MG

Disease of neuromuscular junction

The Neuromuscular Junction is composed of :
• Presynaptic membrane
• Postsynaptic membrane
• Synaptic cleft
• Presynaptic membrane contains vesicles with Acetylcholine (ACh) which are released into synaptic cleft in a calcium dependent manner
• ACh attached to ACh receptors (AChR) on postsynaptic membrane
• The Acetylcholine receptor (Ach R) is a sodium channel that opens when bound by Ach :
There is a partial depolarization of the postsynaptic membrane and this causes an excitatory postsynaptic potential (EPSP)
If enough sodium channels open and a threshold potential is reached" a muscle action potential is generated in the postsynaptic membrane

Myasthenia gravis

It is an acquired autoimmune disorder, clinically characterized by weakness of skeletal muscles and fatigability on exertion.
pathophysiology
In MG, antibodies(lgG) are directed toward the acetylcholine Nicotinic receptors at the neuromuscular junction of skeletal muscles resulting in;
• Decreased number of receptors at the motor end-plate
• Reduced postsynaptic membrane folds
Widened synaptic cleft


Role of thymus
75 % of cases of MG the thymus was abnormal
65% had thymus hyperplasia
10 % had thymoma (rarely in children)
epidemiology
MG has two peak onset;
first at 20-30 years of age, mostly affect Females
The second at 40-60 years of age, mostly affect males
(Overall, female are more frequently affected than male in a ratio of approximately 3-2
familial cases are rare.

Clinical Presentation (fatigable)

Fluctuating weakness increased by exertion
Weakness increases during the day and improves with rest
Extraocular muscle weakness
Ptosis is present initially in 50% of patients.
during the active course of disease in 90% of patients
Head extension and flexion weakness
Weakness may be worse in proximal muscles

Ocular muscle weakness

Asymmetric, usually affects more than one extraocular muscle and is not limited to muscles Innervated by one cranial nerve
Ptosis caused by eyelid weakness
Diplopia is Very common


Bulbar muscle weakness
Palatal muscles
Nasal voice, nasal regurgitation
Chewing may become difficult
Severe jaw weakness may cause jaw to hang open
Swallowing may be difficult and aspiration may occur with fluids--coughing and choking while drinking

Progression of disease

Usually spreads from ocular to facial to bulbar to truncal and limb muscles.
Often, symptoms may remain limited to EOM and eyelid muscles for years
The disease remains ocular in 16% of patients.
Remissions
Spontaneous remission rare
Most remissions with treatment occur within the first three years

Respiratory muscle weakness

weakness of the intercostal muscles and the diaghram may result in C02 retention due to hypoventilation , and may cause a neuromuscular emergency
Weakness of pharyngeal muscles may collapse the upper airway So Monitor vital capacity is important

Co-existing autoimmune disease

Hyperthyroidism:- Occurs in 10-15% MG patients, exophthalmos and tachycardia point to hyperthyroidism ,weakness may not improve with treatment of MG alone in patients with co-existing hyperthyroidism
Rheumatoid arthritis
Scleroderma
Lupus
Note: in MG patients. neurological examination is normal with only PROXIMALWEAKNESS


Differential diagnosis
Amyotrophic Lateral Sclerosis
Brain stem gliomas
Lambert-Eaton"Myasthenic Syndrome
• Thyroid disease
• Botulism

Investigation

• Laboratory study
Anti-acetylcholine receptor antibody Positive in 74%
80% in generalized myasthenia gravis .
50% of patients with pure ocular myasthenia
Antistriated muscle AB
Present in 84% of patients with thymoma who are younger than 40 years

Imaging studies

Chest x-ray
Plain anteroposterior and lateral views may identify a thymoma as an anterior mediastinal mass .
Chest CT scan is mandatory to identify thymoma
MRI of the brain and orbits may help to rule out other causes of cranial nerve deficits but should not be used routinely


Electrodiagnostic studies
I. Repetitive nerve stimulation RNS
2. Single fiber electromyography (SFEMG)
SFEMG is more sensitive than RNS in MG (but it needs much time)
Any decrement over 10% is considered abnormal
Should not test clinically normal muscle
Proximal muscles are better tested
Most common employed stimulation rate is 3Hz, several factors can affect RNS results e.g. lower temperature increases the amplitude of the compound muscle action potential, and many patients report clinically significant improvement in cold temperatures

Pharmacological testing

Edrophonium(Tensolon test)
Patients with MG have low numbers of AChR at the NMJ
Ach released from the motor nerve terminal is metabolized by Acetylcholine esterase
Edrophonium is a short acting Acetylcholine Esterase Inhibitor that improves muscle weakness
Evaluate weakness (i.e. ptosis and ophthalmoplegia) before and after administration

Treatment of MG

Main line of Rx are:
AChE inhibitors
Immunomodulating therapies
Plasmapharesis
Thymectomy (Important in treatment, especially if thymoma is present)


AChE inhibitors
Pyridostigmine bromide (Mestinon)
Starts working in 30-60 minutes and lasts 3-6 hours
Adult dose:
60-360mg/d PO
2mg IV \IM q2- 3h
Caution Check for cholinergic crisis due to depolarisation block of motor end plates, with muscle fasciculation, paralysis, pallor, sweating, excessive salivation and small pupils
myasthenic crisis severe weakness due to exacerbation of myasthenia
This may be distinguished by the clinical features and, if necessary, by the injection of a small dose of Edrophonium.

Others: Neostigmine Bromide

Propantheline( 15mg tablets)
Given if patient develops abdominal pain/diarrhea, l5mg tds or 15 mg taken 30 minutes before each dose of Pyridostigmine
Immunomodulating therapies
prednisolone
Most commonly used corticosteroid in MG
Significant improvement is often seen after a decreased antibody titer which is usually 1-4 months
No single dose regimen is accepted

Azathioprine

Start on 25mg bid
Increase by 25mg/day until patient is on a dose of2.5mg/kg BW per day
Assess full blood count and LFTs before starting treatment and after a few days of initiation, then weekly for 8weeks.
cyclosporine
Methotrexate (in adults) 7.5-20 mg once weekly
mycophenolate mofetil


Thymectomy
Done when indications for thymectomy present
Patient with thymoma - the thymectomy is indicated all .
If no thymoma - the patient age, symptoms, duration, severity, response to medication.
Thymectomy is not recommended for the neonatal type of myasthenia gravis.
In juvenile form - thymectomy for patient with more severe symptoms and lack of response to medical therapy.

plasma exchange and IVIG this is given in :

acute fulminant MG
Preoperative (sometime)
myasthenic crises
As Five exchanges (3-4L/exchange)
IV immunoglobulin- 400mglKg per day for 5 clays

prognosis

Untreated MG carries a mortality rate of 25-30 %
Treated MG has a 4% mortality rate
40% have ONLY ocular symptoms
Complications of MG
Respiratory failure
Dysphagia
Complications secondary to drug treatment e.g. Long term steroid use like
Osteoporosis, cataracts, hyperglycemia,
HTN , gastritis, peptic ulcer disease


Lambert Eaton myasthenic syndrome
It is a Presynaptic disorder of the NMJ
Voltage gates calcium channel antibodies impede release of acetylcholine
Presented as
Weakness
more of Lower extremities than Upper Extremities
bulbar and ocular muscles less often involved
decreased reflexes - post tetanic potentiation
Autonomic Nervous System involvement
Associated with a cancer in the majority of patients( paraneoplastic)
Underlying cancer may be previously unrecognized,
Small cell lung cancer is the most common

Treatment:

Underlying cancer
Guanidine
3,4 diamino pyridine