MUSCLES DISORDERS

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MUSCLES DISORDERS

• Definition
• Diseases involving the muscle fibers (myogenic)
• Unlike neuronopathies secondary to LMN
• Heterogenous etiology, genotype, phenotype
• Devastating evolution
• No specific treatment for most of them

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Myoblasts fusing to form large multi-nucleate
muscle cells
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white fast (speed) red slow (endurance)
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How do the myosin heads coordinate to slide the
actin filament?

• They move independently.
• If so how do the individual myosin heads avoid
  interfering with each other?
• They move together like oars on a 8 oar rowing
  shell, or the multiple oars of a Roman ship

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ATP dependent Calcium pump Ca ATPase pumps
calcium from the cytoplasm surrounding the
sarcomers back into sarcoplasmic reticulum
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Common Features

• ? Clinical
• Muscle weakness main feature
• Gowers sign (proximaly dominating deficit)
• Contractures /- severe advanced stages
• Pain in inflamm. Disorders only
• Atrophy (/- pseudohypertrophy in X-linked)
• Deformity advanced disease
• DTR normal, diminished or absent
• Tone slightly? or normal
• Other systems may be involved

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Common Features

• ? Laboratory Investigations
• CBC, LFT.. Normal
• ESR high in inflammatory only
• UE abnormalities in some endocrinopathies and
  periodic paralysis
• C.K aldolase generaly raised (normal in few
  sittings metabolic, endocrine)
• Lactic acid
• Genetic study location type of chromozomal
  abnormalities

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Common Features

• ? Neurophysiology
• NCS normal
• EMG
• Spontaneous activities /- in inflammatory
  disorders
• Interferential tracing
• MUPs ? small A
• ? Short D
• polyphsics

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Common Features

• Pathology
• /- Severe reduction in the muscle fibers
• Muscles fibers are replaced by fat orfibrosis
• Centralized nuclei
• Fibrosis
• Inflammatory infiltrate in inflamm disorders
• Type / I type II
• Electron microscopy
• abnormal mithochondries in mithochondriopathies

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ETIOLOGY / CLASSIFICATION

• Inherited myopathies
• Muscular dystrophies
• Congenital myopathies
• Inherited channelopathies
• Periodic paralysis
• Inherited metabolic myopathies
• Disorders of glycolysis
• Disorders of oxidative metabolism
• Lipid myopathies
• Mitochondrial myopathies

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• Acquired myopathies
• Inflammatory myopathies
• Acquired metabolic myopathies
• Toxic myopathies

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• ? Hereditary transmitted (Muscles Dystrophies)
• X- linked?
• -Duchenne ( cardiac involv..)
• -Becker
• ?Emery-Dreifuss ( severe cardiomyopathy)
• Non-X linek
• Limb Girdle
• Facio-scapulo-humoral
• Scapulo-peroneal
• Scapulo-humeral
• Ocular-pharyngeal.

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• Inflammatory muscle disorders
• Autoimmune
• Primary dysautoimmune or complicating systemic
  diseases SLE..
• Polymyositis
• Dermatomyositis
• Paraneoplastic
• Viral
• Infective toxoplasmosis,trichinosis..
• Toxic drug induced muscle disorders.

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Muscle Dystrophies
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Muscular Dystrophy
Duchenne/ Becker Emery-Dreifuss, Congenital Limb-Girdle, Distal Myopathy
Onset 2-6 years Childhood to early teens, infancy Late childhood-middle age
Muscle groups affected
Life expectancy Rarely beyond 20s varies Middle age
Inheritance X-linked recessive X-linked recessive, autosomal dom rec. Autosomal dominant recessive
Genetic linkage Dystrophin Emerin, lamin, merosin, etc. Calpain-3, Dysferlin, Caveolin-3, a???-sargoglycans, etc.
Source www.mdausa.org
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X-linked Dystrophinopathies

• Groupe of hereditary myopathies
• Pathophysiology defective or absent Dystrophin
• Dystrophin
• Has integral role in sarcolemmal stability
• Consist in 2 globular heads with flexible
  rod-shaped center
• Associated in a complex with sarcoglycans
  dystroglycans (transmembrane proteins
  glycoproteins)
• Coding gene on Chromosom X short arm Xp21
  location
• Function loss ? cascade of events (including
  loss of other components of dystrophin-associated
  glycoprotein complex, sarcolemmal breakdown with
  attendant Ca ion influx phosphlipase activation,
  oxidative cellular injury) and ultimately
  myonecrosis

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X- Linked Ducenne, Beker..

• X- linked, recessive transmission
• Affects males
• Females are Carrier
• Onset 2-5 years in Duchenne, end 1st decade in
  Becker)
• Proximal muscles mainly , (early)
• Severe disease ( other systemes cardiac..)
• death in the 2d decade

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DUCHENNE MD

• progressive skeletal muscle weakness.
• Absence of the dystrophin protein ? weakens the
  connections between proteins in the muscle fibers
  the cell membrane. (?the cell membrane becomes
  weaker ruptures)
• As a result ions such as Ca can move in out
  of the ruptured cell membrane ? contraction at
  the damaged site ? the muscle fibers will break
  ? the muscle will begin to waste away.

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Prevalence of DMD(1)

• Affects one in 3500 to 5000 newborn males
• 1/3 of these with previous family history
• 2/3 sporadic

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Clinically onset of DMD

• Delayed developmental milestones
• Loss of motor skills
• Characteristic gait
• Calf hypertrophy (pseudohypertrophy)
• Clumsiness/frequent falls

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Symptoms of DMD

• Muscle weakness Difficulty in walking/running
• Difficulty climbing stairs or hills
• Difficulty in rising (Gowers sign)

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• DIAGNOSIS
• Clinical,
• Lab Invest. CPK
• Neurophysiol. (EMG) myogenic changes
• Muscle biopsy
• Genetic study (Immunoblot homogenate allow
  diffenrentiation between Duchenne Becker)
• Asymptomatic female
• Foetus diagnsis possible (as early as 8 weeks)

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DMD where is the Gene?

• The gene for dystrophin production sits on the X
  chromosome.
• If a normal gene for dystrophin is present, then
  the protein will be made.
• If the gene is missing or altered, dystrophin may
  not be produced at all or only in abnormal forms,
  resulting in Duchenne muscular dystrophy

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• Dystrophin connects the myofibrils to a complex
  of proteins
• in the muscle cell membrane. This in turn
  connects to the
• extracellular matrix protein laminin, stabilizing
  the membrane

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Spectrin connects the actin cytoskeleton in Red
Blood Cells to the membrane
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What is Utophin?

• Utophin is a protein that acts the same as
  dystrophin where the nerve cells meet muscular
  tissue.
• Dystrophin and Utophin both help to protect
  muscle tissue through wear and tear.
• Dystrophin works as a shock absorber to the
  muscles. Utophin does also

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What is the connection between Dystrophin and
Utophin?

• Studies done on mice showed that if there is
• an abnormally high amount of Utophin in the
• body, the symptoms of MD reverse.

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Dystrophinopathies. Dystrophic muscle
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Dystrophinopathies dystrophin staining
Normal dystrophin
Intermediate dystrophin Becker MD
Duchenne dystrophy
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Treatments for DMD

• To improve breathing
• O2 therapy
• Ventilator
• Scoliosis surgery
• Tracheotomy

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Treatments (cont.)

• To improve mobility
• Physical therapy
• Surgery on tight joints
• Prednisone
• Non-steroidal medications
• Wheelchair

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Treatments (cont.)

• To improve mobility
• Physical therapy
• Surgery on tight joints
• Prednisone
• Non-steroidal medications
• Wheelchair

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Advances in Gene Therapy

• Researches have developed "minigenes," which
  carry instructions for a slightly smaller version
  of dystrophin, that can fit inside a virus
• Researchers have also created the so-called
  gutted virus, a virus that has had its own genes
  removed so that it is carrying only the
  dystrophin gene

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Problems with Gene Therapy

• Muscle tissue is large and relatively
  impenetrable
• Viruses might provoke the immune system and cause
  the destruction of muscle fibers with the new
  genes

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Other MDLimb Girdle MD
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Common features

• Expression in either male or female sex
• Onset usually in the late first or second decade
  of life (but also middle age)
• Usually autosomal recessive and less frequently
  autosomal dominant
• Involvement of shoulder or pelvic-girdle muscles
  with variable rates of progression
• Severe disability within 20-30 years
• Muscular pseudohypertrophy and/or contractures
  uncommon

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• Molecular genetics revolutionized LGMD
  classification
• Rrecent classification (clinical and molecular
  characteristics)
• autosomal dominant (LGMD1)
• autosomal recessive (LGMD2)
• The list continues to expand
• Genetic linkages have been identified for 6
  autosomal dominant and 11 autosomal recessive
  LGMDs,
• Myofibrillar myopathies share several phenotypic
  characteristics with the LGMDs.

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Limb Girdle MD

• LGMD may show an autosomal recessive (autosomal
  dominant forms reported)
• or sporadic method of inheritance.
• Some forms of LGMD dramatically affect young
  adults, while other types progress so slowly that
  they are not detected until much later in life.

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• LGMD protein defects occur in several pathways
• proteins associated with the sarcolemma
• proteins associated with the contractile
  apparatus
• Various enzymes involved in muscle function.

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Autosomal recessive LGMD

• This childhood form
• Affects both males and females
• First decade of life. In general
• The course is of gradual progression over years.
• Distribution of weakness is typically in the
  pelvis (80-90 of cases)
• later in life, involvement of the shoulder
  girdle (30)
• No hypertrophy of the calves (contrast to other
  forms of MD

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Autosomal recessive LGMD

• CPK elevated (2-3 times)
• The inheritance pattern is strongly autosomal
  recessive with consanguinity
• Positive family history often is reported.
• The abnormal gene is linked to chromosome arm
  15q.

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Pelvifemoral atrophy (Leyden-Mobius)

• Most heterogeneous of all limb-girdle
  dystrophies.
• 60-70 of cases are sporadic (few cases
  familial)
• Symmetric or asymmetric involvement of the pelvic
  girdle.
• Late onset second to sixth decades.
• Slow progression ? clinical arrest (ambulate into
  70s)
• The survival rate seventh decade of life.
• CPK vary from normal to significant elevation.
• No identified gene yet.

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Scapulo-humeral dystrophy (Erb)

• Involves mainly the upper extremities.
• Autosomal recessive in some cases.
• starts later in life (second to the fifth
  decades),
• Benign (years before it is diagnosed).
• Weakness generally is asymmetric may spare the
  deltoid, supra-spinatus, and infra-spinatus
  muscles.
• lower extremities involvement very late in life
  show
• The progression very slow (normal life
  expectancy).
• Minimal, disability

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Late-onset autosomal myopathy

• Third to the fifth decades of life.
• The course is benign
• Upper lower extremity weakness little
  functional impairment.
• Patients ambulate well into their 6th and 7th
  decade
• Affects males and females.

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Oculopharyngeal

• Late onset
• Ocular and bulbar symptoms
• Slowly progressing

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Congenital Muscular Dystrophy

• autosomal-recessive disease
• Severe proximal weakness at birth (or within
  6/12) Slowly progressive or nonprogressive.
  Contractures are common
• central nervous system (CNS) abnormalities can
  occur.
• Biopsy signs of dystrophy, a marked ? in
  endomysial and perimysial connective tissue, and
  fiber size variability with small round
  immature fibers, less commonly, necrosis
• No distinguishing features (as in congenital
  myopathies)

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Congenital Muscular Dystrophy

• The pathophysiology of CMD depend on specific
  associated genetic defect (known with 4 of the
  CMDs)
• Functions of the disrupted proteins defined in
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• Deficiency of laminin-alpha2 (merosin), a
  skeletal muscle extracellular matrix protein that
  binds the dystrophin-associated glycoprotein
  complex (see Picture 1)
• Deficiency of integrin-alpha7 beta1, a skeletal
  muscle membrane protein that binds laminin-2
• The pathophysiology of the other CMDs is unknown

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Muscular dystrophy
Congenital
Limb girdle
Duchenne, Becker
Emery-Dreifuss
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Dysferlinopathies

• Distal myopathy Miyoshi (1967, 1986)
• Locus 2p13.3
• DYSF gene mutation (Bashir et al Liu et al,
  1998)
• Type 2B limb girdle myopathy
• Firstly described in Palestinian families
  (Mahjneh et al, 1992)
• Chromosome 2p linked (Bashir et al, 1994)
• Both MM and LGMD phenotype in the same family
• (Illiaroshkin et al Weiler et al, 1996)

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• Distal myopathy Miyoshi (1967, 1986)
• Locus 2p13.3
• DYSF gene mutation
• (Bashir et al Liu et al, 1998)
• Type 2B limb girdle myopathy
• Firstly described in Palestinian families
  (Mahjneh et al, 1992)
• Chromosome 2p linked
• (Bashir et al, 1994)
• Both MM and LGMD phenotype in the same family
• (Illiaroshkin et al Weiler et al, 1996)

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Dysferlinopathies Epidemiology

• Geographical distribution
• MM identified in Japan
• LGMD (Palestinian, Lybian Jews)
• Dysferlin mutation 1/3000 Lybian Jews (Argov et
  al, 2000)
• Most frequent distal myopathy (except
  Scandinavia)
• LGMD2B second cause of LGMD (Tagawa et al)
• Dysferlinopathies about 25 of unindentified
  muscular dystrophy

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Dysferlin is located to muscle cell membranes,
and is missing in patients with severe limb
girdle muscular dystrophy
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Model for the function of Dysferlin in
muscle repair
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Dysferlinopathies Common traits

• AR inheritance
• Normal developmental milestones, sport possible
  prior to first symptoms
• Onset between 15 35 y (young adults)
• LL distal, proximo-distal, or proximal wk calf
  involvment
• UL biceps atrophy, moderate scapular involvment
• Facial, bulbar muscles spared
• Normal cardiac and respiratory function
• CK (10 to 123 N)
• Unspecific myopathic pattern, necrosis, no
  vacuoles
• Various severity

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• Distal myopathy
• Posterior leg (Miyoshi myopathy)
• Anterior leg compartment
• Proximal myopathy  limb girdle  (LGMD2B)
• High CPK
• Polymyositis-like
• Exercise intolerance

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Myotonic Dystrophy

• Myotonic dystrophy
• Autosommal dominant disorder with highly variable
  expression of the disease phenotype
• The molecular abnormality is an expansion of a
  CTG nucleic acid triplet repeat sequence on the
  nineteenth chromosome
• The muscle weakness can be mild
• Marked facial weakness, ptosis
• Greater distal weakness

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• Difficulty in releasing hand grip. At the
  bedside, myotonia
• Frontal balding usually more prominent in men
• Premature cataracts, arrhythmias, diabetes, and
  testicular atrophy
• Myotonia can be a disturbing symptom or does not
• In disabling myotonia, quinine, Phenytoin,
  henytoin
• Mexiletine should not be used if cardiac
  manifestations

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Myotonic dystrophy

• Type 1 (most common, 98)
• an expansion of CTG repeats in the DMPK gene on
  chromosome 19
• Prevalence in West 13.5 per 100,000
• Type 2
• an expansion of CCTG repeats in the ZNF9 gene on
  chromosome 3
• Type 3 ?

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Inflammatory Myopathies

• Age young/adult
• /- Skin rash
• Main feature weakness Muscle pain
  tenderness
• Investigations
• High C.K.
• EMG
• Muscle biopsy
• Diagnosis
• Treatment Immune suppressive steroids

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Metabolic myopathies

• Thyroid disease
• Hypothyroid or hyperthyroid ophthalmopathy
• periodic paralysis   
• Pituitary and adrenal disease   
• Cushing's syndrome   
• Steroid myopathy   
• Adrenal insufficiency  
•  Primary hyperaldosteronism   
• Acromegaly   
• Hyperparathyroidism   Hypoparathyroidism

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MYASTHENIA GRAVIS
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MYASTHENIA GRAVIS

• DEFINITION Disorder of the NMJ (postsynaptic
  membr)
• Forms
• Transient neonatal (10 of neonate myasthenic
  mothers)
• Different prognosis, effective treatment
  
• Congenital myasthenia
• Common myasthenia gravis
• Any age 2 pics 20-30 (F gt M) 60-70 M gt F)
• Usually progressing (remission are possible but
  relapse later)

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MYASTHENIA GRAVIS

• CLINICAL FEATURES
• Onset insidious
• Fluctuating weakness ? with exercise
• Fatigability (worsening with exercise
  improvement in rest)
• Precipitating factors Infection, Pregnancy,
  stress, hot temperature, drugs muscle
  relaxants, BZDZ,phenytoin antibiotics (neomycin)
• Clinical presentation
• Ocular ptosis, diplopia? opthalmoplegia
• Bulbar dysphagia, dysphonia, /-facial weakness
• Generalized /-respiratory muscles weakness ?
  risk of death

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MYASTHENIA GRAVIS

• Clsassification Osserman classification
• I ocular
• II (A B) mild to moderate generalised, /-
  drug response, no crises
• III Acute fulminant crises, risk of death,
  high mortality
• IV late severe MG
• Associated disorder-
• Dysthyroidism
• Rh. Arthritis, P. anaemia, SLE

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The Spectrum of autoimmune Diseases
Organ specific
Systemic
Hashimotos thyroiditis Pernicious
anaemia Insulin dependent
diabetes Myasthenia gravis
Multiple sclerosis Ulcerative
colitis Rheumatoid arthritis Systemic
lupus erythematous
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PATHOPHYSIOLOGY

• Neuromuscular junction transmission autoimmune
  disorder (Post synaptic membrane)
• Destruction of the Ach. receptors on the post
  synaptic membrane by the AB ? insufficient muscle
  fibers contraction
• Ach.receptor Anti-bodies
• circulating level can be done
• Origine thymus (hyperplasia, thymoma)
• association of HLA, A1 B8.

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Tr
B cell
IL-6, etc
Cytokines
Auto reactive T cell
Genetically predisposed
Tissue damage
CD8
Cytokines
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• ? Diagnosis
• Clinical presentation, excrcise test, rest test
• Tensilon Test 10 mg Edrophonium IV carrefullty
  slowly
• Investigations
• ? Investigations
• Laboratory Investigations.
• Acetycholine receptor antibodies level
• Straited muscle AB, other antibodies
• Neurophsiology
• EMG decrement test
• Imaging Chest x-ray and chest CT scan / MRI
• Others PFT..

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MANAGEMENT

• ? Medical treatment
• Anticholinesterase
• Immunosupressant Steroids
• Azathioprin
• ? Plasmaphoresis
• ? Immunoglobulins
• ? Surgery Thymectomy

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Prognosis

• Remission 30 .
• More likely in patient with short history
• Less in prominent thymic hyperplasia/thymoma
• Approach through suprasternal or transsternal
• (extensive, large thymectomy)
• Medical treatment
• may be D/C, need for low doses, same doses
• or worsening ? other ttt

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Myasthenic crises

• Severe situation
• Needs urgent management
• Diferentiate from cholinergic crises

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Myasthenic syndrome

• Clinically differences
• Pathophysiology presynaptic membrane
• Neurophsiology increament
• Poor response to Anti Ch-esterase
• Etiology paraneoplastic