MYASTHENIA GRAVIS

MYASTHENIA GRAVIS: The Thief

It steals your body, your energy, your health, your family, your friends and the person you used to be

Wake up: Feeling fine→→→ End of the day: Feeling weak

As the name only suggests MY-muscle, ASTHENIA-weakness & GRAVIS-grave.

The Autoimmune disorder affecting the skeletal muscles.

Antibodies (IgG) produced against Nm type of Ach receptors at NMJ.

PATHOPHYSIOLOGY:

Antibodies to Ach receptor protein:

85 % of patients with generalized myasthenia and 60% of those with ocular myasthenia shows AChR Antibodies 

Anti-MuSK Ab (40% of seronegative cases):

An immune response to muscle-specific kinase (MuSK) can also result in myasthenia gravis, possibly by interfering with “ AChR clustering”

How do these antibodies act?

1. Blocks the binding of ACh to the AChR
2. INCREASES THE DEGRADATION rate of AChR
3. A complement-mediated destruction of the postsynaptic folds
   

Pathology:

• The muscle fibers are generally intact
• “Segmental necrosis with variable regeneration” in fatal cases.
• Scattered aggregates of lymphocytes, “Lymphorrhages” especially associated with thymomas
• A reduction in the area of the nerve terminal
• Sparse, shallow, abnormally wide or absent secondary synaptic clefts
• A widening of the primary synaptic cleft
• PRESYNAPTIC VESICLES AND NERVE TERMINALS ARE NORMAL
• Thymus is abnormal in ~75% of patients with MG
• In ~65% the thymus is "hyperplastic"
• 10% of patients have thymic tumors.

CLINICAL FEATURES:

• Prevalence: 1-7 in 10,000 and Affect all age groups
• Usual age at onset: BIMODAL PEAK
• 20-30 yrs(young women), 50-60 yrs(older men)
• < 10% occur in children <10 yrs
• Overall F:M = 3:2

• There is repeated or persistent activity of a muscle group exhausts its contractile power (fatigability), leading to a progressive paresis, and rest partially restores strength.
• Fluctuating weakness increased by exertion
• Head extension and flexion weakness

Fast moving muscles are affected first.

Eyelids, external ocular, facial & pharyngeal →later limb and respiratory muscles

• Ptosis
• Diplopia
• Slurring of speech
• Difficulty in swallowing
• Weakness of extremities
• Difficulty in breathing

OSSERMAN Classification

DIAGNOSIS:

A. Physical findings:

1. Asking the patient look up for several seconds (examining for ptosis or extraocular weakness)
2. Counting aloud upto 100 (listening for nasal or slurred speech)
3. By repetitively testing the proximal muscles.(Holding outstretched arms in abduction)
4. Check for vital capacities to asses the respiratory involvement

B. Lab findings:

1. Anti-acetylcholine receptor antibodies

• Most sensitive and highly specific test
• Positive in 80%-90% of generalized myasthenia and 50%-60% of patients with pure ocular myasthenia

2. Anti MuSK antibodies

• Present in 40% of AChR-ab negative pts with generalized MG

3. Anti-striated muscle antibodies

• Present in 30% of MG patients.
• Present in 84% of patients with Thymoma.

C. Electrodiagnostic studies:

• Repetitive nerve stimulation
• Single fiber electromyography (SFEMG)

D. Pharmacological testing:

1. Edrophonium (Tensilon test)-Ameliorative test: 2-10mg I.V. >>> shows improvement in MG patients but not in other muscular dystrophies
2. Provocative test: 0.5mg of d-tubocurarine>>>marked weakness in MG patients.But, ineffective in non-myasthenics (NOT USED NOWADAYS)

E. Simple bedside test: Ice pack test

• In patient with ptosis, a small cube of ice is placed over the eyelid for about 2 minutes
• Improvement of the ptosis after this procedure suggests a disorder of neuromuscular transmission
• Ptosis due to other conditions will not improve

F. Others:

• By Thyoma identification & CT scanning of thymus.

TREATMENT:

Lifelong immunomodulating therapy is often required!!!

A. SYMPTOMATIC TREATMENT:

1. Acetylcholinesterase inhibitors:

• Inhibit the enzymatic elimination of Ach, increasing its concentration at the post synoptic membrane
• Gives partial improvement in most myasthenic patients although complete improvement in very few patients.
• Pyridostigmine
• starts with 60mg 3-4 times daily, increase up to 120 mg 4 times daily
• preferred - less severe GI side effects, longer duration of action (3-4 h).
• Neostigmine Bromideine-15-30 mg/day
• Ambenonium-2.5-5 mg,6th hourly

2. Plasma exchange

• To remove the circulating immune complexes and AchR-Ab.
• Patients usually undergo a 2-week course of 5 to 6 exchanges (2-3.5L each).
• Useful when treating patients in myasthenic crises or those in preparation for surgery and at the start of immunosuppressive therapy.

3. Intravenous polled Ig -400 mg/kg for 5 days

• An alternate mode of therapy to plasmapheresis.
• Effective short-term treatments (e.g. for MG crisis, stabilization prior to thymectomy)

B. PATHOGENETIC TREATMENT:

1. Corticosteroids - mainstay of immunotherapy

• Prednisone is the most commonly used.
• Initial dose is 15-25 mg/d, increase by 5mg at 2-3days interval until marked clinical improvement achieved or 50-60mg/day is reached
• Taper the dose and asses the effective minimum dose
• Patients may have transient worsening of
• MG symptoms during the first 2 to 3 weeks of prednisone therapy.

2. Cytotoxic therapies

      Indicated in:

• Patients who do not improve after 6 months of PREDNISONE.
• Patients who are not able to achieve sufficiently low doses of PREDNISONE.
• Significant steroid side effects.

Azathioprine-as adjunct to prednisone (some patients respond well enough to discontinue prednisone)

Cyclosporine and Tacrolimus-These agents are usually prescribed for patients who have failed to respond to combination therapy with Prednisone and Azathioprine and those who cannot tolerate azathioprine.

Cyclophosphamide-used only in refractory cases

Mycophenolate Mofetil

3. Thymectomy

85% patients without thymoma show improvement / remission

Indicated for: 

• GENERALIZED MYASTHENIA
• THYMOMA (absolute indication at any age)

MYASTHENIC CRISIS

• RESPIRATORY FAILURE needing assisted ventilation.
• occurs in 10% patients. 
• Mechanisms: a) respiratory muscle weakness b) oropharyngeal weakness → aspiration
• Timely intubation and ventilatory support
• Withhold ACHE inhibitors
• Plasmaparisis and i.v. Ig
• High dose steroids

overmedication of myasthenic crisis can convert it into cholinergic crisis!!!

LIFE OF A  MYASTHENIA GRAVIS WARRIOR:

EVERYDAY IS DIFFERENT. ONE MINUTE YOU COULD BE FULL OF ENERGY AND NEXT YOU ARE LAYING DOWN, STRUGGLING TO MOVE

THANK YOU....!!!!

References: 

Viktor's notes for neurosurgery resident.

Sharma & Sharma's Principles of Pharmacology

Goodman & Gilman's The pharmacological basis of therapeutics