Myasthenia Gravis (MG)

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 ophthalmic and bulbar muscles.

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 NMJ and muscle antibodies found in association with MG:
  • Anti-lipoprotein-related protein 4 (LRP4) antibodies
  • Antibodies against agrin were identified in patients both with anti-AChR antibodies and in seronegative patients
  • Anti-striated muscle antibodies (StrAbs)

• A serological aid in the diagnosis of thymoma, particularly in younger patients (<45 y/o) with MG
• Can be used for disease monitoring the course. Persistence or recurrence of high titers of StrAbs may be indicative of post-thymectomy residual tumor or thymoma recurrence
• Anti-titin (serological marker for MG  age <60 years)
• Anti-ryanodine antibodies also detectable

Epidemiology

• Female: male (overall 2:1), but ~3:1 (F: M) in younger and 1:1 in older adults
• Age of onset: Women are typically affected younger age (<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 the US (MG Foundation of America)

Types of Myasthenia Gravis

Myasthenia Gravis is classified according to the 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 of age (<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 of age (<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 diseases 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.

Pathophysiology

Normal neuromuscular junction (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 overstimulation 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 over time.

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 nasogastric 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)

Differential Diagnosis

CNS pathology:

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

Lambert-Eaton myasthenic syndrome (LEMS):

• Autoimmune disorder characterized by weakness in proximal groups of leg and arm muscles due to the 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 electromyography (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

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 eyelids 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 ophthalmoparesis 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 appear 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, their 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 the 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 repeat 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).

Treatment

Clinical Trials

• IV immunoglobulin in patients with myasthenia gravis

• Phase 3, randomized trial of mycophenolate mofetil in myasthenia gravis

Pipeline Agents

• Phase II trial of methotrexate in myasthenia gravis

Physician Resources

1. Tips for Patient Care

General

• Encourage compliance with medications
• Recognize the 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
  • Eyepatch may help those with diplopia; advice 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 the 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 the 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 the disease, and progression of the 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 the 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 knowledge of the 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, the 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 a 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

References

Core Resources:

• Brust J, ed. Current Diagnosis and Treatment (Neurology). 2nd edition. New York: McGraw-Hill; 2011
• Choi Decroos E, Hobson-Webb LD, Juel VC, Massey JM, et. al. Do acetylcholine receptor and striated muscle antibodies predict the presence of thymoma in patients with myasthenia gravis? Muscle Nerve. 2014; 49:  30-4
• 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. 18thed. 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
• Sanders DB, Wolfe GI, Benatar M, et al., International consensus guidance for management of myasthenia gravis. Executive summary. 2016; 87 (4)
• Skeie GO1, Aarli JA, Gilhus NE. Titin and ryanodine receptor antibodies in myasthenia gravis. Acta Neurol Scand Suppl. 2006; 183:19-23
• Skidmore-Roth L. ed. Mosby’s drug guide for nurses. 9th ed. St. Louis: Elsevier-Mosby; 2011
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• Yamamoto AM, Gajdos P, Eymard B, et al. Anti-titin antibodies in myasthenia gravis: tight association with thymoma and heterogeneity of non-thymoma patients. Arch Neurol. 2001; 58: 885-90
• 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