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Amyotrophic Lateral Sclerosis

Summary: The clinical presentation of classical amyotrophic lateral sclerosis 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 as overactive reflexes and pathological reflexes reflecting corticospinal tract degeneration (Babinski sign, Hoffman sign, increased tone). The cause is rarely inherited (in less than 5%) but is usually amyotropic lateral sclerosis, Lou Gehrig's disease.

The cause of ALS is uncertain but the current hypothesis suggests that there is a loss of intracellular oxidative control producing cellular disruption and spilling excitotoxic amino acids such as glutamate into the extracellular space. The cause of the intracellular dysfunction is uncertain. Mitochondrial dysfunction may lead to free radical generation and increased excitotoxicity. Studies of mitochondrial function has shown a two fold lower specific activity of NADH: CoQ oxidoreductase in patients with ALS suggesting dysfunctional mitochondria. Coenzyme Q is a potent free radical scavenger in mitochondrial membranes . and feeding transgenic ALS animals significantly prolonged transgenic animals with ALS. Exogenous administration of creatine to motor neuron mice showed enhance survival in transgenic mice and protects them from

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, necrosis, regeneration, and sometimes, inflammatory cell infiltrates.

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; the longer the blocking agent was used, the more severe the resulting weakness. The dose and type of blocking agent used was not significantly associated with the occurrence of myopathy. Pathological findings consist of loss of myosin filaments. Similar pathological findings have been reported in acute quadriplegia following liver transplantation 2 and autologous stem cell transfusion for breast cancer.

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. In a trial of simvastatin, 2 patients (0.6%) developed myopathy 4. Combination of niacin and statins have produced the most dramatic effect on blood cholesterol, however, there have been sporadic reports of severe myopathy and rhabdomyolysis; careful monitoring of CK levels and education patient regarding the symptoms of myopathy are important 5. Therefore, although anecdotal reports frequently encounter elevations of CK in patients being treated with statins, studies screening for adverse effects find few patients with this complication. However, no studies specifically monitoring for weakness, CK, and physiological findings have been performed.

Inflammatory Myopathies Associated with Respiratory Distress

Acute respiratory failure is rarely the presenting manifestation of a primary disorder of muscle. However, up to 89% of patients with inflammatory myopathy and antisynthetase antibodies (eg, anti-Jo) have interstitial lung disease. In such patients, respiratory failure may be the first manifestation of the underlying autoimmune disease leading to inappropriate treatment with antibiotics instead of immunosuppressant medication.

 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. Most authors estimate that 3-4% of patient with myasthenia have one of these diseases. Thymic hyperplasia is found in 75% of patients and transcervical thymectomy is the treatment of choice, providing 85% of patients complete remission off medication within 8 years. However, the recommendation for thymectomy for older patients remains controversial. Thymoma is a definite indication for thymectomy and occurs in 10% of patients with myasthenia gravis. Rarely, patients may present with thymoma only to have myasthenia recur after diagnosis or even after thymectomy.

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. Antibodies that bind to the MIR are able to fix complement, passively transfer MG to animals, and modulate function of the AChR when applied to experimental preparations. Clinical assays of blocking antibodies reveal their presence in 52% of patients but rarely (1%) as the only type of antibody detected. Modulating antibodies are present in 90% of sera. Striational antibodies are present in 84% of patients with thymoma. However, they may be found in elderly myasthenic patients with thymic atrophy. Another antibody to titin is also helpful in detecting thymoma.

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. The characteristic electrodiagnostic manifestations include normal nerve conduction studies, normal evoked response amplitudes, and decrement on repetitive stimulation. Single fiber EMG is abnormal. Needle EMG shows no spontaneous activity and motor units that vary in amplitude during repetitive firing.

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.

Myasthenic crisis is a medical emergency and defined as acute respiratory deterioration in a patient with known myasthenic gravis or rarely, as the presenting manifestation. It develops in 15-20% of all myasthenic patients. The most common interval between crisis and first symptom is 8 months. The causes of myasthenic crisis include infection, reduction in medication, initiation of steroid therapy, and uncertain. The mortality rate is approximately 4% and is due to adult respiratory distress syndrome, multiple organ failure, cardiac failure, or