANTIBODIES AND IMMUNOGENETICS:

35. 20% cases – ANA,anticytoplasmic antigens

36. Anticytoplasmic – anti RNP(anti synthetase),

37. Anti jo 1 – 75% cases -80% assosciation with ILD.

38. Anti Jo 1 –ILD ,RP,non erosive arthritis,MHCDR3,DRw52.

39. DRB1 *0301,DQB1*0201 --- 75% PM,IBM

40. DQA1*0501 –juvenile DM IMMUNOPATHOGENIC MECHANISMSDERMATOMYOSITIS:

41. humoral immune mechanisms – microangiopathy.

42. Endomysial inflammatory infiltrates -B cells

43. auto AB -- complement pathway – C5b-9 membranolytic complex- release of proinflammatory cytokines – VCAM1,ICAM 1 on endothelial cells – migration of lymphoid cells to perimysial and endomysial spaces---necrosis,microinfarcts.

44. Remaining capillaries dilated due to ischemia

45. Perifascicular atrophy due to endofascicularhypoperfusion –periphery of muscle fascicles.

46. IMMUNOPATHOGENIC MECHANISMSPOLYMYOSITIS,IBM :

47. T cell mediated cytotoxicity

48. CD8 T cells,macrophages –invade and destroy MHC 1 muscle fibres(absent usually )

49. CD8/MHC 1 complex is characteristic of PM,IBM

50. These cells have perforin,granzyme granules –myonecrosis.

51. Antigen driven T cell response (auto AB in DM )

52. Antigens – endogenous (muscle),exogenous (viral)

53. Co stimulatory molecules are upregulated . ROLE OF NON IMMUNE FACTORSIBM :

54. Degenerative process in addition to autoimmune process.

55. B amyloid deposits within vacuolated muscle fibres,cyto ox –ve mitochondria.

56. Amyloid is APP,chymotrypsin,apoE,tau

57. ?directly pathogenic /secondary

58. MHC I upregulation – ER stress – accumulation of misfoldedglycoproteins ,NFkB –cytokine activation .Association with viral infectionsCoxsackie,influenza,paramyxoviruses,mumps,CMV,EBV.

59. Autoimmune myositis in coxsackie virus

60. Molecular mimicry of Anti RNAsynthetase and genomic RNA .

61. Best evidence of viral connection in PM,IBM –retroviruses.

62. HIV,HTLV 1 – PM,IBM

63. May be the initial manifestation or later of viral infection.

64. Retroviral antigens –endomyosial macrophages ,but not in muscle fibres.

65. AZT induced myopathy –mitochondrial – ragged red fibres.

66. AZT inhibits gamma DNA polymerase. Clinical featuresIn general :PROGRESSIVE AND SYMMETRIC MUSCLE weakness (IBM –asymmetric).

67. Increasing difficulty with tasks – getting up from chair,climbingsteps,liftingobjects,combing hair.

68. Occular muscles are spared –even in advanced ,untreated cases –if involved ? Diagnosis

69. Head drop sign

70. dysphagia

71. Respiratory muscles involved in advanced cases.

72. Muscle wasting in untreated cases .

73. Sensation always normal .

74. DTR preserved.POLYMYOSITISSubacute inflammatory myopathy affecting adults,rarely children.

75. Facial muscles are unaffected

76. Diagnosis by exclusion.

77. As an isolated entity it is rare.

78. Commonly occurs in assosc. With systemic autoimmune disease ,viral,bacterial.Drugs –AZT,D penicillamineDERMATOMYOSITISCharacteristic rash accompanying/preceding muscle weakness. – increased photosensitivity

79. Blue purple discoloration on the upper eyelids with edema.(heliotrope rash)

80. A flat red rash on the face and upper trunk.

81. Erythema of the knuckles with a raised violaceous scaly eruption – gottron’s sign .

82. Erythematous rash on anterior chest – V sign.

83. Back and shoulders – shawl sign .

84. Dilated capillary loops at the base of the finger nails.

85. Mechanic’s hands –irregular dirty horizontal lnies on the palmar surface of fingers.

86. Muscle tenderness,myalgia –connective tissue disease.

87. Dermatomyositis sine myositis– muscle strength normal

88. Perivascularperimysial inflammation

89. INCLUSION BODY MYOSITIS>50 yrs of age,most common inflammatory myopathy.

90. Often misdiagnosed as PM

91. Suspected when doesnot respond to therapy.

92. Weakness and atrophy of distal muscles,footextensors,deep finger flexors –all cases –clue to early diagnosis.

93. Fine motor movements –affected early

94. Falling is common – quadriceps –buckling of knees.

95. DTR –depressed in presence of atrophy .

96. Dysphagia -60% cases

97. Slow and steady progression

98. Assisted devices requiredFamilial IBM20 % CASES -systemic autoimmune or connective tissue disease.

99. Familial IBM

100. Hereditary IBM - heterogenous group of recessive,dominant inherited syndromes,non inflammatory

101. May spare the quadriceps –iranian JEWS

102. Chromosome 9p1

103. Mutations in the UDP – N acetylglucosamine 2- epimerase n –acetylmannosaminekinase GNE gene.

105. Associated clinical findings EXTRAMUSCULAR MANIFESTATIONS:

106. Systemic symptoms --- fever,malaise -- CTD.

107. Joint contractures –DM in children

108. Dysphagia ,GIabn – DM ,IBM

109. Cardiac disturbances –arryhthmias,DCM,CCF

110. Pulmonary dysfunction – ILD,drug induced – t RNA ab – 10%

111. Subcutaneous calcifications –DM

112. Arthralgias,deformingarthropathy – anti jo1 ab

113. MALIGNANCIES– DM>PM,IBM

114. Nasopharyngeal cancer in india

115. Ovarian,breast,melanoma ,colon,NHL

116. OVERLAP SYNDROMES – DM – SSc,PM – RA ,sjogren’s,SLE

117. Anti PM/Scl - overlap syndrome of DM.DIFFERENTIAL DIAGNOSISSUBACUTE OR PROGRESSIVE MUSCLE WEAKNESS :

118. SPINAL MUSCULAR ATROPHY,ALS

119. UMN signs ,denervation signs on EMG

120. MUSCULAR DYSTROPHIES – progress over years ,rarely present >30 yrs.

121. RAPIDLY ADVANCING MUSCULAR dystrophy –fascioscapulohumeral,dysferlin –inflammatory cell infiltration early.

122. Trial of glucocorticoids,MHC/CD8

123. MYOPHOSPHORYLASE /ACID MALTASE deficiency

124. ENDOCRINE

125. TUMOR ASSOCIATED CACHEXIA

126. LAMBERT EATON SYNDROME,MGACUTE MUSCLE WEAKNESS:

127. GBS

128. Transverse myelitis

129. Poliomyelitis

130. Myophosphorylase deficiency

131. PARASITIC polymyositis.

132. Tropical polymyositis –s.aureus

133. Periodic paralysis

134. Chronic ALCOHOLICS

135. MYOFASCITIS – skin induration -eosinophilicmyofascitis

136. NECROTIZING MYOSITIS – CK is high.ILD,CMP,anti SRP.

137. DRUG INDUCED – d penicillamine

138. Weakness due to muscle pain ,tenderness –PMR -type ii muscle fibres,CFS –biopsy normal. LAB INVESTIGATIONS1.SERUM MUSCLE ENZYMES :most sensitive CK .

139. Parallels disease activity (active -50 fold)

140. Normal when CTD +PM,DM

141. serumGOA,GPT,LDH,aldolase – elevated.

142. 2.EMG – short duration,low amplitude polyphasic units on voluntary activation,spontaneuousfibrillations,positive sharp waves.

143. Mixed potentials –IBM

144. Identifies acute/chronic,excludesnuerogenic

145. 3.MRI –muscle biopsy

146. 4.muscle biopsy – definitive test

147. Inflammation is the hallmark Muscle biopsyPOLYMYOSITIS –

148. Primary – T cell infiltrates (endomyosial) surround healthy muscle fibers- phagocytosis.

149. CD8/MHC 1 –confirms the diagnosis.

150. Alkaline phosphatase –react positively.

151. DERMATOMYOSITIS – perivascular,interfascicularseptae

152. Intramuscular BV – endothelial hyperplasia

153. Wedge shaped microinfarcts.

154. Presence of perifascicular atrophy is diagnostic of DM in absence of inflammation also.

155. INCLUSION BODY MYOSITIS – rimmed vacuoles,fatrepalcement,ragged red fibres,amyloid deposits.

156. TREATMENTGOAL : improve muscle strength,ameliorateextramuscular manifestations.

157. Discontinue the drugs if after trial no improvement of muscle strength.

158. 1.GLUCOCORTICOIDS :oral prednisolone –high doses – 1mg/kg/day – 3-4 weeks,taper later 10 weeks – 1mg/kg every other day.

159. Lowest possible dose to be used.

160. Efficacy by third month

161. DM > PM in response.

162. Steroid myopathy – increased weakness –2- 8 weeks.Treatment cont…2.IMMUNOSUPPRESSIVE THERAPY :

163. 75% patients ultimately require.

164. A.AZATHIOPRINE : 3mg/kg/day

165. B.MTX : 7.5 mg weekly for the first 3 weeks -2.5mg/wk- 25 mg/wk --- MTX pneumonitis.

166. C.mycophenolate MOFETIL – 2.5 mg/d

167. D.rituximab - IN DM

168. E.CYCLOSPORINE – inconsistent benefit

169. F.TACROLIMUS - PM difficult cases.

170. 3.IMMUNOMODULATION:

171. IVIg in refractory DM -short term benefit

172. 2g/kg over 2-5 days /course

173. PLASMAPHERESIS,LEUKOPHERESIS - NOT EFFECTIVE IN PM,DMEMPIRICAL APPROACH IN TREATMENTSTEP 1 – HIGH DOSE PREDNISOLONENO RESPONSE TO TREATMENTIBM or metabolic myopathy,musculardystrophy,endocrinopathy.

174. Repeat muscle biopsy

175. Calcinosis of DM –difficult to treat

176. IBM –resistant to immunosupressive therapy

177. Drugs not to be withdrawn

178. IVIg and prednisolone – not effective

179. PROGNOSIS -5 yr surivival – 95%,10 yr -85%

180. Death –pulmonary,cardiac

181. Worse prognosis – older,severemainfestations at prsentation

182. DM responds favorably than PM,IBM

183. IBM –least favorable prognosis.ENDOCRINE MYOPATHIESMuscle fatigue is more common than true weakness.

184. Serum CK LEVELS are normal.

185. Muscle histology –atrophy rather than destruction.

186. All respond to treatment

187. THYROID DISORDERS:

188. HYPOTHYROIDISM –proximal muscle weakness-1/3

189. Slow muscle contraction and relaxation -25% cases.

190. Relaxation phase prolonged –ankle,biceps reflex

191. Serum CK 10 times normal,EMG normal

192. Muscle may be enlarged?,biopsy –no featuresHYPERTHYROIDISM:

193. Proximal muscle weakness,atrophy of muscles.

194. DTRs enhanced response.

195. Bulbar,esophageal,respiratory muscles affected.

196. Fasciculations+DTRs –ALS misdiagnosis

197. Acquired hypokalemic periodic paralysis,MG,gravesophthalmopathy

198. Serum CK levels are normal

199. EMG is normal

200. Muscle histology –atrophy of musclesCHRONIC THYROTOXIC MYOPATHY – nodular goitre.

201. Men>women.

202. Basedow paraplegia.

203. Atrophy – shoulder and hand muscles.

204. Tremor twitches but not fasciculations

205. GRAVES OPTHALMOPATHY- IR,MR,strabismus,diplopia

206. Infiltrative opthalmopathy

207. THYROTOXIC HPP- not familial,fewhours,adult life.

208. Hypothyroidism aggravates the weakness of MG

209. Kocher -debresemelgainesyndrome,hoffmann syndromeAdrenal disordersMost commonly diagnosed endocrine muscle disease.

210. Proximal muscle weakness.

211. Muscle wasting –striking feature+ cushingoidfacies

212. Type 2b fibres atrophy on histology

213. Potassium depletion –CONN’S syndrome –NM complications.

214. Serum CK LEVELS ELEVATED,vacuoles on biopsy.

215. Vitamin D deficiency

216. Parathyroid disorders –hypo,hyper

217. PITUITARY DISORDERS

218. DIABETES MELLITUS—THIGH muscles,pain tenderness in thigh Hard induratedmuscle,vastuslateralis

219. CRITICAL ILLNESS MYOPATHYAcute quadriplegic myopathy/acute steroid myopathy

220. In cases of severe asthma ,sepsis and shock.

221. Neuromuscular blocking agents in 80% cases.

222. High doses of corticosteroids 1mg/kg ,pancuronium -500-4,000 mg

223. Difficulty in weaning from the ventilator

224. Tendon relfexes are normal- diminished –polyneuropathy

225. Serum CK levels elevated.

226. EMG –MYOPATHY.type 2 fibers vacuolation.

227. Striking loss of myosin filaments

228. Severe cases– myoglobinuria,renal failure.

229. Denervation of muscles –increase in glucocorticoid receptors

230. Recovery over 6- 12 weeksCARCINOMATOUS MYOPATHYSyndromes of NMJ – LAMBERT EATON SYNDROME,MG

231. Syndromes of muscle – polymyositis /dermatomyositis,acute necrotizing myopathy.

232. ACUTE NECROTIZING MYOPATHY-rhabdomyolysis

233. Painful myopathy

234. Necrosis of muscle– raised CK,myoglobinuria

235. Urine is cola coloured .

236. Detected by radioimmunoassay

237. Alkalinization of urine –nahco3

238. Mannitol,diuretics,IV fluidsDRUG INDUCED MYOPATHYMYOPATHY FROM LIPID LOWERING AGENTS

239. GLUCOCORTICOID RELATED MYOPATHIES

240. MYOPATHY OF NON DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS

241. DRUG INDUCED MITOCHONDRIAL MYOPATHY

242. DRUGS OF ABUSE AND RELATED MYOPATHY

243. DRUG INDUCED AUTOIMMUNE MYOPATHIES

244. OTHER

245. DISORDERS OF MUSCLE MEMBRANE EXCITABILITY

246. POTASSIUM CHANNEL DISORDERS:

247. 1.ANDERSEN TAWIL SYNDROME:

248. Episodic weakness,dysmorphic features.

249. cardiac arrythmias are life threatening.

250. autosomal dominant –kir 2.1 gene

251. Acetazolamide

252. CHLORIDE CHANNEL DISORDERS:

253. AD –THOMSEN’S DISEASE

254. AR – BEKER’S DISEASE

255. Myotonia worsened by cold,improved by activity

256. Muscle strength normal in thomson’s

257. Quinine,mexiletine,phenytoin.DISTAL MYOPATHIES****LIMITED TO SKELETAL MUSCLES

258. CONGENITAL MYOPATHIESSpecific histochemical and structural abn in muscle.METABOLIC MYOPATHIES

259. Lipid abnmyopathies

260. MITOCHONDRIAL MYOPATHIESTERM RAGGED RED FIBRES –ABNORMAL MITOCHONDRIA ON MODIFIED TRCIHROME STAIN .

261. Mitochondria are enlarged,bizarrelyshaped,crystalline inclusions

262. Most common is CPEO >50% cases of mitochondrial myopathies.WHITE TRICHROME STAINType I fiber atpASE STAIN

263. Pure myopathy syndromesAffects only the muscle

264. Recurrent myoglobinuria without fixed weakness and thus resemble a glycogen storage or CPT deficiency.

265. MITOCHONDRIAL DNA DEPLETION MYOPATHY :

266. Clinically indistinguishgable from muscular dystrophy.

267. Simulates DMD

268. Seizures,CMP may be present.

269. Serum CK 20-30 times normal,EMG –ragged red fibres.

270. AR condition

271. TK2 gene mutation 16 q22—supplies deoxyribonucleotides.MISCELLANEOUSNEUROMYOTONIA –CONTINUOUS MUSCLE FIBER ACTIVITY.

272. Hyperexcitability of terminal motor neuron plates.

273. Rippling of muscle fibers – myokymia –main clinical sign.

274. Walking is laborious –armadillo syndrome.

275. Muscle activity during sleep.

276. Curare abolishes.

277. ISAAC syndromeTRIALS827 STUDIES ON MYOPATHIES

278. MOLECULAR AND GENETIC STUDIES OF CONGENITAL MYOPATHIES.

279. PHARMACOKINETIC STUDY ON N ACETYL NEURAMINIC ACID

280. CHARACTERIZATION OF IBM WITH PAGET’S,FTD

281. IS MYOPATHY PART OF STATIN THERAPY –IMPOSTER 16

282. STEM CELL TRANSPLANTATION IN IDIOPATHIC INFLAMMATORY MYOPATHY DISORDERS

283. ANAKINRA IN MYOSITIS

284. THE EFFECT OF STATINS ON MUSCLE PERFORMANCE –STOMP STUDY

285. METHIMAZOLE FOR DERMATOMYOSITIS

286. ARIMOCOLOL IN SPORADIC INCLUSION BODY MYOSITIS

287. LOG ON TO www.clinicaltrials.gov TAKE HOME MESSAGEMYOPATHIES need to be categorised based on the pattern of weakness intermittent,persistent.

288. Usually present as proximal muscle weakness.

289. The clinical examination reveals wasting>atrophy,DTR being normal.

290. Laboratory wise raised CK levels normally.

291. Confirmatory diagnosis by MUSCLE BIOPSY .EMG –normal.

292. POLYMYOSITIS is usually seen in assosciation with other disorders .diagnosis by exclusion.

293. DERMATOMYOSITIS responds well to treatment.

294. IBM can be misdiagnosed as PM

295. Drug induced myopathy --- check the list for statins,steroids.

296. Critical illness myopathy,neuropathy –increasing entity.

297. Congenital distal myopathies,mitochondrial to be considered in D.D THANK YOU