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Improving Quality of Life: Comparing different medications for Myasthenia Gravis

I analyzed the different medications and their effectiveness on Myasthenia Gravis as a whole. I compared the different prices, side effects, and how many forms each covers.
Julia Kang
Grade 7

Problem

What is the single best possible medication for the forms of Myasthenia Gravis in humans?

Method

n/a

Research

Basic Research

The neuromuscular junction is the site of chemical communication between nerve and fibre cells. Firstly the nerve fibres divide into lots of terminal branches. Each terminal branch ends on the endplate, which has tons of acetylcholine receptors. When the nerve impulse stimulates the terminal, synaptic vesicles containing acetylcholine move to the front of the terminal. The terminal then releases acetylcholine from the synaptic vesicles, and acetylcholine binds onto the receptors. This makes the channels open, and sodium ions flow into the endplate, which initiates endplate potential, and makes the muscles contract.

The endplate is the region of muscle fibre. Acetylcholine receptors are long protein molecules that form channels through the membrane. End Plate potential is the change in the electrical potential of the endplate. When the channels open, positively charged sodium ions flow into the endplate. This distribution of ions depolarizes the endplate. acetylcholinesterase then breaks down the remaining acetylcholine, which closes the channels and Returns the endplate to the polarized state. Acetylcholine is a chemical that works as a transmitter substance of nerve impulses.

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Myasthenia Gravis is most commonly characterized as an autoimmune disease - meaning that the body attacks itself. Symptoms are usually in the eyes and limbs. It has 5 forms: Juvenile, Congenital, Transient Neonatal, Ocular, and Generalized. There are 2 main types of autoantibodies that cause this weakness: Anti-Acetylcholine Receptors, and Anti-Muscle specific kinase protein. There is currently no cure for Myasthenia Gravis, though many are working on it.

Anti-AchR are autoantibodies against the acetylcholine receptors. These autoantibodies block or destroy the receptors, which makes acetylcholine unable to bind. These autoantibodies are the most common and are found in 85% of people with Myasthenia Gravis. Anti-MuSK are autoantibodies against the Muscle-specific kinase protein, which is responsible for allowing acetylcholine to bind when it receives a signal from the agrin when the acetylcholine is released. These antibodies block the MuSK and make the agrin unable to give the MuSK a signal. This autoantibody is present in 8% of people with Myasthenia Gravis

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 Transient Neonatal MG is a disease that is caused when maternal antibodies are passed down to The Unborn infant through the placenta. The symptoms show at or shortly after birth. This happens to 5 to 30% of infants and mothers with myasthenia gravis. Infants with this form of myasthenia gravis may have an ocular or generalized weakness for example a weak cry, difficulty feeding, or lack of expressions. Sometimes difficulty breathing may occur which is called respiratory distress. Only the antibodies are passed down, not the cells creating them so it goes away on its own.

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Congenital Myasthenia Gravis is different from other forms of myasthenia gravis because it is caused by a genetic mutation rather than having an abnormal immune system response. This happens from changes in genes involving the neuromuscular junction. It's usually inherited by an autosomal recessive pattern, which means that you need two copies of the gene to get the disease. if you only have one copy, then you can be a carrier but you will not have the disease or show symptoms. A rarer form of CMS is slow Channel CMS, which has an autosomal dominant pattern, which means you only need one copy of the gene to get the disease.

 The types of Congenital Myasthenia Gravis or CMS are presynaptic, postsynaptic, and synaptic. presynaptic CMS is caused by a genetic mutation that results in the nerve cell not releasing enough acetylcholine into the neuromuscular junction. This creates poor signal strength. postsynaptic CMS is caused by a wide variety of genetic mutations and results in not having enough receptors, or having defective receptors. Some defective receptors don't stay open long enough. These are called Fast Channel receptors.  Other defective receptors stay open for too long. These are called slow Channel receptors. synaptic CMS is caused by a lack of acetylcholinesterase. And too much acetylcholine lingering around in the neuromuscular Junction disrupts the signal. 

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Ocular myasthenia gravis is caused by antibodies that attack the acetylcholine receptors. This disrupts the signal. Ocular Myasthenia Gravis is when you have weakness only in the eyes. Some symptoms include ptosis, which is drooping of your upper eyelid, strabismus which is when your eyes do not line up, and diplopia, which is when you see two images of the same object which is also called double vision. 

Generalized myasthenia gravis has the same causes as ocular myasthenia gravis, though is more prevalent in MuSK cases. It creates muscle weakness in the body. This is a more severe form of this disease. Weakness increases as muscles get used, and they improve when they are rested. This form of myasthenia gravis develops in 50 to 80% of all people with ocular symptoms. Symptoms include difficulty speaking, problems chewing and swallowing, climbing stairs, Etc.

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Juvenile myasthenia gravis is similar to myasthenia gravis in adults. Juvenile myasthenia gravis is caused by immune system generated antibodies, which attack the neuromuscular junction. Juvenile Myasthenia Gravis is when MG occurs in someone under the age of 18. Symptoms mimic the adult version of this disease and can have ocular or generalized weakness. When it starts in a child that has already reached puberty, more generalized weakness typically begins rather than ocular symptoms. 

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Pyridostigmine is an acetylcholinesterase inhibitor. This results in acetylcholine lasting longer and having a higher chance of making it past the antibodies if there are any. More acetylcholine may improve your symptoms.

Corticosteroids limit the number of antibodies your immune system creates. Suppressing the antibodies that may be attacking the neuromuscular junction, might be beneficial. 

3,4-diaminopyridine blocks the potassium channels in nerve terminals. This increases the amount of acetylcholine released from synaptic vesicles. It makes the duration of release longer, which makes more acetylcholine into the neuromuscular junction. 

Fluoxetine blocks the acetylcholine receptor, which reduces the time that they stay open. This is especially useful in slow-channel CMS, where the channels are often open for too long. 

Data

Primary Research:

Pyridostigmine: Pros - helps improve muscle weakness, works for most forms of myasthenia gravis (ocular, generalized, juvenile, transient neonatal, fast Channel CMS, and presynaptic CMS) It takes effect after 30 to 60 minutes. Cons - may cause some side effects (gastrointestinal upset, diarrhea, nausea, excessive salivation, and sweating), it will have no effect on patients with Anti-MuSK, will make slow Channel and synaptic CMS worse. The average price for this medicine is $16 to $80.

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Corticosteroids: Pros - inhibits the immune system from creating as many antibodies, It works for ocular, generalized, and juvenile, treats the Anti-MuSK variation. Cons - This does not work for congenital myasthenia gravis, side effects (diabetes, thinning, weight gain, and increase risk of infection). The average price for corticosteroids is $10 to $30. 

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3,4 diaminopyridine: Pros - helps improve muscle weakness in myasthenia gravis, it works for CMS (presynaptic and fast channel)Cons -  it causes a tingling feeling in the toes and fingers in the first hour, treats a very limited amount of forms, makes slow-channel and synaptic CMS worse, side effects (irregular heartbeat, tremors, coughing, and diarrhea). The average price for this is $32 to $425.

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Fluoxetine: Pros - helps slow Channel CMS. Cons - it only treats slow Channel CMS, it worsens other forms of myasthenia gravis, side effects (heartburn, diarrhea, and nausea). The average price for fluoxetine is $8 to $27.

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Michael W Nicolle's email contained the following information: for neonatal MG, Once the antibodies wear off, the baby improves and will not have problems later in life. sometimes Pyridostigmine, for example, is used until the baby improves. 

Congenital myasthenic syndrome treatment is highly variable but medications used include pyridostigmine, ephedrine, 3, 4 -diaminopyridine, fluoxetine, Salbutamol, Etc. Because it is not caused by an autoimmune response, there is no role for immunosuppression. 

Juvenile myasthenia gravis is when myasthenia gravis develops in someone less than 18 years old. Treatment can include Pyridostigmine or immunosuppression, for example, prednisone(corticosteroids). thymectomy may also be suggested. 

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 Professor James F Howard jr's email contained the following information: the first step he would take to diagnose a patient would be to ask them to close their eyes for 30 seconds. If they show symptoms, then there is a possibility for Myasthenia Gravis. He will then confirm with a single fibre EMG, though some other doctors prefer a less precise test. The medication and dosage are all tailored to the patient, as Myasthenia Gravis is unique to every person. 

Conclusion

My hypothesis was correct because when comparing the medications and their prices, the results I found showed that the medication Pyridostigmine, which is an acetylcholinesterase inhibitor, was the best option for Myasthenia Gravis as a whole. Even though it may make some forms of Myasthenia Gravis worse, it is usually the first medication the doctor will prescribe if you have any other form. The price was also not as expensive as some, and generally affordable. The side effects caused by Pyridostigmine are not as severe as others, for example, instead of having long-lasting side effects such as diabetes, it causes some diarrhea, sweating, etc. Although this is not completely ideal, it is much better than the alternatives.

Citations

Neuromuscular junction. (n.d.). Retrieved December 02, 2020, from https://www.britannica.com/science/neuromuscular-junction
Myasthenia gravis. (2019, May 23). Retrieved December 06, 2020, from https://www.mayoclinic.org/diseases-conditions/myasthenia-gravis/diagnosis-treatment/drc-20352040  
3,4-Diaminopyridine price,buy 3,4-Diaminopyridine. (n.d.). Retrieved December 06, 2020, from https://www.chemicalbook.com/Price/3-4-Diaminopyridine.htm
3,4-Diaminopyridine (3,4-DAP). (n.d.). Retrieved December 06, 2020, from https://www.myaware.org/34-dap-information-sheet
Myasthenic Crisis: A Breathing Emergency. (2020, July 13). Retrieved December 05, 2020, from https://www.webmd.com/brain/myasthenic-crisis#2-6
Jowkar, A. (2019, November 09). What are the classifications of myasthenia gravis (MG)? Retrieved December 05, 2020, from https://www.medscape.com/answers/1171206-92629/what-are-the-classifications-of-myasthenia-gravis-mg
Stewart, M. (2018, May 30). Pyridostigmine for myasthenia gravis/ Pyridostigmine info. Retrieved December 06, 2020, from https://patient.info/medicine/pyridostigmine-for-myasthenia-gravis-mestinon
Myasthenia Gravis Foundation of America (MGFA). (n.d.). Retrieved February 14, 2021, from https://myasthenia.org/
Anti-MuSK (muscle-specific kinase) Antibodies. (n.d.). Retrieved February 16, 2021, from https://labtestsonline.org/tests/anti-musk-muscle-specific-kinase-antibodies
Myasthenia gravis. (2012, October 31). Retrieved December 05, 2020, from https://www.betterhealth.vic.gov.au/health/ConditionsAndTreatments/myasthenia-gravis
Kaminski, H. J. (2019, November 01). Myasthenia Gravis. Retrieved December 05, 2020, from https://rarediseases.org/rare-diseases/myasthenia-gravis/
Walker, M. (2018, February 28). Congenital Myasthenia Gravis. Retrieved December 05, 2020, from https://myastheniagravisnews.com/congenital-myasthenia/
Goodman, E. (2018, February 28). Ocular Myasthenia Gravis. Retrieved December 05, 2020, from https://myastheniagravisnews.com/ocular-myasthenia-gravis/
Tan, V. (2018, February 28). Generalized Myasthenia Gravis. Retrieved December 05, 2020, from https://myastheniagravisnews.com/generalized-myasthenia-gravis/
Iskit, S. (2018, March 05). Juvenile Myasthenia Gravis. Retrieved December 05, 2020, from https://myastheniagravisnews.com/juvenile-myasthenia-gravis/
Tan, V. (2018, February 28). Transient Neonatal Myasthenia Gravis. Retrieved December 05, 2020, from https://myastheniagravisnews.com/transient-neonatal-myasthenia-gravis/
Muscle-specific Kinase Myasthenia Gravis (MuSK MG). (2019, September 29). Retrieved February 15, 2021, from https://cabalettabio.com/science/diseases/muscle-specific-kinase-myasthenia-gravis-musk-mg/

Acknowledgement

Dr. Michael W Nicolle - Expert

Professor James F Howard jr. - Expert