Myasathenia Gravis
Myasthenia Gravis


Yoshitaka Fujii
Nagoya City University Medical School
Department of Surgery II

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Japanese version
since 1 September 2000
last update 3 October 2003
Index
about Myasthenia Gravis
Diagnosis
Treatment
Thymectomy
Why thymectomy is effective
Drugs used for myasthenia gravis
About Cyclosporin A and FK506 (Tacrorimus, Prograf)
Popular drugs that patients must be wary of
Thymoma
Why did I contract myasthenia gravis in the first place?
To the family or friends of a very sick patient--be prepared

for Doctors and Nurses
Guideline for the treatment of Myasthenia Gravis
Indication for thymectomy
Indication for steroid pulse therapy
Use of immunosuppressants
Management of crisis


topics
Myasthenia Gravis without anti-acetycholine receptor antibody
Is myasthenia gravis inherited?
Pregnancy and myasthenia gravis
Children of a myasthenia mother
Myasthenia gravis patients please DO NOT donate blood
Bone marrow transplantation will not work if you have had your thymus removed

Myasthenia Gravis

                                  
Myasthenia Gravis is a disease of the muscle.
Symptom is often described as "easy fatiguability".
When the patient uses a muscle repeatedly, the muscle becomes a kind of "paralyzed".
After a rest, the muscle can be used again.
It is a relatively uncommon disease.
11693 patients are registered in Japan in 1998 (there are total of 126486000 Japanese).

Symptoms depend on which muscle is affected.

muscle around the eyesptotis (dropping eyelids)、double vision、strabismus
shampoo gets in the eye、irritable eyes
muscle around the mouthdifficulty in chewing, swallowing
cannot speak well, nasal tone
muscle of the facehard to smile beautifully (snarling)
muscle of the arm and legdrop even light objects, cannot write well
cannot walk, cannot stand up, cannot climb stairs
cannot shampoo hair, cannot put up laundries
respiratory muscledifficult to breathe
Affected muscle and severity of muscle weakness differ greatly from one patient to another.
Muscle strength recovers after a rest.
Symptoms worsen in the evening.

Muscles of the heart or intestine are not affected (they are different from those of arms and legs).

The weakness of the muscle is the result of reduced number of acetylcholine receptors caused by the binding of antibodies against this receptor.
Acetylcholine receptor relays the signal from the nerve to the muscle.
The reduced number of acetylcholine receptors makes the trasmission of the signal from the nerve to the muscle difficult.


Normal PersonMyasthenia Gravis Patient

In the normal neuromuscular junction, the nerve terminal emits acetylcholine (small blue balls) towards the muscle membrane.
Acetylcholine binds acetylcholine receptor (sausage like structure which is actually a barrel like ion channel) which is activated (red ones) and allows influx of ions which initiates muscle contraction.
Acetylcholine is rapidly degrated by an enzyme called choline-esterase.
The drugs like mestinon used for myasthenia gravis block the activity of this enzyme, thus causing the accumulation of acetylcholine in the neuromuscular junction.

Normal Neuromuscular JunctionNeuromuscular Junction in Myasthenia Gravis Patient
There are enough number of acetylcholine receptor
transmitting the signal from the nerve
to the muscle.
Antibody (Y-shaped) binds and
reduces the number of acetylcholine receptor
and makes the transmission of the signal difficult.

We have the ability to make millions of kinds of antibodies and use these to cure the disease like flu.
In myasthenia gravis patients, somehow there are antibodies which bind acetylcholine receptor of their own and cause the symptoms.
In short, myasthenia gravis patients make the disease causing antibody themselves.
This kind of disease is called an autoimmune disease. Myasthenia gravis is more common in women than men.
Also, thymoma is commonly seen in myasthenia gravis patients(24%).
Patients with myasthenia gravis with thymoma affects men and women equaly.

Among 375 myasthenia gravis patients(Masaoka et al. Annals of Thoracic Surgery 1996)
Patients without thymomaPatients with thymoma
men
72
48
women
214
41

Myasthenia gravis is not genetically inherited.

We do know some instances of patients from the same samily. Also correlation with particular HLA antigens have been reported. However, for a each individual, the immune system is freshly reset when he/she is born; production of anti-acetylcholine antibody is by no way inherited (it is aquired). The tendency towards producing autoantibody may be inherited but it should not be anti-acetycholine receptor antibody specific (it should not be limited to this disease).

There is one form of myasthenia gravis called congenital myasthenia gravis in which one of the genes for acetylcholine receptor is mutated. In these patients, anti-acetycholine receptor antibody is not found and the disease is completely different from the acquired form of the usual myasthenia gravis.

Transient myasthenia gravis of the baby born to a myasthenia mother is not real myasthenia gravis. It is caused by immunoglobulin transfered from the mother to the baby. When the antibody is consumed in a month or so, the symptom subsides and the baby itself is not myasthenic at all.


Myasthenia gravis is diagnosed as follows.

  1. Easy fatiguabilty of skeletal muscles which recovers after a rest
  2. Electromyography shows a characteristic sign (waning).
  3. Circulating antibody to acetylcholine receptor (80% of the patients)
  4. Anti-cholineesterase drugs are effective.

Anti-acetylcholine receptor antibodies are specific to myasthenia gravis.
It is not detected in normal subjects(<0.2pmole/ml).
The presence of this antibody is diagnostic of myasthenia gravis.
The titer of this antibody varies widely (0.2 to more than 1000).
A patient with a titer of 1000 is not necessarily more severely affected than a patient with a titer of 10.
However, a patient with a usual titer of 20 will get worse if the titer rises to 50. She will get much better if the titer falls to 5.

Myasthenia Gravis without anti-acetycholine receptor antibody

Some patients have typical myasthenic symptoms but no detectable anti-acetycholine receptor antibody.
Among these patients, a significant proportion have been reported to have antibodies directed towards a muscle specific kinase protein (MuSK) or LDL receptor related protein 4 (Lrp4).
In these patients, the mechanisms of the disease may be different and also the role of the thymus may be different too. So far, no patient with anti-MuSK antibody is reported to be associated with thymoma.

We must be careful to treat these anti-acetycholine receptor antibody negative patients; especially the effect of thymectomy for these patients have not been definitely proven.
I doubt that it will. A report in 2003 from Duke university describes 12 patients with anti-MuSK antibody.
None of these patients had thymoma.
Seven of these had thymectomy and none was effective.
In 2003 a group in Italy reported 37 anti-AChR negative anti-MuSK positive myasthenic patients.
They consisted 47% of 78 anti-AChR negative patients.
Fifteen patients had thymectomy; none had thymoma or abnormal thymic histology (germinal centers).
In none of these patients, thymectomy was effective.


At the moment we will not perform thymectomy for anti-AChR negative patients because this group of patients will contain those with anti-MuSK (or andi-Lrp4) antibody where the role of the thymus is not established and thymectomy will probably not work.

Myasthenia gravis is treated as follows

 1. Cholinesterase blockers (Myterase, Mestinon, Ubretid)(drugs used for myasthenia gravis
 2. Steroid (prednin)
 3. Thymectomy
 4. Plasma exchange
 5. Immunosuppressant (like cyclosporin)

How you should be treated should be determined by an experienced neurologist.
Increasing the drugs on your own may unexpectedly worsen the disease.

The response to treatment varies widely.
Some patients lead a normal life with only a small amount of anti-cholinesterase.
Some patients require a heavy dose of immunosuppressant and suffer from side effects.

Among the treatments listed above, anti-cholinesterase does not treat the disease itself.
Plasma exchange removes the disease causing antibody from the body but the antibody titer soon resumes the pretreatment value and the effects are usually temporary.
Steroid and thymectomy treat the disease by modulating the body's immune system.
The symptom of myasthenia gravis tends to fluctuate.
It gets worse for example after having a flu.
When you get used to the nature of the disease, you will learn how to control the amount of the drug on your own (within the limit set by your doctor).
You will learn when you tend to get worse and avoid these factors.
If you feel shortness of breath, you must make arrangements so that when it gets really bad, someone can call the ambulance because when you cannot breathe you cannot make a phone call.
Sedatives, painkillers, aminoglycoside antibiotics may worsen the symptoms.(drugs you must be wary of)。

Symptoms tend to get better when pregnant and may get worse after delivery.
Many patients with myasthenia gravis bear and raise children.
Having children is not at all impossible. Consult your doctor when you think of having a child.

Baby born to a myasthenic mothermay show myasthenic symptoms after birth.
This is caused by the antibody transmitted from the mother to the baby via the placenta.
The child him/herself does not have myasthenia gravis and the symptoms eventually subside.
The disease itself is not genetically transmitted.

Myasthenia gravis today is not a fatal disease. It is not grave any more.
However, it is a longstanding disease and hard to be completely cured.
If you are under the supervision of a neurologist, you are very unlikely to die of the disease.
I understand you tend to get depressed if your daily life is hampered. But do not stay home. Go out and see your friends. Your family and friends are necessary for you to get along with the disease.

Warning
If you have a high titer of anti-acetylcholine receptor antibody, DO NOT DONATE BLOOD. The receipient could transiently become myasthenic.


Thymectomy

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Thymectomy is performed in the following cases.
1. The patient has a tumor in the thymus(thymoma).
2. As a therapy for myasthenia gravis.

The Thymus
The thymus is an organ just underneath the sternum, the bone located longitudinally in the front center of the thorax.
It is in front of the great vessels and above the heart.
It is a soft fatty tissue weighing roughly around 50g in an adult.

The thymus and sternum
Right lateral view
of the thorax
A thymus resected
from a myasthenic patient
Electonmicrography of the thymus

The thymus is the principal organ of the immune system. It creates T-lymphocytes, which are the main effector of the immune system.
It is most active in neonatal and young children. After puberty it slowly regresses and in the adult it consists mostly of the fat.
The thymus contains hundreds of millions of lymphocytes in a child.
In an adult it contains usually contains less than ten million cells.
The thymus in a patient with myasthenia gravis have abnormalities like thymomaor germinal center, which are rare in the normal thymus.
These abnormalities are related to the pathogenesis of the myasthenia gravis.
Look at the electronmicrograph above; ball-like structures are lymphocytes and the mesh-like structure is the network of thymic epithelial cells.

The operation
The operation is performed under general anesthesia.
The upper 2/3 to 3/4 of the sternum is cut by a sternal saw and the thymus together with the surrounding fatty tissue is resected (extended thymectomy).
When present, thymoma is resected with the thymus.

The skin incision is 10-15cm in length (depending on the statue of the patient).

In this small female patient, the scar is exactly 10 cm in length.

The operation lasts for 1.5 to 2 hours.
If the patient has a thymoma, it depends on the extent of the invasion by the tumor.
Whenever possible, the involved organ (pleura, pericardium, lung) is also resected and reconstituted if necessary.
When the invasion is extensive, radiation and/or chemotherapy may be indicated before reevaluating the patient for operation.
The complication of the operation includes;

These are relatively rare.
Unless the patient has an invasive thymoma, transfusion is unnecessary.
The operation is a relatively small one and if the patient's symptoms due to myasthenia gravis is mild, he or she will be able to eat and walk the next day

A drainage tube is placed to where the thymus had been.
This tube is removed when blood or discharge subsides.

Probably what requires experience most is the postoperative management of myasthenic symptoms.
Those that have bulbar symptoms (difficulty in swallowing, chewing, speaking) may develop difficulty in breathing and may need mechanical support of breathing.
When prolonged mechanical breathing is necessary, a tracheostomy (a hole made in cervical trachea through which a tube for mechanical ventilation is placed) may be required.
Tracheostomy makes the management of sputum easier and is usually done to avoid pneumonia.

In Japan, patients are admitted for 10-14 days.
Patients with thymoma may need additional radiation therapy which may require longer stay in the hospital.
Thymectomy under thoracoscopy or mediastinoscopy are being evaluated.
At present, it takes more time and it is not certain whether it brings comparable results.
Use of these endoscopes enables thymectomy without cutting the sternum, making the operation more tolerable to the patients.
 
 
The effect of thymectomy
 
It takes several weeks before the effect of thymectomy becomes apparent.
It may take as long as 1 year before you get any better.
In general, 80ー90% of the patients get better and can reduce the amount of the drugs they take.
30-40% of the patients remit completely and can do without any drug.
This operation is different from those for cancer, the effect of which is apparent immediately.

The thymus is an organ which produces T-lymphocytes.
By the time you become an adult, the thymus has finished its role and has become a fat-like disused tissue.


The thymus in a childThe thymus in an adult
Taking the thymus out does not cause any deteriorating effect in an adult at all.
In children, we do not have conclusive data.
However, judging from the effect of vaccines in 1 year old children, we presume that the immune system will have a repertoire wide enough to cope with most infections by the age of 3 to 4 years. Thymectomy after this age is considered safe.

Caution!
Without the thymus, bone marrow transplantation will not work as it is supposed to; to generate new T-lymphocytes, the thymus is absolutely necessary.
Thrapies including bone marrow transplantation should be planned very carefully if you have had your thymus removed.


Why thymectomy is effective for myasthenia gravis

At present, we do not exactly know why thymectomy is effective.
We have clues, though, based on the research we have done using the thymuses resected from myasthenia gravis patients.

Here are some of the findings of our research.                            
Drugs used for Myasthenia Gravis

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1. Anti-cholinesterase
 
2. Steroids (adrenocorticoids)

3. Steroid Pulse Therapy
4. Immunosuppressant――this is not used very often


About cyclosporin A and FK506 (Tacrolimus, Prograf)
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How they work:
These two drugs are not related and when given to patients, bind unrelated proteins (cyclophilin for cyclosporin and FKBP for FK506). However, they both work by suppressing a family of transcription factors called NFAT. This results in suppression of lymphokine production like IL-2 which are necessary for T cell proliferation and T cell's help for B cells to produce antibody. This is achived by suppressing a calcium dependent phosphatase called calcineurin. A little complicated story? In short, they work by suppressing T cells relatively specifically. T in NFAT is for T cells. Steroid (prednin), another immunosuppressive drug, work via another transcription factor called NF-kappa B and suppress many proteins in many types of cells (thus many unwanted side effects).

Child bearing and the drugs.
Cyclosporin A and FK506 both work by suppressing NFAT. By destroying genes for NFAT in the mouse, someone have created mice with no NFAT function. The mice are not born (they die in uterus) by defect in cardiac valve and vascular development. When given in a large enough amount, cyclosporin and FK506 may create a similar situation in the pregnant woman's body and may result in abortion. Thus, it is advised not to get pregnant when you are having cyclosporin or FK506.



Drugs that patients must be wary of

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1. sedatives, narcotics
These drugs may worsen the symptoms.
 
2. aminoglycosides (antibiotics that are often used intramuscularly)
Streptomycin, gentamycin, amycacin, etc.
These antibiotics may worsen the symptoms.
Oral antibiotics like penicillin, cephalosporins usually do not cause problems.

3. part of pain killers (anti-inflamatory drugs)
voltaren, indomethacin, loxonin, etc.
These drugs are not indicated as such but may worsen the symptoms.
 
4. some over the counter drugs for flu
If you take a drug and experience worsening of symptoms, stop that drug and consult your doctor.
In general, getting a flu makes symptoms worse.
 
5. Drugs used for prostate hypertrophy.


6. Some drugs for Parkinsonism

 
Many other drugs bear caution in the drug information for use in patients with myasthenia gravis.
Many of these drugs are often inadvertently given to the patients with myasthenia gravis.
Many patients do not experience any worsening of symptoms.
However, if you do get worse after taking some new drug, stop that drug and consult your doctor.

If you see a doctor for the first time, tell him/her that you have myasthenia gravis.
Take note of the names of the drugs you take and the titre of anti-acetycholine receptor antibody.


Thymoma
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Thymoma is a tumor of the thymus.
Many other tumors arise in the thymus. Thymoma is derived from the epithelial cells of the thymus.
Thymoma contains millions of lymphocytes which are newly generated within the tumor.
The photograph is a micrograph of a thymoma; those dark balls are lymphocytes.
These lymphocytes are not tumors. They are normal and generated by the aid of the tumor cells.
Tumor is epithelial cells surrounding the lymphocytes.

22.4% of thymoma patients have myasthenia gravis.
24% of myasthenic patients have thymoma.
This high coincidence indicates the relationship between the thymoma and myasthenia gravis.
We have evidence suggesting that thymoma is the cause of myasthenia gravis.

Unlike other malignant tumors like lung cancer, thymoma is a relatively benign tumor.
They grow slowly and rarely mestasize to distant organs.
5 year survival if over 80%.
Below is the staging of thymoma patients proposed by our former professor Masaoka and is widely used.
stage5 year survival(%)
Icompletely encapsulated
microscopically no capsular invasion
81.5
IIinvasion to mediastinal pleura, fat
microscopic capsular invasion
85.3
IIIinvasion to adjacent tissues
the lung, pericardium, phrenic nerve, brachiocephalic vein, superior vena cava
79.8
IVadissemination to pleura or pericardium48
IVbblood born or lymphatic metastatis

Thymomas that are completely surrounded with their own capsule (Stage I thymomas) or those with invasion to the mediastinal pleura (membraneous sheet covering the lung) (Stage II thymomas) are cured by thymectomy.

When the thymoma has spread in the thorax or lymph node or distant sites (Stage IV), it is usually not possible to remove all the tumor.
For stage III thymomas, operation is indicated when the invasion of the tumor is limited to brachiocephalic veins.
When the invasion is to superior vena cava or aorta, it is usually better to do chemotherapy and/or radiation therapy first and reevaluate the operability after the chemothrapy.
We often include prednisolone as part of chemotherapy.
When aorta or large veins are involved, artificial blood vessels may be used.

We do not know why thymoma is associated with myasthenia gravis.
We have done, however, some research on this.

When a myasthenic patient with thymoma undergoes thymectomy, the symptoms of myasthenia gravis get better. However, we experience patients with thymoma have some delay in the favorable effect of thymectomy when compared with those patients without thymoma. The reason for this is unclear.




Why did I contract the disease in the first place?
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We do not know the answer to this question at present.
We have done and will continue to do basic immunological experiments to find out why.
I will tell you what we have found out so far regarding this question.

In patients with thymoma, the developmental process of T-lymphocytes in thymoma is different from the one in the normal thymus. Particularly, the mechanism of removing T-lymphocytes that may react to autoantigens (including acetylcholine receptor ) may be lacking in thymoma. This may be related to the onset of myasthenia gravis in thymoma patients.
We know many examples of bone marrow transplantation-related myasthenia gravis.
The mechanism of bone marrow transplantation-related myasthenia gravis is similar to that in thymoma associated myasthenia gravis. Both are induced by nonspecific autoreactive lymphocytes.

For those patients without thymoma, the onset of myasthenia gravis is totally unknown.
These patients have abnormality in the thymus, namely, germinal centers.
However, whether germinal center formation is the cause or result of myasthenia gravis is controversial.
The target of the autoreactive antibody, acetylcholine receptor , may be present in the thymus. But it is not certain whether the amount of acetylcholine receptor in the thymus is sufficient to activate the developping lymphocytes in the thymus.

Other theories suggest virus infection may trigger myasthenia gravis by inducing cross-reacting immunological response.
This is an attractive theory. However, it lacks convincing evidence. Myasthenia gravis is not associated with any particular virus or any particular HLA type.

To plan experiments that can give conclusive evidence to this problem is difficult and the progress is slow.
Even if the cause of myasthenia gravis is discovered, the treatment will not change dramatically. This is because the patients are established ongoing producers of anti-acetycholine receptor antibodies. We have been unable to reduce the antibody even if we know this is the culprit.

For the patients' benefit, we must find out effective ways to reduce the anti-acetycholine receptor antibody production in the patient's body. I myself have hopes in immunosuppression. Future drugs may have more powerful effect with minimal side effects.


For families and friends of very sick patient
Myasthenia gravis is not a fatal disease, if properly handled.

When you need to be alert.

Breathing HAS stopped in the following cases. Immediately perform mouth-to-mouth breathing and call an ambulance.
Learn how to do mouth-to-mouth breathing
Mouth to mouth breathing (the most recommended method of breath support)
When it goes wrong.

You can ask your regional government about courses for cardio-pulmonary resuscitation.

When ambulance arives, tell them that the patient has myasthenia gravis and need respiratory support immediately.
Ask them to take the patient to his/her doctor.
If the doctor is far away, any hospital with emergency room is sufficient.
When the patient gets any better, consider transfering to the specialist.
In practice, myasthenia gravis patients need a specialist to be properly treated.



These are for professionals with medical background.

Guidline for treatment of Myasthenia Gravis
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This is the guideline based on my experience with more than 100 patients with myasthenia gravis yearly seen at the outpatient clinic of Osaka University Hospital.


 
Indication for Thymectomy
 
absolute
good (>90% effective)
offered as a reasonable choice


Thymectomy should be reserved
Thymectomy not recommended

If possible reduce the amount of stroid
If the patient have difficulty in breathing or in poor nutritional condition due to difficulty in eating, consider steroid pulse therapy.
If the patient have difficulty in breathing and need respiratory support, perform thymectomy while intubated.
Follow the "Management of crisis" below when the patient gets worse during the postoperative course.


Indication for steroid pulse therapy
  1. Disabling generalized symptoms (the level of which depends on the social activity of the patient).
  2. Positive anti-acetycholine receptor antibody.


Cyclosporin, Azathipurine, Prednisolone

If the patient needs more than 2 steroid pulse therapies a year and have severe diabling generalized symptoms, consider immunosuppression.
We give low doses of three drugs, cyclosporin, azathiopurine, and prednisolone to reduce the side effects.
Start with the above dose and wait for 1-2 months before evaluating the effect and adjust the dosage.
Measure blood trough level of cyclosporin, BUN, creatinine and perform blood cell count to monitor the side effects.
If effective, continue the therapy. We have used this combination of drugs for 7 years in some patients.
Cyclosporin could be increased to 200-300mg but keep the blood level of the drug between 150-200ng/ml. Also, serum creatinine level should not exceed 1.5mg/dl.
Reduce the doze of azathipurine if the white blood cell count falls below 2000/mm3

If steroid pulse therapy is necessary during the immunosuppression therapy, we give trimethoprim/sulphamethoxazol for prophylaxis of fatal pneumocystis carini infection.
Herpes zoster should be carefuly treated if the patient is receiving immunosuppressant.
If disseminated herpes infection is suggested, admission and intravenous infusion of aciclovir should be considered without delay.

This treatment should be limitted to patients without a possibility of pregnancy.
Young female patients should be advised not to become pregnant.


Management of Crisis
The crisis in myasthenia gravis is dyspnea and could be fatal if not handled properly.
Before the patient becomes dyspneic, they show signs of crisis. Watch carefully for these signs.
Do not leave the pre-crisis patient on his/her own.
They need someone to call the ambulance when they stop breathing.
We usually admit the patient if he/she is dyspneic and shows signs of worsening.

1. Watch carefully.


2. After intubating the patient
3. Extubation

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