Management of Management of myasthenia gravismyasthenia gravisDr s.samuthiravelProf.Dr.A.GOWRI SHANKAR`S unit

Diagnostic work upDiagnostic work upHistoryPhysical findingsLaboratory testsElectro physiological testsPharmacological testSimple bedside test

historyhistoryChangeable diplopia, ptosispatients may also complain of

fatigue and fluctuating weakness. The weakness worsens after

exertion and typically improves with rest.

This pathologic fatigability is the hallmark of MG

Physical findingsPhysical findingsTypical myasthenic facies

Physical findingsPhysical findings Examination of a patient with MG therefore is

directed at muscle strength and demonstrating pathologic fatigability.

A few maneuvers that may be used are

Asking the patient look up for several seconds (examining for ptosis or extraocular weakness),

Counting aloud upto 100 (listening for nasal or slurred speech),

By repetitively testing the proximal muscles.(Holding outstretched arms in abduction)

Check for vital capacities to asses the respiratory involvement

Remainder of the neurologic examinations will be usually normal.

lab work-up Anti-acetylcholine receptor antibodies Demonstration of these anti body virtually confirm the diagnosis Most sensitive and highly specific test Positive in 80%-90% of generalized myasthenia and 50%-60% of

patients with pure ocular myasthenia the degree of “positivity” does not correlate with the

severity of disease but fall during treatment correlate with clinical improvement

Anti MuSK antibodies Present in 40% of AChR-ab negative pts with generalized MG Rarely present in AChR-ab positive pts or in ocular MG pts mostly women, predominently bulbar, facial , neck and shoulder

muscle weakness, often predominate with severe disease and respiratory crisis, without significant ocular involvement

Anti-striated muscle antibodies found to be present in 30% of MG pts Present in 84% of patients with thymoma who are younger than

40 years

Work-upWork-upElectrodiagnostic studies

◦Repetitive nerve stimulation◦Single fiber electromyography

(SFEMG)

◦SFEMG is more sensitive than RNS in MG

Electrodiagnostic Electrodiagnostic studies:studies:Repetitive Nerve StimulationRepetitive Nerve Stimulation

Most commonly used, simple and easy to performLow frequency RNS (1-5Hz)

◦ Most common employed stimulation rate is 3Hz

◦ Electric shocks are delivered at a rate of 2-3/sec to the appropriate nerve and action potentials are recorded from that muscle

◦ In normal individual, the amplitude of the evoked muscle action potentials does not change at this rate of stimulation

Electrodiagnostic studies:Electrodiagnostic studies:Repetitive Nerve StimulationRepetitive Nerve Stimulation

Patients w/ MG AchR’s are reduced and Locally available Ach

becomes depleted at all NMJs and less available for immediate release

so during RNS EPAP’s may not reach threshold and no action potential is generated Results in a (decremental response)

decrease in the compound muscle action potential

Any decrement over 10% is considered abnormal

Proximal muscles are better tested than unaffected distal muscles

Repetitive nerve Repetitive nerve stimulationstimulationThe sensitivity of RNS is 75% in

genaralized MG and 50% in ocular MG

Several factors can affect RNS results◦Lower temperature increases the

amplitude of the compound muscle action potential Many patients report clinically significant

improvement in cold temperatures◦AChE inhibitors prior to testing may

mask the abnormalities and should be avoided for at least 6-24hours prior to testing

Electrodiagnostic studies:Electrodiagnostic studies:Single-fiber electromyographySingle-fiber electromyography

It is a selective EMG recording that allows measurement of neuromuscular transmission in individual end plate in situ

AP are recorded from two muscle fibres in the same motor unit Time variability of the interpotential interval

between two muscle fibers of the same motor unit is called jitter

◦ Findings suggestive of NMJ transmission defect Increased jitter and normal fiber density Increased jitter with intermittent blocking

Electrodiagnostic studies:Electrodiagnostic studies:Single-fiber electromyographySingle-fiber electromyography

◦Requires extensive training experience to perform

◦Generalized MG Abnormal extensor digiti communis found

in 90% Examination of a second abnormal

muscle will increase sensitivity to 99%

◦Occular MG Frontalis muscle is abnormal in almost

100% More sensitive than EDC

WorkupWorkupPharmacological testingPharmacological testing Edrophonium (Tensilon test)

◦ Reserved for pt s with clinical feature suggestive of MG, but negative antibodies and electro physiological test

◦ Edrophonium is a short acting Acetylcholine Esterase Inhibitor that improves muscle weakness 0.1ml of a 10 mg/ml edrophonium solution is

administered as a test If no unwanted effects are noted (i.e. sinus bradychardia),

the remainder of the drug is injected Evaluate weakness (i.e. ptosis and opthalmoplegia)

before and after administration Rapid improvement of weakness over next 2 mts is

positive

False positive test- occurs in ALS, poliomyelitis, and some peripheral neuropathies

False negative test -also possible where we should consider long acting oral neostigmine and that gives more time for evaluation

◦ Require cardiac monitoring, ICU setup is needed

WorkupWorkupPharmacological testingPharmacological testing

Before After

Simple bedside testSimple bedside testIce pack test –A quick bedside technique for

diagnosing MG is the ice test. 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

Local cooling improves safety factor of NMJ, possibly by slowing the kinetics of acetylcholinesterese

Search for associated Search for associated conditioncondition Certain studies should be performed to exclude

other disorders that are in the differential diagnosis.

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

Laboratory Studies TFT, ANA, RF,CBC,RFT,LFT and voltage gated

calcium channel anti bodies and NCS Measurement of ventilatory function to asses the

respiratory impairment in myasthenic pt

TreatmentTreatmentAnti cholinesterase medications

Immunomodulating therapies

Surgical treatment –Thymectomy

Plasmapheresis and IVIg

AChE inhibitorAChE inhibitor

Inhibit the enzymatic elimination of acetylcholine, increasing its concentration at the post synoptic membrane

Gives partial improvement in most myasthenic pts although complete improvement in very few pts◦ Pyridostigmine most widely used

Adult dose: - starts with 60mg 4 times daily, increase up to 120 mg 4 times dailyLong acting drug can be used at bed time Starts working in 15-30 minutes and lasts 3-6

hours but response varies with individual Caution

Check for cholinergic crisis Others: Neostigmine Bromide dose 7.5-30 mg average of 15 mg 6th hrly 1.5mg im for 2hrly and 0.5mg iv

Immunomodulating Immunomodulating therapiestherapies

Glucocorticoid therapy◦ Prednisone is the most commonly used

corticosteroid Should be given in a single dose to

minimize the side effects 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

Maintain the same effective dose for 1-3 months, then modify to alternate day regimen over the additional 1-3 months

Taper the dose and asses the effective minimum dose

Close monitoring is necessary

Patients may have transient

worsening of MG symptoms during the first 2 to 3 weeks of prednisone therapy.

Patients should be warned of these potential adverse effects at the initial stages of therapy and reassured them.

Significant improvement is often seen after a decreased antibody titer which is usually 1-4 months

Azathioprine The most commonly used drug to treat

patients with MG until now . It allows tapering of steroid dosage and

reduces some of the adverse effects of steroid therapy.

starting dose of azathioprine is 50 mg daily for the first week (test dose), and then the dose is titrated up to a maximum of 2- 3 mg/kg body weight daily in two or three divided doses.

The most common adverse effects are neutropenia and liver function abnormalities.

Cyclosporine and tacrolimus -Calcineurin inhibitors

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.

Beneficial effects are more rapid than azathioprine

dose –cyclosporine 3-6mg/d and tacrolimus 0.1mg/kg in two divided doses

The most important adverse effects are nephrotoxicity and hypertension.

Cyclophosphamide—In general, cyclophosphamide is used only in refractory cases

Cyclophosphamide therapy may be started at 25 mg daily and gradually increased up to a maximum of approximately 2- 5 mg/kg/day .

An increased incidence of hemorrhagic cystitis accompanies the use of this medication in some patients

Mycophenolate MofetilInhibits the purine synthesis by the de

novo pathway and so inhibits the proliferation of lymphocytes ,not other cells

Currently is being used as an adjunct to corticosteroids due to relative less side effecs

Recent trials in patients with MG have shown this medication to provide significant benefit.

The standard daily dosage is 1 g to 2 g in two divided doses.

Side effects-occasional diarrhea rarely leucopenia

very useful in long-term treatmentBut high cost.

Prophylaxis of the complications of Prophylaxis of the complications of immunosuppressionimmunosuppression

Osteoporosis prevention -Measure bone density before treatment and yearly while on treatment. Start calcium and vitamin D supplements. Bisphosphonates may reduce bone loss associated with the chronic use of glucocorticoids.

Cardiovascular risk - Risk factor modification , advice to stop smoking, start an exercise program and manage hypertension.

Peptic ulcer prevention -Helicobacter screening and prophylactic treatment with proton pump inhibitors or H2 antagonists .

Infection prophylaxis - Use of inactivated vaccines such as influenza is recommended. Live vaccines are contraindicated. A chest X-ray should be performed prior to treatment. More specific testing for tuberculosis may be indicated depending on history and chest X-ray results.

Malignancy prevention -Skin cancer rates are increased in patients using azathioprine. A full yearly dermatological survey is recommended. Regular cervical smears are recommended.

Eye protection may also limit cataract development.

thymectomythymectomy Surgical Intervention-introduced by blalock Surgical removal of thymoma- If a patient has a

thymoma, it should clearly be removed Thymectomy as a treatment for MG 85% of pts experiences improvement after

thymectomy, of these 35% achieves drug free remission

Clinical improvement is typically delayed by 6 months to 1 year after surgery, but maximum effect occurs after 3 years and offers the long term benefit.

Should be carried out in all pts with generalized MG who are between puberty and 55 years of age.

Pts with anti MuSK anti body may not respond Preferred electively and not during acute crisis Transsternal thoracotomy is preferred and allows for

maximal exposure to ensure that all thymic tissue is removed at the time of surgery.

PlasmapheresisPlasmapheresis

Plasma exchange, or plasmapheresis, is an effective means of therapy but is transient in its response (2-8 wks)

Useful when treating patients in myasthenic crises or those in preparation for surgery and at the start of immunosuppressive therapy.

The goal of this therapeutic intervention is 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).

Removed plasma is replaced with albumin and saline

Risks involved in this treatment include infection, DVT, fluid imbalance and hypercoagulation.

Intravenous Intravenous Immunoglobulin TherapyImmunoglobulin TherapyThe administration of intravenous

immunoglobulin (IVIG) serves as an alternate mode of therapy to plasmapheresis.

This procedure is especially helpful when vascular access is a problem.

Intravenous immunoglobulin is given as a dose of 2 g/kg in divided doses over 2 to 5 days.

Intravenous immunoglobulin therapy is a relatively safe treatment method and has few adverse effects, though headache, chills, and fever have been reported in some patients.

Other rare adverse events include aseptic meningitis and renal failure.

pyridostigmine

Good response

Age<55,AchR+

thymectomy

Good response

continue

Prednisone+azathioprine

Good response

Gradualy prednisone

Poor response

Other immunosuppressive drugs

no

no

yes

Flow chart for management of MG

Treatment for myasthenic Treatment for myasthenic crisiscrisisTimely intubation and ventilatory

supportWithhold ACHE inhibitorsPlasmaparisis and IVIgHigh dose steroids

TreatmentTreatmentBehavioral modificationsBehavioral modifications

Diet◦Patients may experience difficulty chewing

and swallowing due to oropharyngeal weakness If dysphagia develops, liquids should be thickened

Thickened liquids decrease risk for aspiration

Activity◦Patients should be advised to be as active

as possible but should rest frequently and avoid sustained activity

◦Educate patients about fluctuating nature of weakness and exercise induced fatigability

Complications of MGComplications of MGRespiratory failureDysphagiaComplications secondary to drug

treatment◦Long term steroid use

Osteoporosis, cataracts, hyperglycemia, HTN

Gastritis, peptic ulcer disease Pneumocystis carinii

PrognosisPrognosisUntreated MG carries a mortality

rate of 25-31%Treated MG has < 4% mortalitiy

rate40% have ONLY ocular symptoms

◦Only 16% of those with ocular symptoms at onset remain exclusively ocular at the end of 2 years

◦Currently mortality rate due to MG is zero and most pts leads normal lives

future perspectivesfuture perspectivesTargeting specific T cells and B cells,

which are programmed to mediate anti-acetylcholine receptor activity is the focus of recent experimental work

Non selective removal of the T helper cells

Inducing tolerance to self antigens by ingesting them-oral ingestion of anti-AChR-ab has been found to prevent the disease in rat models of MG

THANK YOUTHANK YOU

Lab studiesLab studies

Work-upWork-upLab studies

◦Interleukin-2 receptors Increased in generalized and bulbar

forms of MG Increase seems to correlate to

progression of disease

WorkupWorkupPharmacological testingPharmacological testingEdrophonium (Tensilon test)

◦Steps 0.1ml of a 10 mg/ml edrophonium

solution is administered as a test If no unwanted effects are noted (i.e.

sinus bradychardia), the remainder of the drug is injected

Consider that Edrophonium can improve weakness in diseases other than MG such as ALS, poliomyelitis, and some peripheral neuropathies

Work-upWork-upImaging 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

The drug is usually started at 5 mg daily and may be increased by 5 mg every 4 to 7 days until a clinical benefit is achieved or 1 mg per kilogram of body weight is reached.

Once a therapeutic dose is achieved, the patient should remain on this dose for about 2 months. Then a regimen to switch to alternate-day therapy should be instituted.

Once the patient’s condition is stabilized, the dosage may be slowly tapered downward. In general, the dose should be tapered downward by 5 mg every month.

Immunomodulating Immunomodulating therapiestherapies

◦Glucocorticoid therapy Prednisone is the most commonly used

corticosteroid Significant improvement is often seen

after a decreased antibody titer which is usually 1-4 months

No single dose regimen is accepted Some start low and go high Others start high dose to achieve a quicker

response Clearance may be decreased by

estrogens or digoxin Patients taking concurrent diuretics

should be monitored for hypokalemia

Figure 2. Repetitive nerve stimulation (3 Hz) of the ulnar nerve at the wrist, recording over the abductor digiti minimi muscle. Maximal decrement is noted at the right of the tracings. (A) Baseline reading; (B) Immediately after 10 seconds of exertion (postexercise facilitation); (C) 1 minute after 60 seconds of exertion (postexercise exhaustion); (D) 2 minutes after 60 seconds of exertion (postexercise exhaustion); (E) 3 minutes after 60 seconds of exertion (postexercise exhaustion); (F) Immediately after 10 seconds of exertion again (postexercise facilitation and repair of the decrement). (Reprinted from Electromyography and Neuromuscular Disorders: Clinical-Electrophysiologic Correlations. Preston DC, Shapiro BE. Neuromuscular junction disorders, p 507, Copyright 1997, with permission from Elsevier.)

Prognosis Prognosis Before 1958 1/3 of MG pts died,

1/3 failed to improve and 1/3 improved spontaneously