Myasthenia gravis 2

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  • 1. Myasthenia gravis (MG) is a relatively rare autoimmune disorder of peripheral nerves in whichantibodies form against acetylcholine (ACh) nicotinic postsynaptic receptors at the neuromuscularjunction (NMJ). The basic pathology is a reduction in the number of ACh receptors (AChR) at thepostsynaptic muscle membrane brought about by an acquired autoimmune reaction producing anti-AChR antibodies. MG is broken down into 2 major clinical forms: ocular MG and generalized MG.The reduction in the number of AChRs results in a characteristic pattern of progressively reducedmuscle strength with repeated use and recovery of muscle strength after a period of rest. The bulbarmuscles are affected most commonly and most severely, but most patients also develop some degreeof fluctuating generalized weakness.[1] The most important aspect of MG in emergency situations isdetection and management of the 2 crises: myasthenic and cholinergic.MG is one of the most treatable neurologic disorders. Pharmacologic therapy includesanticholinesterase medication and immunosuppressive agents, such as corticosteroids, azathioprine,cyclosporine, plasmapheresis, and intravenous immune globulin (IVIg). Plasmapheresis andthymectomy are also employed to treat MG. Thymectomy is an especially important option if athymoma is present. Patients with MG require close follow-up care in cooperation with the primarycare physician.EtiologyMG is idiopathic in most patients. Although the main cause behind its development remainsspeculative, the end result is a derangement of immune system regulation. MG is clearly anautoimmune disease in which the specific antibody has been characterized completely. In as many as90% of generalized cases, IgG to AChR is present.[7] Even in patients who do not develop clinicalmyasthenia, anti-AChR antibodies can sometimes be demonstrated.Patients who are negative for anti-AChR antibodies may be seropositive for antibodies against MuSK.Muscle biopsies in these patients show myopathic signs with prominent mitochondrial abnormalities,as opposed to the neurogenic features and atrophy frequently found in MG patients positive for anti-AChR. The mitochondrial impairment could explain the oculobulbar involvement in anti-MuSK–positive MG.[8]Numerous findings have been associated with MG. For example, females and people with certainhuman leukocyte antigen (HLA) types have a genetic predisposition to autoimmune diseases. Thehistocompatibility complex profile includes HLA-B8, HLA-DRw3, and HLA-DQw2 (though these havenot been shown to be associated with the strictly ocular form of MG). Both SLE and RA may beassociated with MG.Sensitization to a foreign antigen that has cross-reactivity with the nicotinic ACh receptor has beenproposed as a cause of myasthenia gravis, but the triggering antigen has not yet been identified.Various drugs may induce or exacerbate symptoms of MG, including the following: Antibiotics (eg, aminoglycosides, polymyxins, ciprofloxacin, erythromycin, and ampicillin) Penicillamine - This can induce true myasthenia, with elevated anti-AChR antibody titers seen in 90% of cases; however, the weakness is mild, and full recovery is achieved weeks to months after discontinuance of the drug Beta-adrenergic receptor blocking agents (eg, propranolol and oxprenolol) Lithium Magnesium Procainamide Verapamil Quinidine Chloroquine Prednisone Timolol (ie, a topical beta-blocking agent used for glaucoma) Anticholinergics (eg, trihexyphenidyl) Neuromuscular blocking agents (eg, vecuronium and curare) - These should be used cautiously in myasthenic patients to avoid prolonged neuromuscular blockade
  • 2. Nitrofurantoin has also been linked to the development of ocular MG in 1 case report; discontinuanceof the drug resulted in complete recovery.Thymic abnormalities are common: Of patients with MG, 75% have thymic disease, 85% have thymichyperplasia, and 10-15% havethymoma. Extrathymictumors may include small cell lung cancer andHodgkin disease. Hyperthyroidism is present in 3-8% of patients with MG and has a particularassociation with ocular MG.PathophysiologyWith every nerve impulse, the amount of ACh released by the presynaptic motor neuron normallydecreases because of a temporary depletion of the presynaptic ACh stores (a phenomenon referredto as presynaptic rundown).In MG, there is a reduction in the number of AChRs available at the muscle endplate and flattening ofthe postsynaptic folds. Consequently, even if a normal amount of ACh is released, fewer endplatepotentials will be produced, and they may fall below the threshold value for generation of an actionpotential. The end result of this process is inefficient neuromuscular transmission.Inefficient neuromuscular transmission together with the normally present presynaptic rundownphenomenon results in a progressive decrease in the amount of nerve fibers being activated bysuccessive nerve fiber impulses. This explains the fatigability seen in MG patients.Patients become symptomatic once the number of AChRs is reduced to approximately 30% ofnormal. The cholinergic receptors of smooth and cardiac muscle have a different antigenicity thanskeletal muscle and are not affected by the disease.The decrease in the number of postsynaptic AChRs is believed to be due to an autoimmune processwhereby anti-AChR antibodies are produced and block the target receptors, cause an increase theturnover of the receptors, and damage the postsynaptic membrane in a complement-mediatedmanner.Clinical observations support the idea that immunogenic mechanisms play important roles in thepathophysiology of MG. Such observations include the presence of associated autoimmune disorders(eg, autoimmune thyroiditis, systemic lupus erythematosus [SLE], and rheumatoid arthritis [RA]) inpatients with MG.Moreover, infants born to myasthenic mothers can develop a transient myasthenialike syndrome.Patients with MG will have a therapeutic response to various immunomodulating therapies, includingplasmapheresis, corticosteroids, intravenous immunoglobulin (IVIg), other immunosuppressants, andthymectomy.Anti-AChR antibody is found in approximately 80-90% of patients with MG. Experimental observationssupporting an autoimmune etiology of MG include the following: Induction of a myasthenialike syndrome in mice by injecting a large quantity of immunoglobulin G (IgG) from MG patients (ie, passive transfer experiments) Demonstration of IgG and complement at the postsynaptic membrane in patients with MG Induction of a myasthenialike syndrome in rabbits immunized against AChR by injecting them with AChR isolated from Torpedo californica (the Pacific electric ray)The exact mechanism of loss of immunologic tolerance to AChR, a self-antigen, is not understood.MG can be considered a B cell–mediated disease, in that it derives from antibodies (a B cell product)against AChR. However, the importance of T cells in the pathogenesis of MG is becomingincreasingly apparent. The thymus is the central organ in T cell–mediated immunity, and thymicabnormalities such as thymic hyperplasia or thymoma are well recognized in myasthenic patients.Antibody response in MG is polyclonal. In an individual patient, antibodies are composed of differentsubclasses of IgG. In most instances, 1 antibody is directed against the main immunogenic region(MIR) on the alpha subunit. The alpha subunit is also the site of ACh binding, though the binding sitefor ACh is not the same as the MIR. Binding of AChR antibodies to AChR results in impairment ofneuromuscular transmission in several ways, including the following:
  • 3. Cross-linking 2 adjacent AChRs with anti-AChR antibody, thus accelerating internalization and degradation of AChR molecules Causing complement-mediated destruction of junctional folds of the postsynaptic membrane Blocking the binding of ACh to AChR Decreasing the number of AChRs at the NMJ by damaging the junctional folds on the postsynaptic membrane, thereby reducing the surface area available for insertion of newly synthesized AChRsPatients without anti-AChR antibodies are recognized as having seronegative MG (SNMG). Manypatients with SNMG have antibodies against muscle-specific kinase (MuSK). MuSK plays a criticalrole in postsynaptic differentiation and clustering of AChRs. Patients with anti-MuSK antibodies arepredominantly female, and respiratory and bulbar muscles are frequently involved. Another group hasreported patients who exhibit prominent neck, shoulder, and respiratory weakness. [5, 6]The role of the thymus in the pathogenesis of MG is not entirely clear, but 75% of patients with MGhave some degree of thymus abnormality (eg, hyperplasia or thymoma). Histopathologic studies haveshown prominent germinal centers. Epithelial myoid cells normally present in the thymus do resembleskeletal muscle cells and possess AChRs on their surface membrane. These cells may becomeantigenic and unleash an autoimmune attack on the muscular endplate AChRs by molecular mimicry.The question of why MG afflicts the extraocular muscles first and predominantly remains unanswered.The answer probably has to do with the physiology and antigenicity of the muscles in question.DiagnosisMG can be a difficult diagnosis, as the symptoms can be subtle and hard to distinguish from both [4]normal variants and other neurological disorders. A thorough physical examination can reveal easyfatigability, with the weakness improving after rest and worsening again on repeat of the exertiontesting. Applying ice to weak muscle groups characteristically leads to improvement in strength ofthose muscles. Additional tests are often performed, as mentioned below. Furthermore, a goodresponse to medication can also be considered a sign of autoimmune pathology.[edit]Physical examination [11]Muscle fatigability can be tested for many muscles. A thorough investigation includes: looking upward and sidewards for 30 seconds: ptosis and diplopia looking at the feet while lying on the back for 60 seconds keeping the arms stretched forward for 60 seconds ten deep knee bends walking 30 steps on both the toes and the heels five situps, lying down and sitting up completely "Peek sign": after complete initial apposition of the lid margins, they quickly (within 30 seconds) [4] start to separate and the sclera starts to show[edit]Blood testsIf the diagnosis is suspected, serology can be performed in a blood test to identify certain antibodies: [4] One test is for antibodies against the acetylcholine receptor. The test has a reasonable sensitivity of 80–96%, but in MG limited to the eye muscles (ocular myasthenia) the test may be negative in up to 50% of the cases. A proportion of the patients without antibodies against the acetylcholine receptor have antibodies [12] against the MuSK protein.
  • 4.  In specific situations (decreased reflexes which increase on facilitation, coexisting autonomic features, suspected presence of neoplasm, especially of the lung, presence of increment or facilitation on repetitive EMG testing) testing is performed for Lambert-Eaton syndrome, in which other antibodies (against a voltage-gated calcium channel) can be found.[edit]ElectrodiagnosticsMuscle fibers of patients with MG are easily fatigued, and thus do not respond as well as muscles inhealthy individuals to repeated stimulation. By stimulating a nerve-muscle motor unit with shortsequences of rapid, regular electrical impulses, before and after exercising the motor unit, thefatiguability of the muscle can be measured. This is called the repetitive nerve stimulation test. Insingle fiber electromyography (SFEMG), which is considered to be the most sensitive (although not [4]the most specific) test for MG, a thin needle electrode is inserted into different areas of a particularmuscle to record the action potentials from several samplings of different individual muscle fibers.Two muscle fibers belonging to the same motor unit are identified and the temporal variability in theirfiring patterns are measured. Frequency and proportion of particular abnormal action potentialpatterns, "jitter" and "blocking," are diagnostic. Jitter refers to the abnormal variation in the timeinterval between action potentials of adjacent muscle fibers in the same motor unit. Blocking refers tothe failure of nerve impulses to elicit action potentials in adjacent muscle fibers of the same motor [13]unit.[edit]Edrophonium testPhotograph of a patient showing right partial ptosis (left picture), the left lid shows compensatory pseudo lid retractionbecause of equal innervation of the levatorpalpabraesuperioris (Herings law of equal innervation). Right picture: afteran edrophonium test, note the improvement in ptosis.The "edrophonium test" is infrequently performed to identify MG; its application is limited to thesituation when other investigations do not yield a conclusive diagnosis. This test requiresthe intravenous administration of edrophonium chloride (Tensilon, Reversol) or neostigmine(Prostigmin), drugs that block the breakdown of acetylcholine by cholinesterase (acetylcholinesteraseinhibitors) and temporarily increases the levels of acetylcholine at theneuromuscular junction. Inpeople with myasthenia gravis involving the eye muscles, edrophonium chloride will briefly relieve [14]weakness.[edit]ImagingA chest CT-scan showing a thymoma (red circle)
  • 5. A chest X-ray is frequently performed; it may point towards alternative diagnoses (e.g. Lambert-Eatonsyndrome due to a lung tumor) and comorbidity. It may also identify widening ofthe mediastinum suggestive of thymoma, but computed tomography (CT) or magnetic resonanceimaging (MRI) are more sensitive ways to identify thymomas, and are generally done for this [15]reason. MRI of the cranium and orbits is also performed to exclude compressive and inflammatory [16]lesions of the cranial nerves and ocular muscles.[edit]Pulmonary function testSpirometry (lung function testing) may be performed for the assessing of respiratory function if thereare concerns about a patients ability to breathe adequately. The forced vital capacity may bemonitored at intervals so as not to miss a gradual worsening of muscular weakness. Acutely, negativeinspiratory force may be used to determine adequacy of ventilation. Severe myasthenia may [17]cause respiratory failure due to exhaustion of the respiratory muscles.[edit]Pathological findingsMuscle biopsy is only performed if the diagnosis is in doubt and a muscular condition issuspected. Immunofluorescence shows IgG antibodies on the neuromuscular junction. (The antibodywhich causes myasthenia gravis does not fluoresce, but rather a secondary antibody directed againstit.) Muscle electron microscopy shows receptor infolding and loss of the tips of the folds, together withwidening of the synaptic clefts. Both these techniques are currently used for research rather than [7]diagnostically.