MUSCLES DISEASES

Dr.Rashad A. ghani

Introduction: structure and function

We possess more than 150 voluntary (skeletal) muscles. Complex voluntary movements of the body are achieved by integrated activity of different skeletal muscle groups.

Each muscle fibre has a membrane (the sarcolemma), it contains cytoplasm (the sarcoplasm), and it has an endoplasmic reticulum (the sarcoplasmic reticulum) as well as other subcellular organelles such as mitochondria. Typically the nuclei are positioned at the edges of the muscle fibre.

A chain of important structural proteins maintain the integrity of the sarcolemma by linking intracellular muscle fibre cytoskeletal proteins to the extracellular matrix. These structural proteins include dystrophin (located in a subsarcolemmal distribution), the dystrophinassociated glycoprotein complex (a trans-sarcolemmal protein complex), and laminin (located extracellularly). These important proteins may be dysfunctional in certain forms of genetic muscle diseases.

After staining, muscle fibres are seen to have regular cross-striations , dividing it up into sarcomeres. The light 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 as myofibrils. A single myofibril contains many protein filaments.

The thick filaments are lined up to form the A bands, whereas the array of thin filaments forms the 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

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.

Causes of myopathies
Inherited Muscular dystrophies Myotonic dystrophy Congenital myopathies Channelopathies Primary metabolic disorder Congenital myasthenic syndromes Acquired Drug and toxin induced Endocrine Secondary metabolic Inflammatory Paraneoplastic Myasthenia gravis Lambert-Eaton myasthenic syndrome

Muscular dystrophies
The muscular dystrophies are a group of inherited disorders characterised by progressive muscle wasting and weakness. The classification of muscular dystrophy is based on both clinical and genetic characteristics.

Progressive muscular dystrophies result from diverse defects in muscle proteins

Disease

Gene

Inheritance

Protein

X-linked dystrophies
Duchenne/Becker Emery-Dreifuss

Xq 21 Xq 28

XR XR

Dystrophin Emerin

Limb-girdle muscular dystrophies

LGMD 1 to CA LGMD 2A to HA

2, 4, 5 13,17

AD AR

Calveolin Sarcoglycans,Calpain

Congenital muscular dystrophies

(With CNS involvement)
Fukuyama CMD Walker - Warburg CMD Muscle - Eye-Brain CMD 9q 31 6q2 Lama2 AR AR AR AR AR 2,79 AR/AD Fukutin ? ? Merosin ? Dysferlin

(Without CNS involvement)

Merosin-deficient classic type Merosin-positive classic type

Distal dystrophies

Facioscapulohumerale Oculopharyngeal Myotonic dystrophy

4q 35 14 19

AD AD AD

Repeat expansion

Type

Onset

Clinical features

Other organ system involed

Duchenne

Before 5 years

Progressive weakness of girdle muscle, calf hypertrophy. Wheelchair bound: after 12 years. Kyphoscoliosis Respiratory failure (death )in the 2nd or 3rd decade Progressive weakness of girdle muscles Able to walk after age 15 Respiratory failure may develop by 4th decade
Elbow contractures, humeral and peroneal weakness Death by the 4th decade unless treated by pacemaker

Cardiomyopathy

Becker

Early childhood to adult

Cardiomyopathy

Emery- drefuss

Childhoo d to adult

Cardiomyopathy Heart block

Limb-girdle

Early childhood to early adult Before age 20

Slow weakness muscles

progressive of girdle

Cardiomyopathy

Facioscapulohumeral

Oculopharyngeal

5th to 6th decade

Slowly progressive weakness of face, shoulder girdle, and foot dorsiflexion Survival generally unaffected Slowly progressive weakness of extraocular, pharyngeal and limb muscles Hypotonia, contractures, delayed milestones, progression to respiratory failure in some, static course in others

Deafness

------

Congenital

At birth or within 1st few months

CNS abnormalities (hypomyelination, malformation) Eye abnormalities

Congenital myopathy

early life or infancy

Hypotonia, dysmorphic Relatively features nonprogressive weakness. Unique morphological features on muscle biopsy

Epidemiology
Incidence:

Duchenne / Becker muscular dystrophy Limb-girdle muscular dystrophy Congenital muscular dystrophy Facioscapulohumeral muscular dystrophy Emery-Dreifuss muscular dystrophy Others

56% 19% 18% 4% 1% 2%

Investigated Approach In Suspected MD Creatinine 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

Immunohistochemistry: Immunohistochemistry utilizing anti-dystrophin, anti-sarcoglycan, and anti-laminin-alpha2 antibodies

Normal Deficient Absent

Genetic testing:

DNA studies are available for Duchenne, becker, facioscapulohumeral, myotonic dystrophy and about half of the limb girdle MD.

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 in virtually all cases of Duchennes and is abnormal in patients with Beckers muscular dystrophies.

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 almost inevitable. 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.

The myotonias Myotonia is the phenomena of impaired relaxation of muscle after forceful voluntary contraction. Myotonia can be triggered either by a voluntary contraction or percussion.

Paramyotonia congenita With paramyotonia congenita, exposure to cold triggers attacks of muscle contraction followed by flaccid weakness. The condition is inherited as an autosomal dominant.

Myotonic dystrophy (Dystrophia myotonica) The gene responsible for myotonic dystrophy is located on the long arm of chromosome 19. The genetic defect is an expansion of CTG trinucleotide repeats.

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 Cardiac conduction defects , testicular atrophy, pituitary abnormalities and diabetes.

Investigations EMG studies reveal myotonic discharges (divebomber sounds ) and a myopathic pattern. Muscle biopsy demonstrates selective atrophy of Type 1 fibres associated with an increased proportion of central nuclei

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 of proximal muscle weakness, often with pain Histological evidence of muscle fibre necrosis with cellular infiltration, An elevated serum CK activity and a characteristic EMG pattern.

Polymyositis and dermatomyositis share the same clinical characteristics in terms of muscle involvement but with additional skin changes in the latter. There is predominant proximal muscle weakness often accompanied by pain and muscle tenderness. Neck weakness is common. Dysphagia secondary to involvement of the pharyngeal muscles also occur.

The dermatomyositis is associated with malignancy in 40% of cases. Polymyositis is associated with conective tissue disorder in 20% of cases. Investigation Serum CK activity is particularly high in the acute forms. EMG changes include spontaneous activity, with fibrillation potentials, and volitional units of small amplitude and duration associated with polyphasia.

Muscle biopsy

Polymyositis: segmental necrosis with lymphocytic infiltration

Dermatomyositis: perifascicular atrophy and prominent perivascular infiltrates.

Treatment: Of all the treatments that are available, prednisolone remains the drug of choice. If treatment with steroids is not successful, other lines of treatment are considered, such as intravenous immunoglobulins (IVIG), immunosuppressive therapy; and antineoplastic agents.

Disorders of neuromuscular junction Myasthenia Gravis Myasthenia gravis (MG) is an acquired autoimmune disorder characterized clinically by muscles weakness and fatigability.

Pathophysiology: The antibodies in MG are directed toward the acetylcholine receptor (AChR) at the neuromuscular junction (NMJ) of skeletal muscles. Anti-AChR antibody is found in approximately 80-90% of patients with generalized MG and 50% for those with ocular 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.

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 male incidence peaks in the sixth or seventh decade. Sex: The female-to-male ratio is said classically to be 6:4.

Clinical features MG is characterized by fluctuating weakness increased by exertion. Weakness increases during the 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 in 90%. 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.

Muscle fatiguability can be confirmed by a variety of bedside tests (counting test).

Characteristic triple forrowed tongue

Edrophonium test (a trial dose of 2mg, followed after about 30s by 8mg) is a valuable means of confirming the diagnosis

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.

RNS produced decremental response & SFEMG shows abnormal jitter

Treatment AChE 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 effective treatment for MG, especially in preparation for surgery or as short-term management of an exacerbation. Thymectomy may induce remission in young patients with a short duration of disease, hyperplastic thymus, and high antibody titer.

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.

Symptomatic myasthenia
Causes Polymyositis or dermatomyositis. Penicillamine Antibiotics and with exposure to botulinum toxin and organophosphate pesticides

Lambert-Eaton syndrome A myasthenic syndrome is recognized to occur in association with various autoimmune diseases and is 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.

There are certain very characteristic EMG findings.