Neuromuscular dis د.رشاد عبدالغني

8/3/2019 Neuromuscular dis .

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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

------

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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Neuromuscular dis د.رشاد عبدالغني