© Borgis - Postępy Nauk Medycznych 6/2010, s. 464-473
*Marek Leszek Kamiński
Myasthenia Gravis in Older People
Miastenia u osób starszych
Klinika Neurologii z Pododdziałem Udarowym i Wczesnej Rehabilitacji Poudarowej, Uniwersytet Medyczny w Lublinie
Kierownik Kliniki: prof. dr hab. Zbigniew Stelmasiak
Miastenia (Myasthenia gravis, MG) jest najczęstszym pierwotnym schorzeniem złącza nerwowo-mięśniowego. W przypadkach typowych spowodowana jest występowaniem przeciwciał przeciwko receptorom acetylocholinowym. Dominującymi objawami są nużliwość i osłabienia siły mięśniowej. Osłabienie może obejmować odosobnione grupy mięśni w mniej lub bardziej odizolowany sposób. Objawy mogą mieć zmienne nasilenie z dnia na dzień lub nawet z godziny na godzinę. Osłabienie mięśni pozagałkowych z asymetrycznym, opadaniem powiek i podwójnym obuocznym widzeniem są najbardziej typowymi objawami w początkowej fazie choroby. U około 15 do 20% pacjentów może wystąpić nagłe nasilenie objawów i uogólnione osłabienie siły mięśniowej zwane przełomem miastenicznym, wymagające pilnego zastosowania oddechu wspomaganego. Przełom miasteniczny występuje częściej w przypadkach MG związanej z grasiczakiem, najbardziej rozpowszechnionym u dorosłych nowotworem śródpiersia przedniego. Związane z występowaniem grasiczaka przypadki autoimmunologicznej miastenii można w związku z tym uznawać za zespół paraneoplazmatyczny. Chociaż początek MG może wystąpić w różnym wieku, wyróżnić można dwie fazy zachorowań z obecnością późnego szczytu pomiędzy 70. i 75. rokiem życia. W przypadku starszych pacjentów obciążenie poważnymi schorzeniami towarzyszącymi, objawami ubocznymi stosowanych leków oraz zależnymi od wieku zmianami układu nerwowo-mięśniowego może mieć wpływ na przebieg i poprawę stanu klinicznego pacjentów.
Myasthenia gravis (MG) is the most common primary disorder of the neuromuscular junction. Classically, this disorder is caused by autoantibodies to the muscle acetylcholine receptors. The hallmark of MG is fatigable muscle weakness. The weakness may affect individual muscle groups in more or less isolated fashion. The symptoms may vary from day to day or even from hour to hour. Extraocular muscle weakness with asymmetric ptosis and binocular diplopia are the most typical initial presentation. Approximately, 15 to 20% of patients may experience a sudden exacerbation of symptoms and generalized muscle weakness known as myasthenic crisis that requires urgent respiratory support. Myasthenic crisis is more common in MG associated with thymoma, most common anterior mediastinal tumor in adults. Thymoma-associated of autoimmune MG may be considered paraneoplastic. Although MG may appear at any age, it has a bimodal peak of age with late-onset peak between ages of 70 and 75 years. Elderly patients tend to have serious comorbidities, drug adverse effects and age-related neuromuscular changes that can interfere with patients' recovery.
Some of the most common neurologic impairments are motor deficits. One common problem in neurology is the existence of disorders that present with neurologic symptoms but do not have an identifiable neurologic basis. A number of psychiatric disorders can mimic neurologic illness. In conversion disorders, the patients display motor or sensory deficits without corresponding lesions in the nervous system (1, 2). A history of pain, sensory disturbances increases the likelihood of neurologic involvement. Patients with neurologic disorders may present with a variety of motor deficits including tremor, lack of coordination, weakness or paralysis, and fatigue. Weakness is a common complaint. Disturbances of motor functions can result from lesions of the motor pathways in the central or peripheral nervous system or from lesions of the muscles and neuromuscular junction themselves. The findings of the neurological exam help localize the level of the lesion. Loss of muscle power may result from disease involving the upper or lower motor neurons.
Classically, there are two distinct patterns of neurological weakness.
1. Signs of upper motor neuron include weakness, hyperreflexia (increased reflexes), spasticity, and Babinski's sign.
2. Lower motor neuron lesions result in loss of strength, tone and reflexes and eventual denervated muscle wasting and fasciculations.
The distribution of weakness is most essential information to be determined from the medical history and physical examination. Weakness due to upper and lower motor neuron lesions is characterized by selective involvement of certain muscle groups. In myopathies, weakness is usually mostly marked proximally in the limbs. In patients with neuromuscular junction disorders, weakness is often of patchy distribution. Fatigue is a symptom of many different conditions, and is usually not due to a serious disease. Specific symptoms may be physical, psychological, or emotional. Physiological fatigue can be a normal response to physical exertion, emotional stress, or lack of sleep. Rest may alleviate fatigue and allow a return to a normal level of functioning in a healthy individual. Fatigue may be acute or chronic. Chronic fatigue, non "cancer-related fatigue”, may be caused by nutritional deficiency, fibromyalgia, chronic fatigue syndrome, low thyroid, or depression. Fatigue has been described as a typical symptom of many medical conditions, e.g. neurological diseases. It might be caused both by changes at the peripheral and at the central level. Severe fatigue has been reported in more than 60% of all neuromuscular patients with post-polio syndrome, myasthenia gravis, Guillain-Barré syndrome, facioscapulohumeral dystrophy, myotonic dystrophy and hereditary neuropathies (3). The non-specific nature of symptoms and signs suggest a broad differential diagnosis, including organic and psychogenic conditions. Diagnosis of MG in the earliest stage appears to be difficult.
NORMAL NEUROMUSCULAR JUNCTION PHYSIOLOGY
The neuromuscular junction (NMJ) is the synapse that is composed of the nerve terminal, the synaptic cleft, and postsynaptic motor "endplate” – the highly organized postjunctional folds on the muscle membrane. When a nerve impulse reaches the motor nerve terminal, the depolarization of terminal membranes causes opening of voltage-gated calcium (Ca2+) channels allowing short-lived entry influx of calcium. The increase in calcium causes fusion of acetylcholine presynaptic vesicles with the nerve terminal membrane. Acetylcholine is subsequently released into the synaptic cleft between the nerve and the surface of the muscle fiber. Acetylcholine binds to acetylcholine receptor sites on the postsynaptic muscle membrane. The binding of acetylcholine to these receptors opens the voltage-sensitive sodium channels situated at the base of each synaptic fold. This leads to transient depolarization called the endplate potential. The action potential is propagated along the muscle fiber and initiates muscle contraction.
Disorders of neuromuscular transmission
The disorders of neuromuscular transmission (NMT) constitute a heterogeneous group of diseases. They can be congenital, acquired autoimmune or toxic. Congenital disorders are not mentioned in this study. Acquired disorders of neuromuscular transmission include myasthenia gravis (MG), the Lambert Eaton myasthenic syndrome (LEMS), disorders caused by several drugs, and botulism. They are all rare conditions, but among them, MG and LEMS are the most common disorders affecting neuromuscular transmission. Neuromuscular transmissions disorders are characterized by impaired transmission of impulses at the neuromuscular junction. The failure of neuromuscular transmission results in diminished end-plate potentials that are insufficient to generate action potentials in a number of muscle fibers. This results in fatigable muscle weakness. In myopathies and neuromuscular junction disorders, weakness is not usually associated with sensory loss or sphincter disturbance. These disorders are generally pure motor syndromes. Fluctuation of muscle weakness is a typical sign of neuromuscular junction disturbances (4, 5).
Myasthenia gravis (MG) is the most common primary disorder of the neuromuscular junction. Classically, this disorder is caused by autoantibodies against the nicotinic acetylcholine receptor (ACh-R), leading to cross-linking, decrease in the number of receptors at the motor endplate, and loss of the complex folding of the postsynaptic skeletal muscle membrane. The hallmark of MG is fatigable muscle weakness (4, 5).
The prevalence of MG has been reported to be about 14.2 cases per 1 million people (6). Although MG may appear at any age, it has a bimodal peak of age at onset. Women demonstrate an early-onset peak incidence between 20 and 40 years of age; among men, the onset is usually at 40 to 60 years of age. Both sexes, though demonstrate a late-life peak between ages 70 and 75 years (7, 8, 9). Familial occurrence of autoimmune MG is extremely rare including cases of Congenital Myasthenia Gravis (10).
MG is an autoimmune disease in which sensitized T-helper cells and an immunoglobulin antibody G (IgG) direct attack on postsynaptic acetylcholine receptor of muscle cells. The receptor binding antibodies are found in approximately 85% of patients with generalized myasthenia and 55% of patients with ocular MG (5, 11, 12). Approximately 20% of patients with generalized MG and in up to 50% of patients with ocular myasthenia do not present detectable antibodies to the acetylcholine receptor. In such cases the disease is commonly referred to as seronegative myasthenia gravis (13, 14). However, the absence of the antibody does not exclude MG. Other antibodies associated with myasthenia gravis have long been detected in MG patients (15). Several types of antibodies are found in the majority of patients with MG.
About 70% of AChR-Ab-seronegative MG patients have serum auto-antibodies against muscle-specific receptor tyrosine kinase (MuSK), an intrinsic protein of the end-plate membrane. MuSK-positive myasthenia gravis is diagnosed in up to 48% of cases with generalized seronegative MG in different populations- in Polish population accounting for only 8.7% of seronegative cases with generalized MG (16). MG with anti-MuSK antibodies is often characterized with prevalent involvement of cranial, bulbar, and neck muscles, high frequency of respiratory crises, muscle atrophy and excellent response to plasma exchanges (17).
Clinical features & Natural History
The presenting symptoms vary from patient to patient, but in more than half of cases, the initial complaints include fatigable visual blurring, diplopia and/or unilateral or asymmetrical ptosis which worsens towards the end of the day, often followed by nasal speech, difficulties in chewing, and swallowing or by weakness of the upper and lower extremities. The weakness may affect individual muscle groups in more or less isolated fashion, but selective diaphragm weakness is rare. These effects are exacerbated by exercise and repeated movement, and typically improves with rest. The facial expression may be changed and unremarkable. The classical presentation includes a difficulty in closing eyes with characteristic transverse smile (myasthenic snarl). Selective patterns of extraocular muscles weakness may simulate cranial nerve palsies or pseudo-internuclear ophthalmoplegia. Approximately 3% of patients could manifest with predominantly distal weakness. Rarely, patients present with respiratory failure as the initial symptom (18, 19, 20). The symptoms may vary from day to day or even from hour to hour. Most people experience periods of generalized weakness from time to time, which is characterized by weakness in the trunk, proximal limbs, and neck. In 15% of patients, the weakness remains localized to the ocular muscles. Within a 2 years of onset, approximately 90% of affected persons develop generalized MG. Between 50 and 70% of patients with solely ocular symptoms will eventually develop generalized disease, and the vast majority will do so within the first two years. MG may be restricted to the ocular muscles and not generalize (4, 5). Spontaneous Remission without treatment occurred in 10% of patients, within the first 2 years (20).
Persons with myasthenia gravis may experience a sudden exacerbation of symptoms and weakness known as myasthenia crisis – paralysis of respiratory muscles that requires an urgent respiratory support, intubation or to delay extubation following surgery. Approximately 15 to 20% of patients will experience a myasthenic crisis, which usually occurs within the first 2 years after diagnosis of MG. Infections are major provoking factors for myasthenic crisis. Corticosteroids and other immunosuppressive drugs may mask the usual clinical signs and symptoms of infections. It can also follow a surgical intervention. The warning signs of an imminent crisis include: shortness of breath, progressive respiratory and neck weakness, swallowing difficulties and slurred speech, pale or cyanotic skin. Myasthenic crisis is more common in MG associated with thymoma. The use of mechanical ventilation and the widespread use of immunotherapies dramatically improved the prognosis of myasthenic crisis The mortality rate has diminished from 75%, four decades ago to less than 5% currently (21, 22).
Thymus, Thymomas, MG, Malignancy, and Paraneoplastic Disorders
Associated thymic disorder occurs in 80 to 90 percent of myasthenics. Approximately 15% of myasthenics have a thymoma. The thymus gland has been considered to be the source of the autoimmune state of patients with MG. Thymoma is the most common anterior mediastinal tumor in adults. Chest pain, cough, and dyspnea are the most common symptoms. Thymomas are associated with several conditions, including pure red cell aplasia, hypogammaglobulinemia, polymyositis, myasthenia gravis, Lambert-Eaton myasthenic syndrome, subacute sensory neuronopathy, systemic lupus erythematosus, and rheumatoid arthritis. Thymoma-associated of autoimmune myasthenia gravis (MG) may be considered paraneoplastic. Patients with thymoma usually have more severe disease and 5% have inflammatory myopathy (23, 24, 25, 26).
Disorders associated with MG
There is an association between MG and thyroid disease, rheumatoid disease, pernicious anemia and SLE other disimmune pathological processes e.g. diabetes mellitus, thyrotoxicosis, rheumatoid disease, systemic lupus erythematosus, pernicious anemia, and vitiligo. Myasthenic patients with diabetes mellitus could be classified in 2 groups, one group with positive organ-specific autoantibodies to many organs (with type 1 diabetes mellitus), and the other group with diabetes mellitus onset during prednisolone administration (with type 2 diabetes mellitus) (4, 5, 27).
The are several types of antibodies which may be present and detected through serological testing in myasthenic patients. Several AChR antibodies can be measured, including binding, blocking, and modulating antibodies. Antibodies binding against the acetylcholine receptor (AChR) are positive in about 85% of patients with generalised myasthenia gravis (MG) and up to 50% of patients with ocular cases (28). Although the specificity of AChR antibodies for MG is very high, it is not 100%. Rarely, false positive results in AChR binding antibody assays have been observed in patients with other autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory neuropathies, motor neuron disease, patients with thymoma without MG, and relatives of patients with MG (29).
Roughly 15%of patients with MG do not have measurable AChR antibodies. In patients who are seronegatives for these antibodies, anti-muscle specific receptor tyrosine kinase (MuSK) antibodies may be present. Patients with MuSK MG are predominantly female and may exhibit prominent bulbar, facial weakness and tongue muscle wasting (17).
These tests are not done routinely in all patients. Anti-striated muscle antibodies are evident in approximately 30% of MG patients and in 80% of patients with thymoma. Patients with MG and thymoma frequently have high titers of anti-striated muscle antibody. The anti-striated muscle antibodies may be used to screen for the presence of a thymoma, and may correlate with myasthenia gravis severity. Their presence may predict an unsatisfactory outcome after thymectomy. In addition, anti-striated muscle antibodies may be the basis for myocarditis and/or myositis (30, 31).
DIAGNOSTIC PROCEDURES FOR DIAGNOSING NEUROMUSCULAR JUNCTION DISORDERS
Needle electromyography and Nerve conduction studies
Neuromuscular junction disorders often pose a diagnostic challenge. Electrophysiology is the centerpiece of the diagnostic evaluation. Electrophysiological techniques are important for diagnosing and developing treatment plans for patients with neuromuscular disorders.In assessing the routine nerve conduction studies and conventional needle electromyography findings in patients with a suspected neuromuscular junction disorder, it must be appreciated that abnormalities may not be detected. Motor and sensory conduction studies are normal in MG. The presynaptic disorder, such as LEMS and botulism, should always be considered and excluded when the baseline amplitude evoked muscle action potential amplitudes are low or borderline. Pathological electromyographic (EMG) spontaneous muscle activity as fibrillation potentials (due to toxin-induced chemodenervation) are most commonly seen in botulism (32).
Repetitive nerve stimulations
Repetitive nerve stimulation (RNS) is the most commonly used electrodiagnostic test for neuromuscular transmission of a motor nerve while recording compound muscle action potentials (CMAP) from a muscle innervated by that nerve. In this test, a nerve is stimulated 5-10 times by supramaximal repetitive electric pulses evoked single muscle contractions – compound motor action potentials (CMAPs) of a selected muscle innervated by that nerve. Abnormal electrical repetitive nerve stimulations (RNSs) are the hallmark of neuromuscular junction defects. Repetitive nerve stimulation (RNS) distinguishes between pre- and post-synaptic neuromuscular junction (NMJ) disorders. In healthy individuals, slow (2 to 5 Hz) or high frequency (30-50 Hz) rates of motor nerve stimulation do not display CMAP significant change (no decrement).In neuromuscular junction disorders after 2 to 5 Hz the amplitude of the CMAP declines (>10%). In patients with a presynaptic defect in neuromuscular transmission, as it is seen with LEMS or botulism, classic electrophysiologic findings include low CMAP amplitudes, significant facilitation (amplitude increase) after brief exercise. Repetitive stimulation at rapid rates produces similar results (usually>100% above baseline) (32).
In contrast to the standard concentric-needle electromyography (EMG), single-fiber electromyography (SF-EMG) allows identification of action potentials from individual muscle fibers. In practice, the single-fiber EMG electrode record action potentials of two muscle fibers of the same motor unit. Action potentials from another fiber in the same motor unit are recorded with some delay. The variability in timing of the second fiber's action potential called "jitter”. In normal muscle, the time difference between discharges from the two fibers remains close to constant. In neuromuscular transmission disorders jitter values are increased in most muscles, including those that are clinically strong. SFEMG is considered to be the most sensitive electrophysiological method to detect neuromuscular transmission abnormalities in over 90% in generalized MG and in up to 97% of the purely ocular cases (32, 33).
Computed tomography and other testing
Computed tomography (CT) should be performed in patients with MG to identify an abnormal thymus gland or the presence of a thymoma. Pharmacological (Tensilon, Polstigmine) tests and ice pack test are sometimes helpful in the diagnostic evaluation of equivocal cases of ocular MG. Pulmonary function testing may help predict respiratory failure. Since MG often coexists with other autoimmune disorders, patients should be screened for common comorbid autoimmune disorders (4, 5).
Drug-induced myasthenic syndromes
If the patient develops the signs or symptoms of possible exacerbation of myasthenia gravis, the treating physician searches for possible causes. Many routinely used drugs have adverse effects on the neuromuscular junction causing a postsynaptic block or through a presynaptic effect on transmitter release, or even induce, the clinical features of MG. Drug-induced myasthenic syndromes are characterized by progressive, and usually proximal and symmetric, muscle weakness. As any drug can potentially worsen neuromuscular transmission, the practitioner should be certain that a given drug does not have these effects before starting therapy in a myasthenic patient. Symptoms and signs of the myasthenic syndrome develop days to weeks after drug administration. The symptoms are generally mild and may be limited to extraocular muscles. However, some patients may develop respiratory failure. The condition usually recovers after cessation of the drug. The list includes many antibiotics (aminoglycosides, macrolides, ampicillin, streptomycin, neomycin, tetracyclines), anesthetics (diazepam, ketamine, propanediol, lidocaine, proparacaine, muscle relaxants), anticonvulsants (phenytoin, barbiturates, carbamazepine, ethosuximide, gabapentin), cardiovascular drugs (verapamil, amlodipine, nifedipine, propranolol, quinidine), anti-rheumatics (chloroquine, penicillamine), antipsychotics (phenothiazines, lithium), hormonal medications (corticosteroids, thyroxine), anti-spasmodics (atropine, oxybutinin, Buscopan) magnesium salts, and intravenous radiographic contrast media. Some drug categories (eg, cholesterol lowering drugs, H-2 receptor antagonists, ophthalmic solution) should be used with caution, but they are not strongly contraindicated (34, 35, 36, 37).
LAMBERT-EATON MYASTHENIC SYNDROME
Lambert-Eaton myasthenic syndrome (LEMS) is a disease of the neuromuscular junction that is distinct from myasthenia gravis. In LEMS antibodies to presynaptic muscle calcium channel components are present in most patients. The reduction in calcium influx causes a reduction in acetylcholine release into the synaptic cleft. Affected individuals develop fatigable muscle weakness predominantly in the proximal muscles of the lower extremities and autonomic dysfunction. Bulbar symptoms, respiratory weakness and ptosis can occur but are generally milder than with myasthenia gravis (38). Muscle weakness is often associated with aching and stiffness. Exercise may initially improve the muscle strength, but the weakness may become more pronounced as activity is sustained. Autonomic features, especially dryness of the mouth, impotence, constipation, dilated, poorly reactive pupils, and sudden drops in blood pressure when rising from lying down to sitting or standing. Exercise may initially improve the muscle strength, but the weakness may become more pronounced as activity is sustained. Cancer is found in approximately 70% of Lambert-Eaton myasthenic syndrome patients. The most common underlying tumour is small cell lung cancer (39). The typical pattern of electrophysiologic abnormalities is the hallmark of LEMS. This includes a low compound muscle action potential at rest and a remarkable increase (facilitation) in the size of the muscle response to stimulation of its motor nerve at high rates (20-50 Hz) or immediately after 15-30 seconds of maximal muscle contraction (40).
Botulism is an illness caused by one of the several types of neurotoxin (usually A, B, or E) produced by the anaerobic bacterium Clostridium botulinum, which blocks the release of ACh from the motor nerve terminal. Gastrointestinal dysfunctions such as diarrhea, nausea, and vomiting precede the onset of cranial weakness with ocular, bulbar manifestations, and respiratory failure (41). The electrophysiologic abnormalities in radiculopathies include long- lasting incremental response at fast rates of stimulation, but not as dramatically as Lambert-Eaton myasthenic syndrome (42).
DIFFERENTIAL DIAGNOSIS AND WORKUP
The diagnosis of generalized MG may be made on clinical basis. However, laboratory testing is recommended, for confirmation. Disorders that may cause symptoms similar to MG include Lambert Eaton syndrome (LEMS), botulism, congenital myasthenic syndromes, Miller-Fisher syndrome cervical-brachial-pharyngeal variants of acute inflammatory demyelinating polyradiculoneuropathy (AIDP), tick paralysis, and chronic fatigue syndrome. For ocular myasthenia, the differential diagnosis includes posterior fossa lesions, thyroid disease and mitochondrial myopathies. Lambert-Eaton myasthenic syndrome, myopathies, botulism, and motor neuropathies must be considered in patients with generalized weakness. In cases with restricted bulbar involvement, brainstem stroke, botulism, motor neuron disease have also been reported to mimic the clinical features of MG. Other conditions that can occasionally cause confusion are oculopharyngeal muscular dystrophy, cranial neuropathies (4, 5, 13, 18, 19).
Therapy for MG has improved dramatically over the past 50 years. Previously, the mortality rate was as high as 30-70%. In the modern era, this has been reduced practically to zero with current therapy. The treatment of myasthenia gravis includes the use cholinesterase inhibitors, corticosteroids, immunosuppressive treatment, immune-directed therapy, and thymectomy. Treatment choices must be individualized according to the degree of functional impairment, the patient's age and gender. The response to treatment is difficult to assess due to fluctuating intensity of the disease symptoms.
Cholinesterase inhibitors such as pyridostigmine (Mestinon) are frequently the initial therapy for symptomatic relief. They are usually the initial drugs used in the treatment of mild myasthenia gravis. Cholinesterase inhibitors help to improve neuromuscular transmission and muscle weakness by preventing the degradation of acetylcholine in the synaptic cleft and prolong its effect. As a sole drug they are not sufficient for most patients with generalized symptoms. Dosage should be individualized. The need for cholinesterase inhibitors varies from day to day and during the same day in response to emotional stress, menstruation, and hot weather. Initial dosing of pyridostigmine bromide is usually 30 mg three times a day and may be increased as tolerated to a maximum of 480 mg/day. Adverse effects of cholinesterase inhibitors relate to increased muscarinic activity and include gastrointestinal complaints (loose stools, nausea, vomiting, abdominal cramping, diarrhea), and increased lacrimation, salivation, and bronchial secretions. The excessive anticholinesterase therapy can cause increasing weakness, due to cholinergic crisis. Cholinergic crisis results from an excess of cholinesterase inhibitor as of a result of the inactivity of the AChE enzyme and may cause nausea, vomiting, bronchospasm with wheezing, respiratory failure, bradycardia, increased sweating, salivation, miosis (constriction of the pupil), and flaccid muscle paralysis that is clinically indistinguishable from weakness due to MG (43, 44).
Patients with generalised MG, in mild to moderate disease that fails to respond fully to acetylcholinesterase inhibitors, usually require corticosteroid therapy. Marked improvement or remission occurs in 80% MG patients treated with prednisone. Increasing age correlated with a favorable outcome. Patients with thymoma have an excellent response to prednisone before or after removal of the tumor. The initial prednisone dose is typically 60-80 mg/day until the onset of improvement, followed by lower-dose alternate-day therapy of several years' duration (45). Side effects of long-term treatment with glucocorticosteroids include weight gain, peptic ulcer, diabetes, hypertension, glaucoma, cataracts,aseptic necrosis of the hip, osteoporosis, cerebral pseudotumor, myopathy, psychosis and depression. Also, high-dose corticosteroids can induce worsening of MG symptoms, including precipitating a myasthenic crisis (46).
Nonsteroidal immunosuppressive drug therapy
Alternative immunosuppressive agents may be considered in patients with incomplete response to corticosteroids or serious side effects associated with long term steroid treatment. Azathioprine and cyclosporine are the most common immunosuppressant used.Azathioprine (Imuran) has been in use for a long time and it is one of the best tolerated immunosuppressive therapeutic agents. Approximately 15% of the patients develop troublesome side effects such as allergic reaction with rash, fever, nausea, abdominal pain, bone marrow suppression, and liver toxicity. Long-term azathioprine therapy is associated with a small increased risk for lymphoma. Cyclosporine has also been shown to be effective in the treatment of MG. Side effects of cyclosporine include hypertension, nephropathy, tremor, headaches, and nausea. Nephrotoxicity is the main reason for discontinuation of the drug (47, 48, 49).
Plasma exchange (plasmapheresis) removes AChR antibodies from whole blood and brings rapid but the only short-lasting clinical improvement. Possible uncommon complications include coagulation disorders, hypotension, fluid overload and congestive heart failure (50).
Intravenous immunoglobulin (IVIg) therapy has the same indications as plasmapheresis including severe myasthenia gravis, myasthenic crisis, and perioperative and postoperative period. IVIg has a similar efficiency to plasmapheresis. Side effects include solute-induced renal failure, malaise, hypersensitivity, aseptic meningitis, and rarely stroke, myocardial infarction, and renal failure (51).
Because most patients with MG have thymic abnormalities, removal of the thymus is recommended. Thymectomy has been considered a potentially beneficial treatment for most patients with generalized symptoms. Thymoma is an indication for thymectomy because the tumor is often locally invasive. In the absence of thymoma, the current practice is generally not to recommend thymectomy for patients over age 60.Removal of thymoma may not improve MG. In some cases post-operatively, a transient but dramatic improvement may be observed that may persist for several days. In most patients, the dose of anticholinesterases is reduced for few days after surgery. Approximately, 80% of affected MG patients have significant benefit and even remission from their myasthenic symptoms. Prolonged clinical improvement is typically delayed by 6 months to 1 year after surgery (23, 24). Myasthenia gravis may be associated with increased risk of extra thymic malignancies. Some studies have also noted a higher than expected incidence of second primary malignancies in patients with a thymoma (52).
THE ELDERLY AND HUMAN AGING
Due to improvements in medical care, healthier lifestyles, and, better nutrition, life expectancy has been prolonged to levels that were unthinkable in previous centuries. The increase in longevity accompanied by the decline in fertility is the universal cause of the aging of the population. The percentage of the population constituted by elderly people is 13-14% in developed countries. This growing elderly population will challenge health and social services in the coming decades (53). Patients with MG have a high prevalence of various comorbid disorders. Most of them present in the elderly also exist in younger patients; however, the incidence and presentation of these diseases can differ greatly between these two age groups. Elderly patients tend to have serious comorbidities that can interfere with patients' recovery. Aging naturally affects a variety of processes in the human body. Most of the body's organs perform less efficiently with advancing age. Several general changes take place in the human body as it ages: hearing and vision decline, muscle strength lessens, bone density gradually decreases, endocrine, immune, respiratory and circulatory functions declines. The elderly are affected by many muscosceletal symptoms as they age, which often have an impact on their health, ability to function, and overall quality of life. The muscle function is disrupted at many levels with aging. The most reported consequence of aging is the loss of skeletal muscle mass, known as sarcopenia. The complex interaction natural neurodegenerative processes, imbalance between protein synthesis and breakdown rates, reduced levels of circulating anabolic hormones, reduction in sensitivity top insulin, growth and sex hormones, modification in the response to inflammatory events, inadequate nutritional intakes and sedentary lifestyle are thought to contribute to the pathogenesis of sarcopenia. Skeletal muscles supply movement for the body and posture. Loss of skeletal muscle mass leads to the gradual changes in posture observed with age. The weakness that accompanies sarcopenia is an important risk factor for falls and fractures, reduced ability to breathe deeply, reduced gastrointestinal activity which can lead to constipation, and contributes to bladder incontinence, particularly in women. Aging is accompanied by many other structural changes, like a flattening of the folds of the endplate at the neuromuscular junction and decrease in spinal cord motor units (54).
MEDICAL PROBLEMS ASSOCIATED WITH AGE AND MYASTHENIA
More than 30% of adults who are older than 65 yr experience one or more falls per year, with a higher incidence of falls being common in frail individuals or those with disabilities (55, 56). Furthermore, falls are the most common cause of injuries and hospital admissions being the ninth most common cause of death in this age group (57). Postural stability requires the interaction and continual activity of musculoskeletal and sensory systems which act to inform the brain of the position and movement of the body in three dimensional space. Normal ageing is associated with changes in function of each of the subcomponents of systems which contribute to postural stability (58, 59). Increased falls incidence is evident in persons with neurological conditions, arthritis and diabetes. Factors found to be highly correlated with increased postural instability include reduced lower extremity muscle strength and reduced visual acuity (59, 60). Falls and fear of falling can result in restriction of activity, reduced quality of life and independence.
Respiratory failure in neuromuscular disorders
Age-related changes in respiratory functions have an impact on pulmonary reserve and decrease the respiratory system's ability to respond to physiological stress and disease. Respiratory failure is more common in the elderly than younger age groups (61). The decline in pulmonary function have been associated with variable prognosis in elderly patients and increased risk of death in older populations (62). Because it is essential that gas exchange with the atmosphere takes place, the respiratory system is highly vulnerable to air pollution, toxic agents and infection. Weakness of the respiratory and bulbar muscles makes breathing, coughing, and swallowing control difficult. A person with bulbar weakness may become hoarse or tired after speaking at length, or speech may become slurred. There is a higher risk of aspiration of food particles or saliva. Aspiration increases the likelihood of lung infection. Pneumonia and aspiration pneumonia is probably the most common precipitating cause of respiratory failure in the elderly population (63). Age-related medical problems are associated with poor outcome in patients with community- acquired pneumonia (64). Respiratory failure is commonly seen in group of patients with previous chronic lung diseases such as chronic obstructive pulmonary disease (COPD), and asthma. The largest group of patients, however, has no underlying disease but has respiratory failure develop because of an acute disorder of one or more components of the respiratory system. Ventilation with pulmonary gas exchange is dependent on diaphragm and chest wall muscle functioning. A neuromuscular diseases cause weakness of respiratory muscles limit ventilation and lead to hypercapnic respiratory failure. Hypoxemia is the major immediate problem faced by all patients with respiratory failure. Failure of carbon dioxide exchange causing respiratory acidosis. Because clinical hypercapnia almost always occurs with some degree of hypoxemia, it is often difficult to determine whether a specific manifestation is the consequence of hypercapnia or hypoxemia. Respiratory muscle weakness can be severe enough to require mechanical ventilation. The clinical manifestations of acute hypercapnia are primarily neurologic. Symptoms of hypercapnia and hypoxemia include headache, altered mental status, drowsiness, depressed consciousness, combativeness, or coma (65). Patients with hypoxemia may display tachycardia, tachypnea, and chest pain from myocardial ischemia.
Cognition, mental fatigue and sleep disturbances in MG
Nicotinic receptors are located in both the central nervous system CNS and in the periphery. Some recent investigators have suggested that antibodies to the peripheral receptors cross-react with central receptors. However, essentially there is no evidence that central nicotinic receptors are affected in MG (66). Many MG patients reported that fatigue produced mild to moderate effects on cognitive function. Severe MG was associated with impaired attention, and constructional praxis. Many studies do not support the hypothesis of CNS cholinergic involvement in MG. The impairments of attention, memory, and control tasks in MG are related to general visual motor slowness and to the concomitant presence of other diseases. Despite of the absence of direct central involvement by MG, approximately 60% of patients describe experiencing memory loss, however, the retention of information did not differ between MG patients and healthy control subjects. This pattern of performance is markedly different from what is observed in affecting the central cholinergic system Alzheimer's disease. There is a strong evidence that peripheral fatigue produces some effects on cognition (67, 68). Older adults frequently experience difficulties with sleep. These disturbances are often secondary to medical disorders, medication use and circadian rhythm disturbances (69). Associations with many sleep abnormalities have been noted in patients with MG. In MG respiratory function is often disturbed in the night, despite of normal daytime respiratory function. Central and obstructive apneas are common complications for patients with muscle disease. In MG 60% of patients have apnea and hypopnea during REM sleep. Significant excessive daytime sleepiness, depression, concentration and memory problems can be symptoms of a sleep related breathing disorder (70, 71).
Extrapyramidal symptoms and botulinum toxin injections
Patients with MG have been reported to have coexistent Parkinson's disease, blepharospasm and dystonic syndromes (72, 73, 74). Jankovic and Patten reported coexistent blepharospasm with myasthenia gravis (75). Borodic reported myasthenic crisis in 80-year-old woman previously injected with botulinum toxin (type A-BOTOX-TM) for essential blepharospasm (76).
Bladder dysfunction and urinary incontinence
Urinary continence results from a complex interaction between the bladder (detrusor), urethra and pelvic floor muscles. Both the male and female sphincter includes the striated muscle surrounding the urethra innervated through the S2-S4 nerve roots via the pudendal nerve (77). Association between MG and voiding dysfunction is unusual, but a number of individual case reports have been published (78, 79, 80, 81, 82). Lower urinary tract dysfunction is a major cause of morbidity and decreased quality of life in elderly men and women. Urinary incontinence is the most common problem and is reported to affect up to 30% of elderly individuals in the community and 50% of those in nursing homes (83, 84). Incontinence is associated with increased the risk of patient falls. Nocturia, urgency, as well as urge incontinence have also been shown to increase the risk of falls. (85). Falls related to incontinence are generally thought to result from loss of balance when rushing to the toilet or urinary incontinence episodes may lead to slips on wet floor surfaces.
Weight loss and malnutrition
Weakness of the facial and bulbar muscles results in impaired speech and swallowing. Difficulty swallowing may be worse with liquids. The most important potential consequences are dehydration and aspiration. Chewing may worsen during meals. Poor nutritional status, inadequate energy intake accompanied by the presence of unex-plained weight loss and muscle wasting, can lead to decreased immunocompetence, depression and an increased rate of disease complications (86, 87). Chronic neurogenic dysphagia with high risk of aspiration and malnutrition are established indications for percutaneous endoscopic gastrostomy (PEG) placement (88).
Heart disease in myasthenia gravis
Myasthenia gravis primarily affects skeletal muscles, but some patients with MG may develop heart diseases with arrhythmia, bundle branch block, and cardiac failure. Patients with MG have antistriational antibodies to the heart and skeletal muscles. The incidence of high cardiac abnormalities in patients with thymomas is usually associated with myocardial involvement (myocarditis or pericarditis) (89, 90, 91).
Anesthesia and Surgery
When possible, patients with MG should be admitted for elective surgery while the patient's physical and emotional states should be optimized. Patients should be admitted few days before surgery to allow detailed preoperative evaluation and review of drug therapy. Plasmapheresis has been used to improve patient's condition prior to major surgery (e.g., thymectomy) to reduce the risk of post-operative complications and postoperative morbidity. Anticholinesterase therapy should be withheld on the morning of surgery to avoid interactions with other drugs used in the operating room. The anesthetic management of the myasthenic patient must be individualized to the severity of the disease and the type of surgery. Myasthenic patients may be at increased risk of developing postoperative respiratory failure and prolonged muscle paralysis. Thus, many patients require prolonged postoperative ventilation (92, 93).
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