Myasthenia gravis

common neurological problem. public can clear their doubts

1. Myasthenia Gravis Dr. K. Vasantha M.S.,F.R.C.S Director RIO Chennai Rtd

2. The basic part of this disease is fatigability of muscles Mya asthenia gravis = muscle weakness serious This is due to decrease in the availability of acetylcholine receptors at neuro muscular junctions Charecteristics

3. This decrease in acetylcholine receptors is due to antibodies against the receptors which act by a. blocking the receptors b. complement mediated membrane damage c. accelerated degradation of the receptors

4. Peak incidence is more in young women less than 40 and old men more than 60 Neonatal myasthenia affects infants born to myasthenic mothers. This is due to passive transfer of the immunoglobulins from the mother. The disorder disappears in 2 to 3 weeks as the immunoglobulin depletes fro the system. Immunosuppression during pregnancy will prevent this Till then supportive therapy with oral anticholinestrase must be given Age group and sex

5. This occurs due to inherited defect in the neuromuscular junction Congenital myasthenia

6. When D- penicillamine and statins are used anti ACh antibodies may be produced. When the drug is stopped the symptoms will disappear. Aminoglycosides, nitrofurantoin, beta- blockers and quinidine will exacerbate myasthenia Exacerbated by respiratory infection, stress, surgery, in vitro fertilization (due to hormone induced fluctuation) Drugs and myasthenia

7. If you see random involvement of extra ocular muscles, levator palpebrae superioris along with orbicularis oculi – suspect myasthenia The main feature in the involvement of muscles in this disorder is its variability Weakness of the muscles increase after prolonged activity The involved muscles will not be uniformly weak It varies during day time, worsening during the evening After physical exertion also it will be worse Signs and symptoms

8. Proximal limb muscles like triceps, deltoids and iliopsoas Muscles of facial expression, mastication and speech Extensors of the neck Other muscles

9. ? Fetal form of acetylcholine receptors are found in the receptors of extra ocular muscles but not in the skeletal muscles. But Levator muscle does not have fetal AC receptors Even a mild involvement of the extra ocular muscle will cause diplopia and the patient becomes symptomatic High firing frequencies make them more susceptible These muscles are warmer May be there is a specific antibody affecting these muscles Why eye muscles are more affected

10. The amount of ACh released in myasthenia is normal But transmission is impaired Normally the amount of Ach released is reduced when there is sustained muscle contraction Because of this reduction added to less number of receptors, in myasthenia the muscle is fatigued This is seen more in bright light Cause for fatigue

11. The anti Ach receptor antibody is due to T-cell dependent B-cell response. The thymus in a myasthenic patient contain more B-cells and produce more antibodies against Ach receptors If a patient is over 30 years and a male, thymoma must be suspected 2/3rds of myasthenia patients have hyperplasia of the thymus About 10% have thymoma Role of thymus

12. Ptosis is the most common presentation It is usually binocular. It may shift from one eye to the other especially when it is asymmetric. Prolonged upward gaze will result in gradual lowering of the lids worsening the ptosis. If you hold one eyelid up, then that eye will not have worsening as no effort is needed to keep the eye open. Signs and symptoms

13. If the ptosis is unilateral the other eye may show lid retraction as more effort will be used to keep the ptotic eye lid elevated When the ptotic lid is held up the other lid will droop. This is called curtaining This is due to Hering’s law The pupils are normal there by differentiating it from Horner’s, third nerve palsy and botulism

14. Cogan’s lid twitch sign:- when the patients are made to look down for 10 to 20 seconds and then asked to look up the upper lid will overshoot upward and twitch a few times before settling down. This upshoot is due to build up of ACh when the lid is resting and, easy weakening of the muscle after rapid elevation. This may occur in brain stem lesions and other oculo motor nerve lesions also Sometimes transient eye lid retraction also can occur Signs and symptoms

15. These muscles are involved more due to the presence of fetal receptors Minimal involvement of these muscles are symptomatic due to diplopia unlike other muscle involvement The nerve connections to these muscles are very high and hence more sensitive to nerve stimulation and fatigue These muscles are warmer compared to limb muscles ? More accessible to antibodies Extra ocular muscles

16. There is no set pattern. It is haphazard One or more muscles may be involved. Even complete external ophthalmoplegia can occur. So one may mistake it for pupil sparing third nerve palsy Must be differentiated from III , IV and VI nerve palsies, supra nuclear palsy and gaze palsies Pattern of involvement

17. Hypermetric saccades – in an attempt to overcome the weakness created by myasthenia the central nervous system increases the pulse Hypometric saccade – starts with normal movement and then slows down Small jerky quivering movements Gaze evoked nystagmus Abnormal saccades

18. On gentle closure of the eye, lids will be apposed. But after sometime the eye will start opening. This looks like as if the person is trying to peek. While washing the face with soap they will experience irritation as the eye will open up after sometime Ectropion of lower lid also may occur towards the evening Because of ptosis orbicularis involvement will not be apparent Peek sign

19. Pupil is not involved in myasthenia But accommodation fatigue can occur. This will cause blurring of near vision Pupil

20. Because of weakness of extensors of the neck the head will hang forward – called head ptosis Speech, swallowing and chewing becomes difficult Inability to smile Nasal regurgitation of food The jaw is likely to hang down, and has to be physically closed Involvement of other muscles

21. Protrusion of the tongue may become weak Involvement of stapedius causes hyperacusis. Less intensity will be needed to elicit acoustic reflex There is no loss of reflexes, or coordination. Sensory system also remains normal Mental status is not affected

22. In women weakness may increase during menstruation This may be due to estrogen induced regulation of antigen presenting cells There is also a decrease in cytokine secretion and increase in the level of interleukin-10 Temporary stoppage of oral contraceptives will also exacerbate the condition In women

23. Steroids can paradoxically induce myasthenia This is due enhanced proliferation of sensitized lymphocytes Highly activated cholinesterase in neuromuscular junctions Decrease in acetylcholine release Increase in immune response Even myasthenic crisis can occur. Corticosteroids

24. If the patient sleeps for 30 minutes an improvement in ptosis is seen when the patient wakes up. This lasts for about 3 – 4 minutes Ice pack test: when a small pack of ice cubes is kept on the eye lid for 2 minutes there is an improvement of ptosis by 2 mm. This lasts only for about a minute. The other eye if involved, serves as a control Clinical tests

25. In these tests acetyl cholinesterase inhibitors are given to the patient and improvement in the signs are noted Edrophonium (tensilon)test: acts very quickly i.e. within30 seconds and the effect disappears within 5 minutes.10 mg of tensilon is taken and a test dose of 2mg is first injected. If no adverse events occur, further 8 mg is injected slowly. If there is no improvement within 3 minutes, the test is considered negative. Diplopia if present may not disappear completely. So the physician has to carefully note the improvement in the movement of the eyes before giving the injection Pharmacologic tests

26. The positive nicotinic response causes improvement in myasthenic symptoms But the muscarinic effect on other muscles will cause a brief over stimulation of the parasympathetic system Bradycardia, loss of consciousness, apnea, dizziness, involuntary defecation, twitching of eye lids can occur. Serious complication- abnormal heart rhythms Complications

27. Slow heart rate, irregular heart beat Asthma Low BP Obstruction in the urinary tract or intestines Sleep apnea Contra indications

28. To prevent complications, intra muscular Atropine sulphate is given as it will annul the muscarinic activity It should not be performed in patients with known cardiac disease False positive and false negative results has been found The response is also transient Tensilon test is also used to find out whether you are over dosed with pyridostigmine

29. Because of the serious complications and the transient effect prostigmine is used If 0.6 mg of atropine and 1.5 mg of neostigmine are given intra muscularly The signs of myasthenia start improving in 15 minutes and peaks in 30 minutes May be positive in brain stem tumors, multiple sclerosis and sometimes even in congenital ptosis Negative results also have been seen Prostigmine test

30. Seen in Thymoma Lambert Eaton syndrome Lung cancer Rheumatoid arthritis patients on Penicillamine False positive results

31. Supramaximal electric stimuli are given to the muscle to be tested. Rapid reduction in action of 10 to 15% is considered abnormal Single fiber EMG test is considered very sensitive in generalized myasthenia. Very useful in pulmonary muscle involvement Myography

32. If the weakness is confined to the extra ocular muscles antibodies are detected only in 35 to 75% False positive results can be seen in amyotrophic lateral sclerosis Other anti bodies like anti musk antibodies (muscle specific kinase). These patients will have more of tongue and facial muscle weakness. This is more difficult to treat Anti bodies

33. Antibodies against low density lipoprotein 4 (LRP4) is sometimes seen in ocular myasthenia Antibodies against Agrin and Titin proteins are also rarely involved

34. Myotonic dystrophy Oculopharyngeal dystrophy – seen in French, Spanish and Jewish people. Autosomal dominant or recessive. Males and females are affected. Age 40 to 50 years. Aspiration pneumonia is common. Muscle biopsy needed Mitochondrial dystrophy- Kearns Sayre syndrome. Cardiac abnormalities are seen. Ragged red fibers due to accumulation of mitochondria Differential diagnosis

35. As this is an autoimmune disease, other autoimmune diseases like SLE, pemphigus, ulcerative colitis, sarcoidosis, Sjogren’s, diabetes and hepatitis may be seen All types of thyroid diseases can be found. Even sub clinical involvement of thyroid gland must be ruled out Rheumatoid arthritis, ankylosing spondilitis Aplastic anemia with thymic tumor, pernicious anemia Associated conditions

36. Cholinesterase inhibitors Thymectomy Immunosuppressives Specific therapy for ocular complications Diabetes and tuberculosis must be ruled out as steroids and immuno suppressives may have to be used Management

37. Thymus tumor (thymoma)must be ruled out with CT or MRI If present thymectomy must be done regardless of patient’s age If the patient is below 50 even without tumor thymectomy can be tried. Beyond that age thymus would have involuted. So thymectomy will not be useful The effect will be seen only after minimum of 6 months and may take even 2 to 5 years Management

38. Injury to phrenic nerve or recurrent laryngeal nerve Atelectasis Pleural effusion Pneumonia Intercurrent pulmonary embolism Sternal instability Myasthenic crisis. Plasmapheresis may have to be done before surgery to prevent this Thymectomy Complications

39. Drugs like pyrido stigmine will prolong the action of ACh by slowing its degradation at the neuromuscular junction Onset of action happens within 30 minutes and peaks at about 2 hours. So one tablet 30 mg is taken every 3 to 4 hrs . It can be increased up to 150 mg every 4 hrs. Side effects- diarrhea, watering of eyes, increased salivation, cramping and fasciculations. Loperamide, glycopyrrolate or diphenoxylate with atropine will help in this condition Anti cholinesterases

40. Tachyphylaxis and over medication can cause cholinergic crisis Excessive use will cause weakness of muscles To differentiate this from low dosage Edrophonium is used. If it gets better with Edrophonium it means the dosage is low Pyridostigmine (Neostigmine)

41. If the patients are intolerant to pyridostigmine steroids can be given The side effects of steroids like osteoporosis, peptic ulcer and diabetic status of the patient must be kept in mind Low doses like 10 mg on alternate days must be tried first Steroids

42. Short term – By doing plasmapheresis the circulating antibodies are removed. There is a temporary improvement (days to weeks) in the symptoms. Used mainly in myasthenic crisis and before thymectomy Intra venous human immunoglobulin can be given to when rapid improvement of symptoms is needed. It takes around five days for the response and lasts for weeks to even months. Very expensive Immunosuppression

43. Azathioprine. Patients must be screened for thiopurine methyltransferase gene mutation before starting therapy Cyclosporine Methotrexate Mycophenolate mofetil?, Tacrolimus? Immunosuppressants

44. Ocular problems especially ptosis is relieved with neostigmine. Crutch glasses can also be used if ptosis is not fully relieved If ptosis is the only problem or if it is refractory to treatment ptosis surgery can be done Treatment for the ocular problems

45. If diplopia is severe and not relieved with drugs or if the patient is intolerant to medicines, one eye can be occluded. It is difficult to prescribe prisms as the muscle imbalance is not fixed Extra ocular muscle surgery is not usually performed for the same reason 10 to 20% of ocular myasthenia patients experience a remission. This may even be permanent. Or else relapses occur after a few years Diplopia

46. Weakness of muscles similar to myasthenia is seen No antibodies Genetic abnormalities in the pre synaptic – defect in acetylcholine resynthesis, synaptic -- end plate acetyl cholinesterase deficiency post synaptic – slow channel syndrome, end plate acetyl cholinesterase deficiency, fast closure of Ach receptor channel. Defect in neuro muscular junction is the cause Congenital myasthenic syndromes

47. Slow channel syndrome is autosomal dominant Other syndromes are autosomal recessive

48. Lambert-Eaton syndrome which rarer than myasthenia is a presynaptic neuro transmission disorder It may primary autoimmune or paraneoplastic( Eg . Small cell ca of lung) Unlike myasthenia only ptosis will be there. No ophthalmoplegia. After sustained up gaze the ptosis may improve due to accumulation of calcium in the neuromuscular junction Diagnosis is by EMG

49. Pathology is in the calcium channels in the presynaptic area affected by antibodies. Acetylcholine which is calcium dependant is not released properly Autonomic symptoms like dry eyes, dry mouth, blurred vision, impotence and constipation Proximal muscle weakness Other auto immune diseases also may be seen Lambert Eaton

50. To find out if there is any malignancy and treat that Acetyl cholinesterase inhibitors Immunomodulation with prednisolone, Azathioprine or Rituximab Treatment