Myasthenia Gravis

Myasthenia gravis (MG) is a neuromuscular disorder characterized by weakness and fatigability of skeletal muscles. The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune attack..

Pathophysiology

Myasthenia1

At the neuromuscular junction acetylcholine (ACh) is synthesized in the motor nerve terminal and stored in vesicles (quanta). When an action potential travels down a motor nerve and reaches the nerve terminal, ACh from 150 to 200 vesicles is released and combines with AChRs that are densely packed at the peaks of postsynaptic folds. When ACh combines with the binding sites on the subunits of the AChR, the channel in the AChR opens, permitting the rapid entry of cations, chiefly sodium, which produces depolarization at the end-plate region of the muscle fiber. If the depolarization is sufficiently large, it initiates an action potential that is propagated along the muscle fiber, triggering muscle contraction. This process is rapidly terminated by hydrolysis of ACh by acetylcholinesterase (AChE), which is present within the synaptic folds, and by diffusion of ACh away from the receptor.

In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane.These changes result in decreased efficiency of neuromuscular transmission. Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of transmission at many neuromuscular junctions results in weakness of muscle contraction.The amount of ACh released per impulse normally declines on repeated activity (termed presynaptic rundown). In the myasthenic patient, the decreased efficiency of neuromuscular transmission combined with the normal rundown results in the activation of fewer and fewer muscle fibers by successive nerve impulses and hence increasing weakness, or myasthenic fatigue.

The neuromuscular abnormalities in MG are brought about by an autoimmune response mediated by specific anti-AChR antibodies. An immune response to muscle-specific kinase (MuSK), a protein involved in AChR clustering at neuromuscular junctions, can also result in myasthenia gravis, with reduction of AChRs. How the autoimmune response is initiated and maintained in MG is not completely understood, but the thymus appears to play a role in this process. The thymus is abnormal in 75% of patients with MG; in 65% the thymus is “hyperplastic,” with the presence of active germinal centers detected histologically, though the hyperplastic thymus is not necessarily enlarged. An additional 10% of patients have thymic tumors (thymomas).

Clinical Featur

It affects individuals in all age groups, but peaks of incidence occur in women in their twenties and thirties and in men in their fifties and sixties.

The cardinal features are weakness and fatigability of muscles. The weakness increases during repeated use (fatigue) or late in the day, and may improve following rest or sleep. Unrelated infections or systemic disorders can lead to increased myasthenic weakness and may precipitate “crisis”.

Diplopia and ptosis are common initial complaints.

Facial weakness produces a “snarling” expression when the patient attempts to smile.

Weakness in chewing is most noticeable after prolonged effort.

Speech may have a nasal timbre caused by weakness of the palate, or a dysarthric “mushy” quality due to tongue weakness.

Difficulty in swallowing may occur as a result of weakness of the palate, tongue, or pharynx, giving rise to nasal regurgitation or aspiration of liquids or food.
Generalized weakness, affecting the limb muscles as well. If weakness of respiration becomes so severe as to require respiratory assistance, the patient is said to be in crisis.

Diagnosis and Evaluation

The diagnosis is suspected on the basis of weakness and fatigability in the typical distribution described above, without loss of reflexes or impairment of sensation or other neurologic function. The suspected diagnosis should always be confirmed definitively before treatment is undertaken; this is essential because (1) other treatable conditions may closely resemble MG and (2) the treatment of MG may involve surgery and the prolonged use of drugs with potentially adverse side effects.

Laboratory testing

Anti-AChR radioimmunoassay: 85% positive in generalized MG; 50% in ocular MG; definite diagnosis if positive; negative result does not exclude MG. 40% of AChR antibody–negative patients with generalized MG have anti-MuSK antibodies.

Repetitive nerve stimulation: decrement of >15% at 3 Hz: highly probable

Edrophonium chloride/Neostigmine test; highly probable diagnosis if unequivocally positive.
myesthenia -neostimine test
myesthenia Gravis

Search for Associated Conditions:

Thyroid and other autoimmune disorders CT scan or MRI of the chest for thymus gland abnormalities

Differential Diagnosis

Other conditions that cause weakness of the cranial and/or somatic musculature include the nonautoimmune CMS discussed above, drug-induced myasthenia, Lambert-Eaton myasthenic syndrome (LEMS), neurasthenia, hyperthyroidism, botulism, intracranial mass lesions, and progressive external ophthalmoplegia. Treatment with penicillamine (used for scleroderma or rheumatoid arthritis) may result in true autoimmune MG, but the weakness is usually mild, and recovery occurs within weeks or months after discontinuing its use. Aminoglycoside antibiotics or procainamide can cause exacerbation of weakness in myasthenic patients; very large doses can cause neuromuscular weakness in normal individuals.

Treatment

The prognosis has improved strikingly as a result of advances in treatment. Nearly all myasthenic patients can be returned to full productive lives with proper therapy. The most useful treatments for MG include

  • Anticholinesterase medications,
  • Immunosuppressive agents
  • Thymectomy, and
  • Plasmapheresis or intravenous immunoglobulin (IVIg)

Anticholinesterase Medications

Anticholinesterase medication produces at least partial improvement in most myasthenic patients, although improvement is complete in only a few. Pyridostigmine is the most widely used anticholinesterase drug.

Thymectomy

Two separate issues should be distinguished: (1) surgical removal of thymoma, and (2) thymectomy as a treatment for MG. Surgical removal of a thymoma is necessary because of the possibility of local tumor spread, although most thymomas are histologically benign. In the absence of a tumor, the available evidence suggests that up to 85% of patients experience improvement after thymectomy; of these, 35% achieve drug-free remission.

Immunosuppression

Immunosuppression using glucocorticoids, azathioprine, and other drugs is effective in nearly all patients with MG.For example, if immediate improvement is essential either because of the severity of weakness or because of the patient’s need to return to activity as soon as possible, IVIg should be administered or plasmapheresis should be undertaken. For the intermediate term, glucocorticoids and cyclosporine or tacrolimus generally produce clinical improvement within a period of 1–3 months. The beneficial effects of azathioprine and mycophenolate mofetil usually begin after many months. For the occasional patient with MG that is genuinely refractory to optimal treatment with conventional immunosuppressive agents, a course of high-dose cyclophosphamide may induce long-lasting benefit by “rebooting” the immune systemGlucocorticoid Therapy

Drugs to Avoid in Myasthenic Patients

Drugs with Interactions in Myasthenia Gravis
Drugs that may exacerbate MG
Antibiotics
Aminoglycosides: e.g., streptomycin, tobramycin, kanamycin
Quinolones: e.g., ciprofloxacin, levofloxacin, ofloxacin, gatifloxacin
Macrolides: e.g., erythromycin, azithromycin,
Nondepolarizing muscle relaxants for surgery
D-Tubocurarine (curare), pancuronium, vecuronium, atracurium
Beta-blocking agents
Propranolol, atenolol, metoprolol
Local anesthetics and related agents
Procaine, Xylocaine in large amounts
Procainamide (for arrhythmias)
Botulinum toxin
Botox exacerbates weakness
Quinine derivatives
Quinine, quinidine, chloroquine, mefloquine (Lariam)
Magnesium
Decreases ACh release
Penicillamine
May cause MG
Drugs with important interactions in MG
Cyclosporine
Broad range of drug interactions, which may raise or lower cyclosporine levels.
Azathioprine
Avoid allopurinol—combination may result in myelosuppression.

Patient Assessment

To evaluate the effectiveness of treatment as well as drug-induced side effects, it is important to assess the patient’s clinical status systematically at baseline and on repeated interval examinations. Because of the variability of symptoms of MG, the interval history and physical findings on examination must be taken into account. The most useful clinical tests include forward arm abduction time (up to a full 5 min), forced vital capacity, range of eye movements, and time to development of ptosis on upward gaze. Manual muscle testing or, preferably, quantitative dynamometry of limb muscles, especially proximal muscles, is also important. An interval form can provide a succinct summary of the patient’s status and a guide to treatment results. A progressive reduction in the patient’s AChR antibody level also provides clinically valuable confirmation of the effectiveness of treatment; conversely, a rise in AChR antibody levels during tapering of immunosuppressive medication may predict clinical exacerbation.