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Label
Myasthenia Gravis (MG) overview

DefinitionEtiologyEpidemiologyPathophysiologyClinical Presentation
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Definition:

A neuromuscular disorder arising from autoimmune mediated injury of the post-synaptic neuromuscular junction and characterized by fluctuating skeletal muscle weakness and fatigability, usually affecting opthalmic and bulbar muscles.

 

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Etiology:
  • Thymus gland dysfunction: Both thymic hyperplasia and thymoma, have been implicated in the formation of autoantibodies through abnormal antigen presentation via MHC class II molecules
  • There are two recognized pathogenic neuromuscular junction (NMJ) autoantibodies:
    • Anti-nicotinic acetylcholine receptors (AchR) antibodies: Present in ~85% of patients with generalized MG and 50% of patients with purely ocular MG. Binds to; or adjacent to, and impairs AchR binding on the postsynaptic NMJ, thereby inhibiting the excitatory effects of acetylcholine on AchR at the motor end-plate. AchR destruction and altered morphology (decrease folds) of the postsynaptic membrane usually ensues ("simplification" of the post-synaptic membrane)
    • Anti-Muscle-Specific receptor tyrosine kinase (MuSK): Present in about 40% of AchR negative patients, AchR and post-synaptic folds are not affected. MuSK protein plays a central role in maintaining the integrity of the NMJ, likely through a signal transduction pathway. Consequently, anti-MuSK antibodies inhibit MuSK activity and decrease the integrity of the NMJ
  • Seronegative MG: Term used for the ~15 % patients who have symptoms of MG and are negative for both anti-AchR and anti-MuSK antibodies (often older adults with primarily ocular MG)
  • Other antibodies found in association with MG include:
    • Anti-striated muscle antibodies (StrAbs)
    • Anti-Titin and ryanodine receptor (RyR) antibodies

However, their significance and prevalence is unknown at this point due to less availability of the tests.

  • Genetic predisposition may be related to the presence of HLA types HLA-B8, DRw3, and DQw2 and haplotypes DR14 and DQ5

 

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Epidemiology:
  • Female: male (overall 2:1), but ~5:1 (F: M) in younger and 1:1 in older adults
  • Age of onset: Women are typically affected younger (< 40 years; range 18-25 years) as compared to men (> 60 years)
  • Incidence is 3-30 cases per million per year
  • Prevalence is 14-40 per 100,000 population in US (MG Foundation of America)

 

Types Of Myasthenia Gravis

Myasthenia Gravis is classified according to involvement of skeletal muscles.

  • Generalized: Diffuse weakness in the trunk, arms, and legs (usually within 1 year of commencement of symptoms) affects ~80% of patients with early onset (<50 years) versus ~60 % of patients with late onset (>50 years)
  • Ocular: Weakness primarily affecting muscles that control eye movements. About 20% of early onset (<50 years) and ~40% of late onset (>50 years) patients will have restricted ocular MG, whereas most ( >90%) of patients will have ocular and/or bulbar symptoms at some time during the course of the disorder
  • Congenital MG: Inherited heterogeneous group of disease caused by genetic defects of the NMJ, which may be presynaptic, synaptic or postsynaptic. Symptoms manifest at or shortly after birth and may cause generalized symptoms but most patients will have bulbar (feeding difficulty) and/or ocular (ptosis) findings
  • Transient neonatal myasthenia gravis: Observed in ~10-20% of infants born to mothers with MG. Mechanism related to transplacental transfer of circulating maternal antibodies (IgG). Symptoms dissipate over a few weeks as the levels of circulating offending antibodies decline
  • The Myasthenia Gravis Foundation of America has a classification scheme with increasing severity of symptoms:
    • Class I: Restricted to ocular muscles
    • Class II: Ocular and mild weakness in muscles other than ocular
    • Class III: Moderate weakness outside of ocular, may have ocular as well
    • Class IV: Severe weakness of muscles outside of ocular, may have ocular as well
    • Class V: Intubation

Ref: Myasthenia gravis: Recommendations for clinical research standards. Neurology July 12, 2000 55:16-23.

 

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Pathophysiology:

Normal NMJ function:

Arrival of an action potential at the presynaptic terminal of the NMJ results in the release of ACh within the synaptic cleft → binding of ACh to the post-synaptic nicotinic AChR → endplate/ muscle membrane depolarisation → DHP/ryanodine receptor interaction in t-tubule → muscle contraction. Acetylcholine esterase present within the synaptic cleft degrades Ach to choline and acetyl-CoA and prevents over stimulation of postsynaptic AChR.

 

Impact of Anti-AChR antibodies on NMJ function:

Anti-AChR antibodies (possible pathogenic mechanisms):

  • Block ACh from binding to the AChR, thereby disrupting/reducing post-synaptic transmission
  • Downregulation of AChR via cross-linking of surface ACh receptors followed by accelerated endocytosis and degradation. This results in less functional surface receptors available for interaction with ACh
  • Promotes local inflammation and complement-mediated damage and remodeling of the post-synaptic membrane leading to less post-synaptic folds and less AChR. This also eventually results in less functional surface receptors available for interaction with Ach

 

The combination of these factors leads to muscle weakness, fatigability and disease progression overtime.

 

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Clinical Presentation:

Depends on the muscles involved

General muscular symptoms

  • Fluctuating weakness and fatigue
    • Affects various groups of skeletal muscles
    • Weakness may fluctuate throughout the day
    • Worsens with activity
    • Transiently improves with rest
    • More evident later in day/evenings
    • Less evident/ absent upon awakening in the morning
  • May manifest as difficulty with:
    • Rising from a seated position
    • Ambulation/ ascending stairs
    • Maintaining muscular contraction (holding arms outstretched, lifting, gripping objects)

 

Ocular symptoms

  • Ptosis - unilateral or bilateral; heightened with sustained upgaze
  • Binocular diplopia due to weakened extraocular muscles (gaze may be disconjugate at rest)
  • Pupils are not affected

 

Bulbar symptoms

  • Dysarthria (often very nasal sounding)
  • Dysphagia
  • Fatigue with chewing
  • Hypophonia
  • Palatal muscle weakness may lead to nasal regurgitation

 

Involvement of neck muscles

  • Weakness of neck extensors more than flexors causes drooping of head usually late in the day (more common in older patients)
  • Muscular pain due to holding of head with weak muscles (may present as a tension-type headache)

 

Involvement of respiratory muscles

  • Difficulty breathing
  • Shortness of breath on exertion
  • Respiratory insufficiency/ failure

 

Facial muscle involvement

  • Bilateral facial weakness
  • Loss of facial expressions/ weak or absent smile
  • In-coordinated lip movements

 

Myasthenic crises

Life-threatening condition stemming from severe weakness/failure of respiratory and oropharyngeal muscles. Intubation and ICU intervention often required with naso-gastric feeds.

Usual precipitating factors:

  • Tapering of immunosuppressive medications
  • Concurrent infection
  • Surgery
  • Pregnancy/ childbirth

 

Cholinergic crises:

Very rare occurrence caused by overmedication with cholinesterase inhibitors leading to bradycardia and/or respiratory distress. Atropine alleviates symptoms.

 

STAGES OF MG

  • Active: Fluctuating symptoms with increased severity within 5-7 years of disease onset
  • Stable: Symptoms persist but stable. May worsen with stressors (e.g. infection) or medication adjustments
  • Remission: Relatively symptom free on immunotherapy ±thymectomy. With prolonged stability, medications might be tapered/stopped (as tolerated)

 

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Differential Diagnosis:

CNS pathology:

  • Stroke (particularly with brain stem involvement)
  • Multiple sclerosis
  • Brain tumor
  • Cervical cord lesion (syrinx, neoplasm)
  • Amyotropic lateral sclerosis (ALS)

 

Lambert-Eaton myasthenic syndrome (LEMS):

  • Autoimmune disorder characterized by weakness in proximal groups of leg and arm muscles due to formation of antibodies against presynaptic voltage-gated calcium channels in the neuromuscular junction

 

Botulism:

  • A paralytic illness caused by botulinum toxin mediated blockade of NMJ transmission. Paralysis typically starts with the facial muscles and spreads towards the limbs

 

Myopathies:

  • In general causes diffuse proximal muscle weakness, with elevation in serum CK and characteristic changes on electromyography. Jitter, blocking is absent if Single fiber EMG (SFEMG) undertaken

 

Neuropathies:

  • Heterogenous conditions that may present as focal, diffuse, symmetric or asymmetric (often distal), non-fluctuating weakness. Electrophysiological studies can readily distinguish these conditions from MG. The Miller-Fischer variant of Guillain-Barre syndrome would be most commonly confused with myasthenia gravis

 

Mitochondrial myopathies:

  • Chronic progressive external ophthalmoplegia (CPEO) presents with progressive ophthalmoparesis and ptosis; however, it is slowly progressive and very symmetric. Many CPEO patients will have a positive SFEMG; however antibody testing is negative and there is minimal (pyridostigmine) to no response (immunosuppression) to therapy. A muscle biopsy showing cytochrome c oxidase negative fibers and a single mtDNA deletion is diagnostic

 

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Investigation and Workup:

History:

  • Weakness (duration, fatigability, exacerbating factors)
  • Family history of MG or other autoimmune disorders (weak association)
  • Medication use, occupational hazards (potential toxin exposure)

 

Physical: Requires a neurological examination that should include assessment of:

  • Gaze induced ptosis and diplopia; may be evident during sustained upwards or horizontal gaze for 30-60 sec. Assess for ptosis and/or abnormal extra-ocular eye movements
  • Coggan's twitch: upon rapid up-gaze, the eye lids lift fully and then rapidly drop down; appearing to "twitch".
  • Weakness: Strength of limbs or neck (weakness in extension > flexion) assessed at rest and after repetitive movement to reproduce/ induce fatigue. Manoeuvres to induce fatigue might include: Prolonged shoulder abduction or neck flexion against resistance; holding arms stretched; ascending a flight of stairs, deep knee bends, walking on toes or heels

 

Tensilon (Edrophonium) test:

  • Short acting, rapid onset acetylcholinesterase inhibitor, edrophonium can improve strength in patients impaired neuromuscular junction transmission
  • The test may be useful in cases where the weakness is readily apparent as with ptosis and/or opthalmoparesis but less useful with generalized weakness
  • A test dose of 2 mg of Edrophonium is given intravenously and repeated after 1 minute with 8 mg
  • Patients must be warned that they may experience an increase in cholinergic effects (tearing, cough, and increased saliva)
  • It is important to have atropine readily available in rare cases of severe bradycardia (0.6 mg)
  • Contraindications to IV edrophonium include heart disease, bronchial asthma, bradycardia, and first degree heart block

Note: Agents with longer duration of action than Edrophonium, e.g. neostigmine (IM) or pyridostigmine (PO) may provide a better assessment in situations where it may be difficult to fully appreciate or quantify the brief response to edrophonium, e.g. infants and children. Often a trial for a week on and a week off of a trial dose of pyridostigmine with a symptom log is very helpful to determine if there is a positive response to acetylcholinesterase blockade.

 

Serology: Antibodies in Myasthenia Gravis

  • Acetylcholine receptor antibodies are detected in
    • Approximately 45% of patients with generalized myasthenia and
    • Approximately 40% of those with ocular myasthenia
    • The serum concentration of anti-AChR antibody does not correlate with disease severity
  • Anti-MuSK antibodies
    • Detected in about 40% of MG patients who are seronegative for AChR antibodies
  • Anti-striated muscle antibodies (StrAbs)
    • Non-specific for MG but may have some predictive value for the presence of thymomas in those with MG
    • Present in >90% of MG patients with thymoma
  • Antibodies to titin
    • Titin is the major autoantigen recognized by anti-striated muscle antibodies
    • Anti-titin antibodies appears to be a sensitive marker of thymoma associated with MG in young (≤50 years) patients
    • Does not correlate with disease severity
  • Antibodies to muscles ryanodine receptor (RyR)
    • Ryanodine is the calcium-release channel of the sarcoplasmic reticulum in striated muscle
    • Anti-RyR have been isolated in MG with thymoma
    • Presence of anti-RyR may correlate with disease severity

Note: While elevated serum concentrations of anti-AChR binding and anti-MuSK antibodies are diagnostic of MG, there absence does not preclude the diagnosis (i.e. these are specific but not sensitive tests).

 

Electrodiagnostic studies

Single fiber electromyography (SFEMG)

  • Most sensitive clinical test of neuromuscular transmission (>95 % sensitivity but lower specificity due to higher jitter observed in chronic neurogenic is orders)
  • Used to detect "Jitter" in muscle action potentials. A thin needle electrode is inserted into the muscle of interest. Action potentials are recorded. The variability in time between successive action potentials is called "jitter" and reflects variance in neuromuscular transmission. Frequency and proportion of abnormal action potential patterns, "jitter" and "blocking" are increased in MG and are diagnostic. It is important that the cut-off values used are age appropriate (normal increase in jitter with aging)

 

Repetitive nerve stimulation (RNS)

  • A compound muscle action potential (CMAP) can be generated by stimulating the nerve to a given muscle (i.e. ulnar stimulation of the ADQM muscle) using a train of 10 stimuli delivered at 2-3 Hertz (low frequency stimulation). The amplitude and area of the resultant CMAPs are recorded. In normal muscles, there is no change in CMAP amplitude. In contrast, in patients with MG there is a progressive decline (decremental response) in the CMAP amplitude (>10% decline). The diagnostic yield can be increased by performing the test and if the CMAP drop is <10%, then perform isometric exercise for 60 seconds, followed by a 60 second rest and repeating the test
  • Helpful in the diagnosis but not specific to MG
  • Often normal in patient with mild or ocular MG

 

Imaging

Chest CT or MRI can be used to assess for thymic abnormalities (thymic hyperplasia or thymoma).

 

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Treatment:

 

SYMPTOMATIC TREATMENT

  • Individualized and based on extent of functional impairment, age and sex
  • Reduction/treatment of stressors (infections, physical and emotional stress) may improve symptoms

Note: In the early stages of MG, remissions and spontaneous improvement can occur without any specific therapy.

 

  • Fifteen percent of MG patients can have thyroid abnormalities (i.e. Hashimoto's thyroiditis) as co-existent conditions; consequently, it is important to check TSH for hypothyroidism symptoms can mimic MG

 

- Cholinesterase inhibitors

  • Often used initially as a diagnostic and therapeutic trial
  • May be discontinued when immunological control of disease is achieved
  • Blocks acetylcholine esterase within the synaptic cleft and prolongs the action of ACh
  • Daily requirements may vary depending on extent of fluctuations/exacerbations
  • In general limb and bulbar symptoms respond better than do ocular symptoms (diplopia is particularly resistant

 

  • Pyridostigmine: Acts within 15-30 minutes, peaks in 2 hours and lasts for 3-4 hours
  • Dose: 30 mg TID and increased as required and as tolerated to a usual dose of 180-360 mg/day. Long acting forms are available for long -term use (180 mg dose-sometimes helpful as an overnight dose in those symptomatic later in the evening)

 

  • Neostigmine: 15 mg/dose every 3-4 hr. Increase as tolerated; Max daily dose: 375 mg (divided)

Common adverse effects:

Gastrointestinal:

  • Queasiness, nausea, vomiting, abdominal cramps, loose stools, and diarrhea

Autonomic:

  • Increased oral and bronchial secretions, sweating, bradycardia

Cholinergic crisis:

  • Results from over-stimulation of NMJ due to an excess ACh (acetylcholinesterase inhibition)
  • Increased sweating, salivation, bronchial secretions
  • Dysphagia, miosis, flaccid paralysis, respiratory failure
  • Treatment:
    • Discontinue cholinergic agent
    • Respiratory support (intubation and ventilation as required)
    • Antimuscarinic drugs (e.g. atropine)
    • Resume cholinergic therapy once patient stabilized and use lower doses

 

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IMMUNOTHERAPY

 

Indications

  • Refractory or progressive MG
  • Inadequate response or side effects with cholinesterase inhibitors
  • Increasing disability
  • One approach is to start all symptomatic proven patients with cholinesterase inhibitors and prednisone and once the disease is under control to stop the cholinesterase inhibitors (should not need them when disease is under control) and slowly taper the prednisone

 

- Corticosteroids (prednisone):

  • Often improves strength within days to weeks after initiation
  • Approximately 1/3 of patients temporarily deteriorate within a week of initiating prednisone (rare if the starting dose is low)
  • Always start at low dose (≤20 mg) and titrate upwards after ~2 weeks by 5 mg/week increments according to clinical response (max = 40 mg/d)
  • Common side effects: Hypertension, glucose intolerance, osteoporosis (long term), weight gain, cushingoid features, mood changes/psychosis
  • If the patient has significant side effects or cannot get to a dose of <10 mg/prednisone/day, then one should consider alternative disease modifying agents (see below)

Dose:

  • Starting Dose: Variable; one approach is to begin with 10-20 mg PO daily; increase by 5 mg per week monitoring clinical response
  • Once stabilized may begin an alternate day regimen, by reducing dose every other day or taper the dose very slowly to the minimal effective dose using an alternate day drop with a fixed daily dose (e.g. 20 mg/d, followed by 20/17.5 mg alternate days, then 17.5 mg/d, followed by 17.5/15 mg alternate days, etc. The time interval for any of these dose changes is variable and dependent on patient response and tolerance to dose changes

 

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- Azathioprine

  • Used as steroid sparing therapy or adjunct to steroids
  • Often initiated in combination with steroids as response to azathioprine is often delayed by 4-8 months
  • Steroids can then be weaned off or reduced depending on response to azathioprine
  • Effective, but relapses may recur 2-3 months after the drug is discontinued or reduced below therapeutic levels
  • Side Effects:
    • Acute: Flu-like illness (~5%) → stop and do not use
    • Chronic: Approximately 7% develop elevation of GGT, bilirubin, 3 X ULN and ~5% develop neutropenia/severe lymphopenia → stop and do not use
  • Note: MCV elevation is expected and indicative of the drug having a biochemical effect → not an indication to stop therapy

Dose:

  • Start at 1.0 mg/kg/d and increase over ~30 days to 2 mg/kg/d and re-check GGT, bilirubin and CBC. If no response in ~4 months may increase dose to a maximum of 3 mg/kg per day
  • Most can take the medication once per day but if they have gastrointestinal upset, it may be divided as a tid dosing. Monitor CBC, bilirubin and GGT every 2 months while on therapy

 

- Cyclosporine A

  • Long-term immunosuppression (steroid sparing)
  • Improvement may be detected 1 to 2 months after initiating treatment
  • Benefits disappear when treatment is stopped or reduced below therapeutic levels
  • Side effects: Renal toxicity and hypertension [monitor plasma creatinine, blood pressure and plasma trough cyclosporine levels (some use peak levels)]

Dose:

  • Start at 50 mg bid and increase to a maximum of 2.5 mg/kg twice a day adjusted according to levels, tolerance and renal function (creatinine)

 

- Mycophenlate Mofetil (MMF)

  • Corticosteroid-sparing agent that may be considered for adjunctive or primary therapy in refractory MG
  • Faster onset of action than azathioprine but generally less consistently effective
  • Side effects: Liver toxicity but considered somewhat less toxic vs azathioprine-follow similar monitoring as per azathioprine

Dose:

  • Start at 500 mg twice daily and increase as tolerated to 1 g BID

 

- Cyclophosphamide

  • Alternative therapy to other immunosuppressive agents
  • Good response in >50% of patients
  • Side effects: Potential for life-threatening infections (watch WBC count and neutrophils), hemorrhagic cystitis, do not use if not familiar with use of the drug and seek local expertise

Dose:

  • 150-200 mg/day PO

 

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PLASMAPHARESIS/ IVIG

Indications

  • Acute exacerbations
  • Myasthenic crises
  • As part of pre-surgical treatment to boost strength and improve respiratory status
  • Intermittent therapy for those sub-optimally controlled with other treatments
  • Bridging therapy until the response to immunotherapy is apparent

 

Plasmapharesis:

  • Use of plasma exchange determined by the clinical scenario
  • Rapid action-benefits may be seen after one exchange
  • Usually 5 exchanges can be done over 10-14 days

 

Human immune globulin (IVIG):

  • Improvement usually occurs within 1 week and may last for months
  • Patients with more severe symptoms seem to have a better response to therapy
  • May be used intermittently (e.g. monthly) as bridge therapy in some patients who cannot tolerate corticosteroids, until immunotherapy takes effect
  • Side effects:
    • Mild headache is common
    • Allergy: Approximately 1/1,000, check IgA levels and do not use if IgA deficient without consulting haematologist
    • Shaking/chills: Use benadryl and/or demerol as a pre-medication
    • Rarely severe headache
  • Often a pre-dose of methyl-prednisolone is given that may lessen side effects and enhance efficacy (low dose <125 mg NOT 1g dose)

Dose:

  • 2 g/kg given over 3-5 days (can be used as 1 g/kg/d X 2 Or 0.4 g/kg X 5 doses)

 

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SURGICAL OPTIONS

Thymectomy

  • Considered in most patients with MG
  • Thymectomy is not indicated for anti-AchR Ab-negative patients even if anti-MuSK Ab is positive
  • Some anti-MuSK Ab-negative patients may still be covered for the procedure
  • However, advancing age, mild or limited MG (e.g primarily ocular) and/or other significant co-morbidities might preclude thymic excision
  • Variable post-surgical clinical course; may take months or years to see benefit (due to persistence of antibody producing plasma cells)
  • Younger patients early in the disease course may have best response
  • Older (>60 years) patients, show little or no benefit
  • Paradoxically, patients with thymomas do not respond as well to thymectomy as do patients without thymoma, but thymoma can locally or distantly metastasize and all suspected thymomas should be removed

 

Procedure: Removal of thymus and tissue mediastinal and cervical adipose as these may contain ectopic thymic tissue. Transcervical and thoracoscopic approaches have been used but there is a concern about residual thymic tissue to remain and most consider a full sternal split thymectomy to be the "gold standard".

 

Potential complications: Risk of injury to recurrent laryngeal, vagus and phrenic nerves.

 

LIFE THREATENING COMPLICATION: Respiratory failure

May occur with both myasthenic and cholinergic crises; respiratory muscle and bulbar weakness may lead to compromised respiratory function. Treatment includes:

  • Vital signs
  • Assessment of respiratory status including oximetry and arterial blood gases
  • Positive pressure ventilation or endotracheal intubation (as required)
  • Plasmapharesis or IVIG treatment is employed
  • Discontinue cholinesterase inhibitor; restart once patient stabilizes and begins to improve
  • Avoid magnesium therapy, aminoglycoside antibiotics as well as muscle blocking agents

 

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MEDICATION

 

Acetylcholinesterase inhibitor

  • ➣ Pyridostigmine
  • ➣ Neostigmine

 

Mechanism:

  • Reversibly inhibits cholinesterase
  • Thus facilitates the transmission of impulses across NMJ

 

Doses:

Pyridostigmine

Regular:

  • Start with 30-60 mg PO TID; may increase dose gradually at intervals of ≥48 hrs, as needed; usual dose range 180-360 mg/day in 3-6 divided doses (i.e. 120 mg every 3-4h). Max dose 540 mg/day total dose (including long acting forms)
  • If excessive muscarinic side effects occur (GI cramps, diarrhea, salivation, increased bronchial secretions, nausea, sweating, bradycardia), then anticholinergic (e.g. glycopyrrolate 1 mg) can be taken with each pyridostigmine dose
  • Dosing is individualized; patients who do well until midday may take 60 mg at lunch and 90 mg 4-8 h later; patients with dysphagia may benefit from taking dose 30 minutes before meals

Sustained release:

  • 180 mg once or twice daily; should have at least 8 hours gap in between doses

Note: It may be used at bedtime if severe persistent weakness occurs upon awakening; not preferred choices during daytime use, due to variable release and delayed absorption, resulting in inconsistent control of symptoms

 

Neostigmine

Oral:

  • 15 mg PO every 3-4h; may increase dose gradually at intervals of ≥48 hours, as needed; usual maintenance dose 15-375 mg/day

 

Injectable:

  • 0.5-2.5 mg IM/ IV/ SC every 1-3 hours, as needed and tolerated; Max. 10 mg/24 hours

 

Renal impairment: Clcr 10-50 mL/minute: Administer 50% of normal dose; Clcr <10 mL/minute: Administer 25% of normal dose

 

Note:

  • Administer atropine sulfate 0.6-1.2 mg IV at the same time with large parenteral neostigmine doses to counteract adverse muscarinic effects
  • Atropine and epinephrine may be required to treat hypersensitivity reactions.

 

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IMMUNOTHERAPY

Corticosteroid

  • ➣ Prednisone

 

Use: Acute exacerbations

 

Mechanism:

  • Decreases inflammation and the normal immune response through multiple mechanisms, also suppresses adrenal function in higher doses

 

Dose:

  • Start 10-20 mg daily; increase gradually by 5 increments every 7 days as tolerated up to max of 40 mg/d. Once stabilized may begin an alternate day regimen, by reducing dose every other day or taper the dose very slowly to the minimal effective dose using an alternate day drop with a fixed daily dose (e.g. 20 mg/d, followed by 20/17.5 mg alt days, then 17.5 mg/d, followed by 17.5/15 mg alt. days, etc.

 

Tumor necrosis factor (TNF) blocker

  • ➣ Azathioprine

 

Use: Immunosuppressant therapy

 

Mechanism:

  • Complete mechanism of immunosuppression is not fully known
  • It antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins
  • May also interfere with cellular metabolism and inhibit mitosis

 

Dose:

  • Begin 50 mg PO daily; titrated by 50 mg every week to therapeutic dose achieved; usual therapeutic dose range 2-3.5 mg/kg/day (typically 150-200 mg/day)

 

Monitor: CBC every other week while adjusting dose; then monthly; LFTs

 

Calcineurin inhibitor, Immunosuppressant agent

  • ➣ Cyclosporine A

 

Mechanism:

  • Exact mechanism of action is not known
  • Inhibits production and release of interleukin II and also inhibits interleukin II-induced activation of resting T-lymphocytes

 

Dose:

  • Start at 50 mg BID and increase to a maximum of 2.5 mg/kg twice a day, doses 12 hour apart; after ~4 weeks adjust the dose according to serum cyclosporine concentration of 100-150 ng/ml, tolerance and renal function (creatinine). Take consistently with regard to time of day and meals

 

Note:

  • Measure serum creatinine every month
  • Measure serum cyclosporine concentration every 2-3 months (to monitor for toxicity in all patients; and efficacy in transplant patients)
  • IV to oral conversion is 1:3 (300 mg per day PO = 100 mg per day IV)

 

Renal impairment:

  • If serum creatinine levels increases to ≥25% above pre-treatment levels: Decrease dose by 25% to 50%
  • Monitor: Creatinine, lipids, K, Mg, uric acid, BP, liver function

 

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Antineoplastic agent, Alkylating agent; Antirheumatic

  • ➣ Cyclophosphamide

 

Use: Immunosuppressant

 

Mechanism:

  • An alkylating agent that prevents cell division by cross-linking DNA strands and inhibiting DNA synthesis
  • Interferes with DNA replication and RNA transcription
  • It is a cell cycle phase nonspecific agent and potent immunosuppressive agent

 

Dose:

  • 150-200 mg/day PO

 

Immunosuppressant

  • ➣ Mycophenolate mofetil

 

Mechanism:

  • Mycophenolate mofetil hydrolyzed to form mycophenolic acid (MPA), a reversibe inhibitor of inosine monophosphate dehydrogenase (IMPDH) in the purine biosynthesis pathway
  • Inhibition of IMPDH results in depletion of guanosine triphosphate and deoxyguanosine triphosphate
  • Thus selectively inhibits the proliferation of activated B and T lymphocytes
  • It also suppresses the formation of antibodies active in complement dependent lysis and antibody dependent, cell-mediated cytotoxicity

 

Dose:

  • Start at 500 mg twice daily and increase as tolerated to 1 g PO BID; range 1-3 g/day
  • Divided doses may reduce abdominal pain and gastritis

 

Monitoring:

  • Pregnancy test prior to treatment
  • CBC, ANC (absolute neutrophil count) every week x 4; then every 2 weeks x 4 then monthly

 

Immune globulin/ Blood product derivative

  • ➣ Immune globulin (IVIG)

 

Mechanism:

  • Exact mechanism of action unknown
  • Probably facilitates immune-regulation through down regulation of offending antibodies

 

Dose:

  • 2 gm/kg given IV over 2-5 days (can also be used as 1 g/kg/d for 2 days Or 0.4 g/kg/day for 5 days)

 

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Clinical Trials:
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Pipeline Agents:
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Physician Resources:

1. Tips for Patient Care

General

  • Encourage compliance with medications
  • Recognize emergence of potentially life threatening symptoms
  • Advise for use of medical alert bracelet, and/or medical identification card
  • Treatment must be individualized for each patient because no single treatment plan is effective for all patients
  • Advise patient not to take other drugs without consulting their physician, as some drugs may aggravate MG
  • Hyperthyroidism and hypothyroidism can be associated with increasing myasthenic weakness

 

Activities (physical, mental, others)

  • Patient should try living as normal a life as possible
  • Exercise can help to minimize the negative effects of corticosteroids and improve strength. Start once the disease is under control and avoid during exacerbations. Start off slowly with frequent rest periods until the patient can tolerate the exercise
  • Lifestyle changes often help in managing daily activities, including
    • Scheduling adequate rest periods during the day
    • Avoid heat exposure including hot baths and hot showers
    • Wear lightweight, comfortable shoes
    • Sit to brush teeth, blow dry hair, shave, etc. if tiring easily
    • Use electric appliances and power tools, such as toothbrushes, can openers, electric mixer etc. to save energy
    • Eye patch may help those with diplopia; advise to use the patch on alternate eyes to ensure some rest for the eyes

 

Counselling

  • Educate patients, caregivers and family about MG and its treatment
  • Explain the fluctuating nature of the weakness and the varying degree of muscle involvement
  • Include family or social support in lifestyle modification
  • Avoid driving, if double vision and/or droopy eyelids are problem
  • Emphasize that stressors might exacerbate symptoms:
    • Systemic illness/infection
    • Extremes in temperature
    • Emotional stress
    • Pregnancy and menstruation

 

Monitoring

  • Caregiver should periodically monitor for behavioural/physical changes
  • Monitor response to therapy, and side effects of treatments
  • Request home occupational therapy consult to assess for fall risk and advice regarding installation of grab bars or railings to help avoid falls

 

Medications

  • Consider co-morbidities and concurrent medication use when prescribing therapy
  • The patient and caregiver should be familiar with medication dosing and potential side effects
  • An individualized management plan is developed based on several factors including age, gender, severity of disease, and progression of disease because no single treatment plan is effective for all patients

 

Alerts

  • Food must be eaten very slowly to prevent aspiration
  • Be careful of swallowing mixed-consistency foods, e.g.
    • Cereal with milk
    • Soups (like chicken noodle or vegetable)
  • There are certain drugs with potential for neuromuscular blockade, which may precipitate weakness in MG, such as
    • Aminoglycosides
    • Beta-blockers, calcium channel blockers
    • Quinidine, procainamide
    • Chloroquine, penicillamine
    • Magnesium
  • Patients and caregivers must have the knowledge of myasthenic crisis, including its precipitating factors such as
    • Intercurrent infections
    • Surgical intervention
    • Stress
    • Pregnancy
    • Tapering of immunosuppressive medications
    • Drugs with potential for neuromuscular blockade
  • They should also be aware that medication excess may trigger cholinergic crises, patient should be familiar with sign and symptoms of this condition

 

Tips

  • Extremely variable clinical course
  • Ptosis and diplopia are the early findings in many patients
  • Ptosis may worsen with sustained upward gaze
  • If patients have difficulty in eating, doses can be taken ~30 mins before eating to optimize strength for chewing and swallowing
  • Some patients may develop fatigue when chewing food, they may need to rest for few moments before chewing can be resumed
  • Symptoms of MG may be exacerbated by exercise
  • MG patients with double vision may alternate the eye patch from one eye to the other while reading or watching TV
  • Hyperthyroidism and hypothyroidism can be associated with increasing myasthenic weakness

 

Expected outcome

  • There is no known cure for myasthenia gravis
  • Overall good, but highly variable
  • Patients who are diagnosed early and receive effective treatment have the best outcomes
  • Many patients achieve sustained remission

 

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References:

Core Resources:

  • Brust J, ed. Current Diagnosis and Treatment (Neurology). 2nd edition. New York: McGraw-Hill; 2011
  • Compendium of Pharmaceuticals and Specialties (CPS). Canadian Pharmacist association. Toronto: Webcom Inc. 2012
  • Day RA, Paul P, Williams B, et al (eds). Brunner & Suddarth's Textbook of Canadian Medical-Surgical Nursing. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2010
  • Foster C, Mistry NF, Peddi PF, Sharma S, eds. The Washington Manual of Medical Therapeutics. 33rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010
  • Gray J, ed. Therapeutic Choices. Canadian Pharmacists Association. 6th ed. Toronto: Webcom Inc. 2011
  • Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology. 11th ed. New York: McGraw-Hill; 2009
  • Longo D, Fauci A, Kasper D, et al (eds). Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2011
  • McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 49th ed. New York: McGraw-Hill; 2010
  • Howard JF, ed. Myasthenia Gravis: A Manual for the Health Care Provider. http://www.myasthenia.org/LinkClick.aspx?fileticket=S472fPAE1ow%3d&tabid=125 The Myasthenia Gravis Foundation of America (MGFA). Published 2008. Accessed 2012
  • Mehrizi M, Fontem RF, Gearhart TR, et al. Medications and Myasthenia Gravis (A Reference for Health Care Professionals) http://www.myasthenia.org/portals/0/draft_medications_
  • and_myasthenia_gravis_for_MGFA_website_8%2010%2012.pdf The Myasthenia Gravis Foundation of America (MGFA). Published August 2012. Accessed December 2012
  • Nicolle MW. Myasthenia Gravis. The Neurologist 2002;8: 2-21
  • Pagana KD, Pagana TJ eds. Mosby's Diagnostic and Laboratory Test Reference. 9th ed. St. Louis: Elsevier-Mosby; 2009
  • Rowland LP and Pedley TA, eds. Merritt's Neurology. 12th ed. Philadelphia: Lippincott Williams and Wilkins; 2010
  • Skidmore-Roth L. ed. Mosby's drug guide for nurses. 9th ed. St. Louis: Elsevier-Mosby; 2011
  • Skidmore-Roth L, ed. Mosby's nursing drug reference. 24th ed. St. Louis: Elsevier-Mosby; 2011
  • Online Resources:
    • National Guideline Clearinghouse (NGC)-Guidelines for treatment of autoimmune neuromuscular transmission disorders http://www.guideline.gov/content.aspx?id=23799

 

Online Pharmacological Resources:

  • e-Therapeutics
  • Lexicomp
  • RxList
  • Epocrates

 

Journals/Clinical Trials:

  • Benatar M, Burns T, Anthony V. Serological, pharmacological and electrophysiological tests for the diagnosis of myasthenia gravis. Cochrane Database of Systematic Reviews. 2010
  • DOI: 10.1002/14651858.CD008904
  • Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD002277
  • DOI: 10.1002/14651858.CD002277.pub4
  • Gajdos P, Chevret S, Toyka KV. Plasma exchange for generalised myasthenia gravis. Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002275
  • DOI: 10.1002/14651858.CD002275
  • Gomez AM, Van Den Broeck J, Vrolix K. Antibody effector mechanisms in myasthenia gravis-pathogenesis at the neuromuscular junction. Autoimmunity. 2010;43(5-6):353-70
  • Hantai D, Richard P, Koenig J et al. Congenital myasthenic syndromes Curr Opin Neurol 2004;17:539-551
  • Katzberg HD, Barnett C, Bril V. Predictors of response to immunomodulation in patients with myasthenia gravis. Muscle Nerve. 2012;45(5):648-652
  • Marx A, Willcox N, Leite MI et al. Thymoma and paraneoplastic myasthenia gravis. Autoimmunity. 2010;43(5-6):413-27
  • DOI: 10.3109/08916930903555935
  • Meriggioli MN. Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci. 2009;26:94-108
  • Mehndiratta MM, Pandey S, Kuntzer T. Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database of Systematic Reviews. 2011, Issue 2
  • DOI: 10.1002/14651858.CD006986.pub2
  • Okumura M, Inoue M, Kadota Y et al. Biological implications of thymectomy for myasthenia gravis. Surg Today. 2010;40(2):102-7
  • Sanders DB, Hart IK, Mantegazza R et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology. 2008;71(6):400-406
  • Schneider-Gold C, Gajdos P, Toyka KV, et al. Corticosteroids for myasthenia gravis. Cochrane Database of Systematic Reviews 2005, Issue 2
  • DOI: 10.1002/14651858.CD002828.pub2
  • Skeie GO, Lunde PK, Sejersted OM. Myasthenia gravis sera containing antiryanodine receptor antibodies inhibit binding of [3H]-ryanodine to sacroplasmic reticulum. Muscle Nerve. 1998;21: 329-335
  • Vincent A, Leite MI. Neuromuscular junction autoimmune disease: muscle specific kinase antibodies and treatments for myasthenia gravis. Curr Opin Neurol. 2005;18(5):519-25
  • Yamamoto AM, Gajdos P, Eymard B, et al. Anti-titin antibodies in myasthenia gravis: tight association with thymoma and heterogeneity of nonthymoma patients. Arch Neurol. 2001;58(6):885-90
  • Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology. 2007; 68 (11):837-41

 

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Reviewers

EXPERT REVIEWER:
Mark Tarnopolsky, MD, PhD, FRCPC, Prof. of Pediatrics (Neuromuscular & Neurometabolic Disease), Hamilton Health Sciences-McMaster Children’s Hospital, McMaster University, ON Canada
.......................................... PHARMACY REVIEWER:
Alison Alleyne, Pharm.D, Clinical Pharmacy Specialist, Neurosciences, Lower Mainland Pharmacy Services, Surrey, BC Canada

 
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