MEDICINE

REVIEW ARTICLE

Myasthenia Gravis:
Pathogenesis and Immunotherapy
Christiane Schneider-Gold, Klaus V. Toyka

SUMMARY
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)

Dtsch Arztebl 2007; 104(7): A 4206 www.aerzteblatt.de

MEDICINE

TABLE 1
Osserman und Genkins (2) classification of myasthenia gravis, modified by the MGFA/Task Force (3)

Class

Clinical form(s)

Symptoms

I*/MGFA I

Ocular form

Ptosis, diplopia

II a*/MGFA II

Mild generalized form

Mild generalized weakness

II b*/MGFA IIb

Faciopharyngeal form

IIa + bulbar weakness

III*

Severe acute generalized form

MGFA III
MGFA IIIa

Medium severity generalized form

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

MGFA IIIb
IV*
MGFA IV
MGFA IVa
MGFA IVb

Severe chronic generalized form

Severe generalized form

V*
MGFA V

Myasthenia with severe residual deficits

Severe MG requiring intubation

Severe, often progressive generalized weakness

Extremities/trunk musculature > faciopharyngeal musculature
Faciopharyngeal/respiratory musculature > extremities/
trunk musculature
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.
TABLE 2
Myasthenia score modified according to Besinger und Toyka (5)*1

No weakness (0)

Mild weakness (1)

Moderate weakness (2)

Marked weakness (3)

Arm outstretched
time*2

> 180 Sec.

60180 Sec.

1060 Sec.

< 10 Sec.

Leg outstretched
time*3

> 45 Sec.

3045 Sec.

530 Sec.

< 5 Sec.

Head outstretched
time*4

> 90 Sec.

3090 Sec.

530 Sec.

< 5 Sec.

Vital capacity*5
FEV1

> 4,0 L (m)

> 3,0 L (w)
> 90 %

2,54 L (m)
2,03,0 L (w)
6090 %

1,52,5 L (m)
1,22 L (w)
4060 %

< 1,5 L (m)

< 1,2 L (w)
< 40 %

Chewing/swallowing

Normal

Fatiguing
(with solid food)

Soft foods only

Gastrostomy
needed

Facial expression

Normal

Lid closure weak

Incomplete lid closing

No facial expression

Diplopia

> 60 Sec.

1060 Sec.

> 010 Sec.

Spontaneous
diplopia

Ptosis

> 60 Sec.

1060 Sec.

> 010 Sec.

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

Dtsch Arztebl 2007; 104(7): A 4206 www.aerzteblatt.de

MEDICINE

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,

Dtsch Arztebl 2007; 104(7): A 4206 www.aerzteblatt.de

MEDICINE

BOX 1

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).

Treatment
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 www.aerzteblatt.de

MEDICINE

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.
BOX 2

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

Dtsch Arztebl 2007; 104(7): A 4206 www.aerzteblatt.de

MEDICINE

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

Dtsch Arztebl 2007; 104(7): A 4206 www.aerzteblatt.de

MEDICINE

TABLE 3
Medications relatively contraindicated in MG *1

Substance group

Examples

Analgesics

Morphine, flupirtine

Antibiotics

Aminoglycosides, macrolides,
ketolides, gyrase inhibitors,
sulphonamides, tetracyclines,
penicillins (high doses)

Antidepressants

Tricyclics

Rheumatological
agents

D penicillamine, chloroquine

Beta-blockers

Pindolol, propranolol, timolol

Calcium antagonists

Verapamil, diltiazem, nifedipine

Magnesium

High dose magnesium,

e. g. in tocolysis

Muscle relaxants

Curare derivatives (max. 1050 %

of the normal dose), succinyl choline

*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.

Dtsch Arztebl 2007; 104(7): A 4206 www.aerzteblatt.de

MEDICINE

REFERENCES
1. Hohlfeld R, Melms A, Schneider C, Toyka KV, Drachman DB: Therapy of myasthenia gravis and myasthenic
syndromes. In: Brandt T, Caplan LR, Dichgans J, Diener HC, Kennard C (eds.): Neurological disorders course
and treatment. Amsterdam: Elsevier 2003: 134162.
2. Osserman KE, Genkins G: Studies in myasthenia gravis: review of a twenty-year experience in over 1 200
patients. Mt Sinai J Med 1971; 38: 497537.
3. Melms A, Gold R, Hohlfeld R, Schalke B, Schumm F, Toyka KV: Myasthenie. In: Diener HC, Putzki N, Berlit P
(Hrsg.): Leitlinien fr Diagnostik und Therapie in der Neurologie. Stuttgart; Thieme Verlag 2005; 56882.
4. Toyka KV: Ptosis in myasthenia gravis: extended fatigue and recovery bedside test. Neurology 2006;
67: 1524.
5. Besinger UA, Toyka KV, Homberg M, Heininger K, Hohlfeld R, Fateh-Moghadam A: Myasthenia gravis:
long-term correlation of binding and bungarotoxin blocking antibodies against acetylcholine receptors with
changes in disease severity. Neurology 1983; 33: 131621.
6. Lindstrom J: An assay for antibodies to human acetylcholine receptor in serum from patients with myasthenia
gravis. Clin Immunol Immunopathol 1977; 7: 3643.
7. Toyka KV, Drachman DB, PestronkA, Kao I: Myasthenia gravis. Passive transfer from man to mouse. Science
1975; 190: 39799.
8. Heininger K, Hartung HP, Toyka KV, Gaczkowski A, Borberg H: Therapeutic plasma exchange in myasthenia
gravis: semiselective adsorption of Anti-AChR autoantibodies with tryptophane-linked polyvinylalcohol gels.
Ann N Y Acad Sci 1987; 505: 898900.
9. Bufler J, Pitz R, Czep M, Wick M, Franke C: Purified IgG from seropositive and seronegative patients with
myasthenia gravis reversibly block currents through nicotinic acetylcholine receptor channels. Ann Neurol
1998; 43: 45864.
10. Hohlfeld R, Wekerle H: The immunopathogenesis of myasthenia gravis. In: Engel AG (Hrsg.): Myasthenia
gravis and myasthenic syndromes. Oxford University Press, Oxford, 1999: 87110.
11. Vincent A, Bowen J, Newsom-Davis J, McConville J: Seronegative generalised myasthenia gravis: clinical
features, antibodies and their targets. Lancet Neurology 2003; 2: 991065.
12. Leite MI, Strobel P, Jones M et al.: Fewer thymic changes in MuSK-positive than in MuSK-negative MG. Ann
Neurol 2005; 57: 44448.
13. Strbel P, Marx A, Zettl A, Mller-Hermelink HK: Thymoma and thymic carcinoma: an update of the WHO
Classification 2004. Surg Today 2005; 35: 80511.
14. Strbel P, Rosenwald A, Beyersdorf N et al.: Selective loss of regulatory T-cells in thymomas. Ann Neurol
2004; 56: 9014.
15. Schneider C, Reiners K: Elektrophysiologische Diagnostik neuromuskulrer bertragungsstrungen. Klin Neurophysiol
2000; 31: 12235.
16. Marienhagen J, Schalke B, Aebert H, Held P, Eilles C, Bogdahn U: Somatostatin receptor scintigraphy in
thymoma imgaing method and clinical application. Pathol Res Pract 1999; 195: 57581.
17. Schneider-Gold C, Gajdos P, Toyka KV, Hohlfeld RR:Corticosteroids for myasthenia gravis. Cochrane Database
Syst Rev 2005; CD002828.
18. Tindall RSA, Phillips JT, Rollins JA, Wells L, Hall K: A clinical therapeutic trial of ciclosporine in myasthenia
gravis. Ann N Y Acad Sci 1993; 681: 53951.
19. Palace J, Newsom-Davis J, Lecky B: A randomized double-blind trial of prednisolone alone or with azathioprine
in myasthenia gravis. Neurology 1998;50: 177883.
20. Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C: Clinical trial of plasma exchange and high-dose
intravenous immunoglobulin in myasthenia gravis. Ann Neurology 1997; 41: 78996.
21. Gronseth GS, Barohn RJ: Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidencebased review). Neurology 2000; 55: 715.
22. Michels M, Hohlfeld R, Hartung HP, Heininger K, Besinger UA, Toyka KV: Myasthenia gravis: discontinuation of
longterm azathioprine. Ann Neurol 1988; 24: 798.
23. Schneider-Gold C, Hartung HP, Gold R: Mycophenolate mofetil and tacrolimus: new therapeutic options in the
therapy of neuroimmunological diseases. Muscle Nerve 2006; 34: 28491.
24. Drachman DB, Jones RJ, Brodsky RA: Treatment of refractory myasthenia gravis: Rebooting with high dose
cyclophosphamide. Ann Neurol 2003; 53: 2934.
25. Thomas CE, Mayer SA, Gungor Y: Myasthenic crisis: clinical features, mortality, complications and risk factors
for prolonged intubation. Neurology 1997; 48: 125360.
Corresponing author
PD Dr. med. Christiane Schneider-Gold
Abteilung Neurologie der
Georg-August-Universitt Gttingen
Robert-Koch Str. 40
37075 Gttingen, Germany
c.schneider-Gold@med.uni-goettingen.de

Dtsch Arztebl 2007; 104(7): A 4206 www.aerzteblatt.de