Myopathies
Myopathy is a muscle disease unrelated to any disorder of
innervation or neuromuscular junction. Etiologies vary
widely.
The common symptoms are muscle weakness, impaired
function in activities of daily life, and, rarely, muscle
pain and tenderness.
Presence of discolored or dark urine suggests
myoglobinuria.

Weakness, usually in a symmetric distribution of
proximal muscle groups.

Symptoms of the patient indicate which muscle groups
are involved.

Difficulty rising from chairs, getting out of the
bathtub, climbing stairs, and/or shaving or combing
the hair suggests proximal muscle weakness.

Weakness of distal muscles will present with
symptoms of weak grasp, handwriting problems, and
walking difficulties, (eg, flapping gait).
Causes

Idiopathic myopathies are thought to result from immunemediated phenomena including sarcoidosis with myopathy,
polymyositis, and dermatomyositis. Some idiopathic myopathies
are associated with connective tissue disease, eg, systemic lupus
erythematosus (SLE), rheumatoid arthritis (RA), and
polyarteritisnodosa.

Acute alcoholic myopathy should be considered in patients who,
after beginning on alcohol, present with muscle pain that mostly
involves limb weakness and myoglobinuria.

Infectious causes :

Cysticercosis (Taeniasolium)

Toxoplasmosis

Human immunodeficiency virus (HIV)

Coxsackie A and B viruses

Lyme disease

Endocrine causes :

Addison disease, particularly when fluid and
electrolyte problems are present

Cushing disease

Hypothyroidism (CK may be mildly elevated)

Hyperthyroidism (CK may be normal)

Hyperparathyroidism

Drug-induced or toxic causes of myopathy :

Steroids especially with prolonged high doses.

statins

Cocaine

Colchicine

Amiodarone when combined with simvastatin

Chloroquine

Vincristine

Acute periodic paralysis may be classified as
hypokalemic, hyperkalemic, or normokalemic.
Thyrotoxic periodic paralysis and Conn syndrome (ie,
primary hyperaldosteronism) occur in Asians and are
considered to have low potassium as the mechanism for
paralysis. Treatment of the underlying disease and
electrolyte disorder are curative.

Muscular dystrophies.

Metabolic Myopathies
Investigation

CK with isoenzymes

Electrolytes, calcium, magnesium

Serum myoglobin

Serum creatinine and BUN

Urine analysis: Myoglobinuria is indicated by positive urine
analysis with few RBCs on microscopic evaluation.

Complete blood count

Erythrocyte sedimentation rate

Thyroid function tests

AST
Electrocardiogram
Findings suggesting hypokalemia include the
following:

Diffuse nonspecific ST-T wave changes

Increased PR interval

U waves

Wide QRS
Other tests that are essential for distinguishing
among the varied causes of myopathy are:

Genetic testing

Antinuclear antibody (ANA)

MRI

Electromyogram (EMG)

Muscle biopsy
Complications

Cardiac arrhythmias

Dysphagia

Acute gastric dilation

Respiratory failure

Endocrinopathies

Early death
Muscular Dystrophy

Muscular dystrophy (MD) is a collective group of inherited
noninflammatory but progressive muscle disorders without a central
or peripheral nerve abnormality.

Despite minor variations, all types of muscular dystrophy have in
common progressive muscle weakness that tends to occur in a
proximal-to-distal direction, although there are some rare distal
myopathies that cause predominantly distal weakness. The
decreasing muscle strength in those who are affected may
compromise the patient's ambulation potential and, eventually,
cardiopulmonary function.
Classification of muscular dystrophy

The etiology of MD is an abnormality in the genetic
code for specific muscle proteins (Dystrophin). They all
are classified according to the clinical phenotype, the
pathology, and the mode of inheritance.

The inheritance pattern includes the sex-linked,
autosomal recessive, and autosomal dominant MDs.
Heritable MDs include the following:



Sex-linked MDs

Duchenne

Becker

Emery-Dreifuss
Autosomal dominant MDs

Facioscapulohumeral

Distal

Ocular

Oculopharyngeal
Autosomal recessive MD – limb-girdle form
Presentation
In Duchenne muscular dystrophy, unless a sibling has been
previously affected to warrant a high index of suspicion,
no abnormality is noted in the patient at birth, and
manifestations of the muscle weakness do not begin until
the child begins to walk. Three major time points for
patients with Duchenne MD are when they begin to walk,
when they lose their ability to ambulate, and when they
die

The child's motor milestones may be normal, but usually
slightly delayed associated with intellectual impairment.

Children with Duchenne MD usually do not begin to
walk until about age 18 months or later.

74% of children with Duchenne MD manifested the
disease by age 4 years. By age 5 years, awareness
increases as the disease is manifested in all affected
children when they experience difficulty with schoolrelated activities (eg, getting to the bus, climbing stairs).

Early features include a gait abnormality, which
classically is a waddling, wide-based gait with
hyperlordosis of the lumbar spine. The waddle is due to
weakness in the gluteus maximus and gluteus medius
muscles and the patient's inability to support a single-leg
stance. The child leans the body toward the other side to
balance his or her center of gravity, and the motion is
repeated with each step. Hip extensor weakness also
results in a forward tilt of the pelvis, which translates to a
hyperlordosis of the spine to maintain posture.

Gradually, noticeable difficulty with step taking
by the child is observed. Frequent falls without
tripping or stumbling often occur and are
described as the feet being swept away from
under the child. The child then begins having
problems getting up from the sitting or supine
position, and he or she can rise to an upright
stance only by manifesting the Gower sign.

The Gower sign is a classic physical examination finding in MD
and results from weakness in the child's proximal hip muscles. To
get up from a sitting or supine position, the child must first become
prone on the elbows and knees. Next, the knees and elbows are
extended to raise the body. Then, the hands and feet are gradually
brought together to move the body's center of gravity over the legs.
At this point, the child may release one hand at a time and support it
on the knee as he or she crawls up their legs to achieve an upright
position. Although the Gower sign is a classic physical examination
finding in Duchenne MD, it is by no means pathognomonic; other
types of MD and disorders with proximal weakness may also cause
this sign.

The second important phase in Duchenne MD is
the loss of ambulation. This usually occurs
between the ages of 7 and 13 years, with some
patients becoming wheelchair bound by age 6
years. If children with MD are still ambulating
after age 13 years, the diagnosis of Duchenne MD
should be questioned

Duchenne MD is a terminal disease in which death usually
occurs by the third decade of life (mostly from
cardiopulmonary compromise).

Other clinical findings in Duchenne MD include absent
deep tendon reflexes in the upper extremities and patella
(though the tendoAchillis reflex remains intact even in the
later stages of this disease), pain in the calves with activity
(< 30% of patients), pseudohypertrophy of the calf (60%),
and macroglossia (30%).

Cardiopulmonary involvement is present from
the beginning of the disease stages, but the
findings are not so clinically obvious.
Electrocardiogram (ECG) tracings show right
ventricular strain, tall R waves, deep Q waves,
and inverted T waves.

Becker MD is similar to Duchenne MD, but
because patients have some measure of
functioning dystrophin, the manifestations of
Becker MD occur later and are more mild.
Patients tend to live past the fourth or fifth
decades.

Emery-Dreifuss MD is an uncommon sex-linked dystrophy that
presents with early contractures and cardiomyopathy (Cardiac
conduction defects) in affected patients; the typical presentation
involves tendoAchillis contractures, elbow flexion contractures,
neck extension contractures, tightness of the lumbar paravertebral
muscles, and cardiac abnormalities.
Death may occur in the fourth or fifth decade as a result of first-
degree atrioventricular (AV) block, a condition that is usually not
present at the initial presentation of this disease.

Autosomal dominant facioscapulohumeral
dystrophy causes facial and upper extremity
weakness, and scapulothoracic motion is decreased,
with winging of the scapula. This type of dystrophy
can occur in both sexes and appear at any age,
although it is more common in late adolescence.
Laboratory Studies
CPK determination is the most specific test for MD.

Elevated CPK levels are indicative of muscle disease.
 All
MDs result in some CPK elevation during the
active phase of the disease.
 Early
in the disease process, CPK levels are 50-300
times greater than normal levels, but the levels tend
to decrease as the muscle mass decreases.
 The
CPK level is highest in Duchenne MD, with less
elevation noted in Becker MD.

Enzyme levels that may be elevated but can be altered by
liver dysfunction include the following:


Transaminase levels

Lactate dehydrogenase levels

Aldolase levels
Ultrasonography is a relatively noninvasive technique that
is used for screening patients with muscular dystrophy

ECG

ECG is expected to show a right ventricular strain, tall
R waves, deep Q waves, and inverted T waves.

EMG

EMG usually demonstrates short-duration, polyphasic,
motor-unit action potentials with decreased amplitudes.

Muscle biopsy
Treatment

Of all the drugs that have come and gone, the only
one with some proven benefit is prednisone.
Inflammatory myopathies

Inflammatory myopathies are defined by the
presence of inflammatory infiltrates within the
muscle.

There are many unrelated causes, the commonest
are idiopathic inflammatory myopathies including

Dermatomyositis.

Polymyositis.

Inclusion body myositis.
Dermatomyositis and polymyositis

Skin rash is present in about 90% of patients with dermatomyositis
and usually absent in polymyositis.

The commonest appearance are erythema of the face and exposed
parts of the upper chest.

Rash may precede or follow the onset of muscle weakness.

Pain and tenderness of the muscles (60% of cases specially with
acute onset)

Onset of muscle weakness is sub-acute in dermatomyositis but it is
chronic in polymyositis.

Dermatomyositis is more common in female and can affect any
age, while polymyositis affect both sex usually after the age of 20
years.

Ocular muscles are not involved.

About 20% of patient with dermatomyositis, specially elderly, have
an associated malignancy, therefore searching for malignancy is
important.

Treatment

Prednisolone 1mg/kg frequently combined with azathioprine at
2.5 mg/kg or methotrexate up to 25 mg/week as steroid sparing
agent.
Periodic paralysis
Hypokalaemic periodic paralysis
Hyperkalaemic periodic paralysis
Age
2nd decade
1st decade
PP factor
High carbohydrate meal
Rest after exercise
Cold, fasting
Exercise
Onset
Usually on awakening in the morning
Immediately after exercise or cold
C. P.
Weakness starts in L.L. and rapidly
becomes generalized.
No bulbar/ respiratory affection
Weakness starts in L.L. and rapidly
becomes generalized.
Myotonia in some cases
Duration
Hours to days
Less than one hour
Serum K
< 3 mEq/L
> 4.5 mEq/L
Acute TTT
KCL I.V. drip (with ECG monitor)
Ca gluconate I.V. drip or glucose and
insulin drip
Prophylactic
TTT
Acetazolamide 250 mg/day
Low carbohydrate diet
Thiazide diuretics
High carbohydrate meal
Myotonias

Myotonic phenomenon is a delayed relaxation of the skeletal
muscles after voluntary, mechanical or electrical stimulation.

Voluntary: when the patient voluntarily clenches his fist, he is
unable to open his hand except after sometime.

Mechanical: if we tap the thenar eminence, adduction of the
thumb occurs with difficulty and delay in abduction. Similarly, if
we tap the tongue a dimple is observed due to delayed relaxation
of the muscle.
Myotonic dystrophies

It is the commonest inherited myopathy seen in adult
life. The molecular basis is unstable nucleotide repeat
expansion.

Onset: late adolescence or early adult life.

Characteristic facial appearance due to ptosis, weakness
and wasting of the facial muscles and muscles of
mastication, with premature balding, which is more
commonly seen in male.

In the limbs there is distal weakness, affecting the hands
and wrists more than the feet and ankles.

As the disease progress the weakness spreads proximally.

In late middle age a small proportion of patients become
wheelchair bound.

Also characterestic is the presence of wasting and
weakness of the sternomastoid and other neck flexor
muscle.

Myotonia that describes delayed muscle
relaxation following voluntary contraction or
percussion.

Associated features include cardiac conduction
problems, cataracts, and testicular atrophy.

Treatment mexilitine, procainamid, and phenytoin
Myotonia congenita

Inherited disease as autosomal dominant and recessive
condition.

The characteristic feature is generalized myotonia, first
evident in childhood, without persistent weakness

The myotonia eases with repetitive contractions, so
called warm up.

In the cranial nerve territory it can cause difficulty
chewing, and in early childhood there may be striking
slowness of relaxation of the periorbital muscles.

In the lower limbs the stiffness may cause the patient to
fall as they start to walk.

Mexiletine is the drug of choice.
Myasthenia Gravis
ANATOMY AND PHYSIOLOGY OF
THE NEUROMUSCULAR JUNCTION
Presynaptic Surface
 As the motor nerve
approaches a muscle it
branches, innervating many
muscle fibers and providing
a single, unmyelinated nerve
terminal to each of the fibers.
The NMJ is a specialized synapse designed to transmit nerve
impulses from the nerve terminal to muscle, via the
chemical transmitter, acetylcholine (ACh), which is stored
at the terminal in synaptic vesicles .
When an action potential reaches the nerve terminal, calcium
channels are activated, calcium enters the presynaptic
terminal, and the local calcium concentration rises
significantly, triggering the vesicles to release their
contents into the synaptic cleft.
Synaptic Cleft
Between the nerve and
muscle plasma membranes
lies a space of ~50 nm
called the ‘‘synaptic cleft’’.
The extracellular matrix of
the synaptic cleft is a
complex collection of
proteins that regulate the
synthesis of postsynaptic
proteins and the
concentration of
acetylcholine esterase
(AChE).

Once released from the synaptic vesicles, diffusion of ACh
across the cleft is rapid because of the small distance to
cross and the high diffusion rate of ACh. AChE is
concentrated in the basal lamina of the postsynaptic
membrane, and its action in hydrolyzing ACh, as well as
the diffusion of ACh out of the cleft, leads to a rapid
decline in ACh concentration. This prevents the AChR
from being activated more than once in response to ACh
AChE inhibitors, such as pyridostigmine and edrophonium,
prolong the duration of action of ACh on the postsynaptic
membrane, slowing the decay of the ACh-induced
endplate current. In postsynaptic diseases of
neuromuscular transmission, AChE inhibition will serve
to enhance ACh action and promote achievement of an
end-plate potential that will lead to action potential
generation.

Postsynaptic Surface
Once ACh traverses the synaptic cleft it binds
the AChR in postsynaptic membrane. This
binding results in opening of the AChR
ion channel and the entry of cations,
mainly sodium, into the muscle, leading to
end-plate potential generation. When a
certain threshold depolarization is
achieved, voltage-gated sodium channels
open allowing the entry of more sodium
ions and generating the muscle action
potential and contraction.
Myasthenia gravis (MG) is a relatively rare autoimmune
disorder of peripheral nerves in which antibodies form
against acetylcholine (ACh) nicotinic postsynaptic
receptors at the neuromuscular junction (NMJ).
The basic pathology is a reduction in the number of ACh
receptors (AChR) at the postsynaptic muscle membrane
brought about by an acquired autoimmune reaction
producing anti-AChR antibodies.

The major clinical features are of weakness, and
characteristically, excessive fatiguability.

It is associated with an increased incidence of other
autoimmune disease, notably thyroid dysfunction,
rheumatoid arthritis, and other connective tissue
disease.

The thymus in seropositive patient typically shows
medullary hyperplasia, and usually it is the source for
anti AChR antibody.

MG can occur at any age. Female incidence peaks in the third decade
of life, whereas male incidence peaks in the sixth or seventh decade.
The mean age of onset is 28 years in females and 42 years in males.
Classically, the overall female-to-male ratio has been considered to
be 3:2

The prevalence of MG is in the order of 5 to 10 per 100,000
population.

Transient neonatal MG occurs in infants of myasthenic mothers who
acquire anti-AChR antibodies via placental transfer of IgG. Some of
these infants may suffer from transient neonatal myasthenia due to
effects of these antibodies.
History

The presentation and progression of myasthenia gravis
(MG) vary. The usual initial complaint is a specific
muscle weakness rather than generalized muscle
weakness. The severity of the weakness typically
fluctuates over hours being least severe in the morning
and worse as the day progresses; it is increased by
exertion and alleviated by rest. The degree of weakness
also varies over the course of weeks or months, with
exacerbations and remissions.

Extraocular muscle 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 a myopathy like
proximal weakness that is greater than the distal muscle
weakness. Isolated limb muscle weakness as the
presenting symptom is rare and occurs in fewer than 10%
of patients.

Patients progress from mild to more severe disease
over weeks to months. Weakness tends to spread
from the ocular to facial to bulbar muscles and then
to truncal and limb muscles. On the other hand,
symptoms may remain limited to the extraocular
and eyelid muscles for years. Rarely, patients with
severe, generalized weakness may not have
associated ocular muscle weakness.

The disease remains exclusively ocular in only
16% of patients. About 87% of patients have
generalized disease within 13 months after onset.
In patients with generalized disease, the interval
from onset to maximal weakness is less than 36
months in 83% of patients.

Exposure to bright sunlight, surgery, immunization,
emotional stress, menstruation, and physical factors might
trigger or worsen exacerbations. Intercurrent illness (eg,
viral infection) or medication can exacerbate weakness,
and rapid respiratory compromise.

Spontaneous remissions are rare. Long and complete
remissions are even less common. Most remissions with
treatment occur during the first 3 years of disease.
Physical Examination

Patients with MG can present with a wide range of signs and
symptoms, depending on the severity of the disease.

Mild presentations may be associated with only subtle findings, such
as ptosis. Findings may not be apparent unless muscle weakness is
provoked by repetitive or sustained use of the muscles involved.
Recovery of strength is seen after a period of rest or with application
of ice to the affected muscle. Conversely, increased ambient or core
temperature may worsen muscle weakness.

Variability in weakness can be significant, and
clearly demonstrable findings may be absent
during examination. This may result in
misdiagnosis (eg, functional disorder). The
physician must determine strength carefully in
various muscles and muscle groups to document
severity and extent of the disease and to monitor
the benefit of treatment.

Typically, extraocular muscle weakness is asymmetric.
The weakness usually affects more than 1 extraocular
muscle and is not limited to muscles innervated by a
single cranial nerve; this is an important diagnostic clue.

Eyelid weakness results in ptosis. Patients may furrow
their foreheads, using the frontalis muscle to compensate
for this weakness. A sustained upward gaze exacerbates
the ptosis; closing the eyes for a short period alleviates it.

Weakness of the facial muscles is almost always present.
Bilateral facial muscle weakness produces a masklike face
with ptosis and a horizontal smile. The eyebrows are
furrowed to compensate for ptosis.

Weakness of palatal muscles can result in a nasal tone to
the voice and nasal regurgitation of food (especially
liquids). Swallowing may become difficult, and aspiration
may occur with fluids, giving rise to coughing or choking
while drinking.

Chewing may become difficult. Severe jaw weakness may
cause the jaw to hang open (the patient may sit with a hand
on the chin for support).

Weakness of neck muscles is common.

Limb weakness can be present in a variety of different
muscles and is usually proximal and symmetric.

Certain limb muscles are involved more commonly than
others (eg, upper limb muscles are more likely to be
involved than lower limb muscles).

Sensory examination and deep tendon reflexes are normal.

Respiratory muscle weakness that produces acute
respiratory failure is a true neuromuscular emergency, and
immediate intubation may be necessary.

Weakness of the intercostal muscles and the diaphragm
may result in carbon dioxide retention as a result of
hypoventilation.

Respiratory failure usually occurs around the time of
surgery (eg, after thymectomy) or during later stages of
the disease.
Investigation
Laboratory Tests
Anti–acetylcholine receptor antibody
 Anti-muscle-specific kinase (MuSK) antibody.
 Testing for rheumatoid factor and antinuclear antibodies
(ANAs).
 Thyroid function tests are indicated to rule out associated
Graves disease or hyperthyroidism.
Electrodiagnostic Studies and Repetitive nerve stimulation
for decremental response
Anticholinesterase test

Edrophonium is a short-acting AChE inhibitor that improves muscle
weakness in patients with MG.

This test evaluates weakness (eg, ptosis, partial or complete
ophthalmoplegia, and forced hand grip) in an involved group of
muscles before and after intravenous (IV) administration of
edrophonium.

To perform the test, a test dose of 0.1 mL of 10 mg/mL edrophonium
solution is administered. If no response and no untoward effects are
noted, remainder of the drug (0.9 mL) is injected.

Sinus bradycardia due to excessive cholinergic stimulation of the
heart is a serious complication; consequently, an ampule of atropine
should be available at the bedside or in the clinic room while the
test is performed.

This test may give both false-negative results and false-positive
results.
Ice Pack Test

The ice pack test (ie, placing ice over the lid) has gained interest
among ophthalmologists for assessing improvement in ptosis and
diplopia in ocular MG.

The thymus is imaged by CT or MRI. Most patients
with thymoma have anti-striated muscle antibodies in
their serum.
Treatment

In the mild form of the disease, Acetylcholine esterase (AChE)
inhibitors are used initially. Most patients respond to
Pyridostigmine in a dose up to 60 mg 6 times daily orally.

Patients with purely ocular myasthenia, patients over the age of 50
years with generalized disease, and patients without anti-AChR
antibodies, treated with alternate-day Prednisolone.

This is introduced slowly up to a dose of 1.5 mg/kg/day.

Azathioprine at a dose of 2.5 mg/kg/day is added as steroidsparing agent

Patients under the age of 50 years with generalized myasthenia and
anti-AChR anti-bodies, thymectomy may induce remession.

Intravenous immune globulin IVIg and plasmapheresis are equally
efficacious and give symptomatic improvement for up to six weeks.
It appears to be a better treatment option for the elderly and those
with complex co-morbid diseases, such as acute respiratory failure.
IVIg is recommended for MG crisis, in patients with severe
weakness poorly controlled with other agents. They are useful
during the initiation of steroid treatment which in itself can cause
transient worsening of the myasthenia, as well as prior to
thymectomy.
Lambert- Eaton myasthenic
syndrome

This is a presynaptic disorder in which the quantal
release of acetylcholine is reduced as a result of
antibodies directed against voltage- gated calcium
channels

In about 60 % of cases it is associated with small cell
lung cancer.

Presentation is usually with gait disturbances, that may
be attributed directly to weakness.

There may be mild ptosis but extraocular signs are
much less evident.

Autonomic features are common and include
impotence, and dryness of the mouth.

On examination, strength and tendon reflexes may
augment transiently following forceful voluntary
contraction of the relevant muscle.

EMG, the characteristic finding is of a small compound
muscle action potential that shows marked increase in
amplitude following voluntary contraction or high
frequency nerve stimulation.

Tumour treatment often improve the neurological
disorder. Symptomatic relief is obtained from 3,4
diaminopyridin.
Botulism

Botulism is caused by a powerful neurotoxin produced
by the anaerobic organism Clostridium botulinum.

The toxin bind to specific acceptors on the cholinergic
nerve terminal, the net result is paralysis and
parasympathetic blockade.

The commonest forms are infant botulism, and food
borne botulism. wound botulism is rare.