Nagoya City University Medical School
Department of Surgery II
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since 1 September 2000
last update 3 October 2003
about Myasthenia Gravis
Why thymectomy is effective
Drugs used for myasthenia gravis
About Cyclosporin A and FK506 (Tacrorimus, Prograf)
Popular drugs that patients must be wary of
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
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 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.
Affected muscle and severity of muscle weakness differ greatly from one patient to another.
|muscle around the eyes||ptotis (dropping eyelids)、double vision、strabismus|
shampoo gets in the eye、irritable eyes
|muscle around the mouth||difficulty in chewing, swallowing|
cannot speak well, nasal tone
|muscle of the face||hard to smile beautifully (snarling)|
|muscle of the arm and leg||drop even light objects, cannot write well|
cannot walk, cannot stand up, cannot climb stairs
cannot shampoo hair, cannot put up laundries
|respiratory muscle||difficult to breathe|
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 Person||Myasthenia 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 Junction||Neuromuscular 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 thymoma||Patients with thymoma|
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.
Anti-acetylcholine receptor antibodies are specific to myasthenia gravis.
- Easy fatiguabilty of skeletal muscles which recovers after a rest
- Electromyography shows a characteristic sign (waning).
- Circulating antibody to acetylcholine receptor (80% of the patients)
- Anti-cholineesterase drugs are effective.
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
We must be careful to treat these anti-acetycholine receptor antibody negative patients; especially the effect of thymectomy for these patients have not been
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
They consisted 47% of 78 anti-AChR negative patients.
Fifteen patients had thymectomy; none had thymoma or abnormal thymic histology
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)
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.
If you have a high titer of anti-acetylcholine receptor antibody, DO NOT DONATE BLOOD. The receipient could transiently become myasthenic.
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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.
25-30% of patients with myasthenia gravis have thymoma. In these cases, we resect the thymoma and the thymus. The thymectomy works for both the tumor and myasthenia gravis.
For myasthenic patients without thymoma, thymectomy is inteded to cure or improve the simptoms of myasthenia gravis. In many cases, anti-AChR antibody is reduced.
The good indication of thymectomy is for patients who are youger than 60 years old with generalized or with ocular symptoms that are bad enough to hamper active daily life AND with positive anti-acetycholine receptor antibody.
Thymectomy is also offered for patients with milder symptoms but with positive anti-acetycholine receptor antibody. If these patients are older than 60, chest CT should be performed and show thymus tissue.
For patients with 60 years or older with very small (atrophied or involuted) thymus, thymectomy would not give beneficial effects.
Also, if the patients have no symptoms, thymectomy is not indicated even if the antibody titer is very high.
If the patients have negative anti-acetycholine receptor antibody test, then thymectomy should be discussed with great care or reserve. Because patients with anti-MuSK
antibodies may have different mechanisms of the disease and so different role
of the thymus, I believe we must not perform thymectomy for these patients.
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 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.
phrenic nerve palsy (causing difficulty in breathing)
recurrent nerve palsy (causing hoarseness)
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.
Taking the thymus out does not cause any deteriorating effect in an adult at all.
|The thymus in a child||The thymus in an adult|
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.
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.
The antibody to acetylcholine receptor, which is the culprit of the disease, is produced within the thymus of the patients.
When we cultured the lymphocytes recovered from the thymus resected from myasthenic patients, we could easily detect anti-acetylcholine receptor antibody secreted into the culture medium.
We also found that the amount of the antibody correlated with the serum anti-acetycholine receptor titer.
This indicates that the lymphocytes in the thymus of myasthenic patients produce the disease-causing anti-acetycholine receptor antibodies.
Taking the thymus out removes some of the anti-acetycholine receptor producing cells from the body.
When observed under microscopy, the thymus from a myasthenic patient has characteristic stuructures called germinal center.
Strangely, however, even in in patients that do get better after thymectomy, the titer of anti-acetycholine receptor antibody remains positive; in very few patients (1-2%) does the antibody become undetectable.
Germinal centers are usually found in lymph nodes or spleen and very infrequently in the thymus.
This structure is full of B-cells which are cells that produces antibodies.
Germinal centers help B-cells become memory cells and antibody producing cells.
The presence of germinal centers are related to the production of anti-acetycholine receptor antibodies in the thymus of myasthenic patients.
This fact indicates that the antibody is produced in places other than the thymus.
So we studied the bone marrow, lymph nodes, and peripheral blood in patients with myasthenia gravis.
We did find lymphocytes that produce anti-acetycholine receptor antibodies in these organs.
This is the reason why the patients still have anti-acetycholine receptor antibodies after thymectomy.
In patients who show good response to thymectomy, the titer of anti-acetycholine receptor do fall to about half the preoperative titer, usually within a year or so..
Why does this happen if the antibody is produced in places other than the thumus?
In the myasthenic thymus, anti-acetycholine receptor antibody is produced, but antibodies directed towards other antigens are produced in very small amounts.
In the bone marrow, anti-acetycholine receptor antibody is produced, but a large amount of antibodies directed towards other antigens is also produced.
Thus, there is something specific to acetylcholine receptor in the thymus.
We do not yet know what it is.
Somehow in the thymus, lymphocytes specific to acetylcholine receptor are specifically activated.
The thymus may be the source of acetylcholine receptor-specific lymphocytes that produce anti-acetycholine receptor antibody in places other than the thymus.
Thymectomy may remove the source of these lymphocytes, reducing the amount of anti-acetycholine receptor antibodies after thymectomy.
Drugs used for Myasthenia Gravis
back to index
white flat tablet 10mg/tablet
pink tablet 60mg/tablet
white tablet 5mg/tablet
usual dose 0.5-3 tablets a day
Acetylcholine is transmitter of the signal from the nerve terminal to the muscle.
Acetylcholine is cleared quite rapidly (in a fraction of a second) by an enzyme called cholinesterase.
These drugs inhibit the action of cholinesterase, causing accumulation of acetylcholine in the neuromuscular junction.
By increasing the concentration of acetylcholine in the neuromuscular junction, muscle can be excited more easily, compensating the reduced number of acetylcholine receptor, the ion channel that transmit the signal.
This works like a choke when you start your car on a cold day.
growling of intestine
Overdose of these drugs paralyses the acetylcholine receptor and make it difficult to accept the new signal from the nerve.
In this case, the drug makes the disease worse.
Although transient, this can be serious in severely affected patients.
When you think you need 4 tablets or more of anti-cholinesterases, you must not increase the dose by yourself. Consult your doctor.
The above mentioned side effects could be partly blocked by atropin sulphate which blocks parasympathetic activity.
Atropins cannot be used in patients with glaucoma.
2. Steroids (adrenocorticoids)
prednin, prednisolone, linderone, and others
This is a hormone secreted by the adrenal cortex.
We need this hormone to maintain our life.
It is used to suppress the immune system of the patient.
It also has some immediate positive effects on the muscle.
Plump face (moon face)
Hirsutism (coarse dark hair)
Osteoporosis, easily broken bone
Body weight gain
Muscle pain, Arthralgia
Steroid has many side effects.
However, most patients with low to moderate doses of steroid (less than 4 tablets for alternate days) can tolerate the side effects.
If the patient takes more than 5 tablets for alternate days for several months or longer, some side effects are inevitable.
You have to also note that many side effects of steroid are irreversible.
We usually use alternate day dosage because adrenocortical insufficiency may result with every day steroid therapy.
If the patient takes a large dose of steroid (10-20 tablets), it usually takes 1-2 years before the dose is reduced and the patient can be completely free of steroid.
3. Steroid Pulse Therapy
Methylprednisolone 1g/day drip infusion for 3 days running
4. Immunosuppressant――this is not used very often
This may be repeated 2-3 times.
A large dose of steroid exerts powerful immunosuppression.
It seems to have some direct effect on muscle contraction.
We consistently observe improvement in most of the myasthenia gravis patients that receive this therapy.
However, most patients experience temporary worsening of the symptom on day 3 or 4 of the pulse therapy.
This is the reason why admission is needed for this therapy.
If the patient has difficulty in breathing before having this therapy, it is quite possible that he/she requires intubation and mechanical ventilation on day 3-4 of this therapy.
Side effects of steroid is uncommon.
The therapy is indicated for patients with compromised active daily life.
It is indicated for severe patients with compromised daily life even after steroid or steroid pulse therapy.
We consider immunosuppressant if the patient needs more than 2 steroid pulse therapies per year.
Side effects are inevitable and must be carefully monitored.
Cyclosporin (Sandimmune) 25mg or 50mg/capsule
2-6 capsules per day is usual.
This drug suppresses production of a lymphokine IL-2 and eventually production of anti-acetycholine receptor antibody.
It is toxic to the kidney.
The blood concentration of the drug and kidney function must be monitored.
It frequently causes thick hair.
Liver disfunction is sometimes reported.
This drug is not indicated for females who want to bare child.
Azathiopurine (Imuran) 50mg/tablet 1-6 tablets per day
Widely used immunosuppressant.
White blood cells decrease and the patient may contract infection more easily.
3 drug regimen
We can reduce side effects of the immunosuppressant by using 3 drugs in combination and thus reducint the dose of each drugs.
We start with the dose listed above, monitor cyclosporin blood level, kidney function, white blood cell count and reduce or increase the dose accordingly.
About cyclosporin A and FK506 (Tacrolimus, Prograf)
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
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.
back to index
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.
|stage||5 year survival(%)|
microscopically no capsular invasion
|II||invasion to mediastinal pleura, fat|
microscopic capsular invasion
|III||invasion to adjacent tissues|
the lung, pericardium, phrenic nerve, brachiocephalic vein, superior vena cava
|IVa||dissemination to pleura or pericardium||48|
|IVb||blood 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.
Thymoma is associated with many millions of lymphocytes which are generated within the thymoma in association with the function of the neoplastic thymoma epithelial cells. In other words, thymoma is a functional tumor which can generate many (normal) T-lymphocytes.
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.
In the normal thymus, the T-lymphocytes generated within the thymus are sensored according to the specificity of the lymphocytes. Those that react to self antigens and that may be harmful to the body are eliminated within the thymus.
Thymoma does not have this sensoring function and allows all the lymphocytes generated within the thymoma to migrate out of the thymoma and reside in the periphery (lymph node, spleen, etc.).
Thus, thymoma is providing autoreactive T cells that can help B cells produce autoantibodies and thus can be harmful to the body.
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
――getting prepared for the worst――
Myasthenia gravis is not a fatal disease, if properly handled.
Even the most severely affected does not have any abnormalities in their lungs or heart.
The defect in neuromuscular transmission in the patient is reversible.
So there is always a chance of complete recovery and full activity.
However, if left for 3 minutes or more without breathing, it could be fatal.
If you have a family member or friend with severe myasthenia gravis, watch carefully and take him/her to the hospital before the breathing actually stops.
If the breathing stops, stay calm and do mouth-to-mouth breathing support--this will save the life.
A patient with myasthenia gravis will not die under supervision of a doctor (usually with knowledge of emergency breath support).
When you need to be alert.
Breathing HAS stopped in the following cases. Immediately perform mouth-to-mouth breathing and call an ambulance.
If you find the above symptoms, take the patient to the doctor.
- When the patient raises their shoulders when breathing.
- When the patient cannot swallow saliva well.
- When you hear noise as the patient breathes.
- When the patient cannot keep their head upright.
Usually, the patient needs admission and close attention.
Do not leave the patient alone.
- The patient's face turned blue (cyanosis).
- The patient does not respond (is unconscious).
Continue the breathing until the rescue team arrives.
Learn how to do mouth-to-mouth breathing
In the majority of myasthenic patients, breathing stops first. So you usually do not need to do heart massage if the patient becomes cyanotic in front of your eyes.
However, when you have found the patient unconscious and you do not know for how long he/she has been left without breathing, heart massage is probably necessary.
But in this case too, do the breathing first.
If you know how to do heart massage then do heart massage.
Give 5 massages and blow once. Repeat.
In most cases, if the breathing is maintained, the patient is OK.
If the heart has really stopped too, it is quite difficult for a non-medical person to properly ventilate and also maintain enough circulation.
So, do breathing, call an ambulance, continue breathing until they arrive.
If you are not sure if the patient is breathing or not, tear off a small piece of tissue paper and see if it moves in front of the patient's nostrils.
If it moves back and forth, the patient is breathing and usually this small amout of breath is just OK to keep the patient alive until he/she is transferred to the hospital.
Myasthenic patients might die at home but only when he/she could not breathe, usually because sputum or saliva obstructs the airway.
Mouth to mouth breathing (the most recommended method of breath support)
When this happens, mouth-to-mouth breathing saves the life of the patient.
To do this, you must learn how to do mouth-to-mouth breathing before the patient gets too sick.
When it goes wrong.
- With the patient lying on his/her back, hold the patient's chin and pull upward.
This makes some room in the throat of the patient so that the breath can be blown in smoothly.
- Hold the patient's nose so that the breath does not leak through the nose.
- Blow your breath through the patient's mouth.
Blow in steadily for about 1-1.5 seconds.
Press your mouth to the patient's mouth so that the breath does not leak.
- See if the patient's breast rises as you blow in. Release your mouth.
If successful, the breath you have blown in will be exhaled.
- Repeat 12-15 times per minuite.
If you feel resistence when you blow in and can feel the leakage around the patient's mouth, check the following.
Thrust the patient's chin upward more.
If you do not see the patient's breast rise as you bow in or no air is exhaled by the patient when you release your mouth, it is likely that your breath support is not successful.
Press your mouth harder to the patient's mouth so that breath does not leak.
Adjust the position of the mouth and the patient's chin until you can blow in smoothly.
It is more likely that you need adjustments than being successful for the first time.
Even if there is some leakage, if you can see that the patient's breast rises as you blow in, that guarantees that the patient is ventilated. Continue.
Try blowing harder.
Sometimes, the patient has remnants of food, saliva, or sputum, accumulated in his/her throat.
This prevents breathing support.
Remove these obstacles with tissue paper, paper towel or a narrow pipe of vacuum cleaner.
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
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.
- A patient which has been newly diagnosed should be treated with anti-cholinesterase. Give myterase of mestinon. Start with 1 tablet a day divided in two doses.
Give atropin sulphate (0.2mg for 1 tablet of anti-cholinesterase).
Discontinue if no diarrhea or muscle twitching appears.
Atropin should not be given to patients with glaucoma.
Check chest CT for screening of thymoma.
- If the patient still has symptoms, and if indicated, offer thymectomy.
Of course thymectomy is a must for a patient with thymoma.
We do not give steroid before thymectomy.
- If the patient has no symptom with only a small dose of anti-cholinesterase, you can follow the patient with that dose for years.
Anti-cholinesterases do not have irreversible side effects like steroids.
- If thymectomy is not indicated, or if the patient declines, or if the patient still has disabling simptoms after thymectomy and anti-cholinesterase is unable to control the symtoms, give prednisolone.
Start with 1 tablet for alternate days.
Increase the dose to up to 5 tablets.
With 5 tablets for alternate days, some side effects are inevitable.
- If prednisolone does not control the symptoms and if the patient has difficulty in leading tactive daily life, consider steroid pulse therapy.
- If the patient needs more than 2 instances of steroid pulse therapy to maintain acceptable level of daily life, consider immunosuppressants.
Indication for Thymectomy
Patient with a thymoma (even without myasthenic symptoms)
good (>90% effective)
<60 years old with
offered as a reasonable choice
generalized or bulbar or ocular symptoms which limit active daily life and
positive anti-acetycholine receptor antibody
mild generalized or ocular symptoms and positive anti-acetycholine receptor antibody
if the patient is older than 60, a chest CT should be performed and show the thymus gland
Thymectomy should be reserved
Patients with negative anti-acetycholine receptor antibody (even with mild to severe symptoms)
Thymectomy not recommended
because patients (such as those with anti-MuSK antibody) may have different pathogenesis and thus the thymus may have different roles.
1. >60 years old with involuted thymus.
2. only mild occular symptoms, leads normal life, negative anti-acetycholine receptor antibody
3. symptoms are severe but with negative anti-acetycholine receptor antibody and other neurological disorders are suspected.
4. severe disabling complication (e.g. post-infact paralysis)
5. symptom free or very mild symptoms with no medication (even with anti-acetycholine receptor antibody)
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
- Disabling generalized symptoms (the level of which depends on the social activity of the patient).
- Positive anti-acetycholine receptor antibody.
Consider this therapy before the patient gets too sick.
If the patient has dyspnea, the steroid pulse may result in intubation and mechanical ventilation.
The patient should be admitted.
Drip infusion of methylprednisolone 1g/day for 3 days.
On the third or fourth day of the therapy, most patients experience worsening of the symptoms.
Patients with dyspnea may need mechanical ventilation and need close watching.
If intubated, follow "Management of Crisis".
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.
prednisolone 10-20mg/alternate day
Start with the above dose and wait for 1-2 months before evaluating the effect and adjust the dosage.
cyclosporin 100mg (2 tablets)
azathiopurine 100mg (2 tablets)
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.
The patient should be admitted to a room with a facility of wall suction.
Have everything needed for intubation at hand.
You usually do not have enough time to look for an endotracheal tube.
Watch for signs of crisis.
The patient should be visited at least once an hour or continuously monitored by a camera.
Increasing the dose of cholinesterase inhibitors.
Tensilon test (edrophonium test) correctly diagnoses cholinergic crisis if the symptom worsens after injection of tensilon.
However, even if the symptoms get better after injection of tensilon, increasing the dose of anti-cholinesterase should be done very carefully.
This is because those patients with severe symptoms usually have had almost saturating doses of anti-cholinesterases.
Increasing the dose can easily induce cholinergic crisis and the patient may unexpectedly get worse.
In patients in crisis, we usually increase the anti-cholinesterase only slightly, and rather prefer to give steroid pulse therapy with the risk of intubation in mind.
In some patients, bed rest and carefully increased dose of anti-cholinesterase may help the patient manage the critical period and get better.
Signs that suggest crisis
Admit the patient if he/she
cannot swallow saliva and need to wipe out the overflowing saliva
Watch patients closely if
cannot keep his/her head straght.
complains of dyspnea and objectively shows shallow breathing (measure tidal volume if possible).
the patient uses sternocleido muscles when breathing.
Get ready for intubation, give oxygen, take blood gas sample if
the patient breathes paradoxically
Intubete immediately if
the patient presents with large respiratory noise (large amount of secretion in large bronchi).
you do not hear breath sound on one side at all
arterial blood gas CO2 >55mmHg
the patient is cyanotic
Characteristic of myasthenic crisis is decreased alveolar ventilation. Oxygen supplement is not necessary. However, with some oxygen administration, the patient's respiratory work may lessen, which may help the patient overcome the crisis.
2. After intubating the patient
Thoroughly clean the airway.
Put the patient under complete mechanical respiration.
If you use the pressure support mode of ventilation, the support pressure should be high enough so that the patient needs no effort to breathe.
Do not assist-ventilate.
It is most important to let the muscles rest completely.
Discontinue all the anti-cholinesterase drugs.
The patient usually is saturated with the drug and has a very narrow range of effective dose.
Completely withdrawing the drug lets the muscle make more acetylcholine receptor.
After 2-3 days without anti-cholinesterase, the responsiveness to the drug restores.
Use sedatives sparelingly.
Most patients get quite relieved after being intubated and ventilated; many fall asleep.
Sedatives have muscle-relaxing effect and should be avoided if possible.
Tell the patient that he/she will surely get better.
Tell him/her that their muscles need some rest.
Complete bed rest.
Many patients who are intubated are candidates for steroid pulse therapy.
Methyprednizolone 1g/day for 3 days.
Remember the patient will get worse on day 3-4 of the pulse therapy.
On day 3 of intubation and ventilatory support (or 4th day of steroid pulse therapy), see how the patient performs by disconnecting the respirator.
Measure tidal volume.
If tidal volume<100ml, it is not likely that the patient can be extubated today.
Put him/her on respirator.
If tidal volume is 300-500ml, try extubating.
If the patient depends on the respirator for more than a week, it is better to do tracheostomy.
Place a nasogastric tube and give myterase 10mg and atropin 0.3mg.
If the patient can breathe on his/her own for half a day, extubate.
After one hour, disconnect the respirator and leave him/her breathe spontaneously.
Leave the patient until he/she feels dyspnea.
Humidify the air.
Do not wene from the respirator. Training is not necessary. It only tires the patient.
If the patient cannot stand 2-3 hours of spontaneous breathing, give 2-3 tablets of anti-cholinesterase and put him/her on respirator again.
Try extubating the next day.
If you are sure he/she will recover soon, change to nasotracheal tube.
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