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Neuromuscular Disease 

Myopathy

Clinical Considerations

Summary: Proximal muscle weakness manifested as difficulty climbing stairs, arising from low chairs (e.g. getting out of cars (legs) and washing or styling hair (arms). Neck weakness is sometimes present. Elevation of creatine kinase is expected. Dramatic elevations (above 10,000) occurs in muscular dystrophies and necrotizing myopathy. Myoglobinuria with subsequent kidney damage is a concern in acute conditions. Nerve conduction studies are normal. Needle electromyography shows short duration motor unit potentials and full recruitment with low amplitude in weak muscles (so called "early recruitment"). Muscle biopsy shows variation in fiber size.

Critical Illness Myopathy

Usually in the setting of acute weakness in the intensive care unit, frequently discovered because of problems weaning from the respirator. The occurrence of weakness is markedly increased when neuromuscular blocking agents are used in conjunction with steroids for severe asthma. A retrospective study designed to determine the most important predictors of acute weakness of weakness developing in patients with severe asthma requiring mechanical ventilation. The use of blocking agents was highly correlated with the development of weakness.

Myopathies As Adverse Effects of Medications

Statins

Coenzyme A reductase inhibitors have been used for more than 10 years to reduce cholesterol and improved outcome from cardiovascular disease. The mechanism for the myopathic effect is uncertain, although its main mode of action, inhibition of mevalonate, a precursor of ubiquinone which is a central compound of the mitochondrial respiratory chain, implicates a mitochondrial origin. Of 2502 patients with hypercholesterolemia in a safety profile with lovastatin (Lipitor), none developed a confirmed myopathy although 0.7% developed elevated transaminases.

Neuromuscular Transmission Disorders

Myasthenia Gravis

Background

There are two peaks of incidence in patients with acquired myasthenia gravis. One peak occurs in early adulthood (25-35). In this group, women outnumber men 2:1. In the older peak (55-70) the ratio of men to women is 1:1. Patients with myasthenia gravis have a high occurrence of co-existing autoimmune disease. For example, antibody mediated thyroid disorders occur in 20% of myasthenic patients. Rheumatoid arthritis, lupus, pernicious anemia, sarcoid, Sjogren's, polymyositis, ulcerative colitis, and pemphigus have been described in patients with myasthenia.

Pathophysiology

Myasthenia gravis is an autoimmune disease caused by an antibody directed against the acetylcholine receptor (AChR). The source of the antibody and its relation to thymic abnormalities is beyond the scope of the discussion; however, there is substantial evidence relating the two. The antibodies are usually polyclonal but most bind to epitopes in a small extracellular portion of the alpha subunit of the receptor. This site is designated as the main immunogenic region (MIR). It is not the site that binds acetylcholine.

There are known associations with different types of myasthenia with specific HLA haplotypes suggesting that the susceptibility to develop MG is genetically controlled. In patients under 40, there is an increased prevalence of HLA A 1, B8, and DRw3 and acetylcholine receptor antibodies are usually present. In patients over 40, there is and increase in HLA A3, B7 and DRw2. Acetylcholine receptor titers are usually low. Thymomas do not occur in these patients. Tumor necrosis factor alpha is a cytokine with prominent effects on the neuroimmune system and is frequently elevated in myasthenic patients. Recent studies have shown that the gene for TNF alpha is just as closely associated with myasthenic patients below 40 with thymic hyperplasia as B8 and DRw3.

Clinical Manifestations

Ocular involvement occurs in more than 90% of all patients in the form of ptosis and impaired ocular movements. Ophthalmoplegia is possible. In 60% of myasthenic patients, nasal speech, slurred speech, and difficulty swallowing occurs. If untreated or in crisis, respiratory impairment or failure occurs. In 30-40% of patients, limb weakness is experienced. The cardinal manifestation of the clinical manifestations of myasthenia is that all symptoms worsen with exertion (and therefore are best in the morning) and are reversible with edrophonium.

Therapy is directed at reducing the level of circulating antibody. The most rapid and effective therapy is plasmapheresis. Target therapy is one blood volume over 5 days. Recent studies suggest a specific immunoabsorbent (Medisorba) column provides more selective therapy. Intravenous immunoglobulin has been recommended as a B level treatment for myasthenia gravis (ie, a treatment of last resort). Chronic therapy usually consists of steroids (prednisone, alternate day therapy if possible), azathioprine, and cyclophosphamide. Recent observations have shown that nasal inhalation of recombinant fragments of the immunogenic extracellular portion of the alpha subunit have produced tolerance in animals with experimental myasthenia gravis and have protected animals from acquiring EAMG suggesting a possible future therapy for humans.

 

Lambert Eaton Syndrome (LEMS)

The weakness in patients with LEMS usually is opposite in distribution to myasthenia. Limb weakness is a prominent symptom. Over 70% of patients complain of dry mouth (from impaired release of acetylcholine in autonomic fibers)and 50% are impotent. Ptosis and ophthalmoparesis are rare.

The cause of LEMS is impaired release of acetylcholine from the pre-synaptic terminal. The normal release of acetylcholine containing vesicles from the presynaptic terminal requires inward moving calcium ions associated with membrane depolarization to bind with a calcium receptor triggering release of the vesicle into the synaptic space. Antibodies to the voltage gated calcium channel receptors appear to be the pathogenic mechanism for LEMS.

 

Peripheral Neuropathy

Summary: Although the symptoms of peripheral nerve dysfunction vary with the etiology and particular nerves affected, the most common presentation is that of a predominantly distal, stocking and glove polyneuropathy. Patients complain of numbness and tingling in the feet more than fingertips, clumsiness in manipulating small objects in their hands (buttoning, zipping, and snaps) and frequent tripping over carpets, curbs, and cracks in sidewalks. Blood studies may be abnormal depending on the cause. Therefore, fasting glucose, BUN/creatinine, thyroid panel, liver

Update

Many of the demyelinating neuropathies are caused by autoimmune disease. The cause of the release of self-recognition is uncertain. However, in one circumstance, Guillan Barre syndrome, the cause seems to be, in some instances, molecular mimicry. Guillain Barre syndrome frequently occurs shortly after systemic infection with agents. The infection may cause diarrhea (eg, Campylobacter ieiuni) or an upper respiratory infection ( cytomegaolovirus, and Haemophilus influenza). In patients with GBS following C. jejuni infection, elevated titers of GM 1 antibodies are detected. The lipopolysaccharide from C. jejuni isolated from GBS patients has a GM1 like structure suggesting nerve damage originates from a crossed immune reaction caused by shared epitopes within the bacterial lipopolysaccharide and the axolemma (1) Similar findings were recently reported with Haemophilus influenzae suggesting molecular mimicry may also account for post URI GBS.

The treatment of immune mediated polyneuropathy has changed with the availability of intravenous immunoglobulin. However, therapy for the acute weakness associated with GBS has not changed. Several studies have shown that neither IVIG or plasmapheresis produces a measurable difference in outcome when the two therapies are compared. Therefore, plasmapheresis remains the treatment of choice in the acute setting.

Peripheral Neuropathy and Hepatitis C

Peripheral neuropathy, usually mononeuritis, is a frequent complication of mixed cryglobulinemia, a common association of hepatitis c infection. Neuropathy is also a frequent complication in hepatitis c infection. Recent evidence has shown that high levels of hepatitis c virus tRNA in homogenates of nerve biopsy suggesting the neuropathy associated with hepatitis c.

Amyotrophic Lateral Sclerosis

Summary: The clinical presentation of classical ALS is characteristic and is mimicked by few illnesses. The pathology involved degeneration of anterior horn cells as well as corticospinal tract neurons. Both sets of neurons regulate motor function and their dysfunction results in the unique manifestation of weakness, wasting, muscle twitching (anterior horn cell loss) in the same limb.