DR. SUNIL KUMAR SHARMASENIOR RESIDENT

DEPT. OF NEUROLOGY

GMC KOTA

MYASTHENIA GRAVIS-RECENT MANAGEMENT GUIDELINE

MYASTHENIA GRAVIS

• MG- an autoimmune disorder of NMJ

• AChR antibody mediated destruction of AChR.

• Impaired transmission of nerve impulse across NMJ

• Incidence -0.3 to 2.8 per 100,000

• Worldwide Prevalance- >700,000

Diagnosis - clinical and confirmed by one or morepharmacological, electrophysiological, or serological tests.

Imaging –to R/O thymoma

Response to treatments - helpful in confirming thediagnosis specially in seronegative cases

MYASTHENIA GRAVIS SUBTYPES

Generalized MG < 40 yr.

AChR AB + , non-thymoma, Thymus hyperplasia

65% of all MG.

M:F - 1:4

AChR antibodies high

HLA -DR3 B8 DR9 (in Asians)

EARLY ONSET MG

>50 yrs AChR antibody positive, non-thymoma,

generalized MG

M=F

AChR antibodies is usually lower.

≈ 50% have titin and RyR AB

HLA-A3, B7, DR2, HLA-DR4, and in titin antibody

positive patients HLA-DR7

LATE-ONSET MG

AChR + in ≈50%, non-thymoma MG with purely ocular

(non-generalized) symptoms.

More common in children and in late-onset males.

10-15% of all MG.

More common in Asia (58%)

HLA-DQ6 , BW46

OCULAR MG

MG patients with thymoma regardless of the extent of

muscular involvement.

M=F

Usually – AChR AB +

15% of MG patients

THYMOMA MG

THYMOMA MG

Peak of onset around 50 years

Frequent occurrence of titin and RyR antibodies.

Thymoma and non-thymoma MG patients have similar MG

long-term prognosis.

HLA DR2 mostly in women.

50% of GMG lacking AChR AB.

Predominantly female.

Begins from childhood through middle age.

Thymic changes are absent or minimal.

Many patients do not improve with cholinesterase inhibitors

Most improve dramatically with PLEX or corticosteroids.

MUSK- ANTIBODY MYASTHENIA GRAVIS

Double seronegative (AChR antibody and Anti-MuSK)

No evidence of thymoma.

Low affinity anti-AChR antibodies can be detected using

specialized assays.

Less severe MG than seropositive MG patients.

SERONEGATIVE MG

LAB Ix.

Anti-acetylcholine receptor antibody

Positive in 74%

80% in GMG

50% of patients with pure ocular myasthenia

Anti-striated muscle

84% of patients with thymoma <40 years

IMAGING STUDIES

Chest x-ray- Plain anteroposterior and lateral views

Chest CT scan – mandatory

MRI of the brain and orbits may help to rule out other causes of cranial nerve deficits

PHARMACOLOGICAL TESTING

Edrophonium (Tensilon test)

Edrophonium -short acting Acetylcholine Esterase Inhibitor

Onset within 30secs

Evaluate weakness (i.e. ptosis and opthalmoplegia) before and after administration

0.1ml(1-2mg) 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

Keep atropine ready

False positive= ALS, poliomyelitis, and some peripheral neuropathies

Neostigmine test

Longer acting

1.5 mg im or 0.5 mg iv

Action begins in 15-20 mins

Ice pack test

RNST

SFEMG

Guidance statements were developed for :

Symptomatic and immunosuppressive (IS) treatments

IV immunoglobulin (IVIg) and plasma exchange (PLEX)

Impending and manifest myasthenic crisis

Thymectomy

Juvenile MG (JMG)

MG with antibodies to muscle-specific tyrosine kinase (MuSK-MG)

MG in pregnancy

Pyridostigmine-initial treatment in most cases

Dose S/B adjusted based on symptoms.

The ability to discontinue pyridostigmine can be anindicator that the patient has met treatment goals andmay guide the tapering of other therapies.

Corticosteroids or IS therapy s/b used in all patients whohave not met Rx goals after an adequate trial ofpyridostigmine

SYMPTOMATIC AND IMMUNOSUPPRESIVE (IS) TREATMENT OF MG

A nonsteroidal IS agent should be used alone whencorticosteroids are contraindicated or refused.

A nonsteroidal IS agent s/b used initially withcorticosteroids when the risk of steroid side effects ishigh .

A nonsteroidal IS agent should be added to

corticosteroids when:

Significant steroid side effects, deemed by the pt. or thetreating physician

Inadequate response to an adequate trial of corticosteroids

Corticosteroid dose cannot be reduced d/t symptomrelapse.

Azathioprine

Mycophenolate mofetil

Cyclosporine

Methotrexate

Tacrolimus

NONSTEROIDAL IMMUNOSUPPRESIVE AGENTS

The following factors should be considered inselecting among these agents:

There is widespread variation in practice with respectto choice of IS agent d/t paucity of literature comparingthem.

Expert consensus and some RCT evidence support theuse of azathioprine as a first-line IS agent in MG.

Evidence from RCTs supports the use of cyclo-sporine inMG, but potential serious adverse effects and druginteractions limit its use.

RCT evidence does not support the use of mycophenolateand tacrolimus but one or both are recommended in severalnational MG treatment guidelines.

Def.-PIS is unchanged or worse after corticosteroids and at least 2 other IS agents, used in adequate doses for an adequate duration, with persistent symptoms or side effects that limit functioning, as defined by patient and physician.

Patients with refractory MG should be referredto physician or a center with expertise in management ofMG.

REFRACTORY MG

Following IS agents may also be used in refractory

MG.

Chronic IVIg and chronic PLEX

Cyclophosphamide

Rituximab, for which evidence of efficacy is building, butfor which formal consensus could not be reached

Once patients achieve treatment goals, the corticosteroiddose should be gradually tapered.

In many patients, continuing a low dose of corticosteroidslong-term can help to maintain the treatment goal.

For nonsteroidal IS agents, once treatment goals have beenachieved and maintained for 6 months to 2 years, the ISdose should be tapered slowly to the minimal effectiveamount.

IS AGENT DOSAGE AND DURATION OF TREATMENT

Dosage adjustments should be made no more frequentlythan every 3–6 months

Tapering of IS drugs is associated with risk of relapse,which may necessitate upward adjustments in dose.

The risk of relapse is higher in patients who aresymptomatic, or after rapid taper.

Usually some maintainance immunosuppression is neededfor many years, sometimes for life.

Patients must be monitored for potential adverse effectsand complications from IS drugs.

Changing to an alternative IS agent should be considered ifadverse effects and complications are medically significantor create undue hardship for the patient.

PLEX and IVIg -used as short-term treatments in patientswith MG with life-threatening signs such as respiratoryinsufficiency or dysphagia

In preparation for surgery in patients with significantbulbar dysfunction

When a rapid response to treatment is needed; whenother treatments are insufficiently effective

Prior to beginning corticosteroids if deemed necessary toprevent or minimize exacerbations

INDICATIONS FOR IVIG AND PLEX

The choice between PLEX and IVIg depends onindividual patient factors and the availability of each.

IVIg and PLEX are probably equally effective in thetreatment of severe generalized MG.

The efficacy of IVIg is less certain in milder MG or inocular MG.

PLEX may be more effective than IVIg in MuSK-MG

The use of IVIg as maintenance therapy can beconsidered for patients with refractory MG or forthose in whom IS agents are relativelycontraindicated.

Impending and manifest myasthenic crisis-emergentsituations - aggressive management and supportive care.

Although cholinergic crises are rare, excessive ChEI cannotbe completely excluded as a cause of clinical worsening.

ChEIs increase airway secretions, which may exacerbatebreathing difficulties.

IMPENDING AND MANIFEST MYASTHENIC CRISIS

PLEX and IVIg are the mainstay of management inmyasthenic crisis.

Impending crisis requires hospital admission and closeobservation of respiratory and bulbar function, with theability to transfer to an ICU if it progresses to manifestcrisis.

PLEX and IVIg are used as short-term treatment forimpending and manifest myasthenic crisis and in patientswith significant respiratory or bulbar dysfunction.

MYASTHENIC CRISIS

Corticosteroids or other IS agents are often started atthe same time to achieve a sustained clinicalresponse.

Because corticosteroids may cause transientworsening of myasthenic weakness, it may beappropriate to wait several days for PLEX or IVIg tohave a beneficial effect before startingcorticosteroids.

Clinical trials - IVIg= PLEX

Expert consensus –PLEX> IVIg

The choice between the 2 therapies depends onpatient comorbidity and other factors, includingavailability.

A greater risk of hemodynamic and venous accesscomplications with PLEX may be minimized byusing peripheral rather than central venous access.

In non-thymomatous MG, thymectomy is performedas an option to potentially avoid or minimize thedose or duration of immunotherapy,

If patients fail to respond to an initial trial ofimmunotherapy or have intolerable side-effects fromthat therapy.

Thymectomy in MG

Thymectomy for MG is an elective procedure-longdelay.

It should be performed when the patient is stableand deemed safe to undergo a procedure wherepostoperative pain and mechanical factors can limitrespiratory function.

The value of thymectomy in the treatment ofprepubertal patients with MG is unclear.

Thymectomy should be considered in children withgeneralized AChR antibody–positive MG-

-If the response to pyridostigmine and IS

therapy is unsatisfactory

-In order to avoid potential complications of

IS therapy.

For children diagnosed with seronegativegeneralized MG, the possibility of a congenitalmyasthenic syndrome or other neuromuscularcondition should be entertained, and evaluation at acenter specializing in neuromuscular diseases is ofvalue prior to thymectomy.

With rare exceptions, all patients with MG withthymoma should undergo surgery to remove thetumor.

Removal of the thymoma is performed to rid thepatient of the tumor and may not produceimprovement in MG

All thymus tissue should be removed along with thetumor.

Further treatment of thymoma will be dictated byhistologic classification and degree of surgicalexcision.

Incompletely resected thymomas should bemanaged after surgery with an interdisciplinarytreatment approach (radiotherapy, chemotherapy).

In elderly or multimorbid patients with thymoma,palliative radiation therapy can be considered in theappropriate clinical setting.

Small thymomas may be followed without treatmentunless they are enlarging or become symptomatic.

Endoscopic and robotic approaches to thymectomy -have a good track record for safety in experiencedcenters.

Thymectomy may be considered in patients withgeneralized MG without detectable AChR antibodiesif they fail to respond adequately to IS therapy, or toavoid/minimize intolerable adverse effects from IStherapy.

Current evidence does not support an indication forthymectomy in patients with MuSK, LRP4, or agrinantibodies.

Children with acquired autoimmune ocular MG aremore likely than adults to go into spontaneousremission.

Thus, young children with only ocular symptoms ofMG can be treated initially with pyridostigmine.

Immunotherapy can be initiated if goals of therapyare not met.

Juvenile MG

Children are at particular risk of steroid side effects-

Eg. - Growth failure, poor bone mineralization, andsusceptibility to infection, due in part to a delay in livevaccinations

Longterm treatment with corticosteroids should use the lowest effective dose to minimize side effects

Maintenance PLEX or IVIg are alternatives to IS drugs in JMG.

Many MuSK-MG pt -respond poorly to ChEIs, andconventional doses frequently induce side effects.

Respond well to corticosteroids and to many steroid-sparing IS agents.

They tend to remain dependent on prednisonedespite concomitant treatment with steroid-sparingagents

MG WITH MuSK ANTIBODIES

MuSK-MG responds well to PLEX, while IVIg seems to be less effective

Rituximab should be considered as an early therapeutic option in patients with MuSK-MG who have an unsatisfactory response to initial immunotherapy

Planning for pregnancy should be instituted well in advanceto allow time for optimization of myasthenic clinical statusand to minimize risks to the fetus

Multidisciplinary communication among relevantspecialists should occur throughout pregnancy, duringdelivery, and in the postpartum period

MG IN PREGNANCY

Provided that their myasthenia is under good control beforepregnancy, the majority of women can be reassured thatthey will remain stable throughout pregnancy.

If worsening occurs, it may be more likely during the firstfew months after delivery.

Oral pyridostigmine is the first-line treatment duringpregnancy.

IV ChEIs may produce uterine contractions and shouldnot be used during pregnancy.

Thymectomy should be postponed until after prenancy , as benefit is unlikely to occur during pregnancy.

Prednisone is the IS agent of choice during pregnancy

Azathioprine and cyclosporine are relatively safe inexpectant mothers who are not satisfactorilycontrolled with or cannot tolerate corticosteroids.

Current evidence indicates that mycophenolatemofetil and methorexate increase the risk ofteratogenicity and are contraindicated duringpregnancy.

There was a strong minority opinion against the useof azathioprine in pregnancy.

Azathioprine is the nonsteroidal IS of choice for MGin pregnancy in Europe but is considered high risk inthe United States.

This difference is based on a small number of animalstudies and case reports.

PLEX or IVIg are useful when a prompt, althoughtemporary, response is required during pregnancy.

Careful consideration of both maternal and fetalissues, weighing the risks of these treatments againstthe requirement for use during pregnancy and theirpotential benefits, is required.

Spontaneous vaginal delivery should be the objectiveand is actively encouraged.

Magnesium sulfate is not recommended

Barbiturates or phenytoin usually provide adequatetreatment.

All babies born to myasthenic mothers should beexamined for evidence of transient myasthenicweakness, even if the mother’s myasthenia is well-controlled, and should have rapid access to neonatalcritical care support.

PHARMACOLOGICAL MANAGEMENT OF MG

Bradley’s Neurology In Clinical Practice;7th Edition.

International Consensus Guidance For Management Of Myasthenia Gravis- Executive Summary; Donald B. Sanders, MD Et. Al. ; Neurology® 2016;87:419–425

Myasthenia gravis: clinical, immunological, and therapeutic advances; Acta Neurol Scand 2005: 111: 134–141 DOI: 10.1111

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