 This schematic diagram shows the neuromuscular junction so this is the nerve terminal and this is the part of the muscle membrane where the nerve terminal is making contact. Now when an action potential arrives at this nerve terminal there is opening of voltage-cated calcium channels and there is entry of calcium right and this calcium causes the fusion of vesicles containing the neurotransmitter acetylcholine onto the presynaptic membrane. This releases the acetylcholine in the synaptic cleft and acetylcholine goes and binds to its receptors which are present in these folds on the postsynaptic membrane. So these receptors are N acetylcholine receptor, nicotinic acetylcholine receptors. Now once acetylcholine binds to these receptors they are actually channels and they open causing the entry of sodium into the postsynaptic membrane and this leads to generation of end plate potential. Normally this end plate potential at the neuromuscular junction always reaches the threshold and once it reaches the threshold it leads to opening of voltage-cated sodium channel. So there are two types of channel N acetylcholine receptor channels and voltage-cated sodium channels. So once EPP reaches the threshold these voltage-cated sodium channels open causing the entry of sodium, more and more entry of sodium and leading to the generation of action potential. So those are the basic steps of neuromuscular transmission. Now there are certain diseases which affected this transmission and very important of those diseases is mysthenia gravis. Now mysthenia gravis is a condition in which there is destruction of these N acetylcholine receptors. Actually it is an autoimmune disease okay, autoimmune disease where there is a production of N acetylcholine receptor antibodies and these antibodies can act in various ways such that either they destroy these receptors so they can act in this way or they can even block these receptors. So there is competitive blockage of this receptor. Third they can also cause increase in endocytosis of these receptors. So all these three mechanisms will prevent the acetylcholine which is released in the synaptic cleft to act on these receptors. So if N acetylcholine receptors are not bound to acetylcholine what will happen? EPP which is there that is the graded potential which occurs that may not reach the threshold and action potential will not generate. So in mysthenia gravis actually what happens is that these N acetylcholine receptors they actually reduce okay. So the number of N acetylcholine receptors on these post synaptic membrane reduce and also you see here there are certain folds shown. There is flattening of these folds. So actually these folds are increasing the surface area so that the number of the receptors which are there they can be more okay. So there is flattening of this fold also and decrease in N acetylcholine receptors. Now remember physiologically something happens known as presynaptic rundown presynaptic rundown that means that when our neuromuscular junction is repeatedly stimulated so these vesicles which are there they are continuously being released okay they are fusing to the membrane and acetylcholine is being released. Due to repeated activity throughout the day what happens the number of vesicles which are there they decrease and the amount of acetylcholine which is there which can be released also decreases that happens physiologically throughout the day but it does not affect the contraction of the muscles physiologically why because normally there is a safety factor that means suppose in the morning the amount of acetylcholine which is released is too much high such that this EPP always reaches the threshold rather not only that the amount of change in potential is much more 2 to 3 times caused by this EPP only that means 2 to 3 times of the threshold okay and action potential that's why is always generated but as this presynaptic rundown occurs the amount of acetylcholine release decreases but because of this safety factor yet EPP is always able to reach the threshold now that doesn't happen in case of mysthenia gravis in the morning when the acetylcholine released is too much high then okay EPP will reach the threshold and action potential will be generated but as the day passes by and the presynaptic rundown which is physiological happens maybe this EPP will not reach to the threshold because less acetylcholine is released and the receptors available are also less okay so it is not able to act that much efficiently causing decrease in EPP and hence action potential may not reach the threshold so that is the pathophysiological basis of mysthenia gravis now let's come to its features so its features include weakness and fatigability now this weakness and fatigability as I told you that in morning it may be okay this weakness and fatigability increases late in day that is very important and it improves following risk why does it improve following risk because the store of vesicles acetylcholine vesicles which is there again gets depleted and again they can be released from the presynaptic terminal in much more amount so that is the characteristic feature of mysthenia gravis then what are the muscles affected most common muscles affected are lids and extra ocular muscles and that is why the most common feature of mysthenia gravis will be ptosis okay so because lids are affected and extra ocular muscles are affected that is responsible for the eye movement so there will be presence of diplopia then there are features suggesting the involvement of other cranial muscles also the muscles which are supplied by cranial knobs so there will be facial weakness they can be chewing weakness problems in deglutation then in speech there may be problem causing nasal regurgitation and in a speech there will be nasal twang not only that in generalized mysthenia gravis other muscles may also be affected and very important if respiratory muscles are affected then respiratory assistance may be required and actually this is known as a crisis in mysthenia gravis whenever respiratory assistance is required it is known as crisis let's come to the diagnosis part how it is diagnosed so for diagnosis obviously the characteristic history is there the characteristic presentation is there then we can do examination also we can look for the problems in eye movement then we can look that how much time is being taken to develop ptosis when the patient is asked to gaze upward then there is a test where the person is asked to abduct his arm and how much long he can hold his arm abducted is noted that is known as forward arm abduction time and finally spirometry is done for looking for the involvement of the respiratory muscles and basically forced vital capacity is very important because this mysthenia gravis muscles are involved so there will be problem in expansion of the chest and this is basically a type of restrictive lung disease it will cause so a pc is going to decrease so this is on history and examination but obviously there are certain tests also investigations which need to be done and these investigation include the detection of n acetylcholine receptor antibodies now these n acetylcholine receptor antibodies if present found present then it is diagnostic of mysthenia gravis however if they are negative it does not mean that the person does not has mysthenia gravis for that then we have to do other test and one of them is detection of anti musk antibodies so it has been found that these type of antibodies anti musk antibodies are present in approximately 40 percent of patients who are even negative of n acetylcholine receptor antibodies actually these are responsible for movement of these n acetylcholine receptors so here it's a cell right so n acetylcholine receptors which are present here they need to be moved here on the postsynaptic membrane in the folds of the postsynaptic membrane and this musk that is the muscle specific kinase protein is responsible for the movement of n acetylcholine receptors to this postsynaptic membrane so this anti musk antibodies may also lead to mysthenia gravis so simply if n acetylcholine receptors antibodies present it is diagnostic if negative then we have to do other test one of this is detecting the present of anti musk antibodies they may be even absent but we have to continue looking for other test and one of them is electro diagnostic testing now what is this is that the neuron is repeatedly stimulated so that is known as repetitive nerve stimulation test neuron is repeatedly stimulated and EPP end plate potential from the muscle is recorded and as we have seen before in the pathophysiology that initially end plate potential may be normal but when repetitive nerve stimulation is being done what will happen there will be depletion of the vesicles which are present in the presynaptic neuron the amount of acetylcholine which is being released will go down and because of decreased n acetylcholine receptors this EPP will also start going down okay so this is known as decremental response decremental response that is decreased in EPP on repetitive nerve stimulation testing so that is the electro diagnostic test now if both these tests are negative both n acetylcholine receptor antibodies or whatever antibodies and electro diagnostic tests all are negative then we have to go ahead with anti-choline hysteria is just what is this what we do in this test is we give a drug that is edrophonium which is very short acting this edrophonium actually inhibits and inhibits acetylcholinesterase enzyme this acetylcholinesterase enzyme what it does as a name suggests is it breaks down acetylcholine acetylcholinesterase so this breaks down acetylcholine normally physiologically hence acetylcholine is removed from the synaptic left very fast now if we inhibit this enzyme what will happen this acetylcholine which is released from the presynaptic terminal it will accumulate here okay and once it accumulates despite decrease in an acetylcholine receptor it will be able to act better so what we do is we give edrophonium which inhibits acetylcholinesterase and then we see improvement in the test so what we do is first maybe ask the person to do forward arm abduction time then we give edrophonium and then see whether the time in forward arm abduction is improving or not it has increased or not if it is increased that means edrophonium is working and that the accumulated acetylcholine is now causing improvement so it is suggestive of myasthenia and gravus okay so how about treatment of this condition obviously one we saw here is that if we let acetylcholine accumulate in the synaptic cleft it will cause improvement in the muscle action so first treatment is acetylcholinesterase inhibitor and when we are giving for treatment we have to choose a drug which is longer acting not like edrophonium which is very short acting so the drug which is used is pyridostic mean okay so this is a little longer acting acetylcholinesterase inhibitor then in case of generalized myasthenia gravus where most of the muscles of the body are affected and especially if respiratory system is affected then thymectomy is recommended now thymectomy why it is recommended what is the physiological basis well the antibodies which are there which we are talking n acetylcholine receptor antibodies anti musc antibodies their action is actually T cell dependent so when we do thymectomy we are removing these T cells and the response of the antibodies is prevented so this thymectomy is very useful in myasthenia gravus so these are the two main treatments however in conditions in which we want a very fast response as in case of crisis okay where respiratory muscles is involved in respiratory assistance as required there we do plasma ferruses to remove the antibodies from the blood very fast or intravenous immunoglobulins can be given how these intravenous immunoglobulins act that is not known but they also help in removing these antibodies very fast and if this doesn't work in that case we require immunosuppression by means of glucocorticoids or maybe some other immunosuppressants so that was all about myasthenia gravus it's pathophysiology the presentation how we do diagnosis and what is the modality of treatment and its physiological basis thanks for watching the video if you liked it do press the like button share the video with others and don't forget to subscribe to the channel Physiology Open thank you