Myasthenia Gravis and Myasthenic Syndromes (continued)

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MYASTHENIA GRAVIS

MG is an autoimmune disorder that affects the postsynaptic portion of NMJ transmission due to a reduction in the number or functioning ACh receptors.

Clinical Spectrum

MG is characterized by easy fatigability and weakness, primarily of ocular, bulbar, truncal, or proximal limb muscles (11), and can be fatal when respiratory muscles weaken enough to require mechanical, so-called myasthenic crisis. It is also characterized by fluctuations that occur over a day, weeks, months, and years, resulting in exacerbations and remissions. The distribution and severity varies among individuals. There are a large number of available treatments, the choice of which is guided by clinical factors. The onset may be sudden or insidious, with mild symptoms that wax and wane. Early symptoms may be so subtle as to escape detection for years such as double vision or mild ptosis. The areas of involvement increase over time. The first useful clinical classification system was developed by Osserman (12) (Table 2) and thereafter modified.

Ocular MG generally includes ptosis and diplopia. Bulbar symptoms of dysphagia and dysphonia may occur early in the course or follow generalized limb involvement. Respiratory involvement is a late manifestation and never occurs alone; however, some patients can have isolated vocal cord paralysis. Muscle weakness in MG is characterized by fatigability. Strength is near normal at the onset, but with effort, particularly against firm resistance testing, muscle weakness is detectible due to fatigue. Respiratory fatigue is more complex but can precipitously worsen after a period of compensation.

Natural History

Untreated, the natural history of MG is difficult to determine because many current therapies such as prednisone were available even early in the clinical description of the disease. In an early series at the turn of the century, it was found that a third of affected patients progressively worsened. Another one third had relapsing and remitting symptoms, and the remainder improved and led active lives for a period of time (13).

The contemporary natural history includes several important clinical points. Despite a large number of therapeutic regimens to enhance strength and promote remission, the most important improvement in clinical care has been the advent of positive pressure ventilation and respiratory critical care units to reduce mortality and morbidity from myasthen1c crisis (14) and to permit safe performance of thymectomy. When the clinical course of a large number of patients are plotted, the maximal state of weakness during an exacerbation is usually experienced within the first 3 years, and the extent and severity will be evident during this time. Therefore, if ocular MG has not progressed to generalized involvement within 3 years, it is unlikely that it will do so (14).

Pathology

The pathologic alterations in MG are at the postsynaptic membrane and include simplification of the postsynaptic end-plate region with fewer and more shallow folds and a reduction in the number of ACh receptors. These changes result from antibody attachment to the receptors and activation of the complement cascade and receptor lysis by membrane attack complex (15,16). There are undoubtedly other mechanisms involved because some antibodies detected in the serum do not directly bind to the ACh receptor. In normal individuals, the half-life of the ACh receptor is approximately 12 days, but 3 days in MG. The various types of ACh receptor antibodies in MG are operationally defined and based on laboratory testing procedures. Binding antibodies are detected by reaction of the patient serum with solubilized human skeletal muscle ACh receptor. Modulating antibodies are detected by reactivity with ACh receptor on living muscle and may be positive when the binding antibody is negative. Blocking antibodies are detected by binding of sera at or near the neurotransmitter binding site on solubilized human ACh receptors. There is a hierarchy of testing based on the frequency of occurrence (Table 3). Despite testing for three types of antibodies, only 80 to 86% of patients are seropositive. The false-positive rate is extremely low (17), and the specificity for MG is high.

TABLE 3. Muscle-specific autoantibodies associated with myasthenia gravis

Approximately 15% of patients with MG are seronegative based on the antibody panel described above. Seronegative patients are believed to have an autoimmune pathogenesis similar to the seropositive cases because defects in NMJ transmission can be passively transferred to experimental animals by serum or by the IgG fraction (18), but their diagnosis can be problematic because 50% have ocular symptoms alone and other diagnostic tests may be equivocal (19). Other organ-specific autoantibodies occur at a higher than expected frequency in patients with MG (20), including those to thyroid microsomes, thyroglobulin, and to gastric parietal cells. In seronegative patients with equivocal but suggestive symptoms of MG, these antibodies are supportive of the diagnosis of autoimmune MG (21).

Autoimmune Features

MG is a prototypic autoimmune autoantibody-mediated disease. Although the clinical focus is on the humoral arm of the immune system and autoantibodies to the ACh receptor, the disease starts with the cellular arm of the immune system, perhaps with a breakdown of T-cell tolerance. The normal process of T-cell tolerance is not fully understood, but it takes place in the thymus gland (22), as does the loss of tolerance in MG. While awaiting a full understanding of the physiologic and pathophysiologic processes of autoantibody diseases, several points are pertinent to the clinical diagnosis and management of MG. Because it is a specific autoantibody disease, there must be exposure of T cells to the ACh receptor, either from myoid cells in the thymus or peripherally The exposure and subsequent breakdown of self-tolerance is a complex process and probably involves genetic susceptibility The result is activation of B cells and the production of specific autoantibodies. Once this process has begun, there are immune mechanism that regulate T-cell activity that affect the production of specific autoantibodies (22).

Pathophysiology

The pathophysiologic abnormality in MG results from a reduced number of ACh receptors. Fewer sodium channels open and the resultant EPPs have a slower rising phase and reduced amplitude. If the EPP amplitude does not depolarize the end-plate membrane to threshold, a muscle fiber AP will not be produced, NMJ transmission will fail, and the fiber will not contract or generate force (Table 4). A slower rise phase of the EPP, if it has sufficient amplitude to reach threshold, will have no clinical effect, although the slight delay in initiating the muscle fiber AP can be detected by SFEMG.

TABLE 4. Descriptive model of the dynamics at an abnormal NMJ due to myasthenia gravis during low-frequency repetitive stimulation

When NMJ transmission fails in MG, any method to increase the concentration of ACh at the receptor site increases the number of channel openings and improves amplitudes. There are two methods to increase the concentration of ACh. One is to increase the quantal release of ACh, which can be accomplished physiologically by increasing the concentration of calcium in the presynaptic terminal. A high-frequency train of presynaptic APs will overcome the calcium buffering capacity and result in greater quantal release. The second method is by reducing the rate of ACh hydrolysis by inhibiting the enzyme AChE. This can be accomplished by several drugs such as edrophonium and pyridostigmine. The effect of Increasing the ACh concentration on a model of NMJ transmission can be seen in Table 4.

Diagnosis

The diagnosis of a defect in NMJ transmission may be clear when the history indicates and examination findings reveal fluctuating weakness and fatigue, especially of ocular, bulbar, and proximal limb muscles. The physical examination should include prolonged testing of strength if necessary to bring out fatigue, particularly when the patient is already medicated with prednisone. It is essential to determine whether an NMJ disorder is due to a postsynaptic or a presynaptic defect, such as Lambert-Eaton myasthenic syndrome (LEMS). Elevated titers of ACh receptor antibodies are highly correlated with MG but can also occur in LEMS (22a). It is important therefore to carry out electrodiagnostic testing to recognize a presynaptic defect by facilitation of the CMAP after exercise. Positive ACh receptor antibodies in patients with LEMS are thought to represent a nonpathologenic epiphenomenon and not the coexistence of both diseases.

Tensilon Test

Defects in NMJ transmission can be demonstrated by showing a brief improvement in transmission in the form of restoration of strength by giving a short acting AChase inhibitor. The rationale is based on demonstration of a clear difference comparing before, during, and after the intravenous administration of Edrophonium (Tensilon), which blocks AChase for two or three minutes. It is important that there be clearly weak muscle groups to follow because when symptoms and signs are mild and limited to ocular muscles, false positive diagnoses of MG may occur (22b). There are protocols for performing the Tensilon test in a double-blinded, placebo -controlled manner (39). It is emphasized that a positive Tensilon test does not distinguish between the various forms of presynaptic and post synaptic NMJ transmission failure.

Repetitive Stimulation

For there to be a demonstrable decrement to repetitive stimulation, a finite number of NMJs must have a failure of transmission. Abnormal NMJs fall during even low levels of repetitive stimulation, which forms the basis for this electrophysiologic test. A practical and effective testing paradigm is to measure the amplitude of the CMAPs to five shocks at 2 to 4 Hz (23,24). The NMJ safety factor ensures sufficient ACh released to produce APs in all muscle fibers, and the CMAP amplitude will not change from shock to shock. However, when there is a reduction in the number of receptors due to a postsynaptic defect or a reduction in ACh release resulting from the presynaptic defect, there may be failure of transmission at some NMJs. This will be evident by a reduction in the CMAP amplitude by the third shock, as the immediate pool of ACh is depleted. This is termed the decremental response (Fig. 5). The extent of the CMAP amplitude decrement depends on the number of NMJs that fail and may not be evident in very mild defects in NMJ transmission. The increase in ACh release by the activation of the mobilizable ACh pool after the third shock will, in turn, result in an increase in the number of NMJs successfully transmitting, and the CMAP amplitude to the fourth shock will show an increase. This results in a U-shaped decremental pattern to the five CMAPs (Fig. 5).

Increasing the presynaptic calcium concentration increases the amount of ACh released and restores NMJ transmission at some failed junctions. This can be accomplished by having the patient voluntarily maximally activate the muscle group being tested for 10 to 15 seconds. If repetitive nerve testing is repeated in I to 2 seconds after exercise, there will be partial repair of the initial decrement. NMJ transmission is most prone to failure 2 to 4 minutes after 10 to 15 seconds of maximal exercise. If repetitive nerve stimulation is performed at this time, a greater degree of decrement will be observed or the subtle defect will be evident (Fig. 5) (24), so-called posttetanic exhaustion.

A number of procedural and technical issues increase the sensitivity of repetitive stimulation. Physiologically, the safety factor suggests that there should be no decrement to repetitive stimulation in a normal muscle (Table 1). However, many texts and reference manuals allow for some decrement in normal muscles and consider up to 8% normal. There are a number of possible reasons for the low percentage decrement in normal muscle. One is a change in stimulation current during the stimulation train due to movement of the limb. This can be reduced by using stimulus intensities of 150% of maximum and by immobilizing the limb (25). Most EMG machines calculate decrement from the negative peak CMAP amplitude. Many also use the isolectric line before the first CMAP as their baseline for amplitude measurement. If there is movement of the isolectric line for subsequent shocks, there may be calculation errors. Measurement of peak-to-peak CMAP amplitude is less susceptible to these types of errors (26).

Repetitive stimulation can be incorporated into routine nerve conduction studies that are usually performed on distal limb muscles. Decrement may not be observed in these muscles if the MG is mild or affects ocular muscles alone; however, testing of a proximal muscle such as trapezius muscle along the spinal accessory nerve may be informative (27). Stimulation of the facial nerve is associated with movement artifact and is therefore technically more difficult. There are issues yet unresolved of the mathematic expression of decrement (25) and the separation of true decrement and facilitation from pseudofacilitation (28).

Several practical guidelines can be offered to enhance the accuracy of repetitive stimulation and to reduce false-positive decremental responses to as low as 3%. First, a true decremental response must be properly pathologic with a U-shaped response, that is, less decrement by the fourth shock. Second, it should be reproducible with the same pathologic decrement seen with varying percentages on several separate trials. Third, it should show a physiologic response to an increase in presynaptic terminal calcium after 10 seconds of exercise, an improvement in the decremental response.

Single-Fiber Electromyography (SFEMG)

This is an electrophysiologic technique that analyzes the variability of NMJ transmission as a discharge-to-discharge variability in timing of single muscle fiber APs (5,29) (Fig. 6). This variability, called jitter, which is measured in microseconds, reflects slow EPP rise times and delayed generation of muscle fiber APs. When the EPP falls to reach threshold, jitter is infinite and the AP is blocked. It should be clear that SFEMG can detect abnormal jitter without blocking, whereas repetitive nerve stimulation only detects blocking (30,31). It requires a special concentric EMG needle with the exposed active electrode surface along the side of the needle and computer software to measure the variability. As most commonly measured, NMJ transmission is initiated by weak voluntary contraction, and the covariability of two NMJs is recorded. Alternatively, transmission can be initiated by electrical stimulation of motor nerve branches, and the variability of one NMJ is recorded. The normal range of jitter values has been determined empirically and differs among muscles and according to age (32). Abnormal jitter does not distinguish between presynaptic and postsynaptic defects of transmission. However, by stimulation of the motor nerve electrically, the discharge frequency at which maximal jitter occurs can help distinguish patterns suggestive of pre- or postsynaptic defects (33).

Comparison of Diagnostic Techniques

A suggestive clinical history and examination provides the impetus to proceed with confirmatory clinical, electrophysiologic, and serologic laboratory studies in MG. Diagnostic specificity for MG comes close to 100% when ACh receptor antibody titers are present, although their absence does not exclude the diagnosis. The edrophonium test, repetitive nerve stimulation, and SFEMG are specific for the defect in NMJ transmission. The sensitivity of the edrophonium test and repetitive nerve stimulation depends on the distribution and severity of symptoms. Ocular and mild generalized MG may present difficulty when the findings are subtle or mild. SFEMG is more sensitive in ocular MG and mild generalized involvement because it detects abnormalities that do not cause blocked transmission. A direct comparison of antibody testing, the Tensilon test, repetitive nerve stimulation, and SFEMG performed in the same patients has been made (Table 5) (34). SFEMG was the most sensitive for both ocular and generalized weakness when affectedmuscles were studied (99% to 89%). Antibody tests were more sensitive for generalized MG (80%) and less for ocular MG (55%). Repetitive nerve stimulation was almost as sensitive in the generalized form (76%), but least in the ocular form (48%).

TABLE 5. Comparison of a series of diagnostic tests performed in 550 patients with myasthenia gravis

Mediastinal Imaging

Approximately 10% of patients with MG will have evidence of a thymoma on computed tomography (CT) of the chest. Thymomas are clinically silent except for their association with weakness in MG; even so, only 40% of thymomas are associated with MG (35). Their presence cannot be predicted by the clinical features of MG, and therefore imaging is necessary. CT of the chest, not magnetic resonance imaging, is still the test of choice (36).

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