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Primary muscular disorders

muschi si boli musculare.ppt

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Primary muscular disorders

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• More than 600 separate muscles• 40% of the human weight in adulthood• A muscle contains thousands of muscle fibers

that extend for variable distances along its longitudinal axis.

• A muscular fiber is a multinucleated cell from a few mm to several cm and from 10-100 micrometers diameter

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• Muscle fibers innervated by an anterior horn cell act as a unit called – “motor unit” – basic physiologic unit in all reflex, postural and voluntar activity.

• A particular muscle may have from a few (3-4 as extraocular muscles) to hundreds of MU (like the cvadriceps muscle)

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Clinical syndrome• Motor deficit not restricted to a particular

motor unit.• Distribution of motor weakness might involve a

certain group of muscles or could be more widespread. In this case proximal muscles are usually more involved – wadling gait is characteristic for pelvian muscles deficit.

• Distal myopaties are not quite exceptional. • Muscle tone is diminished• Muscular atrophy and loss of bulck is common

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• Common activities might get impaired because of weakness related to a muscular disorder:– Walking, running, climbing stairs, arising from sitting

(special sign – Gowers – “patient climbing on himself”), kneeling, squatting or reclining position, working with hands above shoulder’s level.

-- Localized muscle weakness might be a sign of a muscular disorder as well: drooping of the eyelids, diplopia and strabismus, change in facial expression and voice, difficulty in chewing, closing the mouth, swallowing etc..

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• Non muscular abnormalities in muscular diseases– Dislocation of the hips– Skin involvement – Cardiac abnormalities– Retinian changes– Cerebellum and cranial nerves– Fronto-temporal dementia– Dysmorphic features of cranium– Endocrine abnormalities

Skin lesions – typical rash in dermatomyositis

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Differential diagnosis with polineuropathies

• Tendon reflexes are spared• No sensory signs• No sphincterian troubles• No autonomic signsBut we can have:

pain, spasms, cramps, rippling, muscular hypertrophy (true or false), fatigue, myotonia, stiffness, muscle mass or change in muscle volume

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Diagnosis

• Blood tests• Electrophysiology • Imaging studies• Biopsy • Genetic tests• Asses cardiac function for associated

cardiomiopathy

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Blood tests• Check up for:

– Creatinkinase (elevated in active, progressive disorders to thousands of units)

– Aldolase– Transaminases– Electrolites: sodium, potasium, cloride– Tiroidian check up– Autoimmune battery – Toxicology – Serology for viral or parasitic infections

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Electrophysiology • Nerve conduction studies are normal• Needle electrode test of muscular activity at

rest and gradual to maximal contraction– At rest we can find:

• fibrillation potentials - markers for spontaneous contractions of individual muscle fibers as a consequence of membrane instability – very prominent in inflammatory myopathies during the active episodes

• myotonic discharge - repetitive high frequency potentials expression of delayed muscle relaxation after voluntary contraction–action myotonia or mechanical stimulation–percussion myotonia Types Chloride channel-related disorders–eg, myotonia congenita, Thomsen type; protein kinase-related disorders–eg, myotonic dystrophy; sodium channel-related disorders–eg, hyperkalemic periodic paralysis; idiopathic

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• Normal recruitment

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• Early recruitment during gradual contraction in myopathic conditions with low amplitude and short duration of individual motor units

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• Myopathic pattern of amplitude/turn ratio(under the lower part of the cloud)

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Imaging • CT scan, MRI or ultrasound

– Help to define the pattern of involvement being particularly helpful for profound muscles

– Very helpful for detecting inflammation, edema, muscular mass (hematoma, tumor, ossification etc..)

– Normal appearance of thigh muscles

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• Axial T2 weighted spin echo MR image showing edema and inflammation of muscle fibers and skin (solid arrows) in a patient with polimyositis.

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Muscle biopsy• Fragment of muscle is removed surgically and prepared

to be examined by microscope looking for necrosis, inflammation, edema, cytoplasmic inclusions, regeneration activity, increase in lipocytes, fibrosis etc

• and tested by immunostaining looking for specific proteins (distrophin, utrophin, emerina, sarcoglicans etc)

• the selection of the muscle is based on evidence of involvement

• Although involved, a certain muscle should be avoided if the loss of muscle fibers is very prominent and advanced.

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• HE staining showing inflammatory cells (purple) attacking muscle fibers in a patient with polimyositis

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Histopathology of gastrocnemius muscle from patient who died of pseudohypertrophic muscular dystrophy,

Duchenne type. Cross section of muscle shows extensive replacement of muscle fibers by adipose

cells.

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HIV infection• Inflammatory• Infectious• Related to treatment

Primary endomysial inflammation,red-rimmed vacuoles, amyloid deposits,eosinophilic inclusions, and small round fibres in groups, all diagnostic of IBM.

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Genetic testing• Is a blood test• For ex: the muscle-specific isoform of the

dystrophin gene (for Duchenne dystrophy) is composed of 79 exons, and DNA testing and analysis can usually identify the specific type of mutation of the exon or exons that are affected. DNA testing confirms the diagnosis in most cases and detect the carrier status

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Prenatal tests• If one or both parents are 'carriers' of a particular condition there is a risk

that their unborn child will be affected by that condition. • 'Prenatal tests' are carried out during pregnancy, to try to find out if the

fetus (unborn child) is affected. • The tests are only available for some neuromuscular disorders. Different

types of prenatal tests can be carried out after about 11 weeks of pregnancy.

• Chorion villus sampling (CVS) can be done at 11–14 weeks, and amniocentesis after 15 weeks, while fetal blood sampling can be done at about 18 weeks.

• Earlier testing would allow early termination, but it carries a slightly higher risk of miscarriage than later testing (about 2%, as opposed to 0.5%).

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Etiology of muscular disorders• I. Inflammatory myopathies

– A. Infective or presumably infective forms of polymyositis• Trichinosis• Toxoplasmosis• Cysticercosis• HIV, HTLV-1

– B. Idiopathic polymyositis and dermatomyositis – usually associated to connective tissue disorders affect primarily striated muscle and skin

• Sometimes paraneoplastic syndromes• Only DM affects children

• Diagnosis based upon specific changes in muscle and skin biopsy – C. Inclusion body myositis (IBM)

• Predominates in males• Onset in middle or late adult life, more frequent than PM• Diagnosis based on intracytoplasmatic vacuoles and congophilic inclusions in both

cytoplasma and nuclei of degenerated muscular fibers

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• Heritable muscular dystrophies (MD) include the following:

Sex linked- Duchenne- Becker- Emery DreifussAutosomal dominant- Facioscapulohumeral- Distal- Ocular- Oculopharingeal Autosomal recessive- Limb girdle

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Pathophysiology

• Multiple proteins are involved in the complex interactions of the muscle membrane and extracellular environment. For sarcolemmal stability, dystrophin and the dystrophin-associated glycoproteins (DAGs) are important elements

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Other muscular dystrophies

• Myotonic dystrophy (Steinert disease) – 19q• Proximal myotonic myopathy (PROMM) – 3q• Distal myopathies – breaking the rule of proximal distribution of

weakness according to myopathic pattern – affects distal muscles and might resemble a polineuropathy

– Welander type – autosomal dominant– Miyoshi – dysferlin gene on crz 2p – autosomal

recessive– Recently described a distal myopathy associated

with frontotemporal dementia and Paget disease

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Metabolic and toxic myopathies

• Hereditary metabolic abnormality – glycogen storage myopathies, lipid metabolism disorders

• Secondary to a disorder of endocrine function (thyroid – thyrotoxic and hypothyroid myopathy, pituitary, adrenal gland)

• Myotoxic drugs and other chemical agents – rhabdomyolysis to alcohol abuse, statins, cocaine, organophosphates, high doses of corticosteroids (critical ilness myopathy)– Other mecanisms: hypokalemic (diuretics, laxatives, alcohol),

lysosomal storage (amiodarone, chloroquine), inflammatory (procainamide, D-penicilamine) etc

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CONGENITAL NEUROMUSCULAR DISORDERS

• Develop in utero• Relatively nonprogressive• Could have the clinical onset at a later age even in middle adult life• Diagnosis based on specific morphologic changes on muscle biopsy

revealed by systematic application of hystochemical stains to frozen sections and by phase and electron microscopy– Central core

• presence in the central portion of a condensation of myofibrillar material • high risk for malignant hyperthermia (19q – linked to the ryanodine receptor gene)

– Nemaline • Miriads of rods seen beneath the plasma membrane of the muscle fiber

– Centronuclear or myotubular • Central nucleation and smalnees of fibers• X-linked and AR in children and AD in adult onset form

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Channelopathies • Diseases caused by mutations in genes that code proteins

that function as channels in muscle fibers membrane – ion channel disease

• I. Chloride channel diseases– Myotonia congenita (Thomsen disease – AD, early life onset,

myotonia, muscular hypertrophy and nonprogressive course)– Generalized myotonia (Becker disease – AR, manifestation of

myotonia after 10-14 y of age)

• II. Sodium channel diseases– Myotonia fluctuans and permanens– Acetazolamide –responsive myotonia

• III. Calcium channel diseases – Hypokalemic periodic paralysis – AD, attacks evolving over minutes to

hours of diffuse weakness (legs before arms before trunk muscles), usually sparing of faciobulbar muscles

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– Secondary kalemic periodic paralyses – transitory episodes of weakness known to be associated to acquired derangements of potassium metabolism

• Thyrotoxicosis• Aldosteronism• 17 alfa hydroxilase deficiency • Barium poisoning

– Malignant hyperthermia• During general anesthesia – rising body temperature, muscular

rigidity and risk of death (inherited defect of the ryanodine receptor, protein component of the calcium channel in the sarcoplasm)

– Malignant neuroleptic syndrome• Hyperthermia occurs as an idiosyncratic reaction to neuroleptic

drugs with widespread myonecrosis.

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Neuromuscular junction disorders• Myasthenia gravis• Myasthenic – myopathic syndrome of Lambert Eaton

– paraneoplastic sy associated to the oat cell carcinoma of the lung – presynaptic defect of Ach release from the nerve terminals

• Congenital myasthenic syndromes – genetic disorders with pre or postsynaptic defects

• Myasthenic weakness due to antibiotics (neomicin, kanamicin, polymixin, colistin etc) or toxins (clostridium botulinum)

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Myasthenia gravis

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mechanism

• Autoimmune attack against aceticholine receptor on the postsynaptic membrane of the neuromuscular junction.

• The antibodies affect only the nicotinic receptor in the skeletal (striated) muscles. Visceral muscles and myocardium are spared.

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symptoms

• Fluctuating weakness of muscles induced or aggravated by repetitive or persistent activity and recovered during rest.

• Onset usually insidious but some factors like emotional upset or infections might be precipitating.

• The special vulnerability of certain muscles is also a characteristic feature.

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• Craniofacial muscles are in 50% of cases involved at the onset (levator palpebrae and extraocular muscles most of all) and eventually become symptomatic in ~90% of patients.

• So drooping eyelids and intermittent diplopia are common complaints.

• Muscles of facial expression, mastication, swallowing and speech are in 80% of cases affected.

• In patients with weakness of the trunk and limbs – proximal muscles are far more vulnerable than the distal ones.

• Involvement of respiratory muscles is associated with respiratory insuficiency

• Rapid deterioration with respiratory failure and quadriparesis might occur in a range of hours and is termed myasthenic crisis being considered life threatening and a treatment emergency

• Precipitating factors: phisical exercise, cold, hunger, general anesthesia, infections, vaccination

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• No other clinical signs or symptoms apart from the motor ones are present in the clinical picture

• Muscle atrophy is not present.• Course of the illness is extremely variable but

mortality is under 5% and treated correctly most of the patients lead productive lives.

• Thymic gland is involved as primary site of antibody production

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Thymic involvement

• True neoplasm are found in 10-15% of patients

• 65% of the remaining patients shows an important degree of hyperplasia of lymphoid follicles with active germinal centers confined to the medullary part of the thymus gland.

• Mediastinal CT scann is commonly used to document thymus morphologic changes.

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• The disease may begin at any age.• Peak of incidence 20-30 y in women and 50-60 y in men• The danger of death, mainly related of infections or

aspiration, is greatest in the first year of life.• 15-20% of patients have only ocular myasthenia all life long• 30-55 % develop a mild or moderate generalized form, but no

crises• 15% have crises frequently and high risk for death• 10 % have a late severe myasthenia poor-responsive to

medication and high risk for death

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Diagnosis

• Measurement of receptor antibodies in blood – sensitive and highly specific test – RIA is the method of choice– 80-90% of patients with generalized myasthenia

and 60% of those who are restricted to ocular muscles

– Seronegativity does not imply clinical or electrophysiological differences.

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Pharmacologic tests

• Use of edrophonium or neostigmine– Test a group of muscles or determine vital

capacity and then inject the substance and depending on the half-life the test is redone at a certain time interval

– If significant, visible improvement in strength occurs we consider the test positive for myasthenic deficit.

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Electrophysiology

• Nerve conduction studies and EMG are both normal in myasthenic patients

• Repetitive nerve –muscle stimulation– Rapid reduction in amplitude of compound muscle

action potentials after 3/sec stimulation of a peripheral nerve – decremental response and reversal of this response by anticholinesterase drugs is a reliable confirmation of diagnosis.

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Treatment • I. Anticholinesterase drugs – neostigmin (miostin) and pyridostigmine

(mestinon)– Increse the availability of Ach in the synaptic cleft and improve the

myasthenic deficit– Side effects – cholinergic muscarinic (nausea, vomiting, salivation,

diarrhea, miosis, bradycardia)– Cholinergic crisis – rapid escaladation of muscular weakness due bell

shape effect of drugs on neuromuscular junction• Thymectomy – recommended in the first 3 years and in tumoral patients -

is followed by significant improvement and chance of better control with corticosteroids afterward

• Corticosteroids are the most consistently effective form of treatment in moderate to severe generalized weakness. Managing side effects is chalenging

• Immunosupressants - as an adjunct to steroids or the one that fail to respond to corticotherapy

• PE or Iv immune globulin – for myasthenic crisis, reechilibration for surgery, refractory patients.

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Myasthenic crisis

• Careful intubation followed by mechanical ventilation

• Anticholinesteraze drugs withdrawn• PE or Iv Ig – hasten improvement