Myasthenia Gravis

Author(s): Chiawen Lucy Liang, MD

Originally published:11/11/2011

Last updated:04/07/2016

1. DISEASE/DISORDER:

Definition

Myasthenia Gravis (MG) is an autoimmune disorder affecting nicotinic acetylcholine receptors (AChR) of the postsynaptic neuromuscular junction (NMJ). It is clinically characterized by fluctuating weakness without sensory or autonomic dysfunction, fatigability, and a predilection for oculobulbar musculature.

Etiology

  • Idiopathic in most cases.
  • T-cells are primed in the thymus to bind to AChR and stimulate B cells.
  • B cells then differentiate into plasma cells, making immunoglobulin (IgG) antibodies to AChR.
  • Thymic abnormalities are commonly associated with MG. 70% of MG patients have thymic hyperplasia and 10% have thymoma. 55% of patients with a thymoma have MG.1
  • Penicillamine may induce immune-mediated MG, which remits on withdrawal of drug.
  • Transient neonatal autoimmune MG occurs in newborns of mothers with MG. Antibodies to AChR are transferred passively through the placenta.

Epidemiology including risk factors and primary prevention

  • Incidence is between 1 and 9 per million.1
  • Prevalence is between 25 and 142 per million.1
  • Bimodal peak age of onset: 20-35 and 70-75.1
  • Female to male ratio about 6:4.2

Patho-anatomy/physiology

  • Anti-AChR IgG antibodies bind to AChR at the post-synaptic NMJ. This causes decreased binding of the acetylcholine on AChR by multiple potential mechanisms.
    • Physically blocking the AChR and possibly preventing conformation change necessary to carry out function.
    • Endocytosis of AChR-autoantibody complexes, accelerated by cross-linking of antibodies.
    • Complement-mediated destruction of the post-synaptic membrane.
    • Flattened post-synaptic NMJ with fewer invaginations and thus less surface area and increased synaptic space.
  • All above mechanisms decrease acetylcholine on AchR binding, reducing the size of the resultant end-plate potential and decreasing the likelihood of crossing the necessary threshold voltage to cause an action potential.
  • The intermittent failure to reach action potential has electrophysiological and clinical effects: blocking on single fiber EMG (SFEMG), fluctuating motor unit action potentials (MUAP), decremental response on slow repetitive stimulation and weakness1.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

  • Initial symptoms may be transient, but may become generalized and persistent.
  • Symptoms may be limited to only the ocular muscles. 15-40% of MG patients with isolated oculomotor symptoms will not develop generalized disease. Those who develop generalized disease will usually do so in the first 2 years.
  • Refractory MG may present with ventilator insufficiency along with dysphagia.
  • Spontaneous remission is rare.
  • Transient neonatal myasthenia occurs within 3 days of life and lasts about 18-20 days.

Specific secondary or associated conditions and complications

  • MG is associated with other autoimmune diseases: rheumatoid arthritis, lupus, Sjogren syndrome, ulcerative colitis, sarcoidosis, Addison’s disease, and hyper- or hypo-thyroidism.2
  • Pregnancy may improve, worsen, or have no impact on symptoms.
  • Transient neonatal myasthenia occurs in 10% of neonates born to mothers with MG.

2. ESSENTIALS OF ASSESSMENT

History

  • Painless fluctuating weakness and fatigue involving any voluntary muscles.
  • Weakness may be focal, multifocal, or diffuse, affecting voluntary skeletal muscles, especially the bulbar and proximal limb muscles.
  • Common bulbar symptoms include ptosis, diplopia, dysarthria, dysphagia, difficulty chewing, inability to fully close the eyelids, whistle, or puff out the cheeks.
  • Sensory, autonomic fibers, bowel and bladder are spared.
  • Exacerbating factors include exercise, warmth, infections, anxiety, stress, and menses.
  • Transient neonatal myasthenia is characterized by a weak cry, difficulty feeding, and respiratory difficulty.

Physical examination

  • Ptosis: in some patients seen only with sustained upward gaze.
  • Dysconjugate gaze and diplopia due to extraocular muscle weakness.
  • Weakness with tongue protrusion, jaw opening, palate elevation, and neck flexion/extension.
  • “Myasthenic snarl” (horizontal smile) with failure to withdraw the corners of the mouth.
  • Fatigue with proximal limb weakness after sustained repetitive resistive manual testing, usually symmetric.
  • 10% of cases may present focally with distal limb weakness, foot or wrist drop, or head drop.
  • Vital capacity (VC) can be estimated by having the patient count out loud after taking a deep breath: the counted number multiplied by 100 equals the VC in cc.
  • Normal sensory exam.

Laboratory studies

  • AChR antibodies: consist of binding, blocking, modulating antibodies
    • Overall, AChR antibodies are 80-90% sensitive in generalized MG and 50% in ocular MG.
    • False positive in thymoma without MG, Lambert-Eaton myasthenic syndrome (LEMS), lupus, rheumatoid arthritis, autoimmune liver disease.
    • AchR modulating antibody is associated with incidence of thymoma.
  • Muscle specific tyrosine kinase (MuSK) antibody is found in 30-50% of AchR antibody seronegative MG, and is associated with facial, oculobulbar, neck and respiratory symptoms.
  • Striational antibody, targeting titin or ryanodine receptors, is found in 30% of adult MG. This is also associated with thymoma. Rise in titers may indicate recurring thymoma post thymectomy. 3
  • Normal creatine kinase (CK).

Imaging

Chest CT scan is useful to evaluate for presence of thymoma.

Supplemental assessment tools

  • Electrodiagnostic study:
    • Normal motor and sensory nerve conduction studies. In contrast, in the pre-synaptic NMJ disorder, LEMS, the compound muscle action potential (CMAP) amplitude is usually low or borderline low at rest.
    • Fibrillation and positive sharp waves are uncommon but may occur.
    • Due to intermittent junctional blockade and loss of individual myofibers, short duration, low amplitude motor unit action potential (MUAP) with early recruitment may be seen and the MUAP morphology fluctuates on triggered analysis, which are not seen in muscle disorders. Distal as well as proximal muscles should be examined, including biceps, triceps, and deltoid, which are involved in MG.
    • Slow repetitive nerve stimulation (RNS) with 2 or 3 Hz can be performed at abductor digiti minimi, biceps, deltoid, trapezius, or the nasalis. In MG the yield of abnormal findings will be greater with evaluation of facial or proximal muscles than distal musculature. An abnormal decrement of >10% of CMAP amplitude or area can be elicited at baseline, and after 1 minute of exercise due to postactivation exhaustion. A normal study does not rule out MG.
    • Post-exercise facilitation with 10 seconds of maximal voluntary contraction may normalize the decrement created at baseline by slow repetitive stimulation. In contrast, in LEMS, there is more than 100% increment from baseline seen after facilitation.
    • Single fiber electromyography (SFEMG), performed at extensor digitorum communis, nasalis, or frontalis, is the most sensitive test for MG (>95%) but is non-specific.
  • Edrophonium (Tensilon) is a short-acting acetylcholinesterase (AChE) inhibitor, which increases ACh availability at the NMJ and increases strength for several minutes. This is used as bedside test for NMJ disorder, but it is not as sensitive nor as specific as the serological test and RNS/SFEMG for MG.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

  • Thymectomy is recommended in generalized MG with thymoma under age 55. MG Report of the Quality Standards Subcommittee of the American Academy of Neurology:
    “…The benefit of thymectomy in non-thymomatous autoimmune myasthenia gravis has not been established conclusively.”4
  • Ocular myasthenia:
    “Given the absence of evidence, it is not possible to make any evidence-based recommendations regarding the effects of cholinesterase inhibitor, corticosteroids, or other immunosuppressive agents in improving the symptoms of ocular myasthenia.”5
  • Plasmapheresis in MG:
    “Because of the lack of randomized controlled studies with masked outcomes, there is insufficient evidence to support or refute the efficacy of plasmapheresis in the treatment of myasthenic crisis (Level U) or MG.”6

At different disease stages

  • Ocular symptoms
    • Many recommend symptomatic treatment with pyridostigmine or eye crutches for ptosis, and patches or prism lenses for diplopia.
    • The benefit and risk of immunomodulating agents for ocular symptoms are controversial.
  • Generalized symptoms
    • Initiate with pyridostigmine for acute symptomatic control.
    • Immunomodulating agents are usually used. Steroids are ordered most commonly, though steroid-sparing agents are commonly used in combination with or instead of steroids (azathioprine, cyclosporine, mycophenylate mofetil, methotrexate, rituximab and others). Pyridostigmine, steroids and a steroid-sparing immunomodulator are frequently started simultaneously, with the goal of weaning steroids to avoid long-term complications.7
  • Myasthenic crisis with respiratory failure requires immediate intensive care unit (ICU) monitoring and possibly mechanical ventilation (monitor negative inspiratory force [NIF] and VC). Plasma exchange should be initiated, and is more effective than IVIG during crisis. IV methylprednisolone or oral prednisone may be started at the same time but used with caution due to initial exacerbation of symptoms.
  • Modified swallow evaluation for dysphagia, and consider thickened liquid to prevent aspiration pneumonia. Consider modified consistency diet for bulbar/chewing weakness.

Coordination of care

Interdisciplinary approach including neuromuscular medicine, physical medicine and rehabilitation, as well as physical and occupational therapy, speech/swallow therapy, and respiratory therapy.

Patient & family education

  • Long-term complications of immunomodulating agents.
  • Steroid associated risks include: infection, diabetes, hypertension, glaucoma, osteoporosis, peptic ulcer disease, myopathy, and aseptic necrosis of joint.

Emerging/unique Interventions

IMPAIRMENT-BASED MEASUREMENT

Myasthenia Gravis Foundation of America (MGFA) Clinical Classification:

Class I ‑ Any ocular muscle weakness or weakness of eye closure, all other muscle strength is normal

Class II ‑ Class I plus mild weakness affecting muscles other than ocular muscles.

Class IIa ‑ Predominantly affecting limb, axial muscles, or both.

Class IIb ‑ Predominantly affecting oropharyngeal and respiratory muscles.

Class III ‑ Class I plus moderate weakness affecting muscles other than ocular muscles. Also divided into IIIa and IIIb.

Class IV ‑ Class I plus severe weakness affecting other than ocular muscles. Also divided into IVa and IV b.8

MEASUREMENT OF PATIENT OUTCOMES

Quantitative MG score is an objective evaluation for disease severity as recommended by MGFA, with 13 items including evaluation of ocular, bulbar, respiratory, neck, and limb function.8

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

  • MG is a chronic disease with a low spontaneous remission rate.
  • MG has a characteristic clinical profile with fatigable and fluctuating weakness, usually of oculobulbar and proximal musculature, in the absence of sensory or autonomic symptoms.
  • Patients need to recognize respiratory insufficiency which require immediate hospitalization and close monitoring.
  • Possible exacerbation while starting steroids before improvement can be seen; particularly important in myasthenic crisis.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

NA

5.GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

Currently, there is no established standard for thymectomy in non-thymomatous MG, for treatment of ocular MG or in the use of plasmapheresis in MG. However, there is an ongoing active clinical trial to study if thymectomy combined with prednisone therapy is more beneficial in treating non-thymomatous myasthenia gravis than prednisone therapy alone.9

REFERENCES

  1. Amato A, Russell J. Neuromuscular Disorders. 2nd Ed. McGraw-Hill, 2015.
  2. Shah AK. “Myasthenia Gravis.” eMedicine Clinical Knowledge Base. 07 October 2015. http://reference.medscape.com. Accessed 18 October 2015.
  3. Juel VC, Massey JM. Review: Myasthenia Gravis. Orphanet Journal of Rare Disease 2007 (2): 44
  4. Gronseth GS, Barohn RJ. Practice parameter: Thymectomy for autoimmune myasthenia gravis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology.2000 (55) :7-15.
  5. Benatar M, Kaminski HJ.  Practice parameter: The medical treatment of ocular myasthenia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Prepublished online April 25, 2007; DOI 10.1212/01.wnl.0000263481.14289.90
  6. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: Plasmapheresis in neurologic disorders. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011; (76):294‑300.
  7. Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for Myasthenia Gravis (Review). Cochrane Collaboration, 2009.
  8. Jaretzki A, Barohn RJ, Ernstoff RM, et al. Myasthenia Gravis Recommendation for Clinical Research Standards. Neurology. 2000; (55):16-23
  9. Identifier NCT00294658 at clinicaltrials.gov

Original Version of the Topic:

Chiawen Lucy Liang, MD. Myasthenia Gravis. Publication Date: 2011/11/11.

Author Disclosure

Chiawen Lucy Liang, MD
Nothing to Disclose

 

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