MG ورقية pdf - D. Hazim

Disease of Neuromuscular Junction

D. Hazim

Peripheral Neuropathy:

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-

 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

Repetitive nerve stimulation RNS

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

Mubark A. Wilkins