1、MyopathiesDepartment of NeurologyTongji HospitalEmail:Min ZhangCase 1 21 years old,female patient Progressive generalized muscle weakness for 8 years The patient began to notice weakness in the hips and increasing difficulty in arising 8 years ago.Six months later the weakness advanced to the knees
2、and she could arise only by climbing up her legs.”Twelve months later,she felt extreme weakness in her shoulders and upper arms so that she gradually became unable to comb her hair or even lift her arms to shoulder level.2023-2-92Case 1 Difficulty of locomotion slowly became more pronounced until at
3、 the time of admission.There were never any symptoms of tremor,spasticity,sensory or sphincter disturbances.No history of similar disease in her family.2023-2-93Case 1 Marked atrophy of the shoulder girdle and thighs,winged scapula and waddling gait.Tendon reflexes decreased bilaterally.No impairmen
4、t of superficial and deep sensibility.CK 13503 u/L2023-2-94Diagnosis?2023-2-95Introduction Myology Common diseases Affecting all ages Complexity of pathogenesis New diseases to be identified2023-2-96Common manifestations Weakness Atrophy Pseudohypertrophy Myalgia(muscle pain)and cramp Fatigability20
5、23-2-97 Topography of myopathic weakness Ocular palsy:ptosis,diplopia,strabismus Bifacial palsy:smile,expose the teeth,close the eyes Bulbar palsy:dysphonia,dysarthria,dysphagia Cervical palsy:hold the head erect,lift the head from the pillow Weakness of respiratory and trunk muscle2023-2-98Topograp
6、hy of myopathic weakness Bibrachial palsy:hands,arms,shoulders Bicrural palsy:lower leg weakness,inability to walk on the toes/heels Limb-girdle palsy:inability to raise the arms or arise from squatting,kneeling or sitting position Distal bilateral limb palsy:foot drop General paralysis2023-2-99Chan
7、ges of muscle bulk 2023-2-910Myalgia and cramp Spontaneous，symmetrical，proximal Severe pain:Cramp Over exercise Metabolic factors:hypocalcaemia,glycogen storage disease Medication:Statin,Captopril 2023-2-911Myotonia2023-2-912Common myopathies Muscular dystrophies Inflammatory myopathies Disorders of
8、 neuromuscular junction Metabolic myopathies Endocrine myopathies Toxic myopathies Others 2023-2-913Progressive muscular dystrophiesBasic concept Hereditary myopathies Heterogeneity:diversity of gene mutations and presentations Muscular degeneration No effective treatment available2023-2-915Classifi
9、cation of PMDX-linked:Duchenne muscular dystrophy(DMD)Becker muscular dystrophy(BMD)Emery-Dreifuss muscular dystrophy(EDMD)Autosomal dominant:Facioscapulohumeral muscular dystrophy(FSHMD)Myotonic dystrophy Distal muscular dystrophy Oculopharyngeal muscular dystrophy Congenital muscular dystrophyAuto
10、somal rescessive:Limb-girdle muscular dystrophy(LGMD)Congenital muscular dystrophy2023-2-9162023-2-917Muscular degeneration Progressive muscular necrosis Increases in CK and LDH Fat infiltration of muscles Limited regeneration of myofibers No inflammatory response2023-2-918Normal muscle2023-2-919Deg
11、eneration and regeneration2023-2-920Duchenne muscular dystrophy X-linked,recessive The most common and severe Gene defects：dystrophin gene Lack of dystrophin Muscular degeneration 2023-2-921Dystrophin expressions a:normalb:BMDc:DMDd:carrier 2023-2-9222023-2-923Clinical presentations(1)Boys affected
12、Age at onset:2-5 yrs Symptoms:frequent falling weakness of limb-girdles 2023-2-924Clinical presentations(2)Signs:pseudohypertrophy of calves muscle weakness of girdles:Gowers sign Waddling gait Winged scapula Hard to walk with heel2023-2-925Pseudohypertrophy 2023-2-926Winged scapula 2023-2-927Gowers
13、 sign Needing hands when standing from supine position,because of pelvic-girdle weakness2023-2-928Gowers sign2023-2-929Clinical presentations(3)EKG abnormalities Seral enzymes:10100 fold increases in LDH and CK EMG:myopathic(low amp.,poly-phasic APs)Biopsy:muscular degeneration regeneration2023-2-93
14、0DMD Biopsy 12023-2-931DMD Biopsy 22023-2-932Diagnosis Family history Clinical manifestation Enzymes EMG Biopsy Dystrophin IHC，genetic testing2023-2-933Course and prognosis Onset:25 yrs Bedridden:1220 yrs Die:1820 yrs2023-2-934Genetic consultations Female:carrier Male siblings:have chance to be the
15、suffers Female siblings:,carrier2023-2-935Treatment Glucocorticoids significantly slow progression of DMD up to 3 yrs.Gene therapy2023-2-9362023-2-937Gene therapy dystrophin gene vector animal models(mdx)evaluation 2023-2-938Introduction of dystrophin gene2023-2-939Case 1 21 years old,female patient
16、 Progressive generalized muscle weakness for 8 years The patient began to notice weakness in the hips and increasing difficulty in arising 8 years ago.Six months later the weakness advanced to the knees and she could arise only by climbing up her legs.”Twelve months later,she felt extreme weakness i
17、n her shoulders and upper arms so that she gradually became unable to comb her hair or even lift her arms to shoulder level.2023-2-940Case 1 Difficulty of locomotion slowly became more pronounced until at the time of admission.There were never any symptoms of tremor,spasticity,sensory or sphincter d
18、isturbances.No history of similar disease in her family.2023-2-941Case 1 Marked atrophy of the shoulder girdle and thighs,winged scapula and waddling gait.Tendon reflexes decreased bilaterally.No impairment of superficial and deep sensibility.CK 13503 u/L2023-2-942Diagnosis?2023-2-943Inflammatory my
19、opathiesCase 2 male，68 years old.Progressive weakness of limbs,accompanied by atrophy for 2 years.EMG:myopathic pattern.Muscle enzymes:CK:3500u/L.Muscle biopsy：profound necrosis,regeneration and inflammatory cell infiltration.Diagnosis：?Treatment：?2023-2-945Different forms of inflammatory myopathies
20、 Infective:Parasitic:Trichinosis Toxoplasmosis Fungal Viral Idiopathic 2023-2-946Common idiopathic inflammatory myopathies Dermatomyositis（DM）Polymyositis（PM）Inclusion body myositis Other immunological related myositis Eosinophilic fasciitis2023-2-947PM and DM PM：inflammation restricts in striate mu
21、scle DM：accompanied by skin lesion Different at immunological process and pathology2023-2-948PM and DM Idiopathic Subacute or chronic Symmetrical Weakness Proximal limb and trunk muscles Dermatomyositis:with dermatitis2023-2-949Etiology and pathogenesis Unknown Infection Autoimmune mechanism:DM:CIC,
22、IgG,IgM,C3 and membrane-attack complexes are deposited in the walls of vessels PM:CD8,MHC-12023-2-950Common clinical features Onset:usually insidious,preceding history Subacute or chronic The course progressive over a period of several weeks or months Symmetrical weakness Proximal limb and trunk mus
23、cles Neck,larynpharyngeal muscles Respiratory muscles can be involved in severe cases No involvment of extraocular muscles 2023-2-951Common clinical features Impairment of other organs:Cardiac abnormalities：sudden death Myocarditis Arrhythmia Interstitial pneumonia2023-2-952Skin lesions of DM Skin l
24、esion usually preexisted weakness Forms of expression：dermatitis Localized or diffused erythema Maculopapular eruption(斑丘疹)Scaling eczematoid dermatitis(脱屑性湿疹样皮炎)Exfoliative dermatitis(剥脱性皮炎）Features：Patches of a scaly roughness over the extensor surfaces of joints;Heliotrope changes in skin over ey
25、elid,cheeks and forehead.Photosensitivity:V sign;Shawl sign Maybe transient 2023-2-953Skin lesions of DMRed,raised papules presented over exposed surface such as distal and proximal Interphalangeal joint:Gottrons papules2023-2-954Other features of DM Periarticular and subcutaneous calcifications Con
26、current connective tissue disease The Raynaud phenomenon Scleroderma2023-2-955Special forms of DM DM of childhood Concurrent CTD Concurrent carcinoma:lung and colon cancer in men breast and ovarian cancer in women NPC 2023-2-956DM of childhood A distinctive syndrome Intermittent low-grade fever A gr
27、eater involvement of blood vessels Acute gastric or enteric perforation CREST Calcinosis Raynaud phenomenon esophageal involvement sclerodactyly（指趾硬皮病）telangiectasia（毛细血管扩张）2023-2-957Concurrent CTDRheumatoid arthritisSclerodermaLupus erythematosusMixed CTDSjgren syndromeCo-occurrence of MGHashimoto
28、thyroiditis2023-2-958Concurrent Carcinoma Lung and colon cancer in men Breast and ovarian cancer in women Antedates the clinical manifestations of the malignancy,sometimes by 1 to 2 or more years Occasionally,excision of the tumor is attended by remission of the myositis2023-2-959Physical examinatio
29、n Usually not tender Weakness，atrophy Reduction in tendon reflexes Fibrous contracture Skin lesion2023-2-960Investigation Muscle enzymes:CK,LDH,GOT The increase is more markedly in PM Can be used to observe the effect of treatments ESR EMG:myopathic pattern2023-2-961MRIAbnormalities in T1and T2 sign
30、al intensity define regions of increased water content and inflammation in muscle2023-2-962Autoantibodies Anti-component of muscle fibre:anti-Jo1:interstitial pneumonia anti-SRP:severe PM anti-Mi-2：DM P-155：adolescent DM Non-specific antibodies:Antibodies for CTD:ANA,RF,SS-A/B2023-2-9632023-2-964Inv
31、estigationMuscle biopsy:Widespread degeneration,regeneration Inflammatory reaction Tubular aggregates in the endothelial cytoplasm occlusion of vessels by fibrin thrombi DM:perifascicular muscle fiber atrophy PM：IHC:MHC-1 and CD8(+)2023-2-965Biopsy 12023-2-966Biopsy 22023-2-967Biopsy 32023-2-968Biop
32、sy 4MHC-1 immunohistochemical staining2023-2-969Biopsy 52023-2-970Investigation ECG Carcinoma Screening:C-12:specific markers of tumors X-ray or CT2023-2-971Diagnostic criteria of PM1.Myopathic weakness,which:evolves over weeks to months spares facial and eye muscles is manifested in patients above
33、the age of 18 yearsDalakas MC,Hohlfeld R.Diagnostic criteria for polymyositis and dermatomyositis.Lancet 2003;362:176217632023-2-972Diagnostic criteria of PM2.Patient DOES NOT have:rash,characteristic of dermatomyositis a family history of neuromuscular diseases exposure to myotoxic drugs,(D-pencill
34、amine,zidovudine,statins)endocrine disease(hypothyroid,hyperthyroid,hypoparathyroid,hypercortisolism)neurogenic disease(excluded by electromyogram and neurological examination)dystrophies and metabolic myopathies(excluded by history and muscle biopsy)IBM(excluded by clinical examination and muscle b
35、iopsy)2023-2-973Diagnostic criteria of PM3.Disease can be associated with:another autoimmune disease or viral infection4.Polymyositis is rare as a stand-alone entity 2023-2-974Diagnostic criteria of PM5.Reconsider polymyositis if:disease onset below the age of 18 years myopathy has slow onset and ev
36、olves over months to years(in such cases think of IBM or dystrophy)patient has fatigue and myalgia,without muscle weakness,even if a transient CK elevation is seen(such patients may have fibromyalgia or fasciitis and their muscle biopsy is either normal or non-specific)there are no typical histologi
37、cal features of polymyositis,especially when there is an absence of MHC-I or MHC-I/CD8 complex 2023-2-975Differential diagnosis Hereditary myopathies Duchenne dystrophy facioscapulohumeral dystrophy limb-girdle dystrophy IBM Drug induced myopathies2023-2-9762023-2-977Treatment Corticosteroids：first
38、line IVIG:DM,no responds to corticosteroids Other immunosuppressant:refractory or cannot tolerate Azathioprine Methotrexate Cyclophosphamide2023-2-978Treatment Prednisone：1mg/kg/d Carefully monitor by testing of strength and measurement of CK After 4-6w，recovery begin,reduce the dosage gradually Cau
39、tion reduce to 10-20mg/d over a period of 6m to 1 year Discontinuation of the drug:treatment2 years muscle enzymes and strength back to normal2023-2-9792023-2-980Prognosis Adult:most porpotion favorable 20%:recovery Early treatment and acute onset:50%remission Poor prognosis:concurrent malignancy,CT
40、D,Children Mortality:15%2023-2-981Case male，68 years old.Progressive weakness of limbs,accompanied by atrophy for 2 years.EMG:myopathic pattern.Muscle enzymes:CK:3500u/L.Muscle biopsy：profound necrosis,regeneration and inflammatory cell infiltration.Investigations?Diagnosis：?Differential diagnosis?T
41、reatment：?2023-2-982Inclusion body myopathy The 3rd major form of idiopathic inflammatory myopathy Over 1/3 of cases of inflammatory myopathy are of this type.Predominates in males(in a ratio of 3:1)Onset in middle or late adult life Sporadic or inherited2023-2-983Clinical manifestation Painless mus
42、cular weakness and atrophy Often asymmetrically Selective weakness of flexor pollicis（拇长屈肌）or Longus（伸肌）,quadriceps,and neck extensor。Steadily progressive 20%sporatic cases associated with Diabetes,CTD or mild polyneuropathy2023-2-984Clinical manifestation2023-2-985Investigations Muscle enzymes:norm
43、al or slightly elevated lower levels than in cases of PM EMG:myopathic pattern a small proportion display a more frankly neuropathic2023-2-986Biopsy Identical to but usually of lesser severity than those observed in PM Rimmed vacuoles（镶边空泡）Inclusion body：eosinophilic inclusions in both the cytoplasm
44、 and nuclei congophilic:stain positively for A2023-2-987Inflammatory reaction2023-2-988Infiltration of monocyte2023-2-989RVs，HE2023-2-990RVs，Gomori2023-2-9912023-2-9922023-2-993Diagnosis Clinical manifestation Muscle biopsy：inflammation，RVs Staining：Congo-red，SMI-31,tau，Abeta，Ubiquitin,etc Electron
45、microscope2023-2-994Relentlessly progressive2023-2-995Eosinophilic Fasciitis Predominates in male Appear 30-60 years Symptom：low-grade fever，myalgia，diffuse cutaneous thickening and limitation of movement of small and large joints Signs:Scleroderma-like appearance of the skin and flexion contracture
46、s at the knees and elbows 2023-2-996Eosinophilic Fasciitis Elevated ESR and eosinophilia MRI:Thickened fascia Skin and muscle biopsy:Thickened fascia Plasma cells,lymphocytes,eosinophil infiltrate Normal muscle fibers Skin lacked the characteristic histologic changes of scleroderma2023-2-997Treatmen
47、t Remits spontaneously Responds well to corticosteroids2023-2-998Diseases of neuromuscular junctionNMJ2023-2-9100Acetylcholine receptor 2023-2-9101Diseases of NMJ Myasthenia gravis:AchR decrease Eaton-Lambert syndrome Congenital myasthenia：mutations in AChR genes Neurotoxins:black widow:enhance Ach
48、release botulinum toxin:block Ach release alpha-bungarotoxin:bind to AchR2023-2-9102Female black widows 2023-2-9103Impairment of NMJalpha-bungarotoxinEaton-LambertBlack widow(+)MGbotulinum(-)2023-2-9104Case 3 Female,25yrs Dropping of the right eyelid and double vision for 2m.Past history:Hyperthyroi
49、dism PE：Ptosis on the right side.Pupils are normal.Limitation of the abduction of eye ball.Visual acuity and fundus are normal.Treatment:intramuscular injection of“some medication”Prognosis:complete remission after 20mins reoccurrence after 60mins2023-2-9105Myasthenia Gravis(MG)Myasthenia gravis(MG)
50、Incidence:5/100,000 Autoimmune disease Decrease in AChR on the end-plate Impaired neuromuscular transmission2023-2-9107Pathophysiology Antibodies,to alpha subunit of AChR Blocking or degradation of AChR Signal transduction damaged Weakness and fatigability nervenervemusclemuscle2023-2-9108Animal mod
