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Myasthenia Gravis: Pathogenesis and Immunotherapy

Christiane Schneider-Gold, Klaus V. Toyka

Introduction: In autoimmune myasthenia gravis (MG) autoantibodies directed against the postsynaptic nicotinic acetylcholine receptor (ACh-R) lead to a reduction of the number of available ACh-R thereby impeding neuromuscular transmission. Methods: Selective review of literature and available guidelines relating to the pathogenesis and treatment of myasthenia gravis. Results: Disorders of the thymus play a crucial role in the pathogenesis of ACh-R antibody positive MG, particularly by generating Ach-R specific autoreactive T cells. The main clinical symptoms are skeletal/striated muscle weakness and exercise-induced fatigue involving extraocular, facial and bulbar muscles (generalized MG). In the purely ocular form of MG only extraocular muscles are involved. Treatment of MG includes the application of acetylcholineesterase inhibitors and immunosuppressive drugs including glucocorticosteroids, azathioprine, and others most of which are off-label. Myasthenic crisis is characterized by most severe weakness, swallowing difficulties and respiratory failure, therefore requiring intensive care therapy. Dtsch Arztebl 2007; 104(7): A 4206.
Key words: myasthenia gravis, autoimmune disease, neuromuscular disease, treatment, immunotherapy, acetyl-choline

he key manifestation of myasthenia gravis (MG) is fluctuating muscle weakness which typically increases during effort Myasthenia gravis is a chronic autoimmune disease, sub-classified according to the Osserman und Genkins classification (2), and, more recently, that of the MGFA (Myasthenia Gravis Foundation of America) - Task-Force (3) (table 1). According to these criteria, ocular MG is characterized by fluctuating unilateral or bilateral ptosis, and, frequently, double vision, both deteriorating during the day. Generalized MG with additional involvement of arm, leg and trunk muscles as well as respiratory, facial and bulbar muscles is divided into different sub-categories dependent on disease severity. Muscle atrophy is rarely present and only in the late stages of severe, and insufficiently treated MG (1, 3). Generalized forms without typical ocular symptoms pose a particular diagnostic challenge. The prevalence of MG is between 25 and 100 per million population (1). MG presents most commonly between the ages of 20 to 40 and 60 to 70 (female to male ratio 3:2) (1).

Clinical examination
The examination of the extra ocular musculature includes: > the eyelid fatigue test while looking upwards for one minute, with recovery after brief maximal eyelid closure (4) > the diplopia stress test (looking sideways for at least one minute) > the red glass test (red glass in front of the right and light source in front of the left eye, to distinguish double images) > the eliciting of the so-called Cogan sign, transient jerks of the eyelid immediately after looking quickly downwards and then upwards (4) and > weakness of the periocular musculature (eyelash sign). In the modified Besinger and Toyka myasthenia score (5), the weakness and fatigue of the preferentially affected proximal muscle groups, the vital capacity (via spirometry) and
Abteilung Neurologie, Georg-August Universitt Gttingen, (PD Dr. med. Schneider-Gold); Neurologische Klinik und Poliklinik der Julius-Maximilians-Universitt Wrzburg, (Prof. Dr. med. Toyka)

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Osserman und Genkins (2) classification of myasthenia gravis, modified by the MGFA/Task Force (3)


Clinical form(s) Ocular form Mild generalized form Faciopharyngeal form Severe acute generalized form Medium severity generalized form

Symptoms Ptosis, diplopia Mild generalized weakness IIa + bulbar weakness Acute severe general weakness + bulbar symptoms + respiratory insufficiency Medium severity generalized weakness with involvement of the extremities/trunk muscles > faciopharyngeal musculature Faciopharyngeal/respiratory musculature > extremities/ trunk musculature Severe, often progressive generalized weakness Extremities/trunk musculature > faciopharyngeal musculature Faciopharyngeal/respiratory musculature > extremities/ trunk musculature

Severe chronic generalized form Severe generalized form

Myasthenia with severe residual deficits Severe MG requiring intubation

Severe chronic form with muscle atrophy

MGFA, Myasthenia Gravis Foundation Association; the entries marked* refer to the Os-serman and Genkins classification

the spontaneous ocular and faciopharyngeal symptoms and their degree of worsening with effort are presented in a summary score (table 2).

Differential diagnosis of myasthenia gravis

Among the differential diagnoses are mitochondrial myopathy, botulism from food poisoning, myositis, congenital myasthenic syndrome and Lambert Eaton myasthenic syndrome (LEMS). Lambert Eaton myasthenic syndrome is a neuromuscular disorder of presynaptic neurotransmission mediated by auto-antibodies against voltage-gated calcium channels, characterized by muscular weakness and autonomic disorders such as dry mouth, hyposalivation and impotence (3). Its prevalence is around or below 1 to 2 per 100 000.
Myasthenia score modified according to Besinger und Toyka (5)*1

No weakness (0) Arm outstretched time*2 Leg outstretched time*3 Head outstretched time*4 Vital capacity*5 FEV1 Chewing/swallowing Facial expression Diplopia Ptosis > 180 Sec. > 45 Sec. > 90 Sec. > 4,0 L (m) > 3,0 L (w) > 90 % Normal Normal > 60 Sec. > 60 Sec.

Mild weakness (1) 60180 Sec. 3045 Sec. 3090 Sec. 2,54 L (m) 2,03,0 L (w) 6090 % Fatiguing (with solid food) Lid closure weak 1060 Sec. 1060 Sec.

Moderate weakness (2) 1060 Sec. 530 Sec. 530 Sec. 1,52,5 L (m) 1,22 L (w) 4060 % Soft foods only Incomplete lid closing > 010 Sec. > 010 Sec.

Marked weakness (3) < 10 Sec. < 5 Sec. < 5 Sec. < 1,5 L (m) < 1,2 L (w) < 40 % Gastrostomy needed No facial expression Spontaneous diplopia Spontaneous ptosis

*1 This original score has been adapted and extended for clinical trials by the MGFA *2 Dominant arm, outstretched horizontal during sitting; in semi prone, severely ill patients, lift arm by about 30-45 (the outstretched times are only approximate measures) *3 Supine, dominant leg, lifted 45 *4 Supine, head lifted 45 *5 Vital capacity measured while seated; m, men, w, women; FEV1 = forced expiratory volume at one second

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Pathogenesis of myasthenia gravis MG is a prototypical antibody-mediated, T-helper cell dependent autoimmune disease (6, 7, 8, 9, 10). The majority of MG patients have antibodies directed against the alpha subunit of the nicotinergic acetylcholine receptor (Ach-R) of skeletal muscle (6), which lead to loss of receptors and destruction of the postsynaptic membrane (6). Blocking antibodies bind at or in the immediate vicinity of the acetylcholine binding sites and are usually not detected on standard laboratory testing (see below) (9). Autoantibodies directed against the acetylcholine receptor (Ach-R) are produced in the thymus and in the lymphatic system by ACh-R-specific auto-reactive T and B lymphocytes which are generated during thymus maturation (10). In the healthy individual, these autoimmune T-cells are eliminated or adequately controlled by regulatory T-cells. The primary triggering event is as poorly understood as in other autoimmune diseases. Ach-R antibodies are detected in 80% to 90% of patients with generalized MG and in about 50% of patients
Figure: CT scan of a thorax showing a thymoma in the anterior mediastinal region which was confirmed after surgical removal (arrow).

with ocular MG. In up to 40% of patients formerly classified as suffering from sero-negative MG, specific antibodies against muscle-specific tyrosine kinase (MuSK) can be identified (11). In MuSK positive MG bulbopharyngeal and respiratory muscles are preferentially affected (11). This form of MG accounts for around two to five percent of acetyl-choline receptor (Ach-R) antibody negative cases who have generalized myastasis. In around five percent of patients with generalized MG no specific antibodies can be found, meaning that additional target antigens can be assumed to exist. In around 70% of acetyl-choline receptor (Ach-R) antibody positive patients under 40, the thymus shows the histological picture of thymitis with lymphofollicular hyperplasia. In MuSK-antibody-associated myasthenia, the thymus is for the most part morphologically normal (12). Patients over 40 mostly have age-related thymic atrophy (1). Thymomas (figure) or thymic carcinomas (13) are found in five to fifteen percent of patients (paraneoplastic MG). Mature, potentially auto-reactive T-cells are produced in the non-neoplastic area of these tumors; the maturation and export of regulatory T-cells is reduced (14).

Additional investigations
Electrophysiology The exhaustion of neuromuscular transmission due to a reduced number of functional postsynaptic acetylcholine receptors can be demonstrated electrophysiologically by means of supramaximal electrical repetitive 3Hz stimulation (serial nerve stimulation) of, for example, the accessory nerve, or the facial nerve, with measurement of the myoelectric response in the corresponding muscles. A positive decrement (reduction in the amplitude/area by more than 15%/10%) is found in up to 80% of patients with generalized MG and in less than 50% of patients with the ocular form (15). Pharmacological testing In the Tensilon test, 2 ml of edrophonium chloride are given initially in the adult patient intravenously (10 mg edrophonium chloride dissolved in 9 ml physiological saline solution). After a minute, if there is no response and there are no side effects, a further 8 ml are given,

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Stepwise approach to the pharmacological treatment of myasthenia gravis

1. Acetylcholin esterase inhibitors (basic maintenance treatment) Pyridostigmine 60 mg 4 hourly, optional 90180 mg retard (time span) at bedtime *1 2. Glucocorticosteroids 60-100 mg methylprednisolone (or prednisone/prednisolone) p/o (gradual increase or start with maintenance dose, with gradual reduction on remission). Caution: transient worsening is possible 3. Immunosuppressive long term therapy Azathioprine Cyclosporin A 24 50 mg/day (23 mg/kg) *2 2 100200 mg/day *3

Medication for non- or poor responders Mycophenolat mofetil 1.0002.000 mg/day *4 Methotrexate 7.5 mg/week *4 Cyclophosphamide 500 mg/m2 IV every 412 weeks or 12 mg/kg/day p/o *4, *5 Tacrolimus 2 25 mg/day; reserved for intractable cases *6 6 Rituximab (Mabthera) *
*1 Retard preparation only useful with definite over night or morning symptoms *2 Administration in 3 daily doses following meals is better tolerated than 12 doses; prior test dose of 1 50 mg *3 Only with regular monitoring of fasting plasma levels, class 1-evidence based, but not yet licensed for MG *4 Unlicensed but successful in a number of case reports *5 Only in severe refractory disease; higher doses required for "immune ablation" with rescue medication off-label *6 Very limited experience off label

with atropine sulphate held ready for administration as an antagonist, should muscarinic side effects (asthma attack, bradycardia) occur. The Tensilon test can be combined with the serial nerve stimulation test, used before and afterwards, in diagnostically difficult cases (15). In high risk patients and in outpatients, a test with oral pyridostigmine should first be carried out, with subsequent testing after 60 minutes, and a clearly positive response may be sufficient to make the diagnosis.
Laboratory investigations The analysis of patient serum for pathologically raised titers of acetylcholine receptor antibodies using an immune precipitation test (acetylcholine receptor extracts from human amputated muscle) is the most specific tool in the diagnosis of MG (6). Seronegative patients should be tested for antibodies against MuSK.

Imaging investigations Imaging of the thorax with CT or MRI to investigate the thymus is mandatory in all new cases of MG, and should be repeated at intervals of one to two years, even where the initial investigation was normal, to exclude incipient thymoma. Scintigraphy using indium-111DTPA-D-phe-octreotide can be helpful in imaging the extent of growth of a thymoma by means of the somatostatin receptors expressed on the surface, even where there is considerable scarring following surgery (16).

MG is one of the best treatable autoimmune diseases. The cornerstones of treatment are thymectomy, acetylcholinesterase inhibitors, immunosuppressive drugs and plasmapheresis (1, 3). The aim of treatment is remission with the best possible quality of life. In autoimmune MG, the use of glucocorticoids, cyclosporin A, combination therapy with azathioprine and glucocorticoids, as well as plasmapheresis and immunoglobulins, is supported by studies designed to provide class 1 evidence (17, 18, 19, 20). However, some of these studies fail to reach this level, due for example to problems with recruitment (box 1). Only class 2 Dtsch Arztebl 2007; 104(7): A 4206


evidence exists for second line immunosuppressive treatments such as tacrolimus, methotrexate and cyclophosphamide, as well as for MTX and cyclosporin A, and for these there is no formal licence for this indication in many countries. The effect of thymectomy on the progression on MG has only been investigated by evidence class 2 studies (21). A metaanalysis of available class 2 evidence studies on thymectomy in myasthenia gravis (21) suggests that complete thymectomy in patients under 45 can improve prognosis. The upper age limit for thymectomy is at around age 60. In purely ocular disease, thymectomy is not indicated. Where there is suspicion of a thymoma, radical surgery is essential to clarify the histological picture. Invasive or metastasizing cortical thymomas and well differentiated thymus carcinomas can additionally be treated with radiotherapy and chemotherapy, which is thought to improve prognosis. Pyridostigmine, given in a dose of 60 mg three to seven times daily has proved helpful as oral, symptomatic treatment. Its effect can be demonstrated electrophysiologically (6). Pyridostigmine inhibits the hydrolytic cleavage of acetylcholine (15) and thereby improves neuromuscular transmission. Symptomatic treatment with pyridostigmine is, however, seldom sufficient in itself. Initial immunosuppressive treatment begins with glucocorticoids in rising doses (30 to 100 mg p/o) or with an intermediate dose of 60 mg/day. Due to a reinforcement of the acetylcholine receptor ion channel dysfunction, a transient worsening of symptoms may occur between two and twelve days after treatment has been given. Because of their toxicity, steroids as immunosuppressive monotherapy are only used in low doses (1030 mg/day) in ocular myasthenia, and are otherwise tailed down once a significant improvement has been achieved. The effect of glucocorticosteroids is supported by class 1 evidence, although the class 1 criteria are only partially fulfilled in the individual studies (17). In order to limit the use of steroids, immunosuppressive drug maintenance therapy should be given in generalized MG from the acute phase, with azathioprine (AZA) in a dosage of 50 mg b.i.d. or t.i.d. (total daily dose 2.5 to 3 mg/kg) is the treatment of first choice (1) (box 1). From a practical point of view, a single test dose of 50 mg is advisable before commencing maintenance therapy, to exclude occasional severe idiosyncratic reactions (fewer than 0.5% of patients). The biologically active form (6-mercaptopurine) inhibits T and B lymphocyte proliferation, thereby reducing antibody production. The therapeutic efficacy of AZA in combination with corticosteroids is supported by a single study of class 1 level evidence (19). During treatment with AZA the total leucocyte count should not drop down to less than at least 3.500/L and the absolute lymphocyte count should be maintained between 500 and 900/L. In thiopurine methyl transferase deficiency or in simultaneous treatment with allopurinol for gout, AZA is not, or is incompletely, broken down, so that a normal dose can lead to dangerous leucopenia. In these cases 25% to 50% of the normal dose should be used.

Management of myasthenic crisis

1. Acetylcholine esterase inhibitors Physostigmine 824 mg/day IV (initially always with atropine sulphate) 2. Glucocorticosteroids Up to 500 mg methylprednisolone IV or 100 mg p/o (with gradual reduction on remission) 3. Plasma separation techniques Plasmapheresis (non-selective) or additional immune adsorption (semi-selective), Exchange of 12 plasma volumes 23 weekly for 2 weeks 4. Immunoglobulins IV (only for specific indications) 0.4 g/kg on 5 consecutive days 5. Immunosuppressive long term therapy (see above) Begin as soon as possible or continue at a higher dose/combination

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The measurement of thiopurine methyl transferase activity is advisable in early and marked AZA-associated leucopenia. Where enzyme activity is lacking, AZA is contraindicated. Treatment with AZA should be continued for at least two to three years, and be reduced by 25 mg every three months where there is remission and the acetylcholine receptor antibody titers are stable. If AZA is discontinued too abruptly or too soon, relapses can occur (22). Where there is intolerance or inadequate effect, another immunosuppressive drug should be used (box 1). Treatment must be under continual medical review, as must any chemotherapy. Cyclosporin A (CYC A) works by inhibiting calcineurin synthetase, thereby inhibiting the synthesis of cytokines and the activation of T lymphocytes (1). CYC A is given at a dose of 2 50 mg to 2 150 mg orally (2 to 5 mg/kg). Its efficacy is supported by evidence class 1 studies (18). A fasting plasma level of 70 to 100 g/ml after 12 hours should be aimed for, in myasthenia gravis. Significant side effects include arterial hypertension, nephropathy and neurotoxicity (encephalopathy). Around 5% of patients are unable to tolerate AZA or CYC A, or respond inadequately. In these cases, mycophenolat mofetil may be used for long term immunosuppression. Mycophenolat mofetil (2 500 to 1.000 mg/day) is first converted in the body to mycophenolic acid, which selectively, non-competitively and reversibly inhibits inosine monophosphate dehydrogenase and hence inhibits de novo synthesis of guanosine nucleotide synthesis (23). Methotrexate is used on rare occasions (7.5 to 15 mg/week [1]). It inhibits lymphocyte proliferation via inhibiting folate synthesis. Significant side effects include pulmonary fibrosis and bone marrow suppression. Cyclophosphamide is a fallback treatment for the most intractable cases (1). It is cytotoxic and immunosuppressive, and is given either intravenously (500 mg/m2 of body surface area (SA), at intervals of 4 to 12 weeks, or, less commonly, orally (1 to 2 mg/kg BW/day). A maximal cumulative lifetime dose of 45 g should not be exceeded due to cumulative toxicity. A high dose therapy at 50 mg/kg BW and subsequent rescue therapy with granulocyte stimulating factor (G-CSF) (so-called immune ablation) should remain an option for the most intractable cases (24).
"Off label" use With the exception of AZA, none of the above long term immunosuppressive treatments is licensed for use in MG in Germany and in some other European countries. Hence, these may only be used "off label" where AZA is not tolerated. The cost of such treatment is only reimbursable under health insurance arrangements by prior permission. Approaches under investigation Among newer treatment approaches is rituximab, an antibody against a surface antigen expressed by B-cell precursors (CD 20), which may be used off label at a dose of 375 mg/m2 SA in refractory cases of MG. Tacrolimus, like CYC A, blocks calcineurin activity and hence inhibits T lymphocyte proliferation. Although observational studies have shown benefit from tacrolimus in MG (23), its use is not currently established in Germany. Treatment of myasthenic crisis Severe generalized illness, infections and operations can precipitate myasthenic crisis with acute generalized weakness, swallowing difficulties and respiratory failure (1, 25). Myasthenic crises are rare nowadays, and occur primarily in the first two years of disease onset. Where the forced vital capacity falls below 1.2 l (15 ml/kg body weight) or where oxygen is required, artificial ventilation is indicated (1, 25). The intensive care management of myasthenic crisis includes first a switch from pyridostigmine to physostigmine as an i.v. drip or in the perfusor, in combination with subcutaneous atropine, high dose intravenous glucocorticoids and plasmapheresis (1, 3, box 2). In general, one to two times the plasma volume is exchanged three times weekly over a two week period. Only where this is contraindicated (sepsis, poor venous access, age over 70) would we recommend intravenous immunoglobulin G as a first line treatment. This is only marginally less effective than plasmapheresis, given in a dose of 0.4 g/kg in

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Medications relatively contraindicated in MG *1

Substance group Analgesics Antibiotics

Examples Morphine, flupirtine Aminoglycosides, macrolides, ketolides, gyrase inhibitors, sulphonamides, tetracyclines, penicillins (high doses) Tricyclics D penicillamine, chloroquine Pindolol, propranolol, timolol Verapamil, diltiazem, nifedipine High dose magnesium, e. g. in tocolysis Curare derivatives (max. 1050 % of the normal dose), succinyl choline

Antidepressants Rheumatological agents Beta-blockers Calcium antagonists Magnesium Muscle relaxants

*1 These restrictions apply for patients with clinically visible signs, despite treatment with cholinesterase inhibitors; they may be used otherwise with observation during first treatment. MG, myasthenia gravis

five consecutive days (class 1 evidence level 4) (box 2) (20). The efficacy of intravenous immunoglobulins rests in part on the neutralization of circulating antibodies, the inhibition of B-cell activation and complement binding, the blockade of Fc receptors, and the modulation of T-cell function (1). With these measures, myasthenic crisis can usually be brought under rapid control. Adequate ongoing immunosuppression should be commenced or increased, at an early stage. Total mortality in myasthenic crisis, of which elderly patients and those with comorbidity are at greatest risk, has fallen to under 5%, thanks to efficient short and long term treatments and improvements in intensive care (1, 25). These improvements also permit successful management of even complicated cases.

Management during anaesthesia, surgery and pregnancy

Muscle relaxants during anaesthesia should either be withheld, or given only in the form of a tenth of the usual dose, in the form of a medium acting non-depolarizing agent such as atracurium. A prolonged postoperative ventilation requirement is to be expected. For local anaesthesia, an amide type agent should preferably be used, such as lidocaine (1). It is generally not needed to discontinue long term immune suppressants preoperatively. Pregnant women with MG should deliver in a center experienced in the management of this condition, and with neonatal intensive care facilities available. This is important because, regardless of the severity of maternal disease, 10% of neonates will suffer transient myasthenia (1). The maternal disease can also worsen. Medications which can worsen myasthenia gravis include: D penicillamine, antibiotics, antidepressants, beta-blockers, calcium antagonists and magnesium (table 3).
Acknowledgement The electronmicrograph (front cover) of a mouse neuromuscular junction was provided by Dr. Archinto P. Anzil. Conflict of Interest Statement Prof. Dr. med. Klaus Toyka has received consultancy fees from pharmaceutical companies involved in the area of immune therapy and has been paid as a reviewer in the licensing of Imurek (azathioprine) in myasthenia. In addition, he has advised companies on therapeutic studies of immunoglobulins in myasthenia, pro bono; he has authored and co-authored treatment guidelines for pharmaceutical companies and professional bodies, for which costs of printing were in part covered by educational grants from pharmaceutical companies. PD Dr. med. Christiane Schneider-Gold has received remuneration for giving lectures for the company Temmler Pharma, which manufactures the drug Kalymin. Manuscript received on 22 June 2006, final version accepted on 26 August 2006. Translated from the original German by Dr. Sandra Goldbeck-Wood, and edited by the authors.

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Corresponing author PD Dr. med. Christiane Schneider-Gold Abteilung Neurologie der Georg-August-Universitt Gttingen Robert-Koch Str. 40 37075 Gttingen, Germany

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