Primary muscular disorders

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

 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)

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

 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 shoulders 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..

 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

Differential diagnosis with polineuropathies

Tendon reflexes are spared No sensory signs No sphincterian troubles No autonomic signs But we can have: pain, spasms, cramps, rippling, muscular hypertrophy (true or false), fatigue, myotonia, stiffness, muscle mass or change in muscle volume

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

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

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 contractionaction myotonia or mechanical
stimulationpercussion myotonia Types Chloride channel-related disorderseg, myotonia congenita, Thomsen type; protein kinase-related disorderseg, myotonic dystrophy; sodium channel-related disorderseg, hyperkalemic periodic paralysis; idiopathic

 Normal recruitment

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

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

 CT scan, MRI or ultrasound

Imaging

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

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

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.

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

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.

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.

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

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 1114 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%).

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

 Heritable muscular dystrophies (MD) include the following:

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

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

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

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

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

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

 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.

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)

Myasthenia gravis

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.

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.

 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

 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

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.

 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

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.

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.

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.

 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.

Treatment

Myasthenic crisis
Careful intubation followed by mechanical ventilation Anticholinesteraze drugs withdrawn PE or Iv Ig hasten improvement