Transcript Myasthenia gravis evidence based

Myasthenia gravis
Treatment Recommendations
Treatment
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Anticholinesterases
Immunosuppressants
Thymectomy
Plasma exchange and IVIG
Anticholinesterase Drugs
• Neostigmine (Prostigmin)7.5-45 mg/2 to 6 h
• Pyridostigmine (Mestinon) 30 to 90 mg/6 h
• Mild cases without thymic tumor
• partial remission after thymectomy
• purely ocular myasthenia (ocular often responds well to
small doses of corticosteroids).
Anticholinesterase Drugs
Dose
equivalent
Onset
Time to maximum
response
Pyridostigmine (Mestinon)
Neostigmine (Prostigmin)
60 mg
40 min
1h
15 mg
1h
1.5 h
Neostigmine IM
Neostigmine IV
1.5 mg
30 min
1h
0.5 mg
immediate
20 min
Corticosteroids
• Corticosteroids:60 to 100 mg prednisone daily) alone or in
combination with azathioprine
• Ocular myasthenia
• Moderate to severe generalized weakness
• responding inadequately to anticholinesterase
• Side effects of long-term corticosteroid
Corticosteroids
• Prednisone (or corresponding doses of prednisolone),
beginning with 15 to 20 mg/day and increasing the dose
gradually until clinical response is obtained, or a daily dose of
50 to 60 mg is reached.
• Worsening in the first week is common, and hospitalization and
careful observation for respiratory difficulty is advisable.
• Improvement occurs slowly over a few weeks
Corticosteroids
• Once the maximal effect has been attained, the
dosage can be reduced gradually to the lowest
effective dose.
• Alternate-day schedule↓ the side effects.
• At the outset of steroids, anticholinesterase are
given simultaneously; as the patient improves, the
dosage of the latter may be adjusted downward.
Immunosuppressive Drugs
Azathioprine
• Adjunct to steroids and can be effective alone Dose: 50
mg (1 tablet) twice daily for a few days; if tolerated,
raised to 2 to 3 mg/ kg per day (150 to 250 mg daily).
• Improvement is much the same as prednisone, much
more slowly, (months to a year)
• Liver function tests and blood cell count should be
checked regularly.
Immunosuppressive Drugs
• The most severe forms of the disease, particularly those
resistant to prednisone or azathioprine alone, benefit
from the combination of the two medications.
• Many neurologists, begin by both medications early in
the illness with the plan of reducing the corticosteroid
dose in the third or fourth month
Immunosuppressive Drugs
Mycophenolate (CellCept)
• An adjunct to corticosteroids (2000-3000mg/d)
• The clinical improvement sooner than it does with
azathioprine
• Diarrhea was the main adverse effect.
• In some milder cases, may be effective alone
Immunosuppressive Drugs
Cyclophosphamide
• IV pulses, 50 mg/kg/d for 4 consecutive days followed
by granulocyte-stimulating factor to “reboot” the immune
system in refractory cases.
• Justified if all other measures have failed in severe
instances of the disease.
• Liver function and white blood cell count should be
monitored regularly
Immunosuppressive Drugs
Cyclosporine
• Like those of azathioprine but become evident more
rapidly (month or two)
• Two divided doses daily, to a total of about 6 mg/kg
• Serious side effects (hypertension, nephrotoxicity) and
its high cost .
Plasma Exchange and IVIG
plasma exchange
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Severe myasthenia, refractory to treatment
Acute exacerbation (bulbar, severe generalized )
Myasthenic crisis.
Before and after thymectomy
At the start of immunosuppressive drug.
Not adequately respond to treatment
Plasma Exchange and IVIG
• Several exchanges of 2 to 3.5 L each (totaling
approximately 125 mL/kg), performed over a week.
• The removed plasma is replaced with albumin and
saline.
• 2-L exchange will remove 80% of circulating antibodies
Plasma Exchange and IVIG
• In a crisis: plasma exchanges and mechanical
ventilation, discontinue or curtail the use of
anticholinesterase drugs and resume them as the patient
is being weaned from the ventilator.
• Sensitivity to these drugs may be enhanced in the hours
after an exchange, so that their dosages must be
adjusted accordingly
Plasma Exchange and IVIG
• Plasma exchange is also helpful in limiting the afore
mentioned weakness that is often induced by the
institution of high-dose corticosteroids.
• A small number of patients respond so well to plasma
exchange and choose to be maintained with 2 to 3
exchanges every several weeks or months.
Plasma Exchange and IVIG
Immunoadsorption
• A technique similar to plasma exchange that removes
antibodies and immune complexes by running blood over
a tryptophan column
• Less cumbersome than plasma exchange and has been
effective
Plasma Exchange and IVIG
Intravenous immune globulin
• Indications as that of plasma exchange.
• The usual dose is 2 g/kg given in divided doses over 3 to
5 days.
• The effect is equivalent to plasma exchanges.
• they offer only short-term benefit and are not used
regularly in the treatment of most patients
Thymectomy
• In all patients with uncomplicated myasthenia gravis
between puberty and 55 years of age.
• Performed electively (not during an acute deterioration of
myasthenia).
• The remission rate after thymectomy is approximately
35% ( first year or two after onset of the disease)
• Another 50% will improve to some extent
Thymectomy
• Ocular Myasthenia for a year or longer, thymectomy is unnecessary.
• The response is not evident for several months and is maximal by 3
years.
• In responding cases, circulating receptor antibodies are reduced or
disappear entirely.
• A course of plasma exchange or IVIG If the patient is very weak
preoperatively
Thymectomy
• If possible, thymectomy should be postponed until puberty
(importance of the gland in the development of the immune
system) but juvenile myasthenia is also quite responsive.
• Indicated in all patients in whom thymoma is detected by
CT scanning of the chest (radiation, chemotherapy)
• Results are not as predictable in thymoma
Masaoka Clinical Staging of Thymoma as of Most Recent (1994) Modifications
Masaoka Stage
Diagnostic Criteria
Stage I
Macroscopically and microscopically completely
encapsulated
Stage II
A. Microscopic transcapsular invasion
B. Macroscopic invasion into surrounding fatty tissue
or grossly adherent to but not through mediastinal
pleura or pericardium
Stage III
Macroscopic invasion into neighboring organs (i.e.,
pericardium, great vessels, lung)
A. Without invasion of great vessels
B. With invasion of great vessels
Stage IV
A. Pleural or pericardial dissemination
B. Lymphogenous or hematogenous metastasis
Time to Clinical Effect of Therapies for Myasthenia Gravis
Treatment
Time to Clinical Effect
Pyridostigmine
10–15 minutes
Plasmapheresis
1–14 days
IVIg
1–4 weeks
Prednisone
2–8 weeks
Mycophenolate mofetil
2–6 months
Cyclosporine
2–6 months
Azathioprine
3–18 months
Myasthenic Crisis
• Rapid and severe deterioration of the myasthenia
itself, can bring the patient to the brink of
respiratory failure and quadriparesis in a matter
of hours
• Respiratory infection or excessive use of
sedatives or drugs blocking neuromuscular
transmission may precede the myasthenic crisis,
no cause could be determined in one-third
Myasthenic Crisis
Treatment of Myasthenic Crisis
• Careful intubation followed by mechanical ventilation in a
CCU that is equipped to attend to the medical and
neurologic needs of such patients.
• Respiratory failure : by the use of bilevel positive airway
pressure (BiPAP)
• Anticholinergic drugs, which exaggerate secretions, are
best withdrawn at the time of intubation
Myasthenic Crisis
• Plasma exchange or IVIG a week or more is
required for recovery.
• It is best to wait 2 or 3 weeks before committing
a patient to tracheostomy.
• When weaning is anticipated, anticholinesterase
agents are reintroduced slowly, and treatment
with corticosteroids can be instituted if
necessary.
Management of generalised myasthenia gravis
Management of ocular myasthenia
Therapeutic recommendations in MG.
Classification of Congenital Myasthenic Syndromes
Presynaptic defects
CMS with episodic apnea (choline acetyltransferase deficiency)
Paucity of synaptic vesicles
Lambert-Eaton syndrome-like CMS
Synaptic defects
End-plate acetylcholinesterase deficiency
Postsynaptic defects
Primary AChR deficiency with or without kinetic abnormality
Reduced AChR expression due to AChR mutations
Reduce AChR expression due to rapsyn mutations
Reduced AChR expression with plectin deficiency
Primary AChR kinetic abnormality with or without AChR deficiency
Slow-channel CMS
Fast-channel CMS
Sodium-channel CMS (mutations of perijunctional sodium channels)