neuromuscular dis د.رشاد عبدالغني
TRANSCRIPT
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MUSCLES DISEASES
Dr.Rashad A. ghani
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Introduction: structure and functionWe possess more than 150 voluntary (skeletal) muscles.
Complex voluntary movements of the body are achievedby integrated activity of different skeletal muscle groups.
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Each muscle fibre has a membrane (thesarcolemma), it contains cytoplasm (thesarcoplasm), and it has an endoplasmic reticulum
(the sarcoplasmic reticulum) as well as othersubcellular organelles such as mitochondria.Typically the nuclei are positioned at the edges ofthe muscle fibre.
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A chain of important structural proteins maintain the integrity of thesarcolemma by linking intracellular muscle fibre cytoskeletal proteinsto the extracellular matrix. These structural proteins includedystrophin (located in a subsarcolemmal distribution), the dystrophin-
associated glycoprotein complex (a trans-sarcolemmal proteincomplex), and laminin (located extracellularly). These importantproteins may be dysfunctional in certain forms of genetic musclediseases.
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After staining, muscle fibres are seen
to have regular cross-striations ,
dividing it up into sarcomeres. Thelight I band is divided by the dark Z
line and the dark A band has the
lighter H zone in its centre. The
region between two adjacent Z
lines is called a sarcomere. The
cross-striations are due to the
presence of the principal contracile
filamentous proteins, actin and
myosin, in the sacroplasm. These
filamentous proteins are arranged in
rod-like structures known asmyofibrils. A single myofibril
contains many protein filaments.
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The thick filaments are
lined up to form the A
bands, whereas the array
of thin filaments formsthe less dense I bands.
The lighter H bands in
the centre of the A bands
are the regions where,when the muscle is
relaxed, the thin
filaments do not overlap
the thick filaments. The
Z lines transect the
myofibrils and connect
to the thin filaments
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Neuromuscular disorders
Myopathies are disorders in which there is a
primary functional or structural impairment of
skeletal muscle. Myopathies usually cause
proximal symmetric weakness, with or without
other symptoms.
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Causes of myopathies
Inherited
Muscular dystrophies
Myotonic dystrophy
Congenital myopathies
ChannelopathiesPrimary metabolic disorder
Congenital myasthenic syndromes
AcquiredDrug and toxin inducedEndocrine
Secondary metabolic
Inflammatory
Paraneoplastic
Myasthenia gravis
Lambert-Eaton myasthenic
syndrome
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Muscular dystrophiesThe muscular dystrophies are a group of inheriteddisorders characterised by progressive muscle
wasting and weakness.
The classification of muscular dystrophy is based onboth clinical and genetic characteristics.
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Progressive muscular dystrophies result from
diverse defects in muscle proteins
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Disease Gene Inheritance Protein
X-linked dystrophiesDuchenne/BeckerEmery-Dreifuss
Xq 21Xq 28 XRXR DystrophinEmerin
Limb-girdle muscular dystrophiesLGMD 1 to CALGMD 2A to HA
2, 4, 513,17 ADAR CalveolinSarcoglycans,Calpain
Congenital muscular dystrophies(With CNS involvement)Fukuyama CMDWalker - Warburg CMDMuscle - Eye-Brain CMD(Without CNS involvement)Merosin-deficient classic typeMerosin-positive classic type
9q 316q2Lama2ARARARARAR
Fukutin??Merosin?
Distal dystrophies 2,79 AR/AD DysferlinFacioscapulohumeraleOculopharyngealMyotonic dystrophy
4q 351419ADADAD Repeat expansion
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Type Onset Clinical features Other organsystem involedDuchenne Before 5years Progressive weakness ofgirdle muscle, calfhypertrophy.
Wheelchair bound: after12 years.KyphoscoliosisRespiratory failure (death)in the 2nd or 3rd decade
Cardiomyopathy
Becker Earlychildhoodto adultProgressive weakness ofgirdle musclesAble to walk after age 15Respiratory failure maydevelop by 4th decade
Cardiomyopathy
Emery- drefuss Childhood to adult Elbow contractures,humeral and peronealweaknessDeath by the 4th decadeunless treated bypacemaker
CardiomyopathyHeart block
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Limb-girdle Earlychildhoodto earlyadult
Slow progressiveweakness of girdlemusclesCardiomyopathy
Facioscapulo-humeral Beforeage 20 Slowly progressiveweakness of face,shoulder girdle, and footdorsiflexionSurvival generallyunaffected
Deafness
Oculopharyngeal 5th to 6thdecade Slowly progressiveweakness of extraocular,pharyngeal and limbmuscles
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Congenital At birth orwithin 1stfewmonths
Hypotonia, contractures,delayed milestones,progression to respiratoryfailure in some, staticcourse in others
CNSabnormalities(hypomyelination,malformation)Eye abnormalities
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Congenital
myopathy
early life or
infancy
Hypotonia,
Relatively
nonprogressiveweakness.
Unique
morphological
features onmuscle biopsy
dysmorphic
features
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Epidemiology
Incidence:Duchenne / Becker muscular dystrophy 56%
Limb-girdle muscular dystrophy 19%
Congenital muscular dystrophy 18%
Facioscapulohumeral muscular dystrophy 4%
Emery-Dreifuss muscular dystrophy 1%
Others 2%
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Investigated Approach In Suspected MDCreatinine Phosphokinase
The serum levels of CPK are significantly elevated (in
thousands) in DMD/BMD patients.
Electromyography shows decreased amplitude and
duration of motor unit potential.
Muscle biopsy
variation in size
centralization of nuclei
rounded atrophic fibers
endomysial fibrosis
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Immunohistochemistry:
Immunohistochemistry utilizing anti-dystrophin,
anti-sarcoglycan, and anti-laminin-alpha2 antibodiesNormal Deficient Absent
Genetic testing:DNA studies are available for Duchenne, becker,facioscapulohumeral, myotonic dystrophy and about half of thelimb girdle MD.
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Duchennes muscular dystrophy
This is the commonest form of muscular
dystrophy. It is virtually confined to males. The
genetic defect in Duchennes muscular dystrophy
affects the dystrophin gene, located in the X
chromosome. The dystrophin protein is absent invirtually all cases ofDuchennes and is abnormal
in patients with Beckers muscular dystrophies.
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Clinical features
Onset in the 1st decade (3-6 years). Waddling gait
is the first symptom. Walking difficulties appear,followed by difficulty in climbing stairs and in
rising from the floor. Pseudohypertrophy,
particularly of the calf muscles, is almostinevitable. Gowers sign is characteristic
manoeuvre . By about the age of 10, the patient is
unable to walk; the majority of cases die by the
age of 20. Cardiomyopathy is almost always
present and some patients develop cardiac failure.
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The myotoniasMyotonia is the phenomena of impaired
relaxation of muscle after forceful voluntary
contraction. Myotonia can be triggered either by a
voluntary contraction or percussion.
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Paramyotonia congenita
With paramyotonia congenita, exposure to coldtriggers attacks of muscle contraction followed
by flaccid weakness. The condition is inherited
as an autosomal dominant.
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Myotonic dystrophy (Dystrophia myotonica)
The gene responsible for myotonic dystrophy islocated on the long arm of chromosome 19. The
genetic defect is an expansion of CTG trinucleotide
repeats.
Cli i l f t
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Clinical features
The clinical features (onset &severity) are extremely
variable. The condition may be asymptomatic. The
muscle weakness is predominantly distal in both
upper and lower limbs.
Characteristic facies
Cataract is common and may be
the presenting feature. Other
findings include Cardiacconduction defects , testicular
atrophy, pituitary abnormalities
and diabetes.
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Investigations
EMG studies reveal myotonic discharges (dive-
bomber sounds ) and a myopathic pattern. Musclebiopsy demonstrates selective atrophy of Type 1
fibres associated with an increased proportion of
central nuclei
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The Inflammatory Myopathies
Inflammatory disease of muscle (myositis) is
either idiopathic or infective in origin.Polymyositis and dermatomyositis are the
commonest.
Diagnostic criteria include:A clinical picture ofproximal muscle weakness,
often with pain
Histological evidence of muscle fibre necrosiswith cellular infiltration,
An elevated serum CKactivity
and acharacteristic EMG pattern.
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Polymyositis and dermatomyositis share the same
clinical characteristics in terms of muscle
involvement but with additional skin changes in thelatter.
There is predominant proximal
muscle weakness often accompaniedby pain and muscle tenderness. Neck
weakness is common. Dysphagia
secondary to involvement of thepharyngeal muscles also occur.
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The dermatomyositis is associated with
malignancy in 40% of cases.
Polymyositis is associated with conective tissuedisorder in 20% of cases.
Investigation
Serum CK activity is particularly high in the acuteforms. EMG changes include spontaneous
activity, with fibrillation potentials, and volitional
units of small amplitude and duration associatedwith polyphasia.
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Muscle biopsy
Polymyositis: segmental necrosis withlymphocytic infiltration
Dermatomyositis: perifascicular
atrophy and prominent perivascular
infiltrates.
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Treatment:
Of all the treatments that are available,
prednisolone remains the drug of choice. Iftreatment with steroids is not successful, other
lines of treatment are considered, such as
intravenous immunoglobulins (IVIG),immunosuppressive therapy; and antineoplastic
agents.
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Disorders of neuromuscular junctionMyasthenia Gravis
Myasthenia gravis (MG) is an acquired autoimmune
disorder characterized clinically by muscles
weakness and fatigability.
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Pathophysiology:
The antibodies in MG are directed toward the
acetylcholine receptor (AChR) at the neuromuscularjunction (NMJ) of skeletal muscles. Anti-AChR
antibody is found in approximately 80-90% of
patients with generalized MG and 50% for those withocular myasthenia. The thymus is the central organ in
T cellmediated immunity, and thymic abnormalities
such as thymic hyperplasia (50%) or thymoma (15%)
are well recognized in myasthenic patients.
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Epidemiology:
Estimated annual incidence is 2 per 1,000,000.The prevalence rate is 14 per 100,000.
Age: MG presents at any age. Female incidence
peaks in the third decade of life, whereas maleincidence peaks in the sixth or seventh decade.
Sex: The female-to-male ratio is said classically
to be 6:4.
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Clinical features
MG is characterized by fluctuating weakness
increased by exertion. Weakness increases duringthe day and improves with rest. Extraocular muscle
(EOM) weakness or ptosis is present initially in 50%
of patients and occurs during the course of illness in90%. Bulbar muscle weakness is also common,
along with weakness of head extension and flexion.
Weakness may involve limb musculature with
myopathic-like proximal weakness greater than
distal muscle weakness.
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Muscle fatiguability can be confirmed by a variety
of bedside tests (counting test).
Characteristic triple
forrowed tongue
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Edrophonium test (a trial dose of 2mg, followed after
about 30s by 8mg) is a valuable means of confirming
the diagnosis
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Investigations:Anti-acetylcholine receptor antibody: Results are
positive in about 80% of patients with generalized
myasthenia and in 50% of those with pure ocular
myasthenia. CT scanning detects all thymomas, and
may reveal abnormalities in some patients with
thymic hyperplasia.
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RNS produced decremental response & SFEMG showsabnormal jitter
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TreatmentAChE inhibitors (Pyridostigmine, neostigmine)
and immunomodulating therapies are the
mainstays of treatment. Plasmapheresis and
thymectomy are important modalities for treating
MG. Plasma exchange (PE) is an effectivetreatment for MG, especially in preparation for
surgery or as short-term management of an
exacerbation. Thymectomy may induce remissionin young patients with a short duration of disease,
hyperplastic thymus, and high antibody titer.
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Myasthenic crisis: is an acute exacerbation of MG
with severe weakness and/or acute respiratory
failure. This is a true neuromuscular emergency,
and immediate intubation may be necessary.
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Symptomatic myastheniaCauses
Polymyositis or dermatomyositis.
Penicillamine
Antibiotics and with exposure to botulinum toxin
and organophosphate pesticides
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Lambert-Eaton syndrome
A myasthenic syndrome is recognized to occur in
association with various autoimmune diseases andis associated with malignancy in 40% of cases,
particularly small cell carcinoma of the bronchus.
It mainly affects women.
Clinically, the condition often mimics a proximal
myopathy with muscle pain. Fatiguability is
seldom conspicuous.
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There are certain very characteristic EMG findings.
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