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)
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
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 dystrophin-
associated 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.
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.
Myasthenic crisis
Careful intubation followed by mechanical
ventilation
Anticholinesteraze drugs withdrawn
PE or Iv Ig hasten improvement