Myasthenia Gravis (MG)

Review article for non-neurologist

A. Epidemiology

• Most common primary neuromuscular transmission disorder.
• It is acquired autoimmune disorder
• Caused by antibodies that target the post-synaptic membrane.
• MG is a rare neurological disease and pediatric MG is even more uncommon.
• MG is not inherited or contagious.
• Can occur at any age, including childhood.
• Mostly impact young adult women (<40) and older men (>60) with bimodal distribution.
• Around 10% of cases are pediatric, which is defined as onset before age 18.

B. Symptoms of MG

Usually present with painless, fatigable weakness of voluntary muscles.

Onset of MG may be sudden presenting with acute weakness and exhaustion, ocular muscles, and bulbar muscle dysfunctions, as well as limb and respiratory muscles weakness.

Sometime can present with ocular muscle weakness only with ptosis, diplopia and opthalmoplegia and then gradually spread to the limbs and truck.

• Ocular symptoms such as ptosis (asymmetrical fatigable) diplopia
• Changes in facial expressions (weak smile or a “myasthenic snarl”)
• Difficulty swallowing (especially liquid)
• Jaw fatigue when chewing
• Dyspnea
• Dysarthria (Nasal speech after prolonged speaking)
• Dysphonia
• Weakness of arms, hands, fingers, legs, and neck muscles (weakness tends to be more proximal than distal)
• Neck flexion is usually more affected (Dropped head syndrome)
• Fatigable of muscles
• The upper limbs often being more severely affected than the lower limbs
• Characteristic of the disease is its fluctuating course through the patient’s life.
• Weakness and fatigue tend to vary from day to day, often strongest in the morning after a full night of sleep, and weakest in the evening.
• Overexertion, emotional stress, infections, extreme heat, menstruation, and pregnancy and some of the medications might lead to increased weakness in MG
• There are no autonomic symptoms like palpitations, bowel, or bladder disturbances in MG because it only involves the nicotinic cholinergic receptors.

C. MG related antibodies

Fig.1: NMJ with AChR, MuSK and LRP4 as target for directly pathogenic antibodies

1. The most common antibodies (Abs) found in MG patients are directed against the nicotinic acetylcholine receptor (AChR), defining the classic seropositive MG phenotype. These Abs are present in about 85% of patients with generalized MG and in about 50% of patients with ocular MG.
   * 100% specific
   * 90% sensitivity in Generalized Myasthenia
   * 50-70 % sensitivity in Ocular Myasthenia
   * False positives are very rare and may be seen in Lambert Eton syndrome, GVHD, Autoimmune liver disease, RA.
2. Anti-muscle-specific tyrosine kinases (MuSKs) are found in approximately 5% of patients with seronegative AChR MGA. The MuSK protein is involved in the helping to organize AChR on the muscle surface and in the maintenance of the NMJ.
   * Associated with more severe disease
   * Does not responds to Acetylcholinesterase Inhibitors
3. In approximately 15% of patients with generalized MG and 50% of patients with ocular MG, both AChR and MuSK antibodies were absent. These patients are referred to as double-seronegative MG (dSnMG).
4. Within the dSnMG group, 2–27% of patients have Abs direct to the low-density lipoprotein receptor-related protein 4 (LRP4).
   * The specificity of antibodies against agrin, LRP4, or cortactin is less well defined
   * present on the postsynaptic membrane
5. The anti-striated muscle (anti SM) Ab (refers to a class of antibodies against components of skeletal muscle including titin, the ryanodine receptor, myosin, and
6. alpha actin –> non-pathogenic

D. Pathophysiology

The pathophysiologic mechanisms in MG are dependent on the type of antibodies present.

In AChR MG, the antibodies are of the IgG1 and IgG3 subtype. They bind to the nicotinic ACh receptor present in the postsynaptic membrane of the skeletal muscles and activate the complement system leading to the formation of the membrane attack complex (MAC). MAC degrade and block the AChR receptors in postsynaptic membrane.

In MuSK MG and LPR4 MG, the antibodies are of the IgG4 subtype They bind to the Agrin–LRP4–MuSK protein complex in the NMJ. This leads to a reduced number of nicotinic ACh receptors.

The weakness is more pronounced with the repeated use of a muscle group since it causes depletion of the ACh store in the NMJ.

Fig. 2: Pathophysiology of MG

E. Pathogenesis

Fig 3: Pathogenesis and clinical findings of MG

F. Classification of MG

Etiological Classification of MG

1.Congenital myasthenic syndromes (do not weaken respiratory muscles)
2.Acquired myasthenic syndrome
A. Autoimmune

• Pre-synaptic: Lambert Eaton myasthenic syndrome
• Post-synaptic: AChR-MG and MuSK-MG
• Neonatal (passive transfer of maternal antibodies-AChR-MG)
• Drug induced: D-Penicillamine

B. Toxic

• Botulism
• Neuroparalytic envenomation (snake bites or tick bites)
• Organophosphate and carbamate poisoning
• Overdose of anti-cholinesterase

Clinical Classification of MG

• Class I: Involves any ocular muscle weakness only, including weakness of eye closure. All other muscle groups are normal.
• Class II: Involves mild weakness of muscles other than ocular muscles. Ocular muscle weakness of any severity may be present.
• Class II A and B
• Class III: Involves muscles other than ocular muscles moderately. Ocular muscle weakness of any severity can be present.
• Class III A and B
• Class IV: Involves severe weakness of affected muscles. Ocular muscle weakness of any severity can be present.
• Class IV A and B
• Class V: Involves intubation with or without mechanical ventilation, except when employed during routine postoperative management.
• A: Mainly affecting the limbs or muscles around the head, neck, and spine.
• B: Mainly affecting muscles in the throat, and respiratory system

G. Association of MG and Thymoma/Thymic Hyperplasia

The type of thymic pathology is associated with age at onset, clinical manifestations, and serologic status of MG

Thymic hyperplasia is present in 50% to 80% of patients with AChR-positive early-onset MG, less common in late-onset MG and is rare in MuSK MG

A thymoma, found in 10% to 20% of all cases of MG, more common with onset after 40 years of age where it occurs in 25% to 35% of cases

Thymoma related MG is usually more severe and less likely to be ocular type

The vast majority of thymoma related MG cases have positive AChR antibodies, so AChR negativity essentially rules out a thymoma

A thymoma is almost never found in MuSK MG.

H. Diagnosis

The diagnosis of MG is mostly clinical. The laboratory investigations and procedures usually support in confirming the clinical findings.

Clinical examination pearls

1. Single count breath test (SCBT)
   • Much simpler than the functional respiratory tests
   • It consists in making the patient count aloud after inhaling deeply, then counting at two counts per second
   • The result corresponds to the number reached with a normal voice, without having to take a breath
   • It is correlated with vital capacity in myasthenia gravis
   • A threshold count of ≥ 25 as consistent with normal respiratory muscle function
2. Sustained leg elevation
   • Sustain elevation of one leg while lying supine for 90 seconds.
   • Patient can no longer hold leg up or weakness become more apparent with subsequent manual testing.
3. Buttock first maneuver
   • Repeated rising from chair without use of arms (up to 20 times)
   • Fatigue after several attempts.
   • Early or mild weakness may cause exaggerated lean forward

Ice-pack Test:

• An ice-pack placed over the eye for 2-5 minutes
• Then, an assessment for any improvement in ptosis
• Not for the evaluation of extraocular muscles

Edrophonium (Tensilon) Test:

• Edrophonium is a short-acting acetylcholinesterase inhibitor
• Increases the availability of ACh in the NMJ
• Particularly useful for ocular MG
• Given intravenously 1-2 mg test dose and can give maximum of 5-6mg and observe for improvement in the symptoms of ptosis or diplopia within 1 minutes after injection. Effects last <5 minutes
• It has a sensitivity of 71% to 95% for MG diagnosis

Serologic Tests

1. Anti-AChR Ab
   • Very specific, and it confirms the diagnosis in patients with classical clinical findings
   • Present in 80% of generalized MG and only 50% with pure ocular MG
2. Anti-Musk Ab
   • Present in 5% to 10% of MG
   • Sporadically both anti-AChR and anti-MuSK antibodies can present in the same patient
3. Seronegative and Anti-LRP4 Abs
   • The 3% to 50% of the remaining patients are seronegative or positive for anti-LRP4 antibodies
4. Anti SM Ab
   • Anti-striated muscle antibodies are present in 30% of MG patients
   • More useful as a serologic marker for thymoma, especially in younger patients

Electrophysiologic Tests

• Should be use in patients who are seronegative for antibody testing
  • the repetitive nerve stimulation (RNS) test 10% or more decrease in the EPSP (Excitatory Postsynaptic Potential) between the first and fifth stimulus is diagnostic of MG.
  • single-fiber electromyography (SFEMG) increase jitters
• Both the tests assess for conduction delays in the NMJ
• Routine nerve conduction studies are usually performed to determine the functioning of the nerves and muscles before RNS and SFEMG tests

SFEMG is the most sensitive among the diagnostic tests for MG

Imaging

• Chest CT) or MRI — > to assess for thymoma
• In pure ocular MG — > MRI of orbits and the brain to evaluate for any localized mass lesions

Other Laboratory Tests

• Myasthenia gravis commonly coexists with other autoimmune disorders
• ANA, RF, and thyroid functions should be done

I. Management

1.Symptomatic treatment: Anti-cholinesterase drugs

Do not affect the pathological process

Slow the breakdown of acetylcholine at the NM junction and improve NM transmission and increase muscle strength

In early or mild disease –> significant and rapid improvementin muscle

In longstanding or severe disease –> insufficient and there may be minimal clinical effect

(A)Pyridostigmine

• 60 mg PO 3-4 times a day and can increase to dose of 120 mg 3-4 times a day (max 480mg) based on symptoms
• Renal impairment reduced clearance of pyridostigmine and adjust the dose
• Generally well-tolerated, side effects are dose dependent
• May need to reduce the dose or slower titration avoid side effects
• Most side effects arise from the action of pyridostigmine at non-NMJ muscarinic peripheral synapses and include gastrointestinal disturbance (abdominal cramps, bloating, diarrhea, frequency, nausea), urinary frequency, hypotension, bradycardia, sweating, salivation, lacrimation, increased bronchial secretions
• Some elderly patients sensitive to the cardiac side effects syncope
• Some asthmatic patients increased bronchospasm

(B)Neostigmine

• An alternative acetylcholine esterase inhibitor
• Only be given via the subcutaneous route in MG and not intravenously
• 1 mg of neostigmine = 60 mg of pyridostigmine

2. Immuno-modulatory treatment

Suppress autoimmune response

Slow the progression course

2.1. Corticosteroids

• Prednisolone the main immunomodulatory therapy in the long-term management of MG patients
• Will require long term oral therapy (discuss potential side effects)
• Start with 5mg daily increase every third dose (day) by 5mg until we achieve stability in MG symptoms and significant improvement
• Max dose: 50 mg daily
• Marked improvement or complete relief of symptoms ->75% patients
• Usually seen improvement in first 6-8 weeks
• About 35% become weaker temporarily after starting the Rx (usually last for 6-7 days)

2.2. Steroid Sparing Immunosuppressive Agents

• Treat newly-diagnosed MG patients with steroids alone first
• Use immunosuppressive agents as first line in patients with absolutely contraindications to use steroids
• Add A steroid-sparing immunosuppressive agent (if the patient relapsed while reducing their steroid dose)
• Add early if the patient has pre-existing comorbidities such as diabetes, significant depression (with steroids potentially exacerbating their mood), osteoporosis, leg ulcerations etc.

(A)Azathioprine: use commonly in MG

• Dose ;2.5-3.5 mg /kg once a day or 25mg daily increase weekly by 25mg (max dose: 250 mg a day or 2-3 mg/kg per day in 2-3 divided dose)

(B)Mycophenolate mofetil (MMF):

• dose of 500 mg 2 times daily (max dose:2.5 gram a day in 2 divided dose or 1.5 to 2 gram per day

(C)Cyclosporine:

• Dose:2.0 to 2.5 mg/kg PO BD dose (Max dose: 3.5-5 mg/kg/day)
• the most potent immunosuppressive agent
• not teratogenic
• significant side effects including hypertension, alteration in GFR, nephrotoxicity, tremor, and hirsutism (in females)
• avoid in older patients

(D)Tacrolimus: similar efficacy with a similar side effect profile as ciclosporin (dose: 3 mg per day)

(E)Methotrexate: oral weekly dose (20 mg per week) and folic acid supplementation 5 mg daily

3. Biological Monoclonal antibodies

(A) Rituximab: monoclonal antibodies to B-cell CD20

* no clear recommended guideline
* either weekly doses of 375 mg/m2 for 4 consecutive weeks or two doses of 1 g, with a 2-week interval between them
* Repeated cycles may be administered at a 3–6-month interval

(B) Eculizumab: Complement cascade blocker

• 900 mg IV every week for the first 4 weeks, followed by 1200 mg IV at week 5, then 1200 mg IV every 2 weeks

(C) Efgartigimod: antibody fragment target to neonatal Fc receptor (FcRn)

• Weigh< 120 kg: 10 mg/kg IV/SC once weekly for 4 weeks • Weight >120 kg: 1200 mg IV/SC once weekly for 4 weeks
• Subsequent dose: base on the response. (not to be given within 5 weeks of cycle)

(D) Rozanolixizumab: monoclonal antibody target to neonatal Fc receptor (FcRn)

• Both for AChR or MuSK) antibodies positive generalized MG
• Less than 50 kg: 420 mg (3 mL) as a subcutaneous infusion once weekly
• 50 kg to less than 100 kg: 560 mg (4 mL) as a subcutaneous infusion once weekly
• 100 kg and above: 840 mg (6 mL) as a subcutaneous infusion once weekly

4. Treatments Used in Severe MG Exacerbation or Crisis

(A)Intravenous Immunoglobulin (IVIg)

• IVIg has a rapid therapeutic onset
• Symptom improvement within days, maximal response 7–10 days after therapy initiation
• Can be used in situation where PLEX is unavailable or contraindicated
• Treatment effects lasting 1–2 months
• Dose: for an acute MG exacerbation 2 gram/kg divided over a period of 3–5 days,
• Side effects include headache, rash, myalgia, chills, fever, shortness of breath, and nausea
• Check serum IgA level before IVIg Rx. (should not use in IgA deficit patients)
• Caution in older patients with abnormal renal function at baseline
• Maintenance IVIg Rx:

• The most commonly used maintenance dose 0.4 g/kg given as a single dose every 3–6 weeks
• In patients who have failed to achieve optimal symptom control on conventional immunosuppressants
• To stabilize patients before surgery
• Bridging therapy during the initiation of high-dose steroids to minimize or prevent the paradoxical worsening of underlying bulbar or respiratory weakness

(B)Plasma Exchange (PLEX)

* Directly removes Anti-AChR antibodies
* Frequently used as one of the first line acute treatment modalities (the other being IVIG) in MG crisis or in preparation for surgical interventions such as thymectomy in MG patients with bulbar and respiratory symptoms
* More rapid response compared to IVIg
* More effective in MuSK positive MG patient
* Administration 1 plasma volume for 5 sessions in alternative days

The choice between PLEX vs. IVIG in the acute treatment of MG exacerbation and crisis partly depends on the expertise of the treating facility in the administration of PLEX, the cost and patient’s preference

5.Thymectomy

Indications:
• Any subtypes of MG with evidence of thymoma.
• Non-thymomatous n-AChR MG, especially in patients aged 15 to 50 years, performed 1-2 years of disease onset.[14] • Seronegative non-thymomatous MG

Not recommended for the non-thymomatous MuSK MG and non-thymomatous ocular MG without secondary generalization

J. Myasthenic crisis
• A life-threatening neurological emergency
• Respiratory insufficiency may require invasive or non-invasive ventilation
• Respiratory muscle and bulbar weakness with upper airway collapse
• 15-20% of MG experience at least one crisis
• 15-20% usually occur with the first 2-3 years of disease course
• No specific trigger is found in 30-40% of patients
• Immediate interventions airway safety and management as well as removal of triggers if there any
• PLEX is preferred over IVIg as treatment of choice
• Mortality rate <5% and influenced by patient’s age and other comorbidities

With AChR Abs
• Muscle weakness tends to initially affect intercoastal and accessary muscles and then diaphragm
• Inspiratory function vital capacity (VC) and negative inspiratory force (NIF)
• Expiratory function positive expiratory force (PEF)
• Elective intubation is considered:
* FVC < 15
* NIF 0 to 30
* PEF <40 cm H2O

With MuSK Abs
• Commonly present with bulbar muscle weakness (dysphagia, nasal speech, nasal regurgitation, and jaw, bifacial and tongue weakness)
• Respiratory muscle weakness occurs later

Fig. 4: Overall treatment strategy of myasthenia MG

K. Drugs associated with worsening of MG

1.To avoid if possible
1.Antibiotics
• Tetracycline
• Macrolide antibiotics
• Fluroquinolones
• Aminoglycosides

2.Botulinum toxin
3.D-penicillamine
4.Magnesium (especially if given IV)
5.Iodinated radiological contrast agents
6.Chloroquine and Hydroxychloroquine
7. Deferoxamine

2.To be use with caution (if benefit> risk)
1.Beta blockers (Metoprolol, Labetalol etc.)
2.Calcium channel blockers (Diltiazem, Clevidipine etc.)
3.Class 1A anti-arrhythmic (Quinidine, Procainamide etc.)
4.Neuromuscular blockers (Vecuronium, Succinylcholine etc.)
5.Corticosteriods (transient worsening within first two weeks)

Table 1: Comparison of AChR MG and MuSK MG

References:

1. Alhaidar MK, Abumurad S, Soliven B, Rezania K. Current Treatment of Myasthenia Gravis. J Clin Med. 2022 Mar 14;11(6):1597. doi: 10.3390/jcm11061597
2. Dresser L, Wlodarski R, Rezania K, Soliven B. Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations. J Clin Med. 2021 May 21;10(11):2235. doi: 10.3390/jcm10112235.
3. Farrugia ME, Goodfellow JA. A Practical Approach to Managing Patients With Myasthenia Gravis-Opinions and a Review of the Literature. Front Neurol. 2020 Jul 7; 11:604. doi: 10.3389/fneur.2020.00604.
4. Gilhus NE. Myasthenia Gravis. N Engl J Med. 2016 Dec 29;375(26):2570-2581. doi: 10.1056/NEJMra1602678.
5. Jaydeep M Bhatt. Myasthenia Gravis: Treatment Update 2024. Proceeding from American Academy of Neurology 2024 Annual Meeting.
6. Mishra AK, Varma A. Myasthenia Gravis: A Systematic Review. Cureus. 2023 Dec 6;15(12): e50017. doi: 10.7759/cureus.50017

Author InformationThar Thar Oo
MBBS, MD, MPH, FAAN
Senior Consultant Neurologist