Definition:
A
neuromuscular (nerve and muscle) disorder arising from an injury
resulting from abnormal activity of the body's immune system
(autoimmune mediated injury) leading to fluctuating muscle weakness
and tiredness (fatigue). The weakness increases during periods of
activity and improves after periods of rest. In most individuals
with myasthenia gravis (MG), life expectancy is not shortened due
to the disease.
Causes:
Normally the electrochemical signals (impulses) travel down the
nerves; the nerve endings in response release a brain chemical
(neurotransmitter substance) called acetylcholine, which travels
through the neuromuscular junction (where the nerve cells connect
with the muscle they control) and binds to receptors which are
activated and generate a muscle contraction.
In
MG, antibodies block, alter, or destroy these receptors for
acetylcholine at the neuromuscular junction which prevents muscle
contraction.
Antibodies are produced by the body's own immune system, which
normally protects the body from foreign organisms - mistakenly
attacks itself.
Thymus gland dysfunction, including thymic hyperplasia and thymoma,
has been suggested to play a role in the formation of such
antibodies.

The
disease may affect any voluntary muscle (which control and perform
actions such as, moving an arm to pick up a glass of water). The
onset may be sudden, but symptoms are not recognized immediately,
one of the reasons being weakness improves after a period of
rest.
The
initial common symptoms which can easily go unrecognized are as
follows:
- Weakness of the eye muscles
- Blurred vision
- Slurred speech
The
degree of muscle weakness varies among patients, ranging from a
localized form, meaning only limited to eye muscles (ocular
myasthenia), to a severe or generalized form in which many muscles
may be involved.
Symptoms, which vary in type and severity, may include:
- Drooping of one or both eyelids (ptosis)
- Blurred or double vision (diplopia), due ocular muscle
weakness
- Unstable or waddling gait
- Weakness in arms, hands, fingers, legs, and neck
- Change in facial expression
- Difficulty in swallowing and
- Shortness of breath due to the chest wall muscle weakness,
which unable the chest to expand and obstructing the free flow of
air through the lungs

The
patient presents with the history of chronic fatigue and muscle
weakness, especially of face and throat muscles. It is important to
take a detailed history and do a detailed physical and neurological
exam. However, delay in diagnosis of 1-2 years is not unusual,
especially in patients who have mild weakness or weakness
restricted to few muscles.
INVESTIGATION:
The
diagnosis can be confirmed by
Edrophonium challenge test:
Individuals with myasthenia gravis, muscle function will improve
within 30 to 60 seconds after injecting edrophonium (or
neostigmine) into the vein (intravenous). Muscle function
improvement lasts up to 30 minutes.
Note: Agents with longer duration of action than
Edrophonium, e.g neostigmine (intrmuscular) or pyridostigmine
(oral) may provide a better assessment in situations where it may
be difficult to fully appreciate or quantify the brief response to
edrophonium, e.g. infants and children.
Serology (type of blood test which analyzes a
component of a blood constituent- serum):
- Antibodies in myasthenia gravis:
A blood test can detect antibodies to acetylcholine (the chemical
that transmits messages between nerve and muscle cells).
- Acetylcholine receptor antibodies are detected in
- ~74% of patients with generalized myasthenia and
- ~54% of those with ocular myasthenia
- The serum concentration of anti-AChR antibody does not
correlate with disease severity
- Anti-MuSK antibodies
- Detected in up to 50% of MG patients who are seronegative for
AChR antibodies
Note: While elevated serum concentrations of
anti-AChR binding and anti-MuSK antibodies are diagnostic of MG,
but their absence does not rule out the disease.
Other diagnostic tests:
- Electrophysiological (EP) tests:
Done through electromyogram (EMG), a machine which records the
electrical activity of muscles showing changes in response to nerve
stimulation, to assess the transmission of neuromuscular
messages.
- CT scan:
A special x-ray, using a computer to record various views and
measurements of the thymus, may be done to rule out a tumor of the
thymus gland (thymoma), especially in individuals over 40 years of
age.
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TREATMENT:
- ➢ Treatment of the symptoms
(symptomatic
-
treatment)
- ➢ Immunotherapy
- ➢ Plasmapharesis/ IVIG
- ➢ Surgery
Symptomatic treatment:
- Individualized according to the patients complaints; often
based on extent of functional impairment, age and sex
- Prevention or treatment of stressors such as infections,
physical and emotional stress; may improve symptoms
Note: In the early stages of MG, remissions and
spontaneous improvement can occur without any specific therapy.
- Cholinesterase inhibitors
- Often used as initial therapy
- Blocks acetylcholine esterase and prolongs the action of the
chemical acetylcholine
- Daily requirements may vary depending on extent of disease;
increase or decrease of symptoms
Agents used are:
- Pyridostigmine
- Neostigmine
Immunotherapy:
Indications
- Refractory or progressive MG
- Inadequate response to cholinesterase inhibitors (agents
mentioned above)
- Increasing disability
- Corticosteroids (Prednisone)
- Often improves strength within days to weeks
- Physician may consider beginning at low dose and titrating
upwards according to the improvement
- Azathioprine
- Used as steroid sparing therapy or adjunct to steroids
- Steroids can then be gradually discontinued (weaned off) or
reduced depending on response to azathioprine
- Effective, but relapses may recur 2 to 3 months after the drug
is discontinued or reduced below therapeutic levels
- Cyclosporine A
- Long-term immunosuppression (suppresses immunity, in turn
reducing the antibody formation against acetylcholine receptors
antibodies)
- Improvement may be detected 1 to 2 months after initiating
treatment
- Benefits disappear when treatment is stopped or reduced below
required (therapeutic) levels. Some patients may develop adverse
effects such as; renal toxicity and hypertension
- Mycophenlate mofetil (MMF)
- Corticosteroid-sparing agent that may be considered in
combination with other agents (adjunctive) or as single agent
(primary) therapy in refractory MG
- Faster onset of action than azathioprine
- Cyclophosphamide
- Alternative therapy to other immunosuppressive agents to
suppress immunity
- Good response in > 50% of patients initiated on
therapy.
- Potential for life-threatening infections
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Plasmapharesis/ IVIG:
Indications
- Acute exacerbations
- Myasthenic crises: Severe form of MG leading to
life-threatening condition. It can cause severe breathing problems
and respiratory failure
- As a part of pre-surgical treatment to boost strength and
improve respiratory status
- Intermittent therapy with other treatments, when the disease is
not well controlled
- Used to bridge the gap; until the response to immunosuppressive
treatment is apparent
- Plasmapharesis:
- Rapid action - benefits may be seen after one exchange
- Human immune globulin (IVIG):
- Improvement usually occurs within 1 week and may last for
months
- Probably relates to down regulation of offending
antibodies
Neuromuscular Respiratory Failure:
It
is a critical complication; that lead to respiratory muscle
weakness and compromised respiratory function (signs indicating
respiratory failure) requiring:
- Endotracheal intubation (passing a tube under anesthesia
through the nose into the wind pipe to clear the airway
obstruction)
- Non-invasive method using positive pressure ventilation
(respiratory support without endotracheal intubation), which
involves an external device to maintain positive airway pressure
within the lungs through the mask and prevents collapse of airway
passages due to malfunctioning muscles
- Cholinesterase inhibitor are stopped
- Course of plasmapharesis or IVIG is given
- Once patient improves cholinesterase inhibitors are
restarted
Surgery: Thymectomy
Goal: Is to remove thymus, along with the
surrounding tissue as these may contain thymic cells. As with any
other surgery there may be a risk of injury to the surrounding
nerves.
Indication (uses) and outcome of surgery
- Considered in most patients with MG, except in older patients
with other lifelong illnesses or in patients with mild or limited
disease (e.g. primarily ocular)
- Post-surgically it may take months or years to see benefit (due
to persistence of antibody producing plasma cells)
- Best outcomes seen in young patients with early disease
Medications
