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© 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
Streszczenie
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.
Summary
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.



INTRODUCTION
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
Introduction
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).
Epidemiology
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).
Pathophysiology
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).
Myasthenic Crisis
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).
Acetylcholine-Receptor Antibody
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).
MuSK antibodies
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).
Other Autoantibodies
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).
Single-Fiber Electromyography
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
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).
TREAMENT
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

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otrzymano: 2010-04-07
zaakceptowano do druku: 2010-05-20

Adres do korespondencji:
*Marek Leszek Kamiński
Klinika Neurologii z Pododdziałem Udarowym i Wczesnej Rehabilitacji Poudarowej, Uniwersytet Medyczny w Lublinie
ul. Jaczewskiego 8, 20-954 Lublin
tel.: (81) 72-44-541, fax: (81) 72-44-540
e-mail: marekleszek@onet.pl

Postępy Nauk Medycznych 6/2010
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