Myasthenia Gravis and Myasthenic Syndromes (continued)

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Treatment

Concepts

MG is a chronic disease with no cure at this time. The goal of treatment is sustained and complete remission, defined as the absence of symptoms and signs, with no medication. For many patients, complete remission may be elusive, and partial remission is a more practical goal (37). Therapy can be divided into three categories: drugs that improve NMJ transmission and the symptoms of weakness but do not affect the course of the disease, including the AChE inhibitors; procedures that affect the immune system over a limited time period but probably do not affect the natural history of the disease, such as plasmapheresis and intravenous immunoglobulin (IVIg); and drugs and procedures that modify the course of MG such as the immunosuppressants prednisone and azathioprine, and thymectomy.

Quantitative Testing

In certain patients, it may be difficult to determine if a particular therapeutic regimen is effective. For example, some may report worsening of symptoms, whereas strength appears unchanged or even improved. Under these circumstances, it is helpful to have quantitative data for objective comparisons. One quantitative scale that was developed as an end-point measure in a drug trial can be used clinically to determine overall function (38); however, it is important to try to carry out the measurements at the same time of the day or regularly at the time of the last dose of pyridostigmine. A frequently encountered problem Is the differentiation of steroid myopathy from MG, especially when weakness advances on prednisone. Summing the values of decrement to repetitive nerve stimulation of several nerves or average neuromuscular jitter from SFEMG measurements can be helpful. Electrodiagnostic values are usually unchanged or improved in steroid myopathy and worse during an exacerbation of MG, so emphasizing the importance of establishing baseline electrodiagnostic values even in those whose diagnosis is made on the basis of elevated ACh receptor antibody titers.

Acetycholinesterase Inhibitors

Pyridostigmine (Mestinon) is the most commonly used ACK inhibitor. It reversibly binds to AChase and slows the hydrolysis of ACh, raising the concentration of ACh at the junctional folds and increasing the probability of ACh remaining attached to functional receptors. This leads to EPPs with a more rapid rise time and a higher amplitude and thus a greater likelihood of generating APs in previously blocked muscle fibers. It reaches peak serum concentrations in 90 to 120 minutes and has a similar half-life. Doses of 60 to 120 mg every 3 to 4 hours are most effective, but patients may modify their dose to match their level of activity and to reduce the common adverse side effects of cramping and diarrhea. It is rare for pyridostigmine alone to improve transmission to a satisfactory level, and therefore most patients require more definitive therapy (39).

Plasmapheresis and Intravenous Immunoglobulin

Plasmapheresis and IVIg rapidly influence the immune system but are of limited duration (40). A recent comparison of plasmapheresis and IVIg demonstrated equal effectiveness (41) and probably equivalent expense; however, they differ in their proposed mechanisms of action and thus may be complementary therapies in MG. Plasmapheresis removes antibodies, presumably those that act at the NMJ, but may also modulate the immune system. The response to plasmapheresis occurs over hours to days and is useful to treat or abort myasthenic crisis, but it requires special equipment to separate blood into components and trained personnel and is thus not widely available. A therapeutic trial usually consists of four to six exchanges on alternate days. The procedure is well tolerated but requires good venous access, and patients may require placement of a central venous catheter. Most complications are those associated with central catheters. IVIg consists of pooled exogenous antibodies from thousands of donors. Although the precise mechanisms of action are not well understood, exogenous antibodies interact at several different sites, including binding to the autoantibodies, to idiotypic antigenic sites, and to T cells to modulate the immune system (42,43). It does not require special equipment, and infusions can be performed easily with routine nursing care. The recommended total monthly dose is 2 g/kg in five daily doses, administered slowly enough to avert rate-related side effects. Repeat doses are usually I g/kg over I to 2 days. The most effective schedule has not yet been determined; however, the half-life of IVIg is about 4 weeks, and monthly doses are reasonable, with the goal of slowly tapering the frequency of treatments based on the clinical status. Clinical responses occur over 2 to 4 weeks.

Corticosteroids

Corticosteroids occupy a central role in the treatment of MG because of their effectiveness and reliability in initiating and maintaining a prolonged remission. Corticosteroids affect the immune system at several different levels (44), but the mechanism of influence on MG has not been established. Prednisone is the most widely used oral agent given initially at doses of 40 to 60 mg daily for 3 to 6 weeks and then slowly tapered after a beneficial response is seen. For unclear reasons, a high percentage of MG patients experience temporary worsening of their weakness that sometimes culminates in crisis after high initial doses; accordingly, patients receiving 100 g or more should probably be monitored Initially in a hospital setting. Alternatively, the patient can be given a low dose and slowly increased over weeks (40). Although many prednisone taper protocols are followed, one goal is to convert relatively early in the taper schedule to alternative-day dosing to reduce the short-term side effects of weight gain and hyperglycemia, osteopenia, gastric and duodenal erosion, and cataracts (45). A short course of 2 g intravenous methylprednisolone followed by a second infusion 5 days later is sometimes effective in aborting myasthenic crisis, but this has never been formally studied (46).

Azathioprine

Azathioprine (Imuran) has been used in patients with poor responsiveness, intolerance, or frequent relapses with corticosteroids and as a steroid-sparing agent in conjunction with prednisone to reduce the long-term side effects (47); however, azathioprine is less effective than prednisone as monotherapy (48). Dosage varies, with some investigators raising the dose to achieve an elevation in the mean corpuscular volume or a drop in the white blood cell count, whereas others give a fixed dose based on weight, usually 3 to 5.0 mg/kg/day (49). There are several caveats of azathioprine therapy. First, there is a long delay in the onset of action, 24 months for the steroid-sparing effects to become evident (50). Second, side effects occur in about 10% of patients, including flu-like symptoms with nausea, fever, chills, arthralgias, or gastrointestinal complaints that usually resolve promptly with cessation of therapy (51). Third, bone marrow suppression occurs in all patients but is rarely a reason to stop therapy with careful monitoring. Fourth, there is the concern for an increased risk of cancers, primarily lymphomas after 10 to 20 years of therapy (52).

Thymectomy

The thymus has a central position in the pathogenesis of MG, and thymectomy has been an important treatment of MG. The earliest transsternal thymectomies for MG were performed for the removal of thymic tumors (53); however, the beneficial results in nonthymomatous patients were appreciated afterward. Nonetheless, it has been difficult to judge the efficacy of thymectomy for several reasons. First, there has not been a placebo-controlled trial. Second, it has been difficult to ascertain the absolute effectiveness of one type of operative procedure over another and the optimal extent of thymic resection necessary to obtain a maximal clinical response. The surgical approaches to the thymus gland include cervical, transsternal, combined cervical and transsternal, and thoracoscopic procedures (54). Third, there is a delay in the effectiveness that may be prolonged for years after surgery, yet long-term it carries the best likelihood for a sustained remission. Whether all thymic tissue needs to be removed to guarantee the best outcome is not truly known, although most authorities agree that the transsternal approach reduces the risk of leaving thymic tissue behind (54,55,56).

Thymectomy should be included in the initial and primary therapy of patients with generalized limb and bulbar involvement. In one study (56), two thirds of patients were asymptomatic after transsternal surgery, and of those, one sixth had ocular symptoms alone, whereas the remainder had mild generalized weakness. Younger patients, including those with juvenile MG, and older patients respond equally well. Plasmapheresis can improve the preoperative status and later immediate outcome of patients with bulbar weakness and a poor cough that may be a risk for prolonged postoperative intubation. One series (54), based on extensive surgical exploration of the anterior mediastinum and neck for thymic tissue, reported a progressive number of patients in full remission of up to 90% after 7 years of follow-up.

The role of the thymus and thymectomy is one of the more controversial therapeutic issues in MG. Nonetheless, the following guidelines appear to be reasonable. Radiographic evidence of an anterior mediastinal mass on chest CT warrants a thymectomy at any age because approximately 10% of patients with MG will have a thymoma. When there is no mediastinal mass, it seems appropriate to counsel the patient to undergo thymectomy to increase the probability of sustained remission. Plasmapheresis, corticosteroids, and IVIg can be used to optimize the clinical status in the meantime. Transsternal procedures that maximally visualize the anterior mediastinum are preferable to cervical and thoracoscopic procedures that remove less thymic tissue and can miss thymic tissue or a small thymoma.

Cyclosporine

Cyclosporine was found to be effective in a small trial as a steroid-sparing agent (38); however, the associated side effects include renal insufficiency, hypertension, headache, and hirsuitism. It must be emphasized that MG is a highly variable disease and therefore treatment of the myasthenic patient is an art and must be individualized. There are very refractory patients who remain weak and require a variety of medications for unpredicted exacerbations. In these situations, finding the optimum combination of medications can be a challenge.

JUVENILE MYASTHENIA GRAVIS

Clinical Features

Juvenile MG is an immune-mediated disorder that has its onset before age 20 (57). Although similar to the disorder of adults, there are clinical differences. Juvenile MG is less likely to have an ocular presentation. Patients with an onset before puberty are more likely to be seronegative, with the percentage of seropositivity increasing with older age. This is probably due to the propensity of the mature immune system to produce circulating antibodies and the effect of sex hormones on immunoglobulin levels (58). The ACh receptor antibody titer may be a clue in distinguishing between congenital, genetic, or acquired forms of MG. The racial differences in juvenile MG are minor; African-American patients have a female-to-male affected sex predictor of 2: 1, whereas in white patients the ratio is nearly equal. Disease severity and long-term prognosis is better when onset is before puberty. White patients have more frequent spontaneous remissions than African-American patients (59).

Treatment

The specific therapy is similar for juvenile and adult MG patients because seronegative and seropositive children and adult patients with acquired MG respond equally well to treatment (57). However, plasmapheresis may be more difficult to perform in young patients because of their small blood volumes. In children, there is an additional concern of the effect of prednisone on growth retardation. Azathioprine is a second-choice drug in this group because of the long-term risk of lymphoma. Thymectomy is effective in children; in fact, patients with juvenile MG may even have a more favorable prognosis than adults (56,58). There are racial differences that may affect the surgical outcome. The remission rate in African-American children is lower than in whites (59). Although concerns have been voiced for the long-term effects of thymectomy on the maturation of the immune system, such has never been seen in children with MG or among children that have had the thymus gland removed in the course of cardiac surgery for other reasons (56).

NEONATAL MYASTHENIA GRAVIS

Clinical Features

Neonatal MG is a transient form of NMJ transmission failure due to the passive transfer of maternal antibodies across the placenta. Symptoms include a poor suck, cry, facial weakness, dysphagia, and hypotonia (60). Clues to the diagnosis in utero may be the presence of reduced fetal movements. These infants appear to have more severe weakness, including respiratory failure at birth. Weakness in utero may also lead to joint contractures, and neonatal MG is included in the differential diagnosis of arthrogryposis. Although the overall probability of neonatal MG is low, it occurs in about I in 10 births to myasthenic mothers, and most infants born to myasthenic mothers are normal (61). Neonatal MG can occur in infants of myasthenic mothers who are in remission (62). The antibody type can be different between mother and affected infant, suggesting that affected infants can synthesize ACh receptor antibodies. Host factors are probably important in determining whether an infant becomes symptomatic, but the nature of these factors is unclear (61). There are no reliable predictive factors based on maternal severity of disease. However, mothers that have had an infant with neonatal MG have a higher likelihood of another affected child (60). Thus, every infant born to a myasthenic mother should be watched carefully in an intensive care unit for weakness and respiratory failure. Conversely, if there is no sign of neonatal MG after 5 to 10 days, the likelihood of an infant developing weakness because negligible. Once weakness begins, respiratory failure can occur precipitously; however, the course is usually a self-limited disorder with symptoms lasting weeks to months. Diagnosis is made by a test dose of edrophonium or diagnostic repetitive nerve stimulation (63,64).

Treatment

Treatment is based on severity of symptoms (65). Pyridostigmine alone is generally sufficient. Exchange transfusions have been performed with variable results, presumably because some infants with neonatal MG synthesize their own ACh receptor antibodies (61). Respiratory support may be necessary.

CONGENITAL OR GENETIC MYASTHENIA GRAVIS

Congenital MG represents a different spectrum of disorders, each due to a unique genetic defect in NMJ transmission (65). Most are genetic mutations with autosomal dominant and recessive modes of inheritance that alter NMJ structure or enzymatic function (66). Table 6 lists the known forms of congenital MG. Antibodies to the ACh receptor are never present. Before the acquired autoimmune nature of MG was realized, families of patients with congenital MG were known as familial infantile myasthenia.

Congenital MG is clinically characterized by early and relatively fixed degrees of weakness. The pattern of weakness is similar to immune-mediated MG and includes ptosis and extraocular, proximal limb, oropharyngeal, and even respiratory muscle weakness. There can be clinical exacerbations with marked increases that culminate in crisis. Weakness or hypotonia in early childhood may erroneously be ascribed to other genetic or birth problems. Alternatively, early weakness may be so mild as to escape appreciation and not come to clinical attention again until childhood or even adulthood. Under these circumstances, a diagnosis of immune-mediated MG may be entertained. Congenital MG responds poorly to pyridostigmine and usually not at all to immunomodulating therapy. A course of ephedrine given 15 mg orally three times daily may be effective in suspected cases.

The diagnosis of congenital MG should be entertained in any child with a diagnosis of MG that has been refractory to all modes of therapy. Further support for the diagnosis comes from inspection of early childhood pictures, looking for ptosis or hyperextension of the neck to achieve forward gaze. It should also be considered when other family members have had similar symptoms. Routine electrodiagnostic testing does not differentiate between immune-mediated and congenital cases; however, certain presynaptic forms of congenital MG may show facilitation after exercise, and two forms, one due to end-plate AChE deficiency and the other to a slow channel syndrome, may show a repetitive discharge after the CMAP following a single shock (Table 6). The meaningful investigation of these syndrome requires sophisticated morphologic and electrophysiologic studies of the NMJ usually available at only a few centers with a specific interest in these disorders.

LAMBERT-EATON MYASTHENIC SYNDROME

The association of small cell lung cancer (SCLC) and a myasthenic syndrome clinically and electrophysiologically was described by Lambert and coworkers in 1957 (67). The so-called LEMS is one of the best examples of an antibody-mediated paraneoplastic disease.

Clinical Features

Approximately 50 to 60% of patients with LEMS have an associated SCLC; other tumors have been described, including adenocarcinoma and breast cancer, and some may be unrelated to cancer (68). The disorder can thus be divided into two groups based on the presence of a cancer (68). Those without a tumor are generally of younger age, although most patients with LEMS are over age 40 at the onset of symptoms. Male sex is more common in the group with tumors.

The most common symptoms of LEMS are proximal leg and truncal weakness; ptosis and bulbar muscle weakness are less common. Respiratory failure is rare but can occur (68). Some patients have the warming up phenomena where by the first portion of a repetitive movement is more difficult than later ones. This may be apparent clinically with manual muscle testing that culminates in near-normal strength despite easily fatigability. Tendon reflexes may be absent with first testing and later normal after a brief agonist muscle contraction. Autonomic symptoms are common but may be overlooked and can include impotence in men, dry mouth, constipation, and urinary retention.

Natural History

The symptoms of LEMS can begin insidiously and can go undiagnosed for months to years. The most common initial diagnosis is MG (68). Among those with an associated tumor, the prognosis is largely determined by tumor progression and response to tumor treatment. In one series (68), three quarters of patients with a cancer died within a year compared with 80% of patients with

out a tumor who were alive 7 years after diagnosis. The cancer in LEMS may be inapparent for up to 4 years after onset of neurologic symptoms. Accordingly, it is important to differentiate between MG and LEMS and to perform an evaluation for occult SCLC if LEMS is diagnosed. This should include a history for cancer risk factors, a thorough medical evaluation, and CT of the chest with yearly repeat evaluations for the first 5 years after initial detection.

Pathophysiology

The disorder is due to autoantibodies directed against presynaptic voltage-gated calcium channels (VGCC) or related structures. This affects the regulation of channels in both those with and without an associated cancer (69,70). The antibodies are of the IgG class and are heterogeneous in their specificity against the several types of calcium channels (71). The etiology of antibodies in patients without an associated cancer is unclear, but there is likely antigenic similarity between presynaptic VGCC and those on tumors cells (72). In patients with an SCLC, antibody production is probably triggered by the tumor (73). These antibodies reduce the influx of calcium into the presynaptic terminal and reduce the amount of ACh released, in turn decreasing the size of EPPs and the likelihood of reaching threshold for a given muscle fiber AP (Table 7). The result is a low CMAP amplitude in most muscles that is also a measure of the severity of NMJ blockade (72). Similar calcium channels present on autonomic presynaptic nerve parasympathetic and sympathetic terminals account for the autonomic symptoms.

Diagnosis

Electrodiagnostic testing is important in identifying LEMS and distinguishing it from MG. A low CMAP amplitude, often less than 10% of the lower limit of normal and in a diffuse distribution, is an important electrodiagnostic clue (Fig. 7). Repetitive motor nerve stimulation at rates of 2 to 4 Hz may show a decrement as in MG; however, the distinguishing feature of LEMS is a marked facilitation after 10 seconds of exercise or with high-frequency stimulation at 50 Hz. The degree of facilitation depends on the size of the first CMAP but will generally restore the CMAP amplitude to normal. The increment after high-frequency activation may reach 10,000-fold if the first CMAP is extremely small (68).

There is a serum assay for antibodies reactive to P/Q and N-type VGCCs that are detected infrequently except in LEMS or in the context of other paraneoplastic neurologic disorders (70). There is an association between LEMS and both organ-specific and nonorgan-specific autoantibodies in patients with LEMS (20,68). The discovery of VGCC antibodies in a clinically affected patient should prompt a search for occult SCLC; generally, a chest CT or magnetic resonance image will suffice.

Treatment

Many of the same drugs and procedures used to treat MG are also effective in LEMS; however, there are drugs that specifically enhance presynaptic function that are unique to the treatment of LEMS. A laboratory measure that can be used to quantify therapeutic response and has predictive value is the amplitude of the CMAP at the start of therapy; a very low CMAP amplitudes generally suggests a poorer outcome with therapy (73).

Patients with LEMS may benefit from AChE drugs in doses used for MG, although the improvement in strength is likely to be mild. A trial of plasmapheresis may be effective, with rapid improvement in most patients (74,75), and the response may be sustained without an associated cancer. The IgG fraction collected from the plasma separation has been used to transfer symptoms of LEMS to experimental animals (75). IVIg in doses of 2 g/kg over 2 days was temporarily effective in a placebo-controlled crossover trial in LEMS patients without cancer (76). Prednisone was effective in small cohorts with or without cancer (77,78). Azathioprine was tried in patients with LEMS but usually in conjunction with other drugs; accordingly, its effectiveness was difficult to assess (75). There is concern that treatment of patients without an associated cancer could precipitate the development of a later cancer. In one study, several patients treated with azathioprine later showed evidence of SCLC, but several arguments suggest that azathioprine was not the cause. First, it is generally associated with the development of lymphoid tumors, not SCLC. Second, the time interval between initiation of azathioprine and development of cancer in the LEMS patients was 2 to 3 years, a period during which malignant cell changes could progress to a radiographically detectable lesion (68).

3,4-Diaminopyridine enhances synaptic transmission and increases ACh release by blocking potassium channels that prolongs nerve APs and in turn prolongs the activation of VGCC (79). In a double-blinded, placebo-controlled, crossover study, 3,4-Diaminopyridine doses of 25 mg orally four times daily significantly improved strength in patients with LEMS, with or without cancer (80). The drug remains effective after several years of follow-up. Mild side effects include perioral and acral paresthesias, epigastric distress, and rarely seizures. 3,4-Diaminopyridine is an orphan drug. It is not approved and is available in the United States at only a few institutions, such as the Mayo Clinic in Rochester, Minnesota, and Duke University in Durham, North Carolina. Availability outside of the United States is unknown.

Treatment of the underlying SCLC is an option with chemotherapy, radiation therapy, and rarely surgery. The response to primary treatment of the cancer has been variable but most show some initial improvement (73). Apparent cures of the cancer and LEMS after 7 years of follow-up have been reported. In some the cancer may respond but the symptoms of LEMS remained unchanged, whereas others have had initial improvement of their weakness but with later relapse.

CONCLUSION

The diagnosis and management of NMJ disorders is ever challenging. It requires understanding of the anatomy, physiology, pathology, immunology, and pharmacology of the motor unit. Diagnostic errors can be reduced by viewing disorders of the NMJ as a family of diseases, in which systematic electrophysiologic studies separate presynaptic from postsynaptic disorders. A battery of serologic, radiographic, and genetic studies provide support to the exact etiologic diagnosis. When thoughtful evaluation and management principles are followed, it will be apparent that each patient is unique, and some patients will continue to challenge the most experienced clinicians.

REFERENCES

A complete list of references can be found in Motor Disorders, edited by David S. Younger, MD, Lippincott Williams & Wilkins, 1999, pgs. 177-178.

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