Current Treatment Options in Neurology (2010) 12:231–243 DOI 10.1007/s11940-010-0070-0

Neuroimmunology

Myasthenia Gravis Agnes Jani-Acsadi, MD* Robert P. Lisak, MD1 Address *Department of Neurology, Neuromuscular Division, Wayne State University, School of Medicine, 8A University Health Center, 4201 St. Antoine, Detroit, MI 48201, USA Email: [email protected] 1 Department of Neurology, Wayne State University, School of Medicine, 8A University Health Center, 4201 St. Antoine, Detroit, MI 48201, USA Published online: 24 March 2010 * Springer Science+Business Media, LLC 2010

Opinion statement Treatment of patients with acquired (autoimmune) myasthenia gravis should rely on evidence-based therapeutic choices, taking into account the individual’s needs according to disease severity (mild to severe), extent (ocular or generalized), comorbidities (including other autoimmune diseases, infections, thymoma, and pregnancy), age, iatrogenic factors (the risks and benefits of therapy), patient autonomy and quality of life, financial burden to the patient, and associated health care costs. Therapy is aimed at managing symptoms by improving neuromuscular junction transmission (cholinesterase inhibitors) and/or modifying the underlying immunopathogenetic cause of acquired myasthenia gravis via immunosuppression or immunomodulation. Myasthenic patients with operable thymoma should be referred for surgery and closely followed up for tumor recurrence. A concerted international effort is addressing treatment recommendations for thymectomy in myasthenic patients with no radiologic evidence of thymoma who are positive for circulating acetylcholine receptor antibodies. There is a lack of evidence-based treatment guidelines for both acute and long-term management of ocular myasthenia. Acute management of myasthenic crisis requires intensive monitoring of the patient and institution of an efficient and safe treatment such as plasma exchange. Patient education is essential to a comprehensive long-term treatment plan.

Introduction The use of physostigmine in the 1930s by Mary Broadfoot Walker [1] and Lazar Remen [2] marked the start of the era of the use of acetylcholinesterase inhibitors (AChEIs) in the symptomatic management of myasthenia gravis (MG). Thus it was clinical observation that pointed first to the role of the neuromuscular junction in the development of MG. Blalock’s initial description in 1941 of MG remission after surgical removal of the thymus has led to widespread use of thymectomy [3•]. Understanding the immunogenic mechanisms in the pathophysiology of MG paved the road for further efficient therapies.

In autoimmune MG, B-cell/plasma-cell-derived polyclonal antibodies may be directed toward numerous extracellular and intracellular targets that are located at the muscle endplate. The neuromuscular junction region lacks a functional blood-nerve barrier, making it susceptible to circulatory antibodies. The presence of different molecular antigens is likely to contribute to the heterogeneity of clinical presentation and treatment response [4]. Antibodies to the nicotinic acetylcholine receptors (AChRs) are responsible for the failure of neuromuscular junction transmission by blocking and crosslinking the AChRs and leading

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to complement-mediated destruction of the muscle membrane in about 80–90% of patients with generalized MG and 50% of those with ocular myasthenia [4– 6]. Ultimately, the process leads to the simplification of the muscle membrane and downregulation of available AChRs. An autoimmune mechanism in AChR antibody-negative cases has been supported by clinical evidence (the coexistence of other autoimmune diseases such as systemic lupus erythematosus, autoimmune thyroiditis, rheumatoid arthritis, and transient infantile MG) and by passive transfer experiments in which serum of AChR antibody-negative patients led to the development of myasthenia-like symptoms in mice. In many patients without measurable anti-AChR antibodies (so-called seronegative MG [SNMG]), antibodies against other structures of the postsynaptic muscle membrane have recently been found. For example, muscle-specific tyrosine kinase (MuSK) plays an important role in differentiation and clustering of postsynaptic AChRs [7–9]. The typical clinical presentation is that of a female patient with primarily bulbar, respiratory, and neck weakness that responds poorly to the usual treatment [7, 8]. SNMG patients are similar to those with AChR-MG in clinical features and thymic pathology. Low-affinity antibodies (IgG1 subclass) were shown to activate complement and bind to higher-density AChR clusters at the neuromuscular junction [5•]. In many patients with concomitant thymoma, antibodies to other muscle components have been detected. The pathogenicity of antibodies directed toward receptors located intracellularly in the muscle cell (eg, rapsyn, titin, and ryanodine) is uncertain, but they may have a modifying effect on severity. All patients with thymoma and MG have detectable serum AChR antibodies. Most patients with thymoma

and MG also have antibodies to titin and to the ryanodine receptor. Lymphofollicular hyperplasia occurs in about 65% of patients and thymoma occurs in about 15% [3, 6]. Several MG subgroups have been identified on the basis of diagnostic autoantibody testing: AChR antibody-positive MG; early-onset and late-onset MG without thymoma and with thymoma; late-onset titin-positive MG, MuSK MG, and SNMG [4]. MG is considered primarily a B-cell-mediated disease, although antibodies of the IgG isotype, when directed toward protein epitopes, are T-cell-dependent. This fact needs to be addressed when using therapies directed primarily at T cells [6, 10–12]. Myasthenia gravis presents with fluctuating weakness of select voluntary muscles, which is exacerbated by exercise or other triggers such as infection, surgery, or iatrogenic insults (medications) [6, 11, 13, 14•]. The initial presentation in half of the patients may be isolated ocular dysfunction such as diplopia or eyelid ptosis; about 15–20% have bulbar symptoms such as dysarthria, dysphagia, or weakness of neck and proximal muscles. Less than 10% of patients have onset affecting only limb muscles. If muscles of respiration become affected, a crisis may emerge, with the development of acute respiratory insufficiency that may lead to death if left untreated [14•]. The clinical presentation has a primarily bimodal distribution, affecting mainly women in their twenties and men in their late fifties. Developing successful therapies is a challenge because of the variable course of the disease, which makes the interpretation of results difficult. Evidence-based clinical data derived from randomized, prospective, placebo-controlled clinical trials are lacking, so therapies are generally based on consensus expert opinion [6, 10, 11, 13–16].

Treatment &

Treatment of MG should be directed toward the unique needs of each patient. The specific therapies should be optimized to achieve maximum benefits with the fewest adverse effects. This goal requires adjusting the treatment plan not only for the severity of the disease but also for medical comorbidities and for the patient’s age, lifestyle, and psychological status, to obtain the best quality of life; the financial burden of treatment also needs to be considered [10, 11, 13– 15, 17–19].

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Therapy for MG has two arms: 1) symptomatic treatment to increase the availability of acetylcholine (ACh) at the endplate, thus improving neuromuscular junction transmission and 2) alteration of the immunopathogenic mechanism of acquired MG. The intensity of care should be determined by the acuteness and severity of the patient’s presentation. Rapidly declining patients with impending myasthenic crisis require hospitalization and intensive care to control the metabolic and respiratory failure. Timely and effective treatment with plasma exchange and elimination of the precipitating factors must be instituted to stabilize the patient before pharmacologic therapy for control of symptoms can begin [14•]. Cholinesterase inhibitors such as pyridostigmine bromide remain the basis of treatment for mild to moderate MG [6, 10, 15, 16•]. Therapy should be adjusted for more severe weakness by introducing immunomodulatory agents after assessing how quickly the desired effects should be achieved. Patients with distinct clinical needs, such as children or pregnant women, present additional challenges [18, 19].

Diet and lifestyle &

&

&

Long-term management of MG requires patient cooperation. This is best achieved by patient education. A list of patient-support organizations such as the Myasthenia Gravis Foundation of America (MGFA) should be provided at the initial visit. Patients should be advised to wear medical-alert signs. Lists of drugs that frequently exacerbate MG can be found at the MGFA website (www.myasthenia. org). Because of oropharyngeal weakness, patients with MG may have difficulty with chewing and swallowing, and thus may need aspiration precautions with dietary consistency changes (such as thickening of thin liquids). Referral to speech and language therapy and dietary consultation are often needed. Dysphonia often interferes with communication. The use of speechassisting/communication devices may improve quality of life.

Pharmacologic treatment Cholinesterase inhibitors &

Nonselective cholinesterase inhibitors ameliorate muscle weakness by prolonging the presence and availability of ACh in the neuromuscular junction through delay of ACh hydrolysis [11, 16, 20].

Pyridostigmine bromide This is the accepted initial treatment choice for management of mild to moderate MG. After the successful institution of immune treatment, the dose may be tapered according to improved clinical strength. Efficiency may decline with time (likely owing to the development of acetylcho-

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Standard dosage

Contraindications

linesterase-R isoforms). Pyridostigmine may not be effective in MuSK antibody-positive MG patients. For adults, 30–60 mg every 4 h by mouth; titrate as needed. MG affects muscles variably, so the dose should be adjusted accordingly. Very large doses (9150–180 mg every 3 h) are rarely required. Patients with difficulty swallowing or chewing should take their medication 30 min before a meal, with a small amount of food. Sustained-release tablets are available but have variable absorption in critically ill patients and should be used only for nighttime control of myasthenic symptoms in other patients. Avoid intramuscular formulations because of poor absorption. Parenteral pyridostigmine should be given only to patients with gastrointestinal (GI) obstruction. Bulbar or intubated patients unable to take oral medication should be treated via feeding tube. The standard pediatric dosage is 7 mg/kg per day divided every 3–4 h. Documented hypersensitivity, peritonitis, GI/genitourinary obstruction. Relative contraindications include bradycardia, bronchospasm, and use of cardiac glycosides. For pregnant women, this is a category C drug.

Main drug interactions

Pyridostigmine increases the effect of depolarizing neuromuscular blockers and edrophonium; it may lead to toxicity.

Main side effects

Muscarinic side effects (increased secretions, abdominal cramps, diarrhea, sweating, nausea, bradycardia, muscle twitches) respond to anticholinergics such as atropine, loperamide, diphenoxylate-hydrochloride-atropine sulfate (Lomotil), and glycopyrrolate. Cholinergic weakness (and rarely, crisis) may develop from overdoses and may be fatal.

Special points

Muscarinic side effects or the lack of them are not predictive of the cholinergic effects.

Cost-effectiveness

Inexpensive, but prices are variable. (Generic, except sustained-release form.)

Neostigmine Standard dosage

This is a shorter-acting AChEI. 15 mg/dose orally every 3–4 h; 0.5–2.5 mg IV/IM/SC every 1–3 h, not to exceed 10 mg per day. The standard pediatric dosage is 2 mg/kg per day divided every 3–4 h.

Contraindications

For pregnant women, this is a category C drug.

Main side effects

Effects are similar to those for pyridostigmine.

Immunotherapy &

Immunosuppression is indicated in moderately severe MG when AChEIs are not sufficient. The time to symptomatic remission is variable and treatment-dependent. Monotherapy or combination immunotherapies may be used [11, 13, 15]. Some experts suggest that these therapies may also reduce the development of myasthenic crisis [6•].

Prednisone Corticosteroids modulate all levels of the immune and inflammatory system. Prednisone and methylprednisolone are short-acting (effect lasts

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24–36 h) but potent drugs indicated in moderately severe MG if the patient remains symptomatic despite AChEI therapy. Ocular myasthenia may respond to lower doses of corticosteroids, and some have suggested that progression to generalized MG is reduced (26, Class III). Acute and long-term side effects should be monitored and treated. Patient compliance and medical contraindications need to be addressed. Remission/ improvement can be expected in 1–6 months; evidence for short-term benefit at 2 weeks in generalized MG (compared with placebo) is limited. The treatment regimen (whether starting with a high dose or a low dose) is based mostly on individual physician preference [11, 13, 15, 21, 22]. High starting dose: 60–80 mg once daily in the morning. This regimen may produce earlier remission, but it worsens weakness in about half of patients. It also may produce acute myopathy, mainly in patients exposed to nondepolarizing neuromuscular blockade. We recommend this regimen only in controlled settings, preferably intensive care, where the patient is supported by plasma exchange or intravenous immunoglobulin (IVIg) therapy. Once clinical effect has been reached (usually 3–6 months), taper to reach the minimal effective dose. Alternating-day and high-dose/low-dose schedules have been used. Low starting dose: 15–20 mg by mouth once daily in the morning, increasing by 5 mg every 3 days until remission (usually 60–80 mg by mouth daily). Maintenance dosage: Recent expert consensus recommends an alternatingdose schedule (100–120 mg every other day) to minimize side effects with best efficacy; 60–80 mg once-daily dosing may also be used. Pediatric maintenance dosage: 1–2 mg/kg by mouth daily.

Contraindications

Hypersensitivity reaction. Relative contraindications include diabetes mellitus, severe hypertension, acute GI bleeding. This is a pregnancy category C drug.

Main drug interactions

Oral birth control pills (estrogen) may reduce clearance; digitalis, diuretics (hypokalemia); metabolism is increased by phenobarbital, phenytoin, and rifampin. Acute effects include personality changes, emotional lability, blood pressure elevation, hyperglycemia, hypokalemia, masked infection, GI bleeding. Effects of chronic use include cataracts, glaucoma, diabetes, nonketotic hyperosmolar state, avascular necrosis of the hip, peptic or gastric ulcer, GI bleeding, steroid myopathy, acne, cushingoid appearance, weight gain, growth suppression in children, hypertension, water retention, congestive heart failure, opportunistic infections, and osteoporosis. Sudden discontinuation may lead to hypoadrenergic crisis; a short-term perioperative increase of steroid dose (stress-dosing) is needed for surgical procedures. Inexpensive; prices variable (generic formulation available).

Main side effects

Special points

Cost-effectiveness

Azathioprine Azathioprine inhibits T-cell and B-cell proliferation through interaction with purine metabolism and nucleic acid synthesis. It is used as monotherapy or as a steroid-sparing agent in combination with other drugs in moderate to severe MG. It may offer additional benefit when used in patients being treated with plasma exchange [6, 12]. At least one study has shown long-term efficacy to be comparable to that of corticosteroids

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Standard dosage

Contraindications

[22, Class III]. A therapeutic/steroid-sparing effect may not be achieved until after 6–12 months of therapy. Patient cooperation and education are essential for compliance [6, 13]. Start at 1 mg/kg per day and increase gradually to 2–3 mg/kg per day. A recommended schedule would be 50 mg per day for 1 week with close monitoring of red blood cell (RBC) count (rare idiosyncratic reaction), white blood cell (WBC) count and differential, and liver transaminase levels (hepatocellular dysfunction). If there are no marked changes, increase the dose by 25–50 mg per day every 5–7 days. RBC mean corpuscular volume (MCV) may be used to monitor effect either by a relative increase of 16 fL when compared with baseline or by MCV greater than 100 fL [10]. Iron deficiency may affect MCV and interfere with this measurement. There are no clear data regarding the use of WBC count or differential to monitor efficacy. Monitor WBC, RBC, and liver transaminases every week for 3–4 months, then biweekly, then monthly, then every 3 months until stable dosage is reached. At that time, it may be acceptable to monitor these levels twice a year. Dosage increases or changes in the use of other drugs will require closer monitoring. Threefold elevation above baseline may require reduction in the azathioprine dosage. The standard pediatric dosage is 1–2 mg/kg per day by mouth. Hypersensitivity, pregnancy, lactation (category D). Systemic and opportunistic infections need to be treated before starting treatment. Some suggest screening for enzyme deficiency, but with careful dose escalation, we have not found any need to do so.

Main drug interactions

The dosage needs to be reduced by up to 75% for patients taking allopurinol because of xanthin oxidase inhibition. Azathioprine may reduce the efficiency of anticoagulation, methotrexate, cyclosporine.

Main side effects

Severe flulike symptoms at treatment initiation (20–30%). Opportunistic infections, hepatotoxicity, leukopenia, thrombocytopenia, pancreatitis, teratogenesis. May increase the risk for leukemia and lymphoma (controversial with doses used in MG). Prior use of other immunosuppressive or cytotoxic drugs may increase the risk of developing neoplasia. Rare alopecia.

Cost-effectiveness

Inexpensive. Generic formulation available. The overall health care cost is increased by the need for monitoring of blood counts and liver function tests, but these costs are offset by a better side effect profile than experienced with steroids.

Cyclosporine

Standard dosage

Contraindications Main drug interactions

Cyclosporine inhibits T helper cell-mediated synthesis of cytokines and other T helper cell-mediated immune reactions. Serious adverse effects prevent its use as a first-line treatment. Cyclosporine has been used successfully in patients with severe MG in whom steroids and thymectomy have failed, or those unable to tolerate other medications [6, 12, 15, 23, 24]. The time to treatment response is shorter than with azathioprine (≤7 months). 4–10 mg/kg per day by mouth, divided into two or three doses. Initial lower doses (2–3 mg/kg per day) may be better tolerated [9]. Dose titration may be based on trough levels (100–200 ng/mL). The pediatric dosage follows the adult guidelines. Hypersensitivity. For pregnant women, category C. Nephrotoxic drugs should be avoided because of synergy; these include gentamicin, tobramycin, vancomycin, amphotericin B, ketoconazole, mel-

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phalan, diclofenac, cimetidine, ranitidine, trimethoprim-sulfamethoxazole, azapropazone. Interactions also occur when cyclosporine is used with drugs affecting liver microsomal enzymes: cyclosporine serum levels increase with diltiazem, verapamil, ketoconazole, fluconazole and itraconazole, whereas cyclosporine levels are decreased with the use of several antiepileptic drugs (eg, phenytoin, phenobarbital, carbamazepine) and rifampin. Main side effects

Nephrotoxicity and hypertension need to be monitored and treated. Creatinine levels must be followed closely. Elevation more than 70% above baseline may be prohibitory. Osteoporosis and bone marrow suppression may develop with chronic use. The risks of developing opportunistic infections, neoplasia, or posterior reversible encephalopathy syndrome (PRES) may increase.

Mycophenolate mofetil

Standard dosage

As an inosine monophosphate dehydrogenase (IMPDH) inhibitor, mycophenolate mofetil was a highly anticipated addition to the immunosuppressive arsenal for the treatment of MG affecting multiple levels of the immune and inflammatory systems. Its primary mechanism of action is suppressing both T-cell and B-cell proliferation; it also is antiapoptotic and reduces inducible nitric oxide synthase activity After promising preliminary smaller studies, two recent studies have not confirmed its efficacy in regards to steroid sparing [25]. It is unclear whether this result occurred because the study was too short (6 months) in relation to the time required for the drug effect to develop [13]. Some experts still consider it as an add-on in generalized MG or as a first-line drug in pure ocular MG [6, 26]. Start at 500 mg by mouth twice a day for 4 weeks and increase as tolerated to 1 g twice daily. The pediatric dosage (established in transplant patients) is 600 mg/m2 twice daily, up to a maximum of 1 g twice daily.

Contraindications

Hypersensitivity reaction; caution in patients with renal failure, Lesch-Nyhan syndrome, and Kelley-Seegmiller syndrome.

Main drug interactions

This drug should not be co-administered with azathioprine because of increased risk of bone marrow suppression: neutropenia (delayed by 930– 180 days in transplant patients), susceptibility to infection, and GI hemorrhages have been described but are rare (G3–5%).

Main side effects

The US Food and Drug Administration (FDA) is currently investigating postmarketing reports related to the development of latent viral infections (progressive multifocal leukoencephalopathy, PML) and PRES. Potential risk for neoplasia, lymphoma. Teratogenic potential (pregnancy category D). The drug may be excreted in human milk.

Cost-effectiveness

There are not yet any postmarketing data on the generic form in terms of efficiency. The price of the original formulation was high, with variable insurance coverage.

Other immunosuppressive agents Tacrolimus (FK 506) Tacrolimus is a macrolide drug that affects T-cell function by enhancing T-cell regulatory functions and activity. Non-T-cell-mediated actions re-

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Standard dosage

lated to intracellular calcium metabolism and other effects also may support its efficacy in MG. It appears efficacious in steroid-resistant and cyclosporine-resistant MG patients [27, 28]. 0.1 mg/kg per day.

Main drug interactions

Increases toxicity of mycophenolate mofetil in transplant patients (no data in MG).

Main side effects

Recent FDA warning regarding potential development of late viral infections (PML) and PRES. Also risk of BK virus nephropathy, interstitial lung disease.

Cyclophosphamide This alkylating agent directly affects both T cells and B cells. It has limited indications in MG because of poor tolerability and adverse effect profile (carcinogenesis, teratogenesis, infertility).

Rituximab This monoclonal antibody against CD20 B-cell surface membrane marker is currently being investigated for efficacy in MG.

Interventional procedures Plasma exchange

Standard dosage

Plasma exchange (PE) rapidly eliminates pathogenic autoantibodies and other plasma factors (cytokines, adhesion molecules) that are responsible for the weakness in myasthenia. PE can be used acutely for sudden decompensation despite otherwise optimal care, and it is the preferred choice of treatment for myasthenic crisis [13, 14•, Class III]. It is also used in preparation for thymectomy or other surgeries, which may trigger myasthenic exacerbation, and in rare patients as part of chronic management alone or in combination with immunosuppressive treatments until medical therapy reaches efficacy. A historic consensus statement from the National Institutes of Health [29] supported the use of PE, so no placebo-controlled clinical trials have been conducted. The effect is short-lived (2–3 weeks) and frequent treatment with longer-acting immunosuppressive agents is required [10, 30]. In myasthenic crisis, patients are treated with five to six exchanges on alternating days over 2 weeks, using 2–4 L per exchange per 70 kg body weight. Blood homeostasis is maintained by replacement with 5% human albumin and crystalloids or (rarely) fresh frozen plasma. The procedure may be carried out by plasma filtration techniques, plasma separation, or more recently by antigen-specific immunoadsorption techniques, which enable the return to the patient of nonpathogenic blood components. Among the newer apheretic techniques, double-filtration PE and immunoadsorption showed similar clinical effects for patients with generalized myasthenia; only minor differences were noted in post-PE serum immunoglobulin levels.

Contraindications

Lack of venous access. Hemodynamic instability is a relative contraindication.

Main drug interactions

None, but PE may lower drug levels, so medications should be administered following the exchange.

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Main side effects

Cardiac and hemodynamic instability related to volume shifts. Electrolytes (calcium, magnesium, potassium) need to be monitored for imbalance and replenished as needed. Bleeding tendency due to platelet depletion may occur. Other effects include citrate toxicity from anticoagulation, line sepsis or line infections, thrombosis risk from indwelling catheters, pneumothorax during line placement, or air embolism.

Cost-effectiveness

Cost is high because of the need for hospital care, but it may eliminate the need for intensive care. It also may be used in an outpatient setting and reduces the cost of other treatments while eliminating their adverse effects.

Intravenous immunoglobulin

Standard dosage

High-dose IVIg has an application profile similar to that of PE. It is mainly used intermittently as an add-on to other immunomodulatory treatments when the patient has a contraindication to steroids or cannot tolerate other medications. Expert consensus and data from nonrandomized clinical trials and case series show benefit in maintenance therapy of MG [12, 31, 32, Class III]. The Cochrane Database Review reports efficacy similar to PE, but most studies do not describe the speed of response to IVIg or PE [31]. In our experience, PE was more effective and had a more rapid onset of action than IVIg. Currently, there is limited evidence regarding their use in crisis [32].The mode of action of IVIg is complex: modulation of pathogenic autoantibody response, inhibition of complement activation, interference with the formation of membrane attack complex, modulation of Fc receptors, downregulation of pathogenic cytokine responses, suppression of T-cell function, and interference with antigen recognition [11]. 0.4 g/kg body weight IVIg over 3–5 days. Outpatient or maintenance therapy may be administered as 1 g/kg per day for 1–2 days. Infusion should be slow, over 3–6 h. Premedication with acetaminophen (500 mg) and diphenhydramine (25–50 mg) 30 min prior to the start of infusion reduces side effects.

Contraindications

Hypersensitivity, prior severe reactions. IgA deficiency is a relative contraindication only; in this case, use IgA-depleted IgG. The IgA level should preferably be determined in the outpatient setting to avoid delay of treatment in crisis.

Main side effects

Headache, chills, myalgia, and transient hypertension are mostly provoked by rapid treatment initiation. Major complications may include hypersensitivity, renal failure, thrombotic events, and serum sickness. More severe adverse effects are usually seen in patients with significant medical comorbidities such as diabetes mellitus or renal insufficiency.

Cost-effectiveness

High cost and lack of evidence-based clinical data for crisis treatment remain limiting factors.

Surgery Thymectomy Thymectomy in patients with thymoma-associated MG is not only is beneficial as treatment for their myasthenia but also is indicated for

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Standard procedure

removal of the thymoma [33]. Current expert opinion recommends surgical removal of the thymus as an option in patients with nonthymomatous autoimmune MG if there are no contraindications to the resection (33, Class II). Despite the empirical clinical and experimental evidence pointing to a benefit of total thymectomy, considerable controversies continue to exist regarding 1) the effect of the procedure on clinical improvement and remission relative to nonsurgical treatment modalities, 2) the extent of thymectomy (eg, radical/total or limited), 3) the type of surgical approach, 4) preoperative and postoperative management, and 5) patient selection. The need for prospective clinical studies is increasingly being recognized [34]. A current international multicenter prospective single-blind study has been designed to address the efficacy of thymectomy in anti-AChR seropositive patients treated with prednisone only [34–38]. No evidence is available regarding the role of thymectomy in patients with anti-MuSK seropositive or purely ocular MG. Surgery is performed via three major approaches—transcervical, transsternal, and videoendoscopic—with marked variability of the extent of the resection. There are no controlled, randomized clinical trials comparing the extended or limited versions of these techniques in terms of postoperative complications, length of hospital stay, time to remission, or clinical improvement [35–38]. Controversy remains regarding the age of the patients who benefit from surgery. A tailored approach based on individual risk and benefit assessment and the presence of elevated anti-AChR antibodies is preferred to strict age limitations [13]. Thymectomy is strongly considered for all patients with generalized MG without thymoma who are between the ages of 10 and 55 years, as well as for all patients with thymoma, particularly those who do not need immediate treatment with steroids. Transsternal extended thymectomy technique is considered the standard [3•, Class III]. Earlier data suggested that an extended approach may be more beneficial than a limited approach, so this is the preferred method in the ongoing international, multicenter, prospective single-blind clinical trial assessing the efficacy of thymectomy in AChR-seropositive patients treated with prednisone. The Cochrane Collaboration developed a protocol in 2009 to evaluate the efficacy of thymectomy as measured by 1) improvement in weakness within 12 months after surgery, 2) reduced need for medications, 3) remission, and 4) side effects of thymectomy in patients with nonthymomatous MG during 3 years of follow-up [34]. The remission rate after thymectomy is reported to be between 40% and 60% [35]. Controversy exists regarding the contribution of disease duration. Generally, young patients with short duration of disease with no thymoma but with hyperplasia tend to do the best. Transcervical and videoendoscopic procedures, including robotic-assisted surgery, are gaining acceptance because of lesser morbidity, shorter hospital stays, and improved cosmetic effects, despite uncertainty regarding the maximum extent of resection that is necessary to achieve the greatest benefit [33–38]. Pediatric aspects: Autoimmune MG can occur in children, but the diagnosis needs to be clearly established based on anti-AChR seropositivity. There are no evidence-based data regarding the age when thymectomy should be performed or regarding its short-term benefits. Smaller case-study series have shown improved weakness and remission

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rates in 30 children 4–16 years of age with the use of a transsternal approach [37]. Recent studies advocate for less radical, robotic-assisted or videoendoscopic approaches in children because of reduced perioperative complication rates and improved cosmesis [36, 39, 40]. Long-term comparative data regarding the outcome of the radical or limited surgical approaches are limited [39]. The presence of ectopic thymus may worsen outcome and make repeat thymectomy necessary [41]. Contraindications

Medical conditions preventing general anesthesia and cardiothoracic surgery. Nonautoimmune myasthenia and myasthenic syndrome.

Complications

Perioperative complications related to open chest surgery and anesthesia (mortality rates G 1% in recent publications). Acute respiratory failure from myasthenic crisis (6%); risk may be ameliorated with preoperative plasma exchange. Infection (11%). Recurrent laryngeal or phrenic nerve injury (0– 2%). Complication rates are lower with the newer video-assisted techniques [35, 36].

Cost-effectiveness

Thymectomy typically allows myasthenic remission and mitigates the need for expensive pharmacologic treatment. The newer, less invasive surgical approaches have reduced the length of hospital stay and perioperative complications. Thus, thymectomy is considered cost-effective.

Disclosure No potential conflicts of interest relevant to this article were reported.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Keesey JC: Myasthenia Gravis: An Illustrated History. Roseville: Publishers Design Group; 2002. 2. Ohry A: Dr. Lazar Remen (1907-74): a forgotten pioneer in the treatment of myasthenia gravis. J Med Biogr 17(2):73–74. 3. • Jaretzki A, Sonett JR: Thymectomy for non-thymomatous myasthenia gravis. In Myasthenia Gravis and Related Disorders, edn 2. Edited by Kaminski HJ. New York: Humana Press; 2008:185–208. This chapter presents a detailed analysis of current expert opinion and controversies regarding thymectomy. 4. Agius MA, Richman DP, Vincent A: Autoantibody testing in the diagnosis and management of autoimmune disorders of neuromuscular transmission and related disorders. In Myasthenia Gravis and Related Disorders. By Kaminski HJ. Totowa: Humana; 2003:143–156. 5. • Leite MI, Jacob S, Viegas S, et al.: IgG1 antibodies to acetylcholine receptors in “seronegative”

myasthenia gravis. Brain 2008, 131(7):1940– 1952. This paper proves the presence of low-affinity antibodies in “seronegative” MG and their role in complement activation at the neuromuscular junction. 6. • Kaminski HJ: Treatment of myasthenia gravis. In Myasthenia Gravis and Related Disorders, edn 2. Edited by Kaminski HJ. New York: Humana Press; 2008:157–173. This chapter presents a concise overview of treatment options in autoimmune MG. 7. Pasnoor M, Wolfe GI, Nations S, et al.: Clinical findings in MuSK-antibody positive myasthenia gravis: A U.S. experience. Muscle Nerve 2010, 41(3):370– 374. 8. Stickler DE, Massey JM, Sanders DB: MuSK-antibody positive myasthenia gravis: clinical and electrodiagnostic patterns. Clin Neurophysiol 2005, 116 (9):2065–2068.

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