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I.  CLINICAL DEFINITION OF MYASTHENIA GRAVIS:

Myasthenia gravis (MG) is a disorder of the neuromuscular strength that occurs during sustained or repetitive muscle contraction.  It is a painless neuromuscular disease that is very puzzling and confusing to the patient and frequently their physicians.  Patients are often believed to be malingering, because at one time they may function normally and at another time experience significant loss of strength.  In obtaining the history it is essential to document that loss of muscle power occurs in association with continuous effort.  It is also necessary to inquire about common signs and symptoms, such as ptosis, diplopia, dysarthria or dysphagia.  Improvement with rest is an important feature of the disease.

II.  CLINICAL FEATURES OF MG:

          A.  Prevalence:  2/100,000 with no specific geographic distribution.

         B.  Age: Average age of onset is 20, with a preference for young females below the

               age of 40 (ratio females/males = 4.5/1; ratio females/males over age 40 = 1/1).

          C.  Types of MG:

                 1.  Autoimmune ocular:  Many patients present with ocular involvement.  Some

                             have disease restricted to ocular musculature and never have generalized MG.

                 2.  Autoimmune generalized:

                        a.  Many patients present with ocular symptoms.

                                    b.  Most patients have generalized weakness     within 13 months of clinical  onset.

                        c.  40% improve.

                        d.  15% develop irreversible weakness and atrophy.     

     3. Transient neonatal MG is produced by passive transfer of maternal antibodies from a mother with MG.

                 4.  Congenital MG:  Multiple forms occur with different pathophysiological

                            mechanisms such as structural and/or electrophysiologic defects of the

                            neuromuscular junction.  These are congenital syndromes and not related to

                            autoimmunity.           

     5.  Drug Induced MG: Antibody mediated MG is sometimes caused by the drug Penicillamine.  

                 6.  Neuromuscular Junction Blockade (NJM): Gentamicin and other

                           Aminoglycoside antibiotics can cause a pharmacologic block of the NJM which

                           has clinical features similar to MG without autoimmunity.

III.  DIAGNOSIS OF MG:

          A.  History and physical examination:

                   1.  Document weakness occurring with continuous effort and recovering with rest.

                   2.  Common features:  ptosis, diplopia, facial weakness, dysarthria, dysphagia, nasal regurgitation of fluids, nasal 

                          speech, neck muscle weakness, proximal muscle weakness, and weakness of grip.  

                           Note: Combined  weakness of bulbar and respiratory muscles may be life-threatening.

                   3.  Important negative findings:  Normal sensory examination, no sensory symptoms, normal bowel and 

                         bladder function, normal monocular vision.

                   4.  Autoimmune diseases associated with MG:

                        a.  Thyroid disease (both thyroiditis and autoimmune hyperthyroidism)

                        b.  SLE (Systemic Lupus Erythematosus)

                        c.  Rheumatoid arthritis

                        d.  Pernicious anemia

                        e.  Pemphigus vulgaris (an autoimmune skin disease)  

           B.  Special laboratory tests:

                  1.  Repetitive nerve stimulation.

                        a.  Slow:  2-3/second stimulation of a motor nerve innervating an involved muscle.  A reduction in 

                             action  potential amplitude occurs that is >10%.  Exercise may be used to enhance this deficit.

                   b.  Fast:  >10/sec stimulation of motor nerve to an involved muscle--decrement may occur following a 

                         slight  increment.

               2.  Tensilon test:  Edrophonium hydrochloride, a short-acting anticholinesterase given intravenously

                     (<1 mg)  temporarily reverses weakness over a period of several minutes.

       3.  Acetylcholine receptor antibody titer:           

              Elevated in >80% of patients with generalized myasthenia gravis and in 50% of patients with ocular MG.

                   4.  Anti-skeletal muscle antibody titer:  Elevated in 95% of patients with thymoma.

  IV.  PATHOPHYSIOLOGY:

MG results from a decreased number and defective functioning of acetylcholine receptor binding sites at the neuromuscular junction.  An autoimmune state exists in which various subclasses of IgG bind the acetylcholine receptor.

          A.  The acetylcholine receptor:

                     1.  Structure:  There are 5 subunits -- alpha2, beta, gamma and epsilon with a combined molecular weight 

                           of 250,000.  The acetylcholine binding site is present on each alpha subunit.

                    2.  Ach-R is synthesized by membrane-bound ribosomes. Then glycosolated and transported through the 

                           Golgi system to the muscle surface membrane.  It is degraded by endocytosis and has a half-life of Ach-R 

                           is  6-13days.

          B.  Ach-R Function:

                     1.  Current flows through the ion channel on binding with Ach.

                     2.  The channel is open 0.1 to 1.5 msec, with the shortest opening time associated with binding of 1 

                           acetylcholine molecule.  The ion channel may open and close several times before acetylcholine dissociates 

                           from the receptor.  There are 2 binding sites for each acetylcholine receptor.

           C.  Anti-AChR antibodies in MG

                     1.  A large proportion of the anti-AChR antibodies bind to the alpha subunit

                      2.  Antibody binding AChR is pathologically significant.  These antibodies cross-link Ach-R and modulate 

                           Ach-R by endo or exocytosis.  Human anti-AChR antibodies can transfer MG to mice.

                     3.  The antibody response to Ach-R is polyclonal.  IgG1 and IgG2 subclasses predominate in most patients.

                      4.  There is a spectrum of antibodies in any given patient.  The total antibody titer correlates only moderately 

                           well  with the clinical status.  This is due to differences in variable region specificity, affinity and Fc function.

                     5.  Anti-idiotypic antibodies have been identified in patients with MG and may be important in the regulation of 

                           the Ach-R autoantibodies.

             D.  Mechanisms of anti-Ach-R antibody induced pathology.

                      1.  Modulation of receptors.

                      2.  Block Ach binding site or the ion channel.

                      3.  Complement mediated destruction.

             E.  Uses of Ach-R antibody in diagnosis:

                     1.  85% of MG patients are positive for anti-AChR antibody and 15% do not have this antibody and are 

                          termed seronegative MG.  The seronegative patients may have antibodies directed at other components of 

                          the neuromuscular junction and may respond to the same treatments as MG.

                    2.  Subtypes of MG and positive Ach-R antibody tests:

                             a.  Remission - 24%.

                              b.  Ocular - 50%.

                              c.  Mild generalized - 80%.

                              d.  Moderately to acutely severe - 90%.

                              e.  Chronic severe - 89%.

                    3.   Factors which influence Ach-R antibody titer:

                             a.  Treatment with prednisone, azathioprine, thymectomy or plasmapheresis reduces antibody titer.

                              b.  Infection and stress cause increase in antibody titer.

             F.  Transient Neonatal MG:                    

                     1.  Nearly all infants born of MG mothers will have elevated Ach-R antibody titers.

          2.  10-15% of infants born to MG mothers develop symptoms of MG.  As the maternal antibody is replaced 

                the symptoms abate.

V.  THERAPY FOR MG:

           A.  Anticholinesterase drugs: Increase Ach in neuromuscular junction.

                    1.  Pyridostigmine hydrochloride (Mestinon) is useful in all forms of disease.

                    2.  Edrophonium (Tensilon) is useful as a diagnostic reagent.

           B.  Plasmapheresis - removal of Ach-R antibody yields transient improvement in patients with severe involvement.

          C.  Thymectomy

                    1.  Remove thymoma.

                   2.  Removed early in generalized MG hastens onset and increases frequency of remissions; best results in

                         young females with hyperplastic gland and high antibody titers.

            D.  Alternate day corticosteroid treatment:

                  1.  60-80 mg q.o.d. which is slowly tapered

                   2.  3-5 months to see improvement.

                   3.  Dose adjusted slowly - 10%/month.

            E.  Azathioprine

                   1.  Effect is seen in 3-18 months.

                   2.  40% remission.

                   3.  51% improved.

                   4.  Need for long term treatment in most patients.

            F.  Intravenous immunoglobulin is a useful treatment of relapses of MG and is similar to plasmapheresis in overall effect.

  VI.  CONGENITAL MYASTHENIC SYNDROMES:  are not associated with antibody or autoimmunity.  

Examples of these genetic diseases include:

            A.  Putative defect in acetylcholine synthesis or packaging.

             B.  Congenital endplate acetylcholinesterase deficiency.

             C.  Slow channel syndrome:

                        The ion channel has prolonged opening time.

             D.  Congenital endplate Ach-R deficiency.

             E.  Other congenital syndromes:

                  1.  Low endplate potential amplitude.

                  2.  Altered Ach-R numbers.

VII.  LAMBERT-EATON MYASTHENIC SYNDROME (LEMS)

          Weakness and fatigue of proximal muscles is seen.  There is relative sparing of ocular and bulbar muscles.  Strength improves during the first few seconds of voluntary muscle contraction.  There is a common association with carcinoma, specifically oat cell carcinoma of the lung.  When associated with cancer is an example of a paraneoplastic disease.

           A.  Repetitive nerve stimulation:

                   1.  Low amplitude of the evoked muscle action potential.

                   2.  Marked several-fold increase in amplitude stimulating at rates above 10 Hz.

  B.  Reduced probability of release of Ach quanta from the nerve terminal by a nerve impulse:

                   1.  Ach stores are normal.

                   2.  Response to individual Ach quanta is normal at NMJ.

           C.  Electron microscopy studies:

                    1.  Decreased numbers of presynaptic active zones and active zone particles.

                   2.  Active zones represent area of vesicle exocytosis.

       3.  Membrane particles represent voltage-sensitive calcium channels essential for release of Ach.

            D.  LEMS: - An autoimmune paraneoplastic disease in many patients; however a few patients develop the disease and

                   not have a malignancy.  Features of autoimmunity in LEMS include:

                   1.  Responds to steroid, immunosuppressants and plasmapheresis.

                    2.  Passive transfer of LEMS to mice can be     accomplished by IgG.

                    3.  Antibodies which bind votage-gated Ca++ channels

        4.  Non-neoplastic LEMS is associated with other autoimmune disorders, organ-specific autoantibodies and

             HLA-B8, DRw3 histocompatibility antigens.

  VIII.  BOTULISM

A.  Definition:  A rare food-borne illness caused by the exotoxin of clostridium botulinum.  The outbreaks of this illness 

      are most frequent in the Western U.S.  Canned vegetables are the most frequent source of poisoning.  

         B.  Clinical features: Symptoms frequently begin 12 to 36 hours after ingestion of the contaminated food.  Symptoms and

                clinical findings include:

                    1.  Blurred vision and diplopia

                    2.  Ptosis

                    3.  Extraocular muscle palsies

                    4.  Dysarthria and dysphagia

                    5.  Progressive generalized weakness with respiratory failure.

                    6.  Dilated pupils

                    7.  Constipation

         C.  Pathophysiology:  The site of action of the botulinus exotoxin is at the presynaptic side of the neuromuscular

                 junction.  The diagnosis can be confirmed with EMG (electromyographic studies).

          D.   Treatment:  Respiratory and supportive care are the most important.  Trivalent antitoxin should be administered.

                 Guanidine HC1 may improve weakness. Complete recovery may take months. 

  XI.  AMYOTROPHIC LATERAL SCLEROSIS

         A.   Definition:  A progressive disorder involving lower and upper motor systems.

B.  Clinical features:  Wasting and weakness of muscles with visible fasiculations in scattered muscles.  The disease          

                frequently presents in the upper extremities but may initially involve lower extremities or bulbar muscles.  

                Hyper-reflexia and spasticity may be observed.

C.  Pathology:  Shrinkage with sclerosis in the corticospinal tracts and degeneration of the large anterior horn neurons 

      noted in spinal cord and brainstem.  Degeneration is also found in the large Betz cells of the motor cortex.

         D.  Epidemiology and Etiology of ALS:

                   1.  Incidence:  1-2/100,000

                    2.  Prevalence: 2.5-7/100,000

                    3.  Age: Peak at approximately 55 years of age

        4.  The cause is unknown for the vast majority of patients

        5.  5-10% are familial with autosomal dominant inheritance and caused by mutations in copper/zinc superoxide

             dismutase gene.

                    6.  Occasionally patients with a monoclonal gammopathy will have a motor neuropathy with clinical features

                  resembling ALS.  These patients may respond to plasmapheresis and/or immunosuppressive therapy.  

           E.  Treatment:     A small minority of patients may respond to immunosuppressive therapies.  At   present there is   

                 no treatment which is substantially effective for the majority of patients.  ALS patients should be referred to a   

                 center specializing in the diagnosis, treatment and care of these seriously ill individuals. 

References:

1.  Engel AL.  Myasthenia gravis and myasthenic syndromes.  Annals of Neurol 16:519, 1984.

2.  Walton J.  DISORDERS OF VOLUNTARY MUSCLE, Chap. 16: "Myasthenia Gravis and Myasthenic Syndromes", by JA Simpson, Churchill-Livingstone (1981), p. 585.

3.  Rose J and Mcfarlin D.  Myasthenia Gravis, in Immunologic Diseases, 4th edition; Samter, Talmage and Austen (eds) Chapter 52, Lippincott/Williams and Wilkins (2001), In Press.

4.  Drachman D. (ed).  Myasthenia gravis:  Biology and treatment.  Ann N Y Acad Sci vol. 505, 1987.

5.  Walton J.  DISORDERS OF VOLUNTARY MUSCLE, Chap. 21: "The Central Neuronal Muscular Atrophies and Other Dysfunctions of the Anterior Horn Cells", by LA Liversedge and MJ Campbell, Churchill-Livingston (1981), pp. 775-803.

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                                              Last updated:  10/05/2002                                                          © 2000-2002 John Rose, MD  University of Utah School of Medicine